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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Disease requires two damaging AGTPBP1 alleles. Heterozygous parents are unaffected obligate carriers. Consanguinity is common among reported families but is not required, as compound heterozygotes are also reported.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:30976113 SUPPORT Human Clinical

"Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants"

Segregation analysis in two unrelated families established biallelic transmission consistent with autosomal recessive inheritance.

PMID:33909173 SUPPORT Human Clinical

"Targeted Sanger sequencing confirmed the variant in both affected children and in heterozygous form in the parents."

Homozygosity in both affected siblings with unaffected heterozygous parents is the classical autosomal recessive segregation pattern.

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Discussions and Knowledge Gaps

11

Should the severe infantile and milder cerebellar-predominant presentations of AGTPBP1-related disease be modelled as named subtypes?

KNOWLEDGE GAP OPEN condca-subtype-structure

Attached to

genetic#Biallelic AGTPBP1 pathogenic variants

The foundational cohort described two phenotypic extremes - critically ill infants with profound impairment at one end and a 14-year-old with a spastic-ataxic movement disorder and only mild intellectual disability at the other - with an intermediate group between them. This entry deliberately does NOT use `has_subtypes`, because the literature describes a continuous severity spectrum with no named, delimited nosologic entities, and because the original authors explicitly cautioned that it is too early to claim a definitive genotype-phenotype correlation. Introducing subtype names here would invent boundaries the evidence does not draw, and would create foreign-key targets that no published case definition could be matched against. Revisit if an international registry or a natural-history cohort defines reproducible clinical subgroups.

Proposed experiments

Prospective international natural-history registry

exp_condca_natural_history_registry

Enrol genotype-confirmed AGTPBP1 patients internationally with uniform HPO phenotyping, serial brain MRI, and standardised motor and respiratory scales, to establish whether reproducible clinical subgroups exist.

Per-allele residual deglutamylase activity assay

exp_condca_allele_activity_assay

Systematically assay residual CCP1 deglutamylase activity for each reported allele and correlate it with survival and motor outcome, to test whether a quantitative activity threshold rather than variant class predicts severity.

What are the true frequencies of each phenotype in AGTPBP1-related disease?

KNOWLEDGE GAP OPEN condca-frequency-data

Attached to

phenotypes#Cerebellar Atrophy

The available denominators are small, retrospective literature-series samples with variable severity and per-feature assessment. The review reports muscle atrophy in half of patients and reflex alterations in almost all, but the latter combines opposite reflex directions and the former does not require neurogenic verification. Neither aggregate is assigned to a narrower phenotype. Prospective consistently ascertained denominators are lacking.

Proposed experiments

Registry-based phenotype frequency estimation

exp_condca_frequency_registry

Collect uniformly phenotyped, consecutively ascertained AGTPBP1 cases so that per-phenotype frequencies have a common denominator rather than being pooled across severity-ascertained case reports.

Show evidence (2 references)

PMID:34572343 SUPPORT Human Clinical

"Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia."

Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.

PMID:34572343 SUPPORT Human Clinical

"Alterations in tendon reflexes were observed in almost all individuals."

This is an aggregate of altered reflexes, not a separate estimate for hyporeflexia, areflexia or hyperreflexia.

Is cardiomyopathy part of the AGTPBP1 phenotype?

KNOWLEDGE GAP OPEN condca-cardiac-involvement

Attached to

phenotypes#Dilated Cardiomyopathy

Samur et al. reported reversible dilated cardiomyopathy in a single p.Gln816Pro patient. The observation is retained with case-level evidence, but a causal cardiac pathway from CCP1 deficiency has not been established. General cytoskeletal functions in cardiomyocytes do not establish that this patient's cardiomyopathy was caused by AGTPBP1.

Proposed experiments

Baseline cardiac assessment in a prospective cohort

exp_condca_cardiac_surveillance

Perform baseline echocardiography and ECG on prospectively enrolled AGTPBP1 patients to establish whether the single reported dilated cardiomyopathy recurs at a rate that would justify surveillance.

Show evidence (1 reference)

DOI:10.1055/s-0042-1749669 SUPPORT Human Clinical

"In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a..."

Single p.Gln816Pro case; the authors describe the cardiac finding as an expansion of the possible phenotype, not an established penetrant manifestation.

How representative is the first human autopsy of the regional pathology across AGTPBP1 genotypes and ages?

KNOWLEDGE GAP OPEN condca-human-neuropathology-spectrum

Attached to

pathophysiology#Purkinje Neuron Degeneration

The 2018 discovery series lacked postmortem examinations. The 2026 first autopsy now directly establishes Purkinje, granular and anterior horn-cell loss in one infant. It does not establish universal lobule X sparing, the complete mouse death pathway, or the same regional pathology in patients without cerebellar atrophy or lower motor-neuron signs. The remaining uncertainty concerns distribution and representativeness, not whether human Purkinje loss has ever been observed.

Proposed experiments

Neuropathological examination of CONDCA cerebellum

exp_condca_neuropathology

Compare additional genetically confirmed postmortem cases across ages and genotypes, quantifying regional neuronal loss and tubulin glutamylation against controls.

Purkinje-layer-sensitive quantitative cerebellar MRI

exp_condca_quantitative_mri

High-resolution cerebellar imaging in CONDCA patients to test whether the volume loss follows the lobular pattern of the mouse (near-complete loss with relative sparing of lobule X) rather than a diffuse pattern.

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"The cerebellum showed normal-sized folia with a marked loss of Purkinje cells. There was a prominence of Bergmann glial cells."

Direct human autopsy evidence supersedes the discovery-series absence of postmortem examinations.

Which downstream mechanisms established in pcd mice actually operate in human CONDCA neurons?

KNOWLEDGE GAP OPEN condca-human-mechanism-gap

Attached to

pathophysiology#Purkinje Cell Endoplasmic Reticulum Stress

Human muscle hyperglutamylation and human Purkinje/anterior horn-cell loss are documented. The transport, mitochondrial-fusion and ER-stress routes nevertheless rest on model perturbations rather than direct human neuronal measurements. These supported candidate paths are represented with qualifications; the remaining gap is mediation and human translation, not absence of a modeled connection.

Proposed experiments

Patient iPSC-derived neuronal model

exp_condca_patient_ipsc_neurons

Differentiate patient iPSCs into Purkinje-like neurons and spinal motor neurons and assay glutamylation state, cargo transport, mitochondrial motility and UPR activation, to test which mouse-derived downstream steps operate in human cells.

Accessible-tissue polyglutamylation biomarker

exp_condca_glutamylation_biomarker

Develop a pharmacodynamic assay of tubulin polyglutamylation measurable in blood or skin, so that target engagement can be read out in a future trial.

Is there a therapeutic window in humans, and where does it close?

KNOWLEDGE GAP OPEN condca-therapeutic-window

Attached to

treatments#AAV-Mediated AGTPBP1 Gene Replacement

Every successful preclinical rescue - Ttll1 deletion, neonatal AAV Ccp1 delivery, rhVEGF-B - was applied before or during the pre-degenerative phase in a mouse whose Purkinje cell death is compressed into a few postnatal weeks. It is unknown whether the corresponding human window is wider (because the human course is slower) or already closed by the time a child is diagnosed. This is the central translational uncertainty for the disorder.

Proposed experiments

Delayed-onset AAV dosing arms in the pcd mouse

exp_condca_delayed_dosing

Dose Ccp1-deficient mice at progressively later postnatal timepoints to map the point at which Purkinje cell rescue is no longer achievable.

Natural-history imaging cohort

exp_condca_imaging_window

Serially image AGTPBP1 patients to date the onset of measurable cerebellar volume loss relative to symptom onset, bounding the human treatment window.

Which factors determine cerebellar and motor-system involvement?

KNOWLEDGE GAP OPEN condca-variable-anatomy

Attached to

phenotypes#Cerebellar Atrophy phenotypes#Lower Motor Neuron Degeneration

Two siblings with homozygous c.3293G>A had neither cerebellar atrophy on MRI nor lower motor-neuron findings. This is variable expression, not a disease-level negation of either phenotype. The autopsy case also illustrates that an apparently unremarkable cerebellar MRI does not exclude microscopic cell loss.

Show evidence (1 reference)

PMID:33909173 SUPPORT Human Clinical

"However, in our patients, no signs of cerebellar atrophy in cranial MRI were present, so the acronym CONDCA is not applicable; lower motor neuron findings were also absent."

The reported absence is scoped to these patients and does not export a disease-level HPOA NOT.

Is thymic aplasia an AGTPBP1 manifestation?

KNOWLEDGE GAP OPEN condca-immune-attribution

Attached to

pathophysiology#Absent Thymic Tissue phenotypes#Thymic Aplasia phenotypes#Lymphopenia

A single homozygous nonsense case had absent thymus, persistent lymphopenia and fatal adenovirus infection. The authors report no other known immunodeficiency variants, but lymphocyte subsets were not obtained. The downstream thymic contribution to lymphopenia is represented provisionally; a causal gene-to-thymic-development pathway and recurrence in other patients remain unproven. Thymic aplasia names the same anatomical absence as the tissue node, so no causal arrow connects those two labels; the aplasia remains an explicitly unexplained clinical finding. Sepsis-associated hemophagocytosis, hepatic steatosis and pigment cast nephropathy are retained as terminal case findings rather than generalized primary CONDCA manifestations.

Show evidence (2 references)

PMID:42358771 SUPPORT Human Clinical

"The lymphopenia suggests that the disorder may be causing a primary immunodeficiency (PID) in the affected children."

The authors explicitly frame immunodeficiency attribution as a possibility.

PMID:42358771 SUPPORT Human Clinical

"A lymphocyte subset analysis could not be performed as PID was not suspected during life. The whole exome sequencing also did not reveal any other genetic variants linked to known PIDs."

Defines the limits of the immunological and alternative-genetic assessment.

What initiates callosal white-matter loss or dysplasia?

KNOWLEDGE GAP OPEN condca-callosal-origin

Attached to

pathophysiology#Callosal White Matter Loss phenotypes#Abnormal Corpus Callosum Morphology

The autopsy establishes myelin loss underlying callosal thinning in one infant. It does not distinguish primary defective axonal development or myelination from secondary degeneration, nor show that earlier reports of dysplastic callosal morphology share this route. The tissue-loss-to-thinning edge is retained while its upstream cause remains unresolved.

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"The sections from the corpus callosum showed thinned out corpus callosum with marked loss of myelin."

Direct human callosal histology; this does not establish the prenatal or postnatal origin of all callosal abnormalities.

Which neural regions account for the remaining movement, ocular and sensory manifestations?

KNOWLEDGE GAP OPEN condca-regional-clinical-attribution

Attached to

phenotypes#Spasticity phenotypes#Dystonia phenotypes#Oculomotor Apraxia phenotypes#Esotropia phenotypes#Hand Tremor phenotypes#Hearing Impairment phenotypes#Seizures phenotypes#Caudate Atrophy phenotypes#Putaminal Atrophy phenotypes#Microcephaly

Spasticity indicates a central motor component, but the reviewed human studies do not establish the affected descending pathways. Dystonia and seizures coexist with caudate/putaminal atrophy in one case without demonstrating that this lesion causes either symptom. Hand tremor includes rest and action components, and the sporadic hearing loss is unlocalized. The broad eye-movement relation to weakness/cerebellar dysfunction is represented, while the specific origins of apraxia and esotropia are not separated. Microcephaly includes postnatal head-growth decline, but neither cerebellar loss nor peripheral motor-neuron loss alone has been shown to explain it; the first 2019 case also had a potentially contributing NCAPD3 variant. These gaps concern lesion or causal attribution, not simply absent pathway nodes.

Show evidence (4 references)

PMID:30420557 SUPPORT Human Clinical

"Additional constantly observed features were microcephaly, eye movement abnormali- ties, feeding difficulties, ataxia, spasticity, and dystonia."

The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.

DOI:10.1055/s-0042-1749669 SUPPORT Human Clinical

"In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a..."

The single p.Gln816Pro case documents caudate and putaminal atrophy alongside dystonia and seizures. Their co-occurrence does not establish which regional lesion causes either clinical manifestation or whether the basal-ganglia findings recur in other genotypes.

PMID:34572343 SUPPORT Human Clinical

"Other clinical features, such as bilateral hearing loss and hand tremors, were sporadically detected."

Published human observations; no hearing-loss subtype or frequency band is inferred.

+ 1 more reference

Which unusual findings recur in genetically secure cases?

KNOWLEDGE GAP OPEN condca-expanded-case-phenotypes

Attached to

phenotypes#Abnormal Eye Movements phenotypes#Oculomotor Apraxia

The 2024 likely-pathogenic p.Thr884Pro patient had coarse facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips and large ears; arachnodactyly, interphalangeal hyperextensibility, low-inserted thumbs, toe camptodactyly, prominent heels, scoliosis and joint contractures were also described. Table 2 additionally records brisk reflexes, hypometric saccades and poor eye contact, and ERG showed retinal dysfunction. The extensor plantar response in the 4.5-month-old autopsy case is not separately treated as a pathological Babinski sign because that response can be physiological at this age. These are preserved as a case expansion whose individual causal attribution and recurrence are unresolved. The second AGTPBP1 patient carried p.Thr512Ala classified as a VUS and had strabismus, oculomotor apraxia, optic-nerve dysfunction and contractures; that case is not pooled as equally established genetic evidence. Mouse retinal degeneration is not substituted for these human observations.

Show evidence (3 references)

PMID:38153683 SUPPORT Human Clinical

"Patient 3 presented with GDD, dysmorphic facial features “course facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips, and large ears,” oculomotor apraxia, and seizures."

Patient 3 carried homozygous p.Thr884Pro, classified as likely pathogenic. The distinct patient 7 carried a VUS and is not pooled as equivalent genetic evidence.

PMID:38153683 SUPPORT Human Clinical

"He had multiple skeletal deformities “arachnodactyly, bilateral hyperextensibility of the interphalangeal joints, bilateral low inserted thumb, toes camptodactyly, bilateral prominent heel, severe scoliosis and joint contractures” and bilateral fungal infection of both feet (Fig. 3)."

The antecedent is patient 3, the likely-pathogenic AGTPBP1 case; these unusual observations remain explicitly case-scoped.

PMID:38153683 SUPPORT Human Clinical

"Patient 7 had a homozygous missense variant in the AGTPBP1 gene (c.1534A > G; p. (Thr512Ala) causing an amino acid change from Thr to Ala at position 512. It is classified as a variant of uncertain significance (class 3) according to the recommendations of Centogene and ACMG."

Patient 7 is genetically less certain than patient 3.

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Pathophysiology

11

CCP1 Deglutamylase Deficiency

Mechanism confidence: Established

Biallelic AGTPBP1 variants abolish functional cytosolic carboxypeptidase 1. Truncating alleles (nonsense, frameshift, canonical splice, multi-exon genomic deletion) eliminate the protein through nonsense-mediated decay or early truncation; tested missense alleles produce unstable protein that lacks detectable catalytic activity. CCP1 is a zinc metallocarboxypeptidase that shortens polyglutamate side chains on the tubulin C-terminal tail and converts detyrosinated alpha-tubulin into Delta2-tubulin, so its loss removes the eraser arm of the neuronal tubulin code.

cerebellar Purkinje cell CL:0000121

AGTPBP1 hgnc:17258

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline AGTPBP1 alleles. Reported classes include nonsense, frameshift, canonical and intronic splice-site, multi-exon genomic deletion, and missense alleles; truncating alleles eliminate the protein and tested missense alleles produce unstable protein without detectable catalytic activity, so the category is loss of function rather than dominant-negative or gain of function. Zygosity is deliberately left unset: affected individuals are homozygous or compound heterozygous, and ZygosityEnum has no biallelic value that covers both without asserting one of them.

tubulin side-chain deglutamylation GO:0035610 ↓ DECREASED C-terminal deglutamylation generating Delta2-tubulin GO:0035609 ↓ DECREASED

tubulin metallocarboxypeptidase (deglutamylase) activity GO:0004181 ↓ DECREASED

Downstream

Tubulin Hyperglutamylation

Neuronal Maintenance Failure Loss of functional CCP1 compromises neuronal maintenance; the detailed routes beyond the demonstrated hyperglutamylation pathway remain incompletely resolved.

Lower Motor Neuron Degeneration CCP1 loss causes spinal motor-neuron degeneration in the genetic mouse model and is associated with the corresponding human lesion. Human anterior horn-cell loss is directly documented, while the intervening lethal pathway remains unresolved.

Show evidence (4 references)

PMID:30420557 SUPPORT Human Clinical

"We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation."

Directly establishes that the human disease allele set produces absence of functional CCP1, with a demonstrated downstream polyglutamylation defect.

PMID:21074048 SUPPORT In Vitro

"Three enzymes (CCP1, CCP4, and CCP6) catalyze the shortening of polyglutamate chains and a fourth (CCP5) specifically removes the branching point glutamates."

Biochemical characterisation of the CCP family assigns CCP1 the polyglutamate side-chain shortening (deglutamylase) activity that is lost in CONDCA.

PMID:21074048 SUPPORT In Vitro

"we show that these enzymes convert detyrosinated tubulin into Δ2-tubulin and also modify other substrates"

Establishes the second CCP1 activity lost in CONDCA - conversion of detyrosinated alpha-tubulin to Delta2-tubulin by removal of the gene-encoded C-terminal glutamate.

+ 1 more reference

Tubulin Hyperglutamylation

Mechanism confidence: Established

With the CCP1 eraser gone, the TTLL-family glutamylase writers act unopposed and neuronal microtubules accumulate abnormally long polyglutamate side chains. TTLL1, which polyglutamylates alpha-tubulin, is the enzyme principally responsible for the pathological excess in CCP1 deficiency; TTLL7, which modifies beta-tubulin, is not. Delta2-tubulin generation falls in parallel. Genetic removal of TTLL1 normalises glutamylation and rescues the degeneration, which is the strongest available evidence that hyperglutamylation is the pathogenic lesion rather than an epiphenomenon. The rescue is not attributable to TTLL1 alone: a systematic survey across five TTLLs describes Ttll1 loss as attenuating rather than abolishing the degeneration and identifies TTLL4 as a second contributor.

cerebellar Purkinje cell CL:0000121

tubulin polyglutamylation GO:0018095 ↑ INCREASED microtubule cytoskeleton organization GO:0000226 ⚠ ABNORMAL

Downstream

Impaired Microtubule-Based Axonal Transport

Purkinje Cell Endoplasmic Reticulum Stress Model-supported ER-stress pathway; its human relevance and necessity for cell death remain provisional.

Purkinje Neuron Degeneration Genetic rescue establishes hyperglutamylation-induced neuronal loss in mice, while the intervening lethal pathway is incompletely resolved.

Lower Motor Neuron and Peripheral Motor Axon Degeneration Counteracting TTLL1 deletion prevents peripheral motor-axon degeneration in CCP1-deficient mice. This establishes a hyperglutamylation-dependent lesion while its precise intermediates and human translation remain incompletely reconstructed.

Show evidence (4 references)

PMID:30225910 SUPPORT Model Organism

"increased polyglutamylated tubulin was detected in the Nna1 KO cerebellum"

Direct measurement of the hyperglutamylated state in the cerebellum of mice lacking the CCP1 carboxypeptidase domain.

PMID:34309047 SUPPORT Model Organism

"TTLL1, but not TTLL7, catalyses the excessive hyperglutamylation found in mice lacking the deglutamylase CCP1."

Identifies TTLL1 as the specific writer that produces the pathological hyperglutamylation when CCP1 is absent, refining the mechanism and naming the therapeutic target.

PMID:21074048 SUPPORT Model Organism

"We further analyze Purkinje cell degeneration (pcd) mice that lack functional CCP1 and show that microtubule hyperglutamylation is directly linked to neurodegeneration."

Establishes the causal link between microtubule hyperglutamylation and neurodegeneration in CCP1-null animals.

+ 1 more reference

Impaired Microtubule-Based Axonal Transport

Mechanism confidence: Provisional

Excess tubulin polyglutamylation reduces overall cargo motility in cultured mouse neurons. Mitochondria spend more time paused; velocity and run length need not decrease. Cargo specificity differs between hippocampal and cerebellar granule-cell experiments. CCP1-null epithelial cells and pcd neurons also show mitochondrial fragmentation and impaired fusion. These model results motivate a transport/fusion contribution to degeneration, but transport rescue has not established the complete causal sequence in human neurons.

cerebellar Purkinje cell CL:0000121

axo-dendritic transport GO:0008088 ↓ DECREASED mitochondrion transport along microtubule GO:0047497 ↓ DECREASED mitochondrial fusion GO:0008053 ↓ DECREASED

Downstream

Purkinje Neuron Degeneration Proposed transport-mediated contribution to neuronal degeneration. The transport defect is measured in models, but its causal mediation of neuronal death remains incompletely established and is not directly measured in human CONDCA neurons.

Lower Motor Neuron and Peripheral Motor Axon Degeneration Proposed transport-mediated contribution to neuronal degeneration. The transport defect is measured in models, but its causal mediation of neuronal death remains incompletely established and is not directly measured in human CONDCA neurons.

Show evidence (4 references)

PMID:30337352 SUPPORT Model Organism

"We examined the effect of tubulin hyperglutamylation on microtubule-mediated mitochondrial motility in pcd neurons and noted markedly reduced retrograde axonal transport."

Direct measurement of reduced retrograde mitochondrial transport in neurons from the CCP1-null mouse.

PMID:30337352 SUPPORT In Vitro

"we documented reduced mitochondrial fusion in cells lacking CCP1"

Establishes the reduced-fusion component of this node in CCP1-null cells. Split from the companion item below so each carries a single `evidence_source`.

PMID:30337352 SUPPORT Model Organism

"We observed mitochondrial fragmentation in CCP1 null cells and in neurons from pcd mice"

Establishes mitochondrial fragmentation in neurons from the CCP1-null mouse. Split from the companion in-vitro item above.

+ 1 more reference

Purkinje Cell Endoplasmic Reticulum Stress

Mechanism confidence: Provisional

In pcd mouse Purkinje neurons, ER-rich polyribosomal masses, ER-stress markers, unfolded protein response activation and reduced protein synthesis precede cell death. Perturbation experiments support an ER-mediated death pathway, but the authors retain competing mechanisms and uncertain human translation.

cerebellar Purkinje cell CL:0000121

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED

Downstream

Purkinje Neuron Degeneration Provisional mouse ER-mediated apoptotic pathway; necessity of the pathway and its operation in human neurons remain unresolved.

Show evidence (2 references)

PMID:33004692 SUPPORT Model Organism

"the neuronal disorder involved ER stress, unfolded protein response, and protein synthesis inhibition preceding PN death by apoptosis/necroptosis"

Establishes ER stress and the unfolded protein response as events that precede, rather than follow, Purkinje neuron death.

PMID:30225910 SUPPORT Model Organism

"the endoplasmic reticulum stress marker, C/EBP homologous protein (CHOP), was up-regulated in the mutant PCs"

Independent molecular confirmation of ER stress in Purkinje cells of a separate CCP1 loss-of-function mouse line.

Purkinje Neuron Degeneration

Mechanism confidence: Established

Cerebellar Purkinje cells are the most conspicuously vulnerable population. In the pcd mouse the cerebellum is histologically normal at postnatal day 14 and then loses essentially all Purkinje cells within weeks, with reactive microgliosis and astrogliosis; lobule X is relatively spared. The degeneration is cell-autonomous - excessive polyglutamylation is sufficient to kill the neuron from within, independent of its neighbours. That does not exclude a contributing glial component: reactive microgliosis and astrogliosis accompany the loss, and minocycline, a glial-activation inhibitor, delays Purkinje cell death in pcd mice. Human autopsy in 2026 directly demonstrated marked Purkinje-cell and granular-layer loss. The observed human lesion is established, whereas cell-autonomous hyperglutamylation causality, lobule-specific resistance and the detailed death pathways still derive from models.

cerebellar Purkinje cell CL:0000121

neuron apoptotic process GO:0051402 ↑ INCREASED

Animal models

Purkinje cell degeneration (pcd) mouse Mus musculus recapitulates Near-complete Purkinje cell loss with the same molecular lesion (tubulin hyperglutamylation) as the human disease.

Downstream

Cerebellar Ataxia and Movement Disorder Purkinje-cell loss produces cerebellar motor impairment in pcd mice. Human ataxia has a corresponding cerebellar substrate, while the exact functional intermediates are not directly measured in affected children.

Cerebellar Atrophy

Show evidence (6 references)

PMID:30225910 SUPPORT Model Organism

"Most PCs degenerated until 4-week-old, except lobule X."

Quantifies the near-complete and regionally patterned Purkinje cell loss that defines this node.

PMID:30225910 SUPPORT Model Organism

"Activated microglia and astrocytes were also observed in the Nna1 KO cerebellum."

Documents the reactive glial response accompanying Purkinje cell loss.

PMID:34572343 SUPPORT INDIRECT Model Organism

"delays the death of PCs in pcd mice and mildly improves their locomotor performance"

Inhibiting glial activation with minocycline delays Purkinje cell death, showing the glial response contributes to the timing of the loss even though excessive polyglutamylation is cell-autonomously sufficient to cause it. Marked INDIRECT because it establishes a glial contribution by intervention rather than stating it.

+ 3 more references

Lower Motor Neuron and Peripheral Motor Axon Degeneration

Mechanism confidence: Established

In parallel with the cerebellar arm, spinal alpha-motor neurons are lost and peripheral myelinated motor axons degenerate, with reduced axon number and calibre and disorganised axoplasm. Electrophysiology in patients shows denervation and axonal motor neuropathy in proximal and distal muscles, while sensory nerve action potentials are preserved - the neuropathy is motor-predominant. Skeletal muscle change is secondary neurogenic atrophy, not a primary myopathy. Anterior horn-cell loss with reactive gliosis was directly confirmed in a human autopsy in 2026; peripheral motor-axon versus cell-body contributions in other patients remain based on clinical and electrophysiological localization.

spinal alpha-motor neuron CL:0011001 motor neuron CL:0000100

Animal models

Purkinje cell degeneration (pcd) mouse Mus musculus recapitulates Peripheral nerve and spinal motor neuron degeneration in pcd mice was shown to reproduce the human motor neuronopathy.

Downstream

Motor Neuronopathy and Progressive Weakness

Motor Axonal Neuropathy Motor-axon injury is the peripheral component of the clinical motor neuropathy; electrophysiological localization can also reflect anterior horn-cell loss.

Show evidence (5 references)

PMID:30420557 SUPPORT Human Clinical

"Five individuals who underwent nerve conduction studies, electromyography, muscle ultrasound, or muscle histology had signs of peripheral nerve and spinal motor neuron degeneration"

Direct human electrophysiological and histological evidence of the peripheral and lower motor neuron lesion.

PMID:30420557 SUPPORT Model Organism

"We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease."

Shows the pcd mouse reproduces this arm of the human disease, supporting use of the model for the motor neuron phenotype.

PMID:34572343 SUPPORT Human Clinical

"electromyography studies have detected signs of denervation causing muscle atrophy in proximal and distal muscles, including the tibialis anterior and posterior deltoid, suggesting degeneration of both peripheral nerve motor fibres and spinal cord"

Review synthesis of published patient electromyography, localising the lesion to both peripheral motor fibres and spinal cord motor neurons.

+ 2 more references

Cerebellar Ataxia and Movement Disorder

Mechanism confidence: Established

Loss of Purkinje cell output disrupts the cerebellar contribution to motor coordination, producing ataxia. In the most severely affected infants profound weakness may mask the ataxia because the child never achieves independent ambulation. Spasticity and dystonia are also consistently reported in these patients and are curated as phenotypes, but they are NOT attributed to this node: spasticity is a pyramidal/upper-motor-neuron sign and dystonia is extrapyramidal, and neither follows from loss of cerebellar cortical output. A single p.Gln816Pro case now documents caudate and putaminal atrophy, but a causal relationship between those lesions and the movement disorder is unresolved. The affected descending motor pathways are also unestablished.

Downstream

Ataxia The phenotype records the cerebellar incoordination represented by this mechanism.

Abnormal Eye Movements The discovery-series authors propose combined muscle weakness and cerebellar dysfunction as contributors; the relative contribution and specific ocular-motor subtype vary.

Show evidence (2 references)

PMID:30420557 SUPPORT Human Clinical

"feeding difficulties, ataxia, spasticity, and dystonia"

Records ataxia among the consistently observed features of the foundational human cohort. The quoted list also names spasticity and dystonia, which are curated as separate phenotypes and are deliberately not attributed to this cerebellar node.

PMID:34637898 SUPPORT Human Clinical

"Similar neuropathogical and behavioral profiles have been described in childhood-onset human subjects with biallelic variants of AGTPBP1, including cerebellar ataxia and hypotonia."

Confirms cerebellar ataxia as the clinical consequence in humans, not only in the mouse.

Motor Neuronopathy and Progressive Weakness

Mechanism confidence: Established

Denervation of proximal and distal muscles produces progressive generalised weakness, often reaching tetraparesis, with neurogenic muscle atrophy, absent or reduced deep tendon reflexes, and tongue fasciculations. Bulbar and respiratory muscle involvement generates the feeding difficulty and respiratory insufficiency that drive most of the mortality.

Downstream

Progressive Muscle Weakness The documented motor neuronopathy and weakness account for the progressive limb weakness in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Hypotonia The documented motor neuronopathy and weakness account for the muscular hypotonia in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Reduced Tendon Reflexes The documented motor neuronopathy and weakness account for the depressed deep tendon reflexes in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Areflexia The documented motor neuronopathy and weakness account for the absent deep tendon reflexes in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Neurogenic Muscle Atrophy The documented motor neuronopathy and weakness account for the neurogenic muscle atrophy in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Tongue Fasciculations The documented motor neuronopathy and weakness account for the tongue fasciculations in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Motor Delay The documented motor neuronopathy and weakness account for the failure to acquire motor milestones in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Feeding Difficulties The documented motor neuronopathy and weakness account for the feeding difficulties in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Respiratory Insufficiency The documented motor neuronopathy and weakness account for the respiratory insufficiency in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Weak Cry The documented motor neuronopathy and weakness account for the weak cry in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Poor Suck The documented motor neuronopathy and weakness account for the weak suck in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Dysphagia The documented motor neuronopathy and weakness account for the swallowing difficulty in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.

Abnormal Eye Movements The discovery-series authors propose combined muscle weakness and cerebellar dysfunction as contributors; the relative contribution and specific ocular-motor subtype vary.

Show evidence (2 references)

PMID:34572343 SUPPORT Human Clinical

"mainly characterised by hypotonia and generalised muscle weakness, frequently causing tetraparesis"

Review synthesis of published patients describing the weakness phenotype and its progression to tetraparesis.

PMID:30976113 SUPPORT Human Clinical

"developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties"

Directly links the progressive weakness to the feeding and respiratory complications that constitute the clinical burden.

Neuronal Maintenance Failure

Mechanism confidence: Established

CCP1 loss disrupts maintenance of central and peripheral neurons and leads to progressive motor and cognitive deficits. Human neurodegeneration is established clinically and pathologically, but the circuits and developmental versus degenerative contributions to intellectual impairment remain incompletely localized.

Downstream

Global Developmental Delay The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.

Intellectual Disability The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.

Developmental Regression The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.

Progressive Neurological Deterioration The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.

Show evidence (2 references)

PMID:42358771 SUPPORT Human Clinical

"These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits."

The human report explicitly relates defective neuronal maintenance to the clinical motor and cognitive decline.

PMID:30420557 SUPPORT Human Clinical

"In this study, we have shown that rare biallelic variants in the gene encoding the protein deglutamylase CCP1 cause degeneration of the central and peripheral nervous systems in humans."

The discovery study establishes central and peripheral degeneration caused by biallelic CCP1 variants.

Absent Thymic Tissue

Mechanism confidence: Provisional

Thymic tissue was absent at autopsy in one infant with AGTPBP1-related neurodegeneration. The authors propose that this contributes to lymphopenia and infection susceptibility. The genetic cause of the thymic lesion and precise lymphocyte subset defect remain unresolved.

Downstream

Lymphopenia The report proposes immune deficiency secondary to thymic involvement. Lymphocyte subsets were unavailable, so the specific developmental mechanism and degree of T-cell depletion remain uncertain.

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"The thymus could not be identified grossly. Anterior mediastinal soft tissue was extensively sampled for histological examination and did not reveal any remnant of thymus."

Direct anatomy in one genetically confirmed case; the causal genetic relation remains provisional.

Callosal White Matter Loss

Mechanism confidence: Provisional

The autopsied infant had a thin corpus callosum with marked myelin loss. This supports tissue loss as the substrate of thinning in that case, without establishing whether defective axonal development, primary myelin injury or secondary degeneration initiated the lesion.

Downstream

Thin Corpus Callosum Reduced white matter is the documented tissue substrate of callosal thinning in the autopsy case.

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"The sections from the corpus callosum showed thinned out corpus callosum with marked loss of myelin."

Direct human callosal histology; this does not establish the prenatal or postnatal origin of all callosal abnormalities.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

38

Blood 1

Lymphopenia Decreased total lymphocyte count HP:0001888

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"Peripheral blood count revealed persistent lymphopenia (ALC range: 1,270/μL to 2,482/μL)."

Measured absolute lymphocyte counts in the single autopsy case; these values do not define disease-wide prevalence.

Cardiovascular 2

Dilated Cardiomyopathy HP:0001644

Show evidence (1 reference)

DOI:10.1055/s-0042-1749669 SUPPORT Human Clinical

"In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a..."

Single p.Gln816Pro case; the authors describe the cardiac finding as an expansion of the possible phenotype, not an established penetrant manifestation.

Thymic Aplasia Aplasia of the thymus HP:0005359

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"The thymus could not be identified grossly. Anterior mediastinal soft tissue was extensively sampled for histological examination and did not reveal any remnant of thymus."

Direct anatomy in one genetically confirmed case; the causal genetic relation remains provisional.

Digestive 3

Feeding Difficulties HP:0011968

Sequelae: Failure to Thrive

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy."

The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.

Poor Suck HP:0002033

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"Examination revealed a thin-built, lethargic baby, with weak suck, pooling of oral secretions, a frog-like posture, and right convergent squint."

Direct examination of the autopsied infant.

Dysphagia HP:0002015

Sequelae: Aspiration

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"Repeated aspirations due to dif ﬁculty in eating solid food and slow weight gain led to gastrostomy insertion at two years of age."

The second patient aspirated repeatedly while eating solid food and gained weight slowly, leading to gastrostomy.

Ear 1

Hearing Impairment HP:0000365

Show evidence (1 reference)

PMID:34572343 SUPPORT Human Clinical

"Other clinical features, such as bilateral hearing loss and hand tremors, were sporadically detected."

Published human observations; no hearing-loss subtype or frequency band is inferred.

Eye 3

Abnormal Eye Movements Abnormality of eye movement HP:0000496

Show evidence (2 references)

PMID:30420557 SUPPORT Human Clinical

"Additional constantly observed features were microcephaly, eye movement abnormali- ties, feeding difficulties, ataxia, spasticity, and dystonia."

The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.

PMID:30420557 SUPPORT Human Clinical

"the eye movement abnormalities in the humans are likely to be the result of muscle weakness and cerebellar dysfunction, with no known evidence of ... retinal degeneration."

The authors explicitly attribute the human eye-movement abnormalities to weakness and cerebellar dysfunction; the sentence continues with absence of known retinal degeneration in that 2018 series.

Oculomotor Apraxia HP:0000657

Show evidence (1 reference)

PMID:38153683 SUPPORT Human Clinical

"Patient 3 presented with GDD, dysmorphic facial features “course facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips, and large ears,” oculomotor apraxia, and seizures."

Patient 3 carried homozygous p.Thr884Pro, classified as likely pathogenic. The distinct patient 7 carried a VUS and is not pooled as equivalent genetic evidence.

Esotropia HP:0000565

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"Examination revealed a thin-built, lethargic baby, with weak suck, pooling of oral secretions, a frog-like posture, and right convergent squint."

Convergent squint supports esotropia rather than unspecified strabismus.

Head and Neck 2

Microcephaly HP:0000252

Show evidence (2 references)

PMID:34572343 SUPPORT Human Clinical

"Other brain alterations, such as microcephaly or dysplastic corpus callosum, were also frequently detected."

Published clinical observations support microcephaly; this combined sentence does not specify a separate frequency.

PMID:30976113 SUPPORT Human Clinical

"A progressive decline in the head circumference percentile ... for age was noted (Fig. S1), and at last examination at 45 months of age was measured to be 46 cm ( −2.7 SD)."

Postnatal head-growth decline in the second patient; the NCAPD3 confound was reported in the first patient. The quoted sentence is interrupted in the source PDF by the Fig. 1 legend and a running page header, which the elision removes.

Tongue Fasciculations HP:0001308

Show evidence (2 references)

PMID:34572343 SUPPORT Human Clinical

"Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia."

Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.

PMID:30976113 SUPPORT Human Clinical

"Tongue fasci- culations were evident."

Direct observation in the second 2019 patient with severe motor neuronopathy.

Musculoskeletal 4

Hypotonia HP:0001252

Show evidence (2 references)

PMID:30420557 SUPPORT Human Clinical

"Patients generally presented with muscular hypotonia, global developmental delays, and cerebellar atrophy on brain imaging (Fig 2A) from early infancy, followed by progressive worsening of neurological func- tion and a fatal course in six individuals."

Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.

PMID:42358771 SUPPORT Human Clinical

"The child in this case exhibited hallmark phenotypic features of AGTPBP1 mutations (Table 1), including motor unit hypotonia, global developmental delay, and cerebellar atrophy with significant Purkinje cell loss."

The autopsied infant had motor-unit hypotonia with anterior horn-cell degeneration; this does not establish the same localization in all patients.

Progressive Muscle Weakness HP:0001324

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy."

The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.

Spasticity HP:0001257

Show evidence (1 reference)

PMID:30420557 SUPPORT Human Clinical

"Additional constantly observed features were microcephaly, eye movement abnormali- ties, feeding difficulties, ataxia, spasticity, and dystonia."

The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.

Neurogenic Muscle Atrophy Skeletal muscle atrophy HP:0003202

The review reports muscle atrophy in half of the published patients. Neurogenic histology or electrophysiology was not assessed uniformly, so that denominator is not a frequency estimate of verified neurogenic atrophy.

Show evidence (2 references)

PMID:34572343 SUPPORT Human Clinical

"Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia."

Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.

PMID:42358771 SUPPORT Human Clinical

"Postmortem muscle biopsy showed numerous angulated atrophic fibres. There were some foci showing group atrophy."

The case had histologically documented neurogenic atrophy; the review proportion concerns muscle wasting, not uniform biopsy ascertainment.

Nervous System 18

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:30420557 SUPPORT Human Clinical

"Patients generally presented with muscular hypotonia, global developmental delays, and cerebellar atrophy on brain imaging (Fig 2A) from early infancy, followed by progressive worsening of neurological func- tion and a fatal course in six individuals."

Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.

Motor Delay HP:0001270

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"He had not achieved mile- stones such as sitting or standing or talking."

The second child had not acquired sitting or standing; this is delayed acquisition, distinct from subsequent loss of skills.

Cerebellar Atrophy HP:0001272

Loss of Purkinje and additional cerebellar neurons is the documented tissue substrate of atrophy in the autopsy case. The extent and timing vary; normal neonatal cerebellar development has not been documented in every patient. This clinical finding is reached from upstream neuronal loss, without a separate synonymous tissue-atrophy node.

Show evidence (2 references)

PMID:30420557 SUPPORT Human Clinical

"Patients generally presented with muscular hypotonia, global developmental delays, and cerebellar atrophy on brain imaging (Fig 2A) from early infancy, followed by progressive worsening of neurological func- tion and a fatal course in six individuals."

Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.

PMID:42358771 SUPPORT Human Clinical

"The autopsy revealed the atrophy of cerebellar folia with a striking reduction of Purkinje and granular cells and preserved molecular layer."

Direct human neuropathology establishes the cellular lesion underlying cerebellar tissue loss in this case.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:30420557 SUPPORT Human Clinical

"Additional constantly observed features were microcephaly, eye movement abnormali- ties, feeding difficulties, ataxia, spasticity, and dystonia."

The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:30420557 SUPPORT Human Clinical

"Additional constantly observed features were microcephaly, eye movement abnormali- ties, feeding difficulties, ataxia, spasticity, and dystonia."

The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.

Abnormal Corpus Callosum Morphology HP:0001273

Show evidence (1 reference)

PMID:34572343 SUPPORT Human Clinical

"Other brain alterations, such as microcephaly or dysplastic corpus callosum, were also frequently detected."

Supports dysplastic callosal morphology without conflating it with proven hypoplasia.

Reduced Tendon Reflexes HP:0001315

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"Muscle tone was low and deep tendon re ﬂexes were decreased."

The second genetically confirmed patient had decreased deep tendon reflexes, supporting this specific direction of abnormality.

Motor Axonal Neuropathy HP:0007002

Show evidence (2 references)

PMID:34572343 SUPPORT Human Clinical

"Electrophysiological recordings revealed motor neuropathy affecting the lower limbs and arms."

Supports motor neuropathy in investigated patients.

PMID:30976113 SUPPORT Human Clinical

"conclusion, the electrophysiological studies indicated a severe motor neuronopathy with widespread severe active denervation with late MUP recruitment and late chronic reinnervation, and normal sensory studies. These ﬁndings were compatible with anterior horn cell disease."

Severe denervation and normal sensory studies support the motor-predominant process in the tested patient.

Lower Motor Neuron Degeneration Degeneration of anterior horn cells HP:0002398

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"Sections from the spinal cord showed loss of neurons in the anterior horn, associated with reactive gliosis."

Direct human histology resolves the earlier reliance on electrophysiological inference and mouse pathology for anterior horn-cell degeneration.

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:30420557 SUPPORT Human Clinical

"We recog- nized two phenotypic extremes, critically ill infants (A1, B1, E1, E2, E3, H1, J1) with profound impairment of motor and cognitive development as opposed to one 14-year-old individual (D1) with a spastic–ataxic movement disorder and only mild intellectual disability."

The 14-year-old patient had explicitly documented mild intellectual disability, distinct from developmental impairment assessed in infants.

Progressive Neurological Deterioration Neurodegeneration HP:0002180

Course: PROGRESSIVE

Show evidence (2 references)

PMID:42358771 SUPPORT Human Clinical

"These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits."

The clinical report identifies neuronal-maintenance failure as the basis of progressive neurological impairment.

PMID:30420557 SUPPORT Human Clinical

"Other individuals (C1, F1, F2, G1, I1) represented an intermediate phenotype with longer survival, but still severe devel- opmental delays and progressive neurological deficits resulting in significant disability."

The intermediate-severity patients had progressive neurological deficits as well as developmental delay.

Developmental Regression HP:0002376

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"Thereafter, the parents observed a gradual decline in abilities characterized by thinning of the muscles, reduced limb movements, diminished interaction, poor object tracking, a weak cry, and the appearance of a squint."

The child had initially attained social smiling and head control, then lost abilities beginning at 2.5 months.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"Deep tendon reflexes were absent with extensor plantar response."

Direct examination of the infant subsequently shown to have anterior horn-cell degeneration.

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"The sections from the corpus callosum showed thinned out corpus callosum with marked loss of myelin."

Direct human callosal histology; this does not establish the prenatal or postnatal origin of all callosal abnormalities.

Hand Tremor HP:0002378

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"Tremor of the hands was seen both in movement and at rest and he could not reach for objects."

Direct human observation distinguishes this finding from mouse movement phenotypes.

Seizures HP:0001250

Show evidence (1 reference)

PMID:38153683 SUPPORT Human Clinical

"Patient 3 presented with GDD, dysmorphic facial features “course facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips, and large ears,” oculomotor apraxia, and seizures."

Patient 3 carried homozygous p.Thr884Pro, classified as likely pathogenic. The distinct patient 7 carried a VUS and is not pooled as equivalent genetic evidence.

Caudate Atrophy HP:0002340

Show evidence (1 reference)

DOI:10.1055/s-0042-1749669 SUPPORT Human Clinical

"In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a..."

The p.Gln816Pro patient had caudate nuclear atrophy together with putaminal and cerebellar atrophy. This single-case observation does not establish recurrence across AGTPBP1 genotypes or identify the cause of the accompanying movement disorder.

Putaminal Atrophy Abnormal putamen morphology HP:0031982

Show evidence (1 reference)

DOI:10.1055/s-0042-1749669 SUPPORT Human Clinical

"In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a..."

The p.Gln816Pro patient had putaminal atrophy together with caudate and cerebellar atrophy. This supports the case-level imaging finding, not established penetrance or a proven putaminal cause of dystonia or seizures.

Respiratory 2

Respiratory Insufficiency HP:0002093

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy."

The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.

Aspiration HP:0002835

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"Repeated aspirations due to dif ﬁculty in eating solid food and slow weight gain led to gastrostomy insertion at two years of age."

The second patient aspirated repeatedly while eating solid food and gained weight slowly, leading to gastrostomy.

Voice 1

Weak Cry HP:0001612

Show evidence (1 reference)

PMID:42358771 SUPPORT Human Clinical

"Thereafter, the parents observed a gradual decline in abilities characterized by thinning of the muscles, reduced limb movements, diminished interaction, poor object tracking, a weak cry, and the appearance of a squint."

The child had initially attained social smiling and head control, then lost abilities beginning at 2.5 months.

Growth 1

Failure to Thrive HP:0001508

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"The child was hospitalized at age 4 months due to feeding dif ﬁculty, choking and failure to thrive and underwent insertion of a feeding gastrostomy."

The first 2019 patient had failure to thrive with choking and feeding difficulty.

🧬

Genetic Associations

1

Biallelic AGTPBP1 pathogenic variants (CAUSAL)

Gene: AGTPBP1 hgnc:17258 variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (5 references)

PMID:30420557 SUPPORT Human Clinical

"We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation."

Establishes biallelic AGTPBP1/CCP1 variants as the cause, with functional confirmation that the protein is absent.

PMID:30420557 SUPPORT Human Clinical

"Patients with fatal and severe forms of the disease usually had biallelic protein-truncating"

Documents the genotype-severity trend recorded in the `notes` field.

PMID:30420557 SUPPORT INDIRECT Human Clinical

"it is probably too early to claim any definitive genotype"

Cited in support of the `notes` statement that the truncating/missense severity trend must NOT be treated as an established genotype-phenotype correlation. This is the original authors' own caveat qualifying the preceding evidence item; it does not bear on the causal role of biallelic AGTPBP1 variants, which is what this `genetic` entry asserts. Marked INDIRECT because it supports the recorded caveat rather than stating it of this entry directly.

+ 2 more references

💊

Medical Actions

10

Multidisciplinary Supportive Care

Action: multidisciplinary supportive care Ontology label: Supportive Care NCIT:C15747

There is no disease-modifying therapy. Management is supportive and multidisciplinary: nutrition and swallow-safety management, airway clearance and respiratory support, contracture and scoliosis surveillance, management of spasticity and dystonia, communication support, and palliative care in advanced disease.

Show evidence (1 reference)

PMID:40754822 SUPPORT Other

"Despite its severe clinical course, no effective treatments have been developed."

Establishes the absence of any disease-modifying option, which is why care is supportive. Evidence source is OTHER because this is the paper's framing statement about the clinical field, not its own experimental data.

Physical and Occupational Therapy

Action: physical and occupational therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Rehabilitation to maintain range of motion, prevent contractures, support positioning and seating, and provide mobility aids. Directed at the functional consequences of weakness, spasticity and ataxia; it does not modify the underlying neurodegeneration.

Target Phenotypes: Muscle weakness HP:0001324 Spasticity HP:0001257

Gastrostomy and Nutritional Support

Action: gastrostomy tube placement Ontology label: Gastrostomy Tube Procedure NCIT:C157864

Platform: Surgery

Enteral feeding via gastrostomy when bulbar weakness produces unsafe swallow, aspiration risk or inadequate caloric intake.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:30976113 SUPPORT INDIRECT Human Clinical

"developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy"

Documents the feeding difficulty this intervention addresses. Marked INDIRECT because the source establishes the indication, not the efficacy of gastrostomy in CONDCA specifically.

Noninvasive Ventilation

Action: noninvasive mechanical ventilation Ontology label: Mechanical Ventilation NCIT:C70909

Platform: Device

Respiratory support for neuromuscular respiratory insufficiency, with airway clearance and prompt treatment of respiratory infections.

Target Phenotypes: Respiratory insufficiency HP:0002093

Show evidence (1 reference)

PMID:34572343 SUPPORT INDIRECT Human Clinical

"regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency"

Documents the respiratory insufficiency this intervention addresses. Marked INDIRECT because the source establishes the indication, not ventilation efficacy in CONDCA.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Autosomal recessive recurrence counselling (25% per pregnancy for carrier couples), carrier testing of relatives, and discussion of prenatal diagnosis and preimplantation genetic testing once the familial variants are known.

Show evidence (1 reference)

PMID:33909173 SUPPORT INDIRECT Human Clinical

"Targeted Sanger sequencing confirmed the variant in both affected children and in heterozygous form in the parents."

Demonstrates the carrier-parent structure that recurrence counselling and cascade testing are built on. Marked INDIRECT because it establishes the genetic basis for counselling rather than a counselling outcome.

AAV-Mediated AGTPBP1 Gene Replacement

Action: Gene Therapy NCIT:C15238

Platform: Gene therapy

PRECLINICAL ONLY - no human study. Neonatal delivery of a blood-brain-barrier-penetrating AAV vector expressing an N-terminally truncated but catalytically active Ccp1 prevented Purkinje cell degeneration and partially improved motor function in Ccp1-deficient mice. This is the most direct mechanistic rescue strategy for a recessive loss-of-function disorder, but no clinical trial, safety data, or human dosing information exists, and the mouse result required intervention before Purkinje cell loss.

Mechanism Target:

RESTORES CCP1 Deglutamylase Deficiency — Restores deglutamylase activity by supplying a functional CCP1 transgene, acting at the initiating molecular lesion.

Show evidence (2 references)

PMID:40754822 SUPPORT Model Organism

"Expression of the N-terminally truncated form of Ccp1 (Ccp1Δ1), which retains deglutamylase activity, in neurons of Ccp1-deficient neonatal mice via a blood-brain barrier-penetrating AAV vector strongly prevented Purkinje cell degeneration during postnatal development."

Demonstrates preclinical efficacy of gene replacement on the central histopathological lesion in the mouse model.

PMID:40754822 SUPPORT Model Organism

"gene therapy using Ccp1Δ1 partially, albeit significantly, improved motor functions in these mice, notably enhancing voluntary gait stability"

Supports the functional-benefit claim in the treatment description while recording its stated limit: the motor improvement was partial rather than complete, even though histological rescue was strong.

TTLL1-Directed Reduction of Tubulin Polyglutamylation

Platform: Other

PRECLINICAL TARGET VALIDATION ONLY - no drug, no human study. Genetic deletion of the glutamylase TTLL1 fully rescues degeneration of vulnerable neurons and of peripheral myelinated axons in CCP1-deficient mice, identifying TTLL1 as the best-validated target in the disorder. No selective TTLL1 inhibitor suitable for clinical use has been reported. `treatment_term` deliberately carries no `term:` - the only candidate action term, NCIT:C49236 Therapeutic Procedure, is far broader than the concept and would assert a clinical intervention that does not exist. Needs term / NTR: "tubulin polyglutamylase inhibition".

Mechanism Target:

INHIBITS Tubulin Hyperglutamylation — Removing the writer enzyme that produces the pathological polyglutamate side chains normalises the glutamylation state without restoring CCP1 itself.

Show evidence (3 references)

PMID:30420556 SUPPORT Model Organism

"Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1."

Complete genetic rescue establishes TTLL1 as a validated target, though as a germline knockout rather than a pharmacological intervention.

PMID:34309047 SUPPORT Model Organism

"deletion of TTLL1, but not of TTLL7, prevents degeneration of Purkinje cells and of myelinated axons in peripheral nerves in these mice"

Confirms that the rescue is specific to TTLL1 and extends to the peripheral nerve arm of the disease, sharpening the target definition.

PMID:35404950 SUPPORT Model Organism

"Ttll1 deficiency attenuates Purkinje cell loss and function and reduces olfactory bulb mitral cell death and retinal photoreceptor degeneration."

A systematic survey across five TTLLs confirms TTLL1 as the dominant target but describes the protection as attenuating rather than absolute across all vulnerable populations, and identifies TTLL4 as a second contributor. This supports the target while showing the single-target picture is incomplete.

Microtubule Depolymerizer (Glutamylation Rebalancing)

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

PRECLINICAL ONLY - no human study. Treating pcd Purkinje neurons with a microtubule depolymerizer corrected the glutamylation/deglutamylation ratio and increased Purkinje neuron survival, acting on the glutamylation imbalance itself rather than on CCP1 or TTLL1 protein levels. The agent is not named in the cited abstract, no dosing or safety data exist, and microtubule-destabilising drugs are themselves neurotoxic, so this is a mechanistic proof of concept rather than a therapeutic candidate.

Mechanism Target:

MODULATES Tubulin Hyperglutamylation — Shifts the glutamylation/deglutamylation balance back toward normal without restoring the missing deglutamylase.

Show evidence (1 reference)

PMID:33004692 SUPPORT Model Organism

"treatment with a microtubule depolymerizer corrected the glutamylation/deglutamylation ratio, increasing PN survival"

Demonstrates that pharmacologically rebalancing the glutamylation state rescues Purkinje neuron survival in the CCP1-deficient mouse, which is the claim this treatment entry makes.

Recombinant Human VEGF-B

Action: Pharmacotherapy NCIT:C15986

Agent: recombinant human VEGF-B NCIT:C1272

Platform: Other

PRECLINICAL ONLY - no human study. Moderate-dose recombinant human VEGF-B was neuroprotective in the pcd mouse, increasing Purkinje cell survival and improving motor, cognitive and social behaviour, apparently by partial inhibition or delay of apoptosis. The dose-response was inverted-U: more frequent dosing was detrimental to Purkinje cell survival. Recombinant human IGF-1 tested in the same study showed no neuroprotective effect. No paediatric safety or efficacy data exist.

Mechanism Target:

INHIBITS Purkinje Neuron Degeneration — Acts downstream of the tubulin lesion as a neuroprotectant, delaying or partially inhibiting Purkinje cell apoptosis rather than correcting the glutamylation defect.

Show evidence (3 references)

PMID:39859255 SUPPORT Model Organism

"rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice"

Demonstrates preclinical neuroprotective efficacy in the established CONDCA mouse model. The quoted claim is about treated mice, not treated patients.

PMID:39859255 SUPPORT Model Organism

"increasing the frequency of rhVEGF-B administration had a detrimental effect on Purkinje cell survival, suggesting an inverted U-shaped dose-response curve of this substance"

Supports the inverted-U dose-response stated in the treatment description. This is a limiting finding: it establishes a narrow therapeutic window and shows that more frequent dosing is harmful.

PMID:39859255 SUPPORT INDIRECT Model Organism

"treatment with rhIGF-1 did not demonstrate any neuroprotective effect"

Supports the description's statement that the comparator neurotrophic factor rhIGF-1, tested in the same experiment, showed no benefit. This is a null result about a DIFFERENT agent, so it is not evidence against rhVEGF-B. Marked INDIRECT for that reason. Note it also conflicts with an earlier pcd report summarised in PMID:34572343, which describes IGF-1 as improving weight, survival and motor performance; the discrepancy is unresolved and is recorded in this treatment's `notes`.

Lacosamide (CRMP2 Modulation)

Action: Pharmacotherapy NCIT:C15986

Agent: lacosamide CHEBI:135939

Platform: Small molecule

PRECLINICAL ONLY - no human study in CONDCA. AGTPBP1 knockout raises CRMP2 expression and causes mitochondrial dysfunction in differentiated neurons; lacosamide, which modulates CRMP2, improved cell morphology and mitochondrial function in vitro and rescued brain volume and swimming performance in AGTPBP1-deficient zebrafish. Lacosamide is an approved antiseizure medication in other indications, but its use here rests entirely on cell and zebrafish data.

Mechanism Target:

MODULATES Impaired Microtubule-Based Axonal Transport — Proposed to act through CRMP2, which links cytoskeletal dynamics to mitochondrial function. The source measures CRMP2 levels, neurite outgrowth, mitochondrial function and dopaminergic state; it does NOT measure axonal transport, so the link to this node is inferred from the shared microtubule/mitochondrial substrate rather than demonstrated.

Show evidence (2 references)

PMID:40347376 SUPPORT In Vitro

"Lacosamide treatment in vitro improved cell morphology and restored mitochondrial function"

Cell-based arm: lacosamide restored mitochondrial function in AGTPBP1-knockout cells. Split from the in vivo arm below so each item carries a single `evidence_source`.

PMID:40347376 SUPPORT Model Organism

"it rescued brain volume deficits and enhanced swimming performance in AGTPBP1-deficient zebrafish"

In vivo arm: lacosamide rescued brain volume and motor performance in AGTPBP1-deficient zebrafish. Split from the in vitro arm above.

🔬

Diagnosis

1

Trio Exome or Genome Sequencing

Molecular diagnosis rests on identifying biallelic AGTPBP1 variants, usually by trio exome or genome sequencing, or by a childhood ataxia / neurodegeneration / motor neuropathy panel that includes AGTPBP1. Candidate variants are confirmed by Sanger sequencing with parental segregation. Copy-number-sensitive analysis is required because a multi-exon genomic deletion is part of the reported allelic spectrum. There are no consensus clinical diagnostic criteria and no biochemical or metabolite assay for the disorder.

Show evidence (2 references)

PMID:38153683 SUPPORT Human Clinical

"Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants' effect on the protein structure."

Establishes exome sequencing as the diagnostic modality that identifies AGTPBP1 within the phenotypically overlapping childhood cerebellar-atrophy group.

PMID:30976113 SUPPORT Human Clinical

"Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants"

Illustrates the diagnostic workflow of exome sequencing plus family segregation, with cDNA studies used to resolve splice-affecting alleles.

🩻

Imaging Findings

1

Cerebellar Atrophy on Brain MRI

MRI may reveal small cerebellar hemispheres and vermis. A single early scan can be described as hypoplasia or atrophy and does not prove normal prenatal development. Cerebellar findings overlap PCH1; genotype and the broader clinical pattern aid diagnosis. A normal-appearing cerebellar MRI does not exclude CONDCA or microscopic degeneration.

Mri Diagnostic

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:34572343 SUPPORT Human Clinical

"Brain MRI revealed detected cerebellar atrophy with respect to non-affected, control individuals"

Review synthesis of published patient MRI showing cerebellar atrophy against unaffected controls.

📈

Progression

3

Onset

Age: Birth to approximately 20 months

Presentation is congenital to infantile and insidious rather than acute, typically with hypotonia, delayed motor milestones, feeding difficulty or abnormal eye movements.

Show evidence (1 reference)

PMID:34572343 SUPPORT Human Clinical

"the patients display early-onset developmental delays (between birth and 20 months of age) with a progressive degenerative course"

Review synthesis of published patients giving the onset window and the progressive character of the course.

Progressive decline

Progressive worsening of neurological function follows, with weakness, motor neuronopathy, ataxia, spasticity and dystonia, and increasing feeding and respiratory dependence.

Show evidence (1 reference)

PMID:30420557 SUPPORT Human Clinical

"progressive neurological deficits resulting in significant disability"

Describes the progressive neurological decline in the intermediate-severity patients of the foundational cohort.

Fatal outcome

A substantial fraction of affected children die in infancy or childhood. Six of the 13 patients in the foundational cohort had a fatal course, but that is a severity-ascertained research series, not a population case-fatality rate, and no survival curve or median life expectancy has been published. Milder survivors reach adolescence.

Show evidence (2 references)

PMID:30420557 SUPPORT Human Clinical

"a fatal course in six individuals"

Six of 13 affected individuals in the foundational cohort had a fatal course.

PMID:40754822 SUPPORT Human Clinical

"These patients typically exhibit progressive motor and cognitive impairment, often leading to childhood mortality."

Independent restatement of childhood mortality in human patients. The sentence summarises the human clinical literature, so it is graded HUMAN_CLINICAL even though the paper's own experiments are in mice.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population prevalence or incidence estimate has been published. The foundational cohort described 13 affected individuals from 10 unrelated families, and later syntheses count roughly 20 reported patients worldwide, which is too few to compute a rate. `ULTRA_RARE` records the qualitative order of magnitude, not a measured figure.

Show evidence (1 reference)

PMID:30420557 SUPPORT Human Clinical

"We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration"

The foundational multicentre international ascertainment yielded only 13 affected individuals, consistent with an ultra-rare disorder. This supports the qualitative class only; it is not a prevalence measurement.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Neurodegeneration Childhood-onset With Cerebellar Atrophy:

Pontocerebellar hypoplasia type 1

Overlapping Features PCH1 combines cerebellar hypoplasia or atrophy with bulbar and spinal motor-neuron disease and closely overlaps AGTPBP1-related disease. Early imaging terminology alone does not separate them; molecular diagnosis resolves the underlying gene.

Distinguishing Features

Pathogenic variants in distinct established PCH1 genes, including EXOSC3, EXOSC8, EXOSC9, VRK1 and SLC25A46
Interpret serial imaging, motor-neuron involvement and the molecular result together; a single hypoplasia-versus-atrophy label is insufficient

Show evidence (1 reference)

PMID:30976113 SUPPORT Human Clinical

"We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy."

The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.

Spinal muscular atrophy (5q-SMA)

Overlapping Features Infantile hypotonia, weakness and anterior horn cell degeneration overlap with 5q-SMA, and CONDCA is typically considered after SMN1 testing is negative. Cerebellar atrophy and the cerebellar movement disorder are not features of 5q-SMA.

Distinguishing Features

Homozygous SMN1 deletion or SMN1 point mutation
Absence of cerebellar atrophy on MRI
Absence of ataxia, spasticity and dystonia

Show evidence (1 reference)

PMID:31102495 SUPPORT Human Clinical

"Infantile hereditary lower motor neuron disorders beyond 5q-spinal muscular atrophy (5q-SMA) are usually caused by mutations other than deletions or mutations in SMN1."

Positions CONDCA within the non-5q-SMA infantile lower motor neuron disorder group, which is the diagnostic context in which 5q-SMA must be excluded.

🐁

Animal Models

1

Purkinje cell degeneration (pcd) mouse Spontaneous and engineered loss-of-function

The pcd mouse is the established genetic model of CONDCA and predates the human disease by decades. Homozygotes have a histologically normal cerebellum at postnatal day 14 and then lose almost all Purkinje cells within weeks, with ataxia from around P20. Retinal photoreceptors, olfactory bulb mitral cells, selected thalamic neurons and alpha-motor neurons also degenerate, and males are infertile. Peripheral nerve and spinal motor neuron degeneration were recognised only after the human disease was described, and they are what make the model a genuine phenocopy rather than a cerebellum-only model.

Species

Mus musculus

Genotype

Agtpbp1 (Nna1) loss-of-function; spontaneous alleles pcd, pcd2J, pcd3J, plus engineered knockouts

Genes

AGTPBP1 hgnc:17258

Publication

PMID:11884758

Pathograph links

Purkinje Neuron Degeneration recapitulates fidelity: high Near-complete Purkinje cell loss with the same molecular lesion (tubulin hyperglutamylation) as the human disease.

Limitations: Purkinje cell death in the mouse is temporally compressed into a few postnatal weeks, whereas human disease ranges from rapidly fatal infancy to survival into adolescence, so the therapeutic window observed in mice may not translate.

Lower Motor Neuron and Peripheral Motor Axon Degeneration recapitulates fidelity: high Peripheral nerve and spinal motor neuron degeneration in pcd mice was shown to reproduce the human motor neuronopathy.

Mouse data must not be used as the sole support for any human phenotype in this entry. Every human phenotype recorded here carries at least one HUMAN_CLINICAL evidence item; MODEL_ORGANISM items are used for mechanism and for model fidelity only.

Show evidence (3 references)

PMID:11884758 SUPPORT Model Organism

"The classical recessive mouse mutant, Purkinje cell degeneration (pcd), exhibits adult-onset degeneration of cerebellar Purkinje neurons, retinal photoreceptors, olfactory bulb mitral neurons, and selected thalamic neurons, and has defective spermatogenesis."

Defines the full pcd phenotype and identifies Nna1 (the AGTPBP1 ortholog) as the mutated gene.

PMID:30420557 SUPPORT Model Organism

"We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease."

Establishes the fidelity of the model for the peripheral and motor neuron arm of the human disease.

PMID:34572343 SUPPORT Other

"Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the AGTPBP1 gene."

Review assessment that the human course matches the established mouse model. Evidence source is OTHER because this is a review's overall judgement rather than a primary result.

{ }

Source YAML

click to show

name: Neurodegeneration Childhood-onset With Cerebellar Atrophy
creation_date: "2026-08-31T00:00:00Z"
category: Mendelian
description: >-
  Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA; OMIM 618276)
  is an ultra-rare autosomal recessive neurodegenerative disorder caused by
  biallelic loss-of-function or damaging missense variants in AGTPBP1, which
  encodes cytosolic carboxypeptidase 1 (CCP1, also called NNA1). CCP1 is the
  principal deglutamylase that shortens the polyglutamate side chains written onto
  the C-terminal tails of alpha- and beta-tubulin by the TTLL family of
  glutamylases, and it also removes gene-encoded C-terminal glutamates from
  detyrosinated alpha-tubulin to generate Delta2-tubulin. Loss of CCP1 leaves the
  writers unopposed, so neuronal microtubules become hyperglutamylated. This
  corruption of the neuronal "tubulin code" degrades microtubule-based cargo
  transport, impairs mitochondrial motility and fusion, provokes endoplasmic
  reticulum stress, and drives cell-autonomous degeneration of selectively
  vulnerable neurons - most conspicuously cerebellar Purkinje cells, but also
  spinal alpha-motor neurons and peripheral myelinated motor axons. Affected
  children present between birth and roughly 20 months with hypotonia, global
  developmental delay, and progressive cerebellar atrophy on MRI, and go on to
  develop weakness, motor neuronopathy, ataxia, spasticity and dystonia, feeding
  difficulty and respiratory insufficiency. The course is progressive and often
  fatal in childhood, although the reported spectrum extends to a milder,
  cerebellar-predominant presentation surviving into adolescence. The long-studied
  Purkinje cell degeneration (pcd) mouse carries Agtpbp1 loss-of-function alleles
  and is the established genetic model. No disease-modifying therapy exists;
  management is supportive.
disease_term:
  preferred_term: Childhood-onset neurodegeneration with cerebellar atrophy
  term:
    id: MONDO:0032650
    label: neurodegeneration, childhood-onset, with cerebellar atrophy
synonyms:
- CONDCA
- AGTPBP1-related neurodegeneration
- CCP1 deficiency
- infantile-onset neurodegeneration due to CCP1 loss
parents:
- inherited neurodegenerative disorder
- autosomal recessive cerebellar ataxia
- hereditary motor neuron disease

classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:34572343
      reference_title: >-
        The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
        Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
        Mouse as an Animal Model for the Study of this Human Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "rare and severe autosomal recessive disease that affects the central and peripheral nervous systems"
      explanation: >-
        The disease is defined by degeneration of central and peripheral nervous
        system structures, placing it in Harrison's Neurologic Disorders Part.
        Evidence source is OTHER because this is a review article.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration"
      explanation: >-
        CONDCA is a monogenic biallelic Mendelian disorder, which is the subject
        matter of Harrison's Genetics and Disease Part.
    notes: >-
      No `mechanistic_category` value is assigned: the MechanisticNosologyEnum has
      no tubulinopathy / microtubule post-translational-modification category, and
      none of the existing values (ciliopathy, proteotoxic disease, mitochondrial
      disease) describes a tubulin-code deglutamylation defect.

prevalence:
- population: Worldwide
  prevalence_class: ULTRA_RARE
  measure_type: CASES_IN_LITERATURE
  notes: >-
    No population prevalence or incidence estimate has been published. The
    foundational cohort described 13 affected individuals from 10 unrelated
    families, and later syntheses count roughly 20 reported patients worldwide,
    which is too few to compute a rate. `ULTRA_RARE` records the qualitative
    order of magnitude, not a measured figure.
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration"
    explanation: >-
      The foundational multicentre international ascertainment yielded only 13
      affected individuals, consistent with an ultra-rare disorder. This supports
      the qualitative class only; it is not a prevalence measurement.

inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires two damaging AGTPBP1 alleles. Heterozygous parents are
    unaffected obligate carriers. Consanguinity is common among reported families
    but is not required, as compound heterozygotes are also reported.
  evidence:
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants"
    explanation: >-
      Segregation analysis in two unrelated families established biallelic
      transmission consistent with autosomal recessive inheritance.
  - reference: PMID:33909173
    reference_title: >-
      A novel pathogenic variant in the 3' end of the AGTPBP1 gene gives rise to
      neurodegeneration without cerebellar atrophy: an expansion of the disease
      phenotype?
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted Sanger sequencing confirmed the variant in both affected children and in heterozygous form in the parents."
    explanation: >-
      Homozygosity in both affected siblings with unaffected heterozygous parents
      is the classical autosomal recessive segregation pattern.

pathophysiology:
- name: CCP1 Deglutamylase Deficiency
  description: >-
    Biallelic AGTPBP1 variants abolish functional cytosolic carboxypeptidase 1.
    Truncating alleles (nonsense, frameshift, canonical splice, multi-exon
    genomic deletion) eliminate the protein through nonsense-mediated decay or
    early truncation; tested missense alleles produce unstable protein that lacks
    detectable catalytic activity. CCP1 is a zinc metallocarboxypeptidase that
    shortens polyglutamate side chains on the tubulin C-terminal tail and converts
    detyrosinated alpha-tubulin into Delta2-tubulin, so its loss removes the
    eraser arm of the neuronal tubulin code.
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  molecular_functions:
  - preferred_term: tubulin metallocarboxypeptidase (deglutamylase) activity
    term:
      id: GO:0004181
      label: metallocarboxypeptidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: tubulin side-chain deglutamylation
    term:
      id: GO:0035610
      label: protein side chain deglutamylation
    modifier: DECREASED
  - preferred_term: C-terminal deglutamylation generating Delta2-tubulin
    term:
      id: GO:0035609
      label: C-terminal protein deglutamylation
    modifier: DECREASED
  genes:
  - preferred_term: AGTPBP1
    term:
      id: hgnc:17258
      label: AGTPBP1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline AGTPBP1 alleles. Reported classes include nonsense,
      frameshift, canonical and intronic splice-site, multi-exon genomic
      deletion, and missense alleles; truncating alleles eliminate the protein
      and tested missense alleles produce unstable protein without detectable
      catalytic activity, so the category is loss of function rather than
      dominant-negative or gain of function. Zygosity is deliberately left
      unset: affected individuals are homozygous or compound heterozygous, and
      ZygosityEnum has no biallelic value that covers both without asserting
      one of them.
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation."
    explanation: >-
      Directly establishes that the human disease allele set produces absence of
      functional CCP1, with a demonstrated downstream polyglutamylation defect.
  - reference: PMID:21074048
    reference_title: A family of protein-deglutamylating enzymes associated with neurodegeneration.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Three enzymes (CCP1, CCP4, and CCP6) catalyze the shortening of polyglutamate chains and a fourth (CCP5) specifically removes the branching point glutamates."
    explanation: >-
      Biochemical characterisation of the CCP family assigns CCP1 the
      polyglutamate side-chain shortening (deglutamylase) activity that is lost in
      CONDCA.
  - reference: PMID:21074048
    reference_title: A family of protein-deglutamylating enzymes associated with neurodegeneration.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we show that these enzymes convert detyrosinated tubulin into Δ2-tubulin and also modify other substrates"
    explanation: >-
      Establishes the second CCP1 activity lost in CONDCA - conversion of
      detyrosinated alpha-tubulin to Delta2-tubulin by removal of the gene-encoded
      C-terminal glutamate.
  - reference: PMID:11884758
    reference_title: >-
      Purkinje cell degeneration (pcd) phenotypes caused by mutations in the
      axotomy-induced gene, Nna1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we identify Nna1 as the gene mutated in the original pcd and two additional pcd alleles (pcd2J and pcd3J)."
    explanation: >-
      Identifies the orthologous gene lesion in the pcd mouse, establishing the
      genetic model for CCP1 loss. Nna1 is the mouse ortholog of human AGTPBP1.
  downstream:
  - target: Tubulin Hyperglutamylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30225910
      reference_title: >-
        Deletion of exons encoding carboxypeptidase domain of Nna1 results in
        Purkinje cell degeneration (pcd) phenotype.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Since the Nna1 protein acts as a de-glutamatase on the C-terminus of α-tubulin and β-tubulin, increased polyglutamylated tubulin was detected in the Nna1 KO cerebellum."
      explanation: >-
        Targeted deletion of the carboxypeptidase domain alone is followed by
        accumulation of polyglutamylated tubulin, showing that loss of the
        enzymatic activity is what causes hyperglutamylation. Evidence source is
        MODEL_ORGANISM because the data come from conditional Nna1 knockout mice.
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation"
      explanation: >-
        In patient-derived material the absence of CCP1 is accompanied by
        dysregulated tubulin polyglutamylation, linking the two nodes in humans
        rather than only in the mouse.

  - target: Neuronal Maintenance Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of functional CCP1 compromises neuronal maintenance; the detailed routes beyond the demonstrated hyperglutamylation pathway remain incompletely resolved.
    evidence:
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        In this study, we have shown that rare biallelic variants in the gene
        encoding the protein deglutamylase CCP1 cause degeneration of the
        central and peripheral nervous systems in humans.
      explanation: >-
        The discovery study establishes central and peripheral degeneration caused by biallelic CCP1 variants.
  - target: Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      CCP1 loss causes spinal motor-neuron degeneration in the genetic mouse model and is associated with the corresponding human lesion. Human anterior horn-cell loss is directly documented, while the intervening lethal pathway remains unresolved.
    evidence:
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease.
      explanation: >-
        Degeneration in the CCP1-deficient genetic model supports this qualified upstream causal relation; the lethal intermediates in human motor neurons remain unresolved.
      directness: INDIRECT
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sections from the spinal cord showed loss of neurons in the anterior horn, associated with reactive gliosis.
      explanation: >-
        Direct human histology resolves the earlier reliance on electrophysiological inference and mouse pathology for anterior horn-cell degeneration.
- name: Tubulin Hyperglutamylation
  description: >-
    With the CCP1 eraser gone, the TTLL-family glutamylase writers act unopposed
    and neuronal microtubules accumulate abnormally long polyglutamate side
    chains. TTLL1, which polyglutamylates alpha-tubulin, is the enzyme
    principally responsible for the pathological excess in CCP1 deficiency;
    TTLL7, which modifies beta-tubulin, is not. Delta2-tubulin generation falls in
    parallel. Genetic removal of TTLL1 normalises glutamylation and rescues the
    degeneration, which is the strongest available evidence that
    hyperglutamylation is the pathogenic lesion rather than an epiphenomenon. The
    rescue is not attributable to TTLL1 alone: a systematic survey across five
    TTLLs describes Ttll1 loss as attenuating rather than abolishing the
    degeneration and identifies TTLL4 as a second contributor.
  biological_scale: MOLECULAR
  role: amplifier
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: tubulin polyglutamylation
    term:
      id: GO:0018095
      label: protein polyglutamylation
    modifier: INCREASED
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:30225910
    reference_title: >-
      Deletion of exons encoding carboxypeptidase domain of Nna1 results in
      Purkinje cell degeneration (pcd) phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "increased polyglutamylated tubulin was detected in the Nna1 KO cerebellum"
    explanation: >-
      Direct measurement of the hyperglutamylated state in the cerebellum of mice
      lacking the CCP1 carboxypeptidase domain.
  - reference: PMID:34309047
    reference_title: >-
      Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TTLL1, but not TTLL7, catalyses the excessive hyperglutamylation found in mice lacking the deglutamylase CCP1."
    explanation: >-
      Identifies TTLL1 as the specific writer that produces the pathological
      hyperglutamylation when CCP1 is absent, refining the mechanism and naming
      the therapeutic target.
  - reference: PMID:21074048
    reference_title: A family of protein-deglutamylating enzymes associated with neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We further analyze Purkinje cell degeneration (pcd) mice that lack functional CCP1 and show that microtubule hyperglutamylation is directly linked to neurodegeneration."
    explanation: >-
      Establishes the causal link between microtubule hyperglutamylation and
      neurodegeneration in CCP1-null animals.
  - reference: PMID:33004692
    reference_title: >-
      Nna1 gene deficiency triggers Purkinje neuron death by tubulin
      hyperglutamylation and ER dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hyperglutamylated microtubules and dimeric tubulins accumulated in pcd PNs and were involved in pcd PN death by glutamylase/deglutamylase imbalance."
    explanation: >-
      Laser-capture microdissection of individual Purkinje neurons localises the
      hyperglutamylated species to the dying cells themselves.
  downstream:
  - target: Impaired Microtubule-Based Axonal Transport
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30420556
      reference_title: >-
        Excessive tubulin polyglutamylation causes neurodegeneration and perturbs
        neuronal transport.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Excessive polyglutamylation reduces the efficiency of neuronal transport in cultured hippocampal neurons, suggesting that impaired cargo transport plays an important role in the observed degenerative phenotypes."
      explanation: >-
        Directly measures the transport consequence of the hyperglutamylated
        state, establishing this specific edge rather than merely either node.
        Evidence source is IN_VITRO because the measurement was made in cultured
        hippocampal neurons.
  - target: Purkinje Cell Endoplasmic Reticulum Stress
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33004692
      reference_title: Nna1 gene deficiency triggers Purkinje neuron death by tubulin hyperglutamylation and ER dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Taken together, these findings strongly suggest that Nna1 deficiency not only triggers ER stress and UPR but also inhibits protein synthesis via the high accumulation of hyperglutamylated free tubulins in pcd PNs in vivo and in PN cultures.
      explanation: >-
        Experimental mouse and cultured-neuron perturbations support this proposed causal arm, beyond temporal co-occurrence.
      directness: INDIRECT
    description: >-
      Model-supported ER-stress pathway; its human relevance and necessity for cell death remain provisional.
  - target: Purkinje Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34309047
      reference_title: >-
        Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "deletion of TTLL1, but not of TTLL7, prevents degeneration of Purkinje cells and of myelinated axons in peripheral nerves in these mice"
      explanation: >-
        The rescue experiment is the decisive test of this edge: removing the writer that creates the hyperglutamylation prevents the degeneration, showing that hyperglutamylation causes the cell loss.
    - reference: PMID:30420556
      reference_title: >-
        Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1."
      explanation: >-
        Independent demonstration of complete genetic rescue by removing the counteracting glutamylase, confirming causality of the edge.

    description: >-
      Genetic rescue establishes hyperglutamylation-induced neuronal loss in mice, while the intervening lethal pathway is incompletely resolved.
  - target: Lower Motor Neuron and Peripheral Motor Axon Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Counteracting TTLL1 deletion prevents peripheral motor-axon degeneration in CCP1-deficient mice. This establishes a hyperglutamylation-dependent lesion while its precise intermediates and human translation remain incompletely reconstructed.
    evidence:
    - reference: PMID:34309047
      reference_title: Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This demonstrates that similar to Purkinje cells in the cerebellum, peripheral nerves degenerate as a result of hyperglutamylation generated by the polyglutamylase TTLL1, but not from TTLL7‐mediated glutamylation.
      explanation: >-
        The experiment supports hyperglutamylation-dependent peripheral degeneration, not proof that transport alone mediates it.
- name: Impaired Microtubule-Based Axonal Transport
  description: >-
    Excess tubulin polyglutamylation reduces overall cargo motility in cultured mouse neurons. Mitochondria spend more time paused; velocity and run length need not decrease. Cargo specificity differs between hippocampal and cerebellar granule-cell experiments. CCP1-null epithelial cells and pcd neurons also show mitochondrial fragmentation and impaired fusion. These model results motivate a transport/fusion contribution to degeneration, but transport rescue has not established the complete causal sequence in human neurons.
  biological_scale: CELLULAR
  role: amplifier
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: axo-dendritic transport
    term:
      id: GO:0008088
      label: axo-dendritic transport
    modifier: DECREASED
  - preferred_term: mitochondrion transport along microtubule
    term:
      id: GO:0047497
      label: mitochondrion transport along microtubule
    modifier: DECREASED
  - preferred_term: mitochondrial fusion
    term:
      id: GO:0008053
      label: mitochondrial fusion
    modifier: DECREASED
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:30337352
    reference_title: >-
      CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell
      neuron loss in pcd mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We examined the effect of tubulin hyperglutamylation on microtubule-mediated mitochondrial motility in pcd neurons and noted markedly reduced retrograde axonal transport."
    explanation: >-
      Direct measurement of reduced retrograde mitochondrial transport in neurons
      from the CCP1-null mouse.
  - reference: PMID:30337352
    reference_title: >-
      CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell
      neuron loss in pcd mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we documented reduced mitochondrial fusion in cells lacking CCP1"
    explanation: >-
      Establishes the reduced-fusion component of this node in CCP1-null cells.
      Split from the companion item below so each carries a single
      `evidence_source`.
  - reference: PMID:30337352
    reference_title: >-
      CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell
      neuron loss in pcd mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We observed mitochondrial fragmentation in CCP1 null cells and in neurons from pcd mice"
    explanation: >-
      Establishes mitochondrial fragmentation in neurons from the CCP1-null mouse.
      Split from the companion in-vitro item above.
  - reference: PMID:34309047
    reference_title: >-
      Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of TTLL1 leads to increased mitochondria motility in neurons"
    explanation: >-
      Removing the glutamylase restores mitochondrial motility, confirming that
      the transport deficit is a consequence of the glutamylation state.
  downstream:
  - target: Purkinje Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34309047
      reference_title: Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        While a causative link between the transport defects and the degeneration ofCcp1−/−neurons has so far not been established, our finding that mitochondria are more motile inTtll1−/−neurons suggests that the rescue of hyperglutamylation‐mediated neurodegeneration by knockout of TTLL1 is linked to a recovery of the reduced axonal transport in these neurons.
      explanation: >-
        The authors explicitly propose, rather than establish, transport mediation. Genetic rescue of hyperglutamylation is not by itself a transport-specific rescue.
      directness: INDIRECT
    description: >-
      Proposed transport-mediated contribution to neuronal degeneration. The transport defect is measured in models, but its causal mediation of neuronal death remains incompletely established and is not directly measured in human CONDCA neurons.
  - target: Lower Motor Neuron and Peripheral Motor Axon Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34309047
      reference_title: Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        While a causative link between the transport defects and the degeneration ofCcp1−/−neurons has so far not been established, our finding that mitochondria are more motile inTtll1−/−neurons suggests that the rescue of hyperglutamylation‐mediated neurodegeneration by knockout of TTLL1 is linked to a recovery of the reduced axonal transport in these neurons.
      explanation: >-
        The authors explicitly propose, rather than establish, transport mediation. Genetic rescue of hyperglutamylation is not by itself a transport-specific rescue.
      directness: INDIRECT
    description: >-
      Proposed transport-mediated contribution to neuronal degeneration. The transport defect is measured in models, but its causal mediation of neuronal death remains incompletely established and is not directly measured in human CONDCA neurons.
- name: Purkinje Cell Endoplasmic Reticulum Stress
  description: >-
    In pcd mouse Purkinje neurons, ER-rich polyribosomal masses, ER-stress markers, unfolded protein response activation and reduced protein synthesis precede cell death. Perturbation experiments support an ER-mediated death pathway, but the authors retain competing mechanisms and uncertain human translation.
  biological_scale: CELLULAR
  role: amplifier
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:33004692
    reference_title: >-
      Nna1 gene deficiency triggers Purkinje neuron death by tubulin
      hyperglutamylation and ER dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the neuronal disorder involved ER stress, unfolded protein response, and protein synthesis inhibition preceding PN death by apoptosis/necroptosis"
    explanation: >-
      Establishes ER stress and the unfolded protein response as events that
      precede, rather than follow, Purkinje neuron death.
  - reference: PMID:30225910
    reference_title: >-
      Deletion of exons encoding carboxypeptidase domain of Nna1 results in
      Purkinje cell degeneration (pcd) phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the endoplasmic reticulum stress marker, C/EBP homologous protein (CHOP), was up-regulated in the mutant PCs"
    explanation: >-
      Independent molecular confirmation of ER stress in Purkinje cells of a
      separate CCP1 loss-of-function mouse line.
  notes: >-
    `mechanism_confidence` is PROVISIONAL rather than ESTABLISHED because the ER
    stress arm rests entirely on mouse data; no equivalent measurement has been
    made in human CONDCA tissue, and no rescue experiment has shown that blocking
    the UPR prevents Purkinje cell loss.
  downstream:
  - target: Purkinje Neuron Degeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33004692
      reference_title: Nna1 gene deficiency triggers Purkinje neuron death by tubulin hyperglutamylation and ER dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In both pcd PNs in vivo and in PNs in vitro, Nna1 deficiency induced ER dysfunction and triggered dark PN apoptosis, cell shrinkage, caspase activation, and DNA fragmentation.
      explanation: >-
        The authors propose ER-mediated death based on the combined experiments; the causal pathway remains provisional.
      directness: INDIRECT
    description: >-
      Provisional mouse ER-mediated apoptotic pathway; necessity of the pathway and its operation in human neurons remain unresolved.
- name: Purkinje Neuron Degeneration
  description: >-
    Cerebellar Purkinje cells are the most conspicuously vulnerable population. In the pcd mouse the cerebellum is histologically normal at postnatal day 14 and then loses essentially all Purkinje cells within weeks, with reactive microgliosis and astrogliosis; lobule X is relatively spared. The degeneration is cell-autonomous - excessive polyglutamylation is sufficient to kill the neuron from within, independent of its neighbours. That does not exclude a contributing glial component: reactive microgliosis and astrogliosis accompany the loss, and minocycline, a glial-activation inhibitor, delays Purkinje cell death in pcd mice. Human autopsy in 2026 directly demonstrated marked Purkinje-cell and granular-layer loss. The observed human lesion is established, whereas cell-autonomous hyperglutamylation causality, lobule-specific resistance and the detailed death pathways still derive from models.
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:30225910
    reference_title: >-
      Deletion of exons encoding carboxypeptidase domain of Nna1 results in
      Purkinje cell degeneration (pcd) phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Most PCs degenerated until 4-week-old, except lobule X."
    explanation: >-
      Quantifies the near-complete and regionally patterned Purkinje cell loss
      that defines this node.
  - reference: PMID:30225910
    reference_title: >-
      Deletion of exons encoding carboxypeptidase domain of Nna1 results in
      Purkinje cell degeneration (pcd) phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Activated microglia and astrocytes were also observed in the Nna1 KO cerebellum."
    explanation: >-
      Documents the reactive glial response accompanying Purkinje cell loss.
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "delays the death of PCs in pcd mice and mildly improves their locomotor performance"
    explanation: >-
      Inhibiting glial activation with minocycline delays Purkinje cell death,
      showing the glial response contributes to the timing of the loss even though
      excessive polyglutamylation is cell-autonomously sufficient to cause it.
      Marked INDIRECT because it establishes a glial contribution by intervention
      rather than stating it.
  - reference: PMID:30420556
    reference_title: >-
      Excessive tubulin polyglutamylation causes neurodegeneration and perturbs
      neuronal transport.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we demonstrate that excessive polyglutamylation induces neurodegeneration in a cell-autonomous manner and can occur in many parts of the central nervous system"
    explanation: >-
      Establishes cell autonomy, which distinguishes this mechanism from
      inflammation-driven or network-driven models of neuronal loss.
  - reference: PMID:41226418
    reference_title: >-
      Specific Glutamylation Patterns of the Cytoskeleton Confer Neuroresistance
      to Lobe X of the Cerebellum in a Model of Childhood-Onset Neurodegeneration
      with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This study revealed in wild-type mice that lobe X expresses less Ccp1 compared to other lobes, correlating with its delayed degeneration in PCD mice.
    explanation: >-
      This study examines regional vulnerability in mice. Its introductory human claim is not treated as new human histological evidence.
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cerebellum showed normal-sized folia with a marked loss of Purkinje cells. There was a prominence of Bergmann glial cells.
    explanation: >-
      Direct human autopsy evidence supersedes the discovery-series absence of postmortem examinations.
  downstream:
  - target: Cerebellar Ataxia and Movement Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Purkinje-cell loss produces cerebellar motor impairment in pcd mice.
      Human ataxia has a corresponding cerebellar substrate, while the exact
      functional intermediates are not directly measured in affected children.
    evidence:
    - reference: PMID:34572343
      reference_title: >-
        The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
        Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
        Mouse as an Animal Model for the Study of this Human Disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mutations in AGTPBP1 lead to early cerebellar ataxia, which correlates with the massive loss of cerebellar Purkinje cells"
      explanation: >-
        The review identifies Purkinje-cell degeneration as responsible for
        cerebellar ataxia in pcd mice. This supports the cellular-loss-to-motor
        consequence relation; its detailed functional mediation in human CONDCA
        remains inferred from the model and clinical correspondence.
    - reference: PMID:34637898
      reference_title: The AGTPBP1 gene in neurobiology.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The salient behavioral phenotypes include cerebellar ataxia, a loss in motor coordination, and cognitive deficits."
      explanation: >-
        Names the behavioural output of the cerebellar degeneration in Agtpbp1
        mutants, which is the consequence this edge terminates in.
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30976113
      reference_title: >-
        Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the mutant mice, cerebellar atrophy due to Purkinje cell degeneration is observed, likely due to increased tubulin polyglutamylation in affected brain areas."
      explanation: >-
        States the causal relationship between Purkinje cell degeneration and the cerebellar atrophy, which is precisely what this edge asserts.

    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The autopsy revealed the atrophy of cerebellar folia with a striking reduction of Purkinje and granular cells and preserved molecular layer.
      explanation: >-
        Human pathology supports neuronal loss as the substrate of cerebellar folial atrophy.
- name: Lower Motor Neuron and Peripheral Motor Axon Degeneration
  description: >-
    In parallel with the cerebellar arm, spinal alpha-motor neurons are lost and peripheral myelinated motor axons degenerate, with reduced axon number and calibre and disorganised axoplasm. Electrophysiology in patients shows denervation and axonal motor neuropathy in proximal and distal muscles, while sensory nerve action potentials are preserved - the neuropathy is motor-predominant. Skeletal muscle change is secondary neurogenic atrophy, not a primary myopathy. Anterior horn-cell loss with reactive gliosis was directly confirmed in a human autopsy in 2026; peripheral motor-axon versus cell-body contributions in other patients remain based on clinical and electrophysiological localization.
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: spinal alpha-motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five individuals who underwent nerve conduction studies, electromyography, muscle ultrasound, or muscle histology had signs of peripheral nerve and spinal motor neuron degeneration"
    explanation: >-
      Direct human electrophysiological and histological evidence of the
      peripheral and lower motor neuron lesion.
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease."
    explanation: >-
      Shows the pcd mouse reproduces this arm of the human disease, supporting use
      of the model for the motor neuron phenotype.
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "electromyography studies have detected signs of denervation causing muscle atrophy in proximal and distal muscles, including the tibialis anterior and posterior deltoid, suggesting degeneration of both peripheral nerve motor fibres and spinal cord"
    explanation: >-
      Review synthesis of published patient electromyography, localising the
      lesion to both peripheral motor fibres and spinal cord motor neurons.
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accompanied by severe motor neuronopathy"
    explanation: >-
      Independent human confirmation of severe motor neuronopathy in two unrelated
      patients with biallelic AGTPBP1 variants.
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sections from the spinal cord showed loss of neurons in the anterior horn, associated with reactive gliosis.
    explanation: >-
      Direct human histology resolves the earlier reliance on electrophysiological inference and mouse pathology for anterior horn-cell degeneration.
  downstream:
  - target: Motor Neuronopathy and Progressive Weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34572343
      reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In particular, electromyography studies have detected signs of denervation causing muscle atrophy in proximal and distal muscles, including the tibialis anterior and posterior deltoid, suggesting degeneration of both peripheral nerve motor fibres and spinal cord α-motor neurons.
      explanation: >-
        The clinical synthesis explicitly links denervation to muscle atrophy and localizes motor-system injury.
  - target: Motor Axonal Neuropathy
    causal_link_type: DIRECT
    description: >-
      Motor-axon injury is the peripheral component of the clinical motor neuropathy; electrophysiological localization can also reflect anterior horn-cell loss.
    evidence:
    - reference: PMID:34572343
      reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Electrophysiological recordings revealed motor neuropathy affecting the lower limbs and arms.
      explanation: >-
        Supports motor neuropathy in investigated patients.
- name: Cerebellar Ataxia and Movement Disorder
  description: >-
    Loss of Purkinje cell output disrupts the cerebellar contribution to motor
    coordination, producing ataxia. In the most severely affected infants profound
    weakness may mask the ataxia because the child never achieves independent
    ambulation. Spasticity and dystonia are also consistently reported in these
    patients and are curated as phenotypes, but they are NOT attributed to this
    node: spasticity is a pyramidal/upper-motor-neuron sign and dystonia is
    extrapyramidal, and neither follows from loss of cerebellar cortical output.
    A single p.Gln816Pro case now documents caudate and putaminal atrophy, but
    a causal relationship between those lesions and the movement disorder is
    unresolved. The affected descending motor pathways are also unestablished.
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Ataxia"
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "feeding difficulties, ataxia, spasticity, and dystonia"
    explanation: >-
      Records ataxia among the consistently observed features of the foundational
      human cohort. The quoted list also names spasticity and dystonia, which are
      curated as separate phenotypes and are deliberately not attributed to this
      cerebellar node.
  - reference: PMID:34637898
    reference_title: The AGTPBP1 gene in neurobiology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar neuropathogical and behavioral profiles have been described in childhood-onset human subjects with biallelic variants of AGTPBP1, including cerebellar ataxia and hypotonia."
    explanation: >-
      Confirms cerebellar ataxia as the clinical consequence in humans, not only
      in the mouse.

  downstream:
  - target: Ataxia
    causal_link_type: DIRECT
    description: >-
      The phenotype records the cerebellar incoordination represented by this mechanism.
  - target: Abnormal Eye Movements
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The discovery-series authors propose combined muscle weakness and cerebellar dysfunction as contributors; the relative contribution and specific ocular-motor subtype vary.
    evidence:
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the eye movement abnormalities in the humans are likely to be the result of muscle weakness and cerebellar dysfunction, with no known evidence of ... retinal degeneration.
      explanation: >-
        The authors explicitly attribute the human eye-movement abnormalities to weakness and cerebellar dysfunction; the sentence continues with absence of known retinal degeneration in that 2018 series.
- name: Motor Neuronopathy and Progressive Weakness
  description: >-
    Denervation of proximal and distal muscles produces progressive generalised
    weakness, often reaching tetraparesis, with neurogenic muscle atrophy, absent
    or reduced deep tendon reflexes, and tongue fasciculations. Bulbar and
    respiratory muscle involvement generates the feeding difficulty and
    respiratory insufficiency that drive most of the mortality.
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mainly characterised by hypotonia and generalised muscle weakness, frequently causing tetraparesis"
    explanation: >-
      Review synthesis of published patients describing the weakness phenotype and
      its progression to tetraparesis.
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties"
    explanation: >-
      Directly links the progressive weakness to the feeding and respiratory
      complications that constitute the clinical burden.

  downstream:
  - target: Progressive Muscle Weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the progressive limb weakness in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the progressive limb weakness among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy.
      explanation: >-
        The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the muscular hypotonia in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the muscular hypotonia among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Patients generally
        presented with muscular hypotonia, global developmental delays,
        and cerebellar atrophy on brain imaging (Fig 2A) from early
        infancy, followed by progressive worsening of neurological func-
        tion and a fatal course in six individuals.
      explanation: >-
        Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.
  - target: Reduced Tendon Reflexes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the depressed deep tendon reflexes in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the depressed deep tendon reflexes among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Muscle tone was low and deep
        tendon re ﬂexes were decreased.
      explanation: >-
        The second genetically confirmed patient had decreased deep tendon reflexes, supporting this specific direction of abnormality.
  - target: Areflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the absent deep tendon reflexes in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the absent deep tendon reflexes among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Deep tendon reflexes were absent with extensor plantar response.
      explanation: >-
        Direct examination of the infant subsequently shown to have anterior horn-cell degeneration.
  - target: Neurogenic Muscle Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the neurogenic muscle atrophy in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the neurogenic muscle atrophy among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:34572343
      reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia.
      explanation: >-
        Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.
  - target: Tongue Fasciculations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the tongue fasciculations in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the tongue fasciculations among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:34572343
      reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia.
      explanation: >-
        Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.
  - target: Motor Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the failure to acquire motor milestones in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the failure to acquire motor milestones among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        He had not achieved mile-
        stones such as sitting or standing or talking.
      explanation: >-
        The second child had not acquired sitting or standing; this is delayed acquisition, distinct from subsequent loss of skills.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the feeding difficulties in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the feeding difficulties among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy.
      explanation: >-
        The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.
  - target: Respiratory Insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the respiratory insufficiency in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the respiratory insufficiency among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy.
      explanation: >-
        The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.
  - target: Weak Cry
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the weak cry in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the weak cry among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thereafter, the parents observed a gradual decline in abilities characterized by thinning of the muscles, reduced limb movements, diminished interaction, poor object tracking, a weak cry, and the appearance of a squint.
      explanation: >-
        The child had initially attained social smiling and head control, then lost abilities beginning at 2.5 months.
  - target: Poor Suck
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the weak suck in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the weak suck among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Examination revealed a thin-built, lethargic baby, with weak suck, pooling of oral secretions, a frog-like posture, and right convergent squint.
      explanation: >-
        Direct examination of the autopsied infant.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The documented motor neuronopathy and weakness account for the swallowing difficulty in the severe motor-unit presentation. This is a qualified clinical attribution; central contributions or additional causes may coexist.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Most of our patients ’ symptoms
        likely derived from Purkinje cell degeneration and motor
        neuronopathy.
      explanation: >-
        The original clinicians attribute most patient symptoms, the swallowing difficulty among them, to Purkinje degeneration and motor neuronopathy. This is a qualified clinical interpretation of the series as a whole, not a measurement made for this finding.
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Repeated
        aspirations due to dif ﬁculty in eating solid food and slow
        weight gain led to gastrostomy insertion at two years of age.
      explanation: >-
        The second patient aspirated repeatedly while eating solid food and gained weight slowly, leading to gastrostomy.
  - target: Abnormal Eye Movements
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The discovery-series authors propose combined muscle weakness and cerebellar dysfunction as contributors; the relative contribution and specific ocular-motor subtype vary.
    evidence:
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the eye movement abnormalities in the humans are likely to be the result of muscle weakness and cerebellar dysfunction, with no known evidence of ... retinal degeneration.
      explanation: >-
        The authors explicitly attribute the human eye-movement abnormalities to weakness and cerebellar dysfunction; the sentence continues with absence of known retinal degeneration in that 2018 series.
- name: Neuronal Maintenance Failure
  description: >-
    CCP1 loss disrupts maintenance of central and peripheral neurons and leads to progressive motor and cognitive deficits. Human neurodegeneration is established clinically and pathologically, but the circuits and developmental versus degenerative contributions to intellectual impairment remain incompletely localized.
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits.
    explanation: >-
      The human report explicitly relates defective neuronal maintenance to the clinical motor and cognitive decline.
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      In this study, we have shown that rare biallelic variants in the gene
      encoding the protein deglutamylase CCP1 cause degeneration of the
      central and peripheral nervous systems in humans.
    explanation: >-
      The discovery study establishes central and peripheral degeneration caused by biallelic CCP1 variants.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.
    evidence:
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits.
      explanation: >-
        The human report explicitly relates defective neuronal maintenance to the clinical motor and cognitive decline.
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Patients generally
        presented with muscular hypotonia, global developmental delays,
        and cerebellar atrophy on brain imaging (Fig 2A) from early
        infancy, followed by progressive worsening of neurological func-
        tion and a fatal course in six individuals.
      explanation: >-
        Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.
    evidence:
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits.
      explanation: >-
        The human report explicitly relates defective neuronal maintenance to the clinical motor and cognitive decline.
    - reference: PMID:30420557
      reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        We recog-
        nized two phenotypic extremes, critically ill infants (A1, B1, E1,
        E2, E3, H1, J1) with profound impairment of motor and cognitive
        development as opposed to one 14-year-old individual (D1) with a
        spastic–ataxic movement disorder and only mild intellectual
        disability.
      explanation: >-
        The 14-year-old patient had explicitly documented mild intellectual disability, distinct from developmental impairment assessed in infants.
  - target: Developmental Regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.
    evidence:
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits.
      explanation: >-
        The human report explicitly relates defective neuronal maintenance to the clinical motor and cognitive decline.
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thereafter, the parents observed a gradual decline in abilities characterized by thinning of the muscles, reduced limb movements, diminished interaction, poor object tracking, a weak cry, and the appearance of a squint.
      explanation: >-
        The child had initially attained social smiling and head control, then lost abilities beginning at 2.5 months.
  - target: Progressive Neurological Deterioration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The clinical cognitive and developmental manifestations are attributed to neuronal dysfunction and degeneration. Regional circuitry and the balance of delayed development versus acquired loss are incompletely defined, so this is an indirect relation.
    evidence:
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits.
      explanation: >-
        The human report identifies disrupted neuronal maintenance as the basis of progressive motor and cognitive deficits, supporting the neurological-deterioration edge.

- name: Absent Thymic Tissue
  description: >-
    Thymic tissue was absent at autopsy in one infant with AGTPBP1-related neurodegeneration. The authors propose that this contributes to lymphopenia and infection susceptibility. The genetic cause of the thymic lesion and precise lymphocyte subset defect remain unresolved.
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The thymus could not be identified grossly. Anterior mediastinal soft tissue was extensively sampled for histological examination and did not reveal any remnant of thymus.
    explanation: >-
      Direct anatomy in one genetically confirmed case; the causal genetic relation remains provisional.
  downstream:
  - target: Lymphopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The report proposes immune deficiency secondary to thymic involvement. Lymphocyte subsets were unavailable, so the specific developmental mechanism and degree of T-cell depletion remain uncertain.
    evidence:
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This case highlights the structural consequences of the AGTPBP1 gene-associated enzyme deficiency crucial for post-translational modifications of tubulin, resulting in the degeneration of specific sets of neurons and immune deficiency secondary thymic involvement.
      explanation: >-
        The authors attribute immune compromise to the thymic lesion, but the gene-to-thymus causal relation is unreplicated and no lymphocyte subset assay was available.
      directness: INDIRECT
- name: Callosal White Matter Loss
  description: >-
    The autopsied infant had a thin corpus callosum with marked myelin loss. This supports tissue loss as the substrate of thinning in that case, without establishing whether defective axonal development, primary myelin injury or secondary degeneration initiated the lesion.
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sections from the corpus callosum showed thinned out corpus callosum with marked loss of myelin.
    explanation: >-
      Direct human callosal histology; this does not establish the prenatal or postnatal origin of all callosal abnormalities.
  downstream:
  - target: Thin Corpus Callosum
    causal_link_type: DIRECT
    description: >-
      Reduced white matter is the documented tissue substrate of callosal thinning in the autopsy case.
    evidence:
    - reference: PMID:42358771
      reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The sections from the corpus callosum showed thinned out corpus callosum with marked loss of myelin.
      explanation: >-
        Direct human callosal histology; this does not establish the prenatal or postnatal origin of all callosal abnormalities.
phenotypes:
- category: Neurological
  name: Global Developmental Delay
  description: >-
    Global delay in the acquisition of developmental milestones, present from
    early infancy and followed by progressive loss of neurological function.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patients generally
      presented with muscular hypotonia, global developmental delays,
      and cerebellar atrophy on brain imaging (Fig 2A) from early
      infancy, followed by progressive worsening of neurological func-
      tion and a fatal course in six individuals.
    explanation: >-
      Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.
- category: Neurological
  name: Motor Delay
  description: >-
    Motor milestones may be delayed from early infancy, including failure to acquire independent sitting or standing. Developmental regression is represented separately.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      He had not achieved mile-
      stones such as sitting or standing or talking.
    explanation: >-
      The second child had not acquired sitting or standing; this is delayed acquisition, distinct from subsequent loss of skills.
- category: Neurological
  name: Hypotonia
  description: >-
    Early muscular hypotonia can be congenital or emerge during infancy. Motor-unit hypotonia is documented in severe neuronopathic cases, but hypotonia also occurs in patients without demonstrated lower motor-neuron involvement or cerebellar atrophy.
  phenotype_term:
    preferred_term: Muscular hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patients generally
      presented with muscular hypotonia, global developmental delays,
      and cerebellar atrophy on brain imaging (Fig 2A) from early
      infancy, followed by progressive worsening of neurological func-
      tion and a fatal course in six individuals.
    explanation: >-
      Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The child in this case exhibited hallmark phenotypic features of AGTPBP1 mutations (Table 1), including motor unit hypotonia, global developmental delay, and cerebellar atrophy with significant Purkinje cell loss.
    explanation: >-
      The autopsied infant had motor-unit hypotonia with anterior horn-cell degeneration; this does not establish the same localization in all patients.
- category: Neurological
  name: Progressive Muscle Weakness
  description: >-
    Generalised muscle weakness of neurogenic origin that progresses over time and
    frequently reaches tetraparesis, limiting or preventing ambulation.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy.
    explanation: >-
      The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.
- category: Neurological
  name: Cerebellar Atrophy
  description: >-
    Cerebellar volume loss is characteristic but not obligatory. Early scans may not distinguish hypoplasia from atrophy, and normal-appearing cerebellar MRI does not exclude microscopic neuronal loss. A 2026 autopsy documented marked Purkinje and granular cell loss despite an antemortem MRI reported as unremarkable apart from callosal thinning.
  notes: >-
    Loss of Purkinje and additional cerebellar neurons is the documented tissue
    substrate of atrophy in the autopsy case. The extent and timing vary;
    normal neonatal cerebellar development has not been documented in every
    patient. This clinical finding is reached from upstream neuronal loss,
    without a separate synonymous tissue-atrophy node.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  diagnostic: true
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Patients generally
      presented with muscular hypotonia, global developmental delays,
      and cerebellar atrophy on brain imaging (Fig 2A) from early
      infancy, followed by progressive worsening of neurological func-
      tion and a fatal course in six individuals.
    explanation: >-
      Clinical presentation of the 13-person discovery series; this does not quantify each feature in all AGTPBP1 disease.
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The autopsy revealed the atrophy of cerebellar folia with a striking reduction of Purkinje and granular cells and preserved molecular layer.
    explanation: >-
      Direct human neuropathology establishes the cellular lesion underlying cerebellar tissue loss in this case.
- category: Neurological
  name: Ataxia
  description: >-
    Cerebellar incoordination of gait and limbs. In children able to sit or walk
    it may combine with spasticity to produce a spastic-ataxic movement disorder;
    in the most severely affected infants it is masked by profound weakness.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Additional constantly
      observed features were microcephaly, eye movement abnormali-
      ties, feeding difficulties, ataxia, spasticity, and dystonia.
    explanation: >-
      The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.
- category: Neurological
  name: Spasticity
  description: >-
    Velocity-dependent increase in muscle tone reflecting upper motor neuron
    involvement, coexisting with the lower motor neuron and cerebellar signs.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Additional constantly
      observed features were microcephaly, eye movement abnormali-
      ties, feeding difficulties, ataxia, spasticity, and dystonia.
    explanation: >-
      The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.
- category: Neurological
  name: Dystonia
  description: >-
    Sustained or intermittent involuntary muscle contractions producing abnormal
    postures, part of the mixed movement disorder of CONDCA.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Additional constantly
      observed features were microcephaly, eye movement abnormali-
      ties, feeding difficulties, ataxia, spasticity, and dystonia.
    explanation: >-
      The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.
- category: Neurological
  name: Microcephaly
  description: >-
    Reduced head circumference is reported, including progressive postnatal decline in head growth. It is an anthropometric finding. One of the two 2019 cases also carried a homozygous NCAPD3 variant that the authors could not exclude as a contributor; progressive microcephaly was also observed in the second case.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other brain alterations, such as microcephaly or dysplastic corpus callosum, were also frequently detected."
    explanation: >-
      Published clinical observations support microcephaly; this combined sentence does not specify a separate frequency.
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A progressive decline in the head circumference percentile ... for age was
      noted (Fig. S1), and at last examination at 45 months of age was measured
      to be 46 cm ( −2.7 SD).
    explanation: >-
      Postnatal head-growth decline in the second patient; the NCAPD3 confound was reported in the first patient. The quoted sentence is interrupted in the source PDF by the Fig. 1 legend and a running page header, which the elision removes.
- category: Neurological
  name: Abnormal Corpus Callosum Morphology
  description: >-
    Callosal dysplasia is reported in the discovery cohort. Thin corpus callosum is separately documented in an autopsied infant. These findings do not establish congenital callosal hypoplasia in every patient.
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:34572343
    reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other brain alterations, such as microcephaly or dysplastic corpus callosum, were also frequently detected.
    explanation: >-
      Supports dysplastic callosal morphology without conflating it with proven hypoplasia.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding impairment includes weak suck, difficulty managing solid food and aspiration. Some children require gastrostomy. Severe motor neuronopathy is a likely contributor, although the relative bulbar and central contributions have not been measured in every child.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy.
    explanation: >-
      The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.
  sequelae:
  - target: Failure to Thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired intake contributes to poor growth in the feeding-impaired presentation; the report describes choking, failure to thrive and gastrostomy together.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        The child
        was hospitalized at age 4 months due to feeding dif ﬁculty,
        choking and failure to thrive and underwent insertion of a
        feeding gastrostomy.
      explanation: >-
        The first 2019 patient had failure to thrive with choking and feeding difficulty.
- category: Ophthalmological
  name: Abnormal Eye Movements
  description: >-
    Heterogeneous oculomotor abnormalities are reported. The discovery-series authors consider muscle weakness and cerebellar dysfunction likely contributors. Oculomotor apraxia and esotropia have independent, more specific case evidence; hypometric saccades and poor eye contact were tabulated in the 2024 patient with a likely pathogenic variant.
  phenotype_term:
    preferred_term: Eye movement abnormality
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Additional constantly
      observed features were microcephaly, eye movement abnormali-
      ties, feeding difficulties, ataxia, spasticity, and dystonia.
    explanation: >-
      The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the eye movement abnormalities in the humans are likely to be the result of muscle weakness and cerebellar dysfunction, with no known evidence of ... retinal degeneration.
    explanation: >-
      The authors explicitly attribute the human eye-movement abnormalities to weakness and cerebellar dysfunction; the sentence continues with absence of known retinal degeneration in that 2018 series.
- category: Respiratory
  name: Respiratory Insufficiency
  description: >-
    Respiratory compromise may require assisted ventilation or tracheostomy in severe motor neuronopathy. Aspiration, atelectasis and infection can contribute. The autopsied infant had fatal adenovirus pneumonitis and bronchopneumonia, so a purely neuromuscular explanation does not account for every episode.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy.
    explanation: >-
      The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.
- category: Neurological
  name: Reduced Tendon Reflexes
  description: >-
    Decreased deep tendon reflexes occur in the motor-neuron-predominant presentation. Areflexia is documented separately. Increased reflexes also occur in other patients, so the review's aggregate statement about almost universal reflex alterations cannot be assigned to the reduced-reflex subtype.
  phenotype_term:
    preferred_term: Reduced tendon reflexes
    term:
      id: HP:0001315
      label: Reduced tendon reflexes
  evidence:
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Muscle tone was low and deep
      tendon re ﬂexes were decreased.
    explanation: >-
      The second genetically confirmed patient had decreased deep tendon reflexes, supporting this specific direction of abnormality.
- category: Musculoskeletal
  name: Neurogenic Muscle Atrophy
  description: >-
    Skeletal muscle wasting secondary to denervation, affecting proximal and
    distal muscles. Muscle histology shows chronic neurogenic change rather than a
    primary myopathy.
  phenotype_term:
    preferred_term: Neurogenic muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia.
    explanation: >-
      Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postmortem muscle biopsy showed numerous angulated atrophic fibres. There were some foci showing group atrophy.
    explanation: >-
      The case had histologically documented neurogenic atrophy; the review proportion concerns muscle wasting, not uniform biopsy ascertainment.
  notes: >-
    The review reports muscle atrophy in half of the published patients. Neurogenic histology or electrophysiology was not assessed uniformly, so that denominator is not a frequency estimate of verified neurogenic atrophy.
- category: Neurological
  name: Tongue Fasciculations
  description: >-
    Tongue fasciculations occur in the motor-neuron-predominant presentation and contribute to the clinical overlap with spinal muscular atrophy. They are not obligatory; the autopsied infant lacked tongue fasciculations despite anterior horn-cell loss.
  phenotype_term:
    preferred_term: Tongue fasciculations
    term:
      id: HP:0001308
      label: Tongue fasciculations
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia.
    explanation: >-
      Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Tongue fasci-
      culations were evident.
    explanation: >-
      Direct observation in the second 2019 patient with severe motor neuronopathy.
- category: Neurological
  name: Motor Axonal Neuropathy
  description: >-
    Motor-predominant axonal neuropathy or neuronopathy is supported by denervation on electromyography and preserved sensory responses in investigated patients. Electrophysiology alone may not separate anterior horn-cell injury from peripheral motor-axon injury; sensory sparing is not established in every affected individual.
  phenotype_term:
    preferred_term: Motor axonal neuropathy
    term:
      id: HP:0007002
      label: Motor axonal neuropathy
  diagnostic: true
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiological recordings revealed motor neuropathy affecting the lower limbs and arms."
    explanation: >-
      Supports motor neuropathy in investigated patients.
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      conclusion, the electrophysiological studies indicated a
      severe motor neuronopathy with widespread severe active
      denervation with late MUP recruitment and late chronic
      reinnervation, and normal sensory studies. These ﬁndings
      were compatible with anterior horn cell disease.
    explanation: >-
      Severe denervation and normal sensory studies support the motor-predominant process in the tested patient.
- category: Neurological
  name: Lower Motor Neuron Degeneration
  description: >-
    Degeneration of spinal alpha-motor neurons in the anterior horn, producing a
    motor neuronopathy that overlaps clinically with spinal muscular atrophy and
    pontocerebellar hypoplasia type 1.
  phenotype_term:
    preferred_term: Degeneration of anterior horn cells
    term:
      id: HP:0002398
      label: Degeneration of anterior horn cells
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sections from the spinal cord showed loss of neurons in the anterior horn, associated with reactive gliosis.
    explanation: >-
      Direct human histology resolves the earlier reliance on electrophysiological inference and mouse pathology for anterior horn-cell degeneration.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Intellectual disability is reported in surviving children, including mild disability in the 14-year-old discovery-series patient. Severe developmental impairment in infants is described as global developmental delay rather than treated as a uniform formal intellectual-disability assessment.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We recog-
      nized two phenotypic extremes, critically ill infants (A1, B1, E1,
      E2, E3, H1, J1) with profound impairment of motor and cognitive
      development as opposed to one 14-year-old individual (D1) with a
      spastic–ataxic movement disorder and only mild intellectual
      disability.
    explanation: >-
      The 14-year-old patient had explicitly documented mild intellectual disability, distinct from developmental impairment assessed in infants.
- category: Neurological
  name: Progressive Neurological Deterioration
  description: >-
    Progressive decline in neurological function is characteristic, with variable severity and survival. Regression can follow apparently normal early milestones or an initial developmental delay; not every cognitive deficit is proven to arise from the same regional lesion.
  phenotype_term:
    preferred_term: Neurodegeneration
    term:
      id: HP:0002180
      label: Neurodegeneration
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations disrupt neuronal maintenance, leading to progressive motor and cognitive deficits.
    explanation: >-
      The clinical report identifies neuronal-maintenance failure as the basis of progressive neurological impairment.
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Other individuals (C1, F1, F2, G1, I1) represented an
      intermediate phenotype with longer survival, but still severe devel-
      opmental delays and progressive neurological deficits resulting in
      significant disability.
    explanation: >-
      The intermediate-severity patients had progressive neurological deficits as well as developmental delay.
- name: Developmental Regression
  category: Neurological
  description: >-
    Loss of acquired motor and interactive abilities can follow an initially uneventful developmental period.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thereafter, the parents observed a gradual decline in abilities characterized by thinning of the muscles, reduced limb movements, diminished interaction, poor object tracking, a weak cry, and the appearance of a squint.
    explanation: >-
      The child had initially attained social smiling and head control, then lost abilities beginning at 2.5 months.
- name: Areflexia
  category: Neurological
  description: >-
    Absent deep tendon reflexes occur in motor-unit disease; increased reflexes in other cases are a separate phenotype.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deep tendon reflexes were absent with extensor plantar response.
    explanation: >-
      Direct examination of the infant subsequently shown to have anterior horn-cell degeneration.
- name: Thin Corpus Callosum
  category: Neurological
  description: >-
    Callosal thinning was seen on MRI and at autopsy; histology showed marked myelin loss in the reported infant.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sections from the corpus callosum showed thinned out corpus callosum with marked loss of myelin.
    explanation: >-
      Direct human callosal histology; this does not establish the prenatal or postnatal origin of all callosal abnormalities.
- name: Oculomotor Apraxia
  category: Ophthalmological
  description: >-
    Oculomotor apraxia was described in the 2024 patient with a likely pathogenic AGTPBP1 variant. The same feature in a second patient is less secure genetically because that variant was classified as uncertain.
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:38153683
    reference_title: The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 3 presented with GDD, dysmorphic facial features “course facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips, and large ears,” oculomotor apraxia, and seizures.
    explanation: >-
      Patient 3 carried homozygous p.Thr884Pro, classified as likely pathogenic. The distinct patient 7 carried a VUS and is not pooled as equivalent genetic evidence.
- name: Esotropia
  category: Ophthalmological
  description: >-
    A right convergent squint was observed in the genetically confirmed autopsy case.
  phenotype_term:
    preferred_term: Esotropia
    term:
      id: HP:0000565
      label: Esotropia
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Examination revealed a thin-built, lethargic baby, with weak suck, pooling of oral secretions, a frog-like posture, and right convergent squint.
    explanation: >-
      Convergent squint supports esotropia rather than unspecified strabismus.
- name: Weak Cry
  category: Neurological
  description: >-
    Weak cry occurs with progressive motor impairment in infancy.
  phenotype_term:
    preferred_term: Weak cry
    term:
      id: HP:0001612
      label: Weak cry
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thereafter, the parents observed a gradual decline in abilities characterized by thinning of the muscles, reduced limb movements, diminished interaction, poor object tracking, a weak cry, and the appearance of a squint.
    explanation: >-
      The child had initially attained social smiling and head control, then lost abilities beginning at 2.5 months.
- name: Poor Suck
  category: Gastrointestinal
  description: >-
    Weak sucking is documented as part of the feeding impairment in severe infantile disease.
  phenotype_term:
    preferred_term: Poor suck
    term:
      id: HP:0002033
      label: Poor suck
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Examination revealed a thin-built, lethargic baby, with weak suck, pooling of oral secretions, a frog-like posture, and right convergent squint.
    explanation: >-
      Direct examination of the autopsied infant.
- name: Dysphagia
  category: Gastrointestinal
  description: >-
    Difficulty eating solid food with recurrent aspiration is described in severe neuronopathy.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Repeated
      aspirations due to dif ﬁculty in eating solid food and slow
      weight gain led to gastrostomy insertion at two years of age.
    explanation: >-
      The second patient aspirated repeatedly while eating solid food and gained weight slowly, leading to gastrostomy.
  sequelae:
  - target: Aspiration
    causal_link_type: DIRECT
    description: >-
      The clinical report explicitly attributes repeated aspiration to difficulty eating solid food.
    evidence:
    - reference: PMID:30976113
      reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Repeated
        aspirations due to dif ﬁculty in eating solid food and slow
        weight gain led to gastrostomy insertion at two years of age.
      explanation: >-
        The second patient aspirated repeatedly while eating solid food and gained weight slowly, leading to gastrostomy.
- name: Aspiration
  category: Respiratory
  description: >-
    Recurrent aspiration during feeding was documented; it should not be inferred from feeding difficulty alone in every patient.
  phenotype_term:
    preferred_term: Aspiration
    term:
      id: HP:0002835
      label: Aspiration
  evidence:
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Repeated
      aspirations due to dif ﬁculty in eating solid food and slow
      weight gain led to gastrostomy insertion at two years of age.
    explanation: >-
      The second patient aspirated repeatedly while eating solid food and gained weight slowly, leading to gastrostomy.
- name: Failure to Thrive
  category: Growth
  description: >-
    Poor weight gain or failure to thrive may accompany feeding impairment and lead to gastrostomy placement.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      The child
      was hospitalized at age 4 months due to feeding dif ﬁculty,
      choking and failure to thrive and underwent insertion of a
      feeding gastrostomy.
    explanation: >-
      The first 2019 patient had failure to thrive with choking and feeding difficulty.
- name: Hand Tremor
  category: Neurological
  description: >-
    Hand tremor was observed both during movement and at rest in the second 2019 patient; a specifically cerebellar tremor is not established.
  phenotype_term:
    preferred_term: Hand tremor
    term:
      id: HP:0002378
      label: Hand tremor
  evidence:
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Tremor of the hands was seen
      both in movement and at rest and he could not reach for
      objects.
    explanation: >-
      Direct human observation distinguishes this finding from mouse movement phenotypes.
- name: Hearing Impairment
  category: Otological
  description: >-
    Bilateral hearing loss was reported sporadically in the clinical synthesis. The source does not establish a sensorineural mechanism or auditory-pathway localization.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:34572343
    reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other clinical features, such as bilateral hearing loss and hand tremors, were sporadically detected.
    explanation: >-
      Published human observations; no hearing-loss subtype or frequency band is inferred.
- name: Seizures
  category: Neurological
  description: >-
    Seizures were reported in the 2024 likely-pathogenic-variant case and in the p.Gln816Pro cardiomyopathy case. Seizure type and disease-wide frequency remain insufficiently defined.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38153683
    reference_title: The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 3 presented with GDD, dysmorphic facial features “course facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips, and large ears,” oculomotor apraxia, and seizures.
    explanation: >-
      Patient 3 carried homozygous p.Thr884Pro, classified as likely pathogenic. The distinct patient 7 carried a VUS and is not pooled as equivalent genetic evidence.
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Dilated cardiomyopathy occurred in one reported p.Gln816Pro patient and improved with supportive treatment. Causal attribution to CCP1 deficiency is unreplicated.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: DOI:10.1055/s-0042-1749669
    reference_title: 'Childhood-Onset Neurodegeneration with Cerebellar Atrophy Syndrome: Severe Neuronal Degeneration and Cardiomyopathy with Loss of Tubulin Deglutamylase Cytosolic Carboxypeptidase 1'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a patient with a seizure, dystonia, dilated cardiomyopathy (DCM), and accompanying atrophy of caudate nuclei, putamen, and cerebellum.
    explanation: >-
      Single p.Gln816Pro case; the authors describe the cardiac finding as an expansion of the possible phenotype, not an established penetrant manifestation.
- name: Caudate Atrophy
  category: Neurological
  description: >-
    Caudate nuclear atrophy accompanied putaminal and cerebellar atrophy in the p.Gln816Pro case; this does not establish the lesion in other genotypes.
  phenotype_term:
    preferred_term: Caudate atrophy
    term:
      id: HP:0002340
      label: Caudate atrophy
  evidence:
  - reference: DOI:10.1055/s-0042-1749669
    reference_title: 'Childhood-Onset Neurodegeneration with Cerebellar Atrophy Syndrome: Severe Neuronal Degeneration and Cardiomyopathy with Loss of Tubulin Deglutamylase Cytosolic Carboxypeptidase 1'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a patient with a seizure, dystonia, dilated cardiomyopathy (DCM), and accompanying atrophy of caudate nuclei, putamen, and cerebellum.
    explanation: >-
      The p.Gln816Pro patient had caudate nuclear atrophy together with putaminal and cerebellar atrophy. This single-case observation does not establish recurrence across AGTPBP1 genotypes or identify the cause of the accompanying movement disorder.
- name: Putaminal Atrophy
  category: Neurological
  description: >-
    Putaminal atrophy was reported in the p.Gln816Pro case. The available broader putamen-morphology term retains atrophy as the display specificity.
  phenotype_term:
    preferred_term: Putaminal atrophy
    term:
      id: HP:0031982
      label: Abnormal putamen morphology
  evidence:
  - reference: DOI:10.1055/s-0042-1749669
    reference_title: 'Childhood-Onset Neurodegeneration with Cerebellar Atrophy Syndrome: Severe Neuronal Degeneration and Cardiomyopathy with Loss of Tubulin Deglutamylase Cytosolic Carboxypeptidase 1'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a patient with a seizure, dystonia, dilated cardiomyopathy (DCM), and accompanying atrophy of caudate nuclei, putamen, and cerebellum.
    explanation: >-
      The p.Gln816Pro patient had putaminal atrophy together with caudate and cerebellar atrophy. This supports the case-level imaging finding, not established penetrance or a proven putaminal cause of dystonia or seizures.
- name: Thymic Aplasia
  category: Immunological
  description: >-
    No thymus was identified grossly or after extensive mediastinal histological sampling in the 2026 autopsy case. Its attribution to AGTPBP1 is a proposed extension requiring replication.
  phenotype_term:
    preferred_term: Aplasia of the thymus
    term:
      id: HP:0005359
      label: Aplasia of the thymus
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The thymus could not be identified grossly. Anterior mediastinal soft tissue was extensively sampled for histological examination and did not reveal any remnant of thymus.
    explanation: >-
      Direct anatomy in one genetically confirmed case; the causal genetic relation remains provisional.
- name: Lymphopenia
  category: Immunological
  description: >-
    Persistent absolute lymphopenia was observed in the infant with absent thymus and fatal adenovirus infection. Lymphocyte subsets were not measured, so specific T-cell deficiency is not asserted.
  phenotype_term:
    preferred_term: Decreased total lymphocyte count
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peripheral blood count revealed persistent lymphopenia (ALC range: 1,270/μL to 2,482/μL).
    explanation: >-
      Measured absolute lymphocyte counts in the single autopsy case; these values do not define disease-wide prevalence.
progression:
- phase: Onset
  age_range: Birth to approximately 20 months
  notes: >-
    Presentation is congenital to infantile and insidious rather than acute,
    typically with hypotonia, delayed motor milestones, feeding difficulty or
    abnormal eye movements.
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients display early-onset developmental delays (between birth and 20 months of age) with a progressive degenerative course"
    explanation: >-
      Review synthesis of published patients giving the onset window and the
      progressive character of the course.
- phase: Progressive decline
  notes: >-
    Progressive worsening of neurological function follows, with weakness,
    motor neuronopathy, ataxia, spasticity and dystonia, and increasing feeding
    and respiratory dependence.
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive neurological deficits resulting in significant disability"
    explanation: >-
      Describes the progressive neurological decline in the intermediate-severity
      patients of the foundational cohort.
- phase: Fatal outcome
  notes: >-
    A substantial fraction of affected children die in infancy or childhood. Six
    of the 13 patients in the foundational cohort had a fatal course, but that is
    a severity-ascertained research series, not a population case-fatality rate,
    and no survival curve or median life expectancy has been published. Milder
    survivors reach adolescence.
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a fatal course in six individuals"
    explanation: >-
      Six of 13 affected individuals in the foundational cohort had a fatal
      course.
  - reference: PMID:40754822
    reference_title: >-
      AAV-based gene therapy ameliorates neurological deficits in a mouse model of
      childhood-onset neurodegeneration with cerebellar atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients typically exhibit progressive motor and cognitive impairment, often leading to childhood mortality."
    explanation: >-
      Independent restatement of childhood mortality in human patients. The
      sentence summarises the human clinical literature, so it is graded
      HUMAN_CLINICAL even though the paper's own experiments are in mice.

imaging_findings:
- name: Cerebellar Atrophy on Brain MRI
  modality: MRI
  description: >-
    MRI may reveal small cerebellar hemispheres and vermis. A single early scan can be described as hypoplasia or atrophy and does not prove normal prenatal development. Cerebellar findings overlap PCH1; genotype and the broader clinical pattern aid diagnosis. A normal-appearing cerebellar MRI does not exclude CONDCA or microscopic degeneration.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  diagnostic: true
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed detected cerebellar atrophy with respect to non-affected, control individuals"
    explanation: >-
      Review synthesis of published patient MRI showing cerebellar atrophy against
      unaffected controls.

genetic:
- name: Biallelic AGTPBP1 pathogenic variants
  gene_term:
    preferred_term: AGTPBP1
    term:
      id: hgnc:17258
      label: AGTPBP1
  association: CAUSAL
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    CONDCA is caused by biallelic damaging variants in AGTPBP1 (9q21.33), which
    encodes cytosolic carboxypeptidase 1. The reported allelic spectrum spans
    nonsense, frameshift, canonical and intronic splice-site, multi-exon genomic
    deletion, and missense alleles, most of which affect the conserved N-terminal
    region or the zinc-carboxypeptidase motifs. All reported disease alleles are
    germline; no somatic mechanism, repeat expansion or mitochondrial lesion is
    established.

    A genotype-severity trend has been noted - biallelic protein-truncating
    genotypes cluster among the fatal and severe cases and missense genotypes among
    the milder ones - but the original authors explicitly declined to call it a
    genotype-phenotype correlation, and exceptions exist in both directions. It
    should not be used prognostically. Because a multi-exon genomic deletion is
    part of the reported spectrum, copy-number-sensitive analysis is needed when
    sequencing finds only one variant.
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation."
    explanation: >-
      Establishes biallelic AGTPBP1/CCP1 variants as the cause, with functional
      confirmation that the protein is absent.
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with fatal and severe forms of the disease usually had biallelic protein-truncating"
    explanation: >-
      Documents the genotype-severity trend recorded in the `notes` field.
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is probably too early to claim any definitive genotype"
    explanation: >-
      Cited in support of the `notes` statement that the truncating/missense
      severity trend must NOT be treated as an established genotype-phenotype
      correlation. This is the original authors' own caveat qualifying the
      preceding evidence item; it does not bear on the causal role of biallelic
      AGTPBP1 variants, which is what this `genetic` entry asserts. Marked
      INDIRECT because it supports the recorded caveat rather than stating it of
      this entry directly.
  - reference: PMID:31102495
    reference_title: >-
      Biallelic variant in AGTPBP1 causes infantile lower motor neuron
      degeneration and cerebellar atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a biallelic missense AGTPBP1 variant (NM_001330701.1:c.2396G>T, p.Arg799Leu) was identified by whole exome sequencing"
    explanation: >-
      A specific recurrent missense allele associated, in this family, with the
      severe infantile end of the spectrum - one of the exceptions to the
      missense-equals-milder trend.
  - reference: PMID:38153683
    reference_title: >-
      The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare
      Neurological Disorders Associated with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX"
    explanation: >-
      A consanguineous Egyptian exome cohort continuing to expand the AGTPBP1
      allelic spectrum, and illustrating that AGTPBP1 sits alongside other genes in
      the childhood cerebellar-atrophy differential.

diagnosis:
- name: Trio Exome or Genome Sequencing
  description: >-
    Molecular diagnosis rests on identifying biallelic AGTPBP1 variants, usually by
    trio exome or genome sequencing, or by a childhood ataxia / neurodegeneration /
    motor neuropathy panel that includes AGTPBP1. Candidate variants are confirmed
    by Sanger sequencing with parental segregation. Copy-number-sensitive analysis
    is required because a multi-exon genomic deletion is part of the reported
    allelic spectrum. There are no consensus clinical diagnostic criteria and no
    biochemical or metabolite assay for the disorder.
  evidence:
  - reference: PMID:38153683
    reference_title: >-
      The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare
      Neurological Disorders Associated with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants' effect on the protein structure."
    explanation: >-
      Establishes exome sequencing as the diagnostic modality that identifies
      AGTPBP1 within the phenotypically overlapping childhood cerebellar-atrophy
      group.
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants"
    explanation: >-
      Illustrates the diagnostic workflow of exome sequencing plus family
      segregation, with cDNA studies used to resolve splice-affecting alleles.

differential_diagnoses:
- name: Pontocerebellar hypoplasia type 1
  description: >-
    PCH1 combines cerebellar hypoplasia or atrophy with bulbar and spinal motor-neuron disease and closely overlaps AGTPBP1-related disease. Early imaging terminology alone does not separate them; molecular diagnosis resolves the underlying gene.
  distinguishing_features:
  - Pathogenic variants in distinct established PCH1 genes, including EXOSC3, EXOSC8, EXOSC9, VRK1 and SLC25A46
  - Interpret serial imaging, motor-neuron involvement and the molecular result together; a single hypoplasia-versus-atrophy label is insufficient
  evidence:
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy.
    explanation: >-
      The two unrelated patients had progressive weakness and severe motor neuronopathy with feeding and respiratory compromise.
- name: Spinal muscular atrophy (5q-SMA)
  description: >-
    Infantile hypotonia, weakness and anterior horn cell degeneration overlap with
    5q-SMA, and CONDCA is typically considered after SMN1 testing is negative.
    Cerebellar atrophy and the cerebellar movement disorder are not features of
    5q-SMA.
  distinguishing_features:
  - Homozygous SMN1 deletion or SMN1 point mutation
  - Absence of cerebellar atrophy on MRI
  - Absence of ataxia, spasticity and dystonia
  evidence:
  - reference: PMID:31102495
    reference_title: >-
      Biallelic variant in AGTPBP1 causes infantile lower motor neuron
      degeneration and cerebellar atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infantile hereditary lower motor neuron disorders beyond 5q-spinal muscular atrophy (5q-SMA) are usually caused by mutations other than deletions or mutations in SMN1."
    explanation: >-
      Positions CONDCA within the non-5q-SMA infantile lower motor neuron disorder
      group, which is the diagnostic context in which 5q-SMA must be excluded.

treatments:
- name: Multidisciplinary Supportive Care
  description: >-
    There is no disease-modifying therapy. Management is supportive and
    multidisciplinary: nutrition and swallow-safety management, airway clearance
    and respiratory support, contracture and scoliosis surveillance, management of
    spasticity and dystonia, communication support, and palliative care in advanced
    disease.
  treatment_term:
    preferred_term: multidisciplinary supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40754822
    reference_title: >-
      AAV-based gene therapy ameliorates neurological deficits in a mouse model of
      childhood-onset neurodegeneration with cerebellar atrophy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite its severe clinical course, no effective treatments have been developed."
    explanation: >-
      Establishes the absence of any disease-modifying option, which is why care is
      supportive. Evidence source is OTHER because this is the paper's framing
      statement about the clinical field, not its own experimental data.

- name: Physical and Occupational Therapy
  description: >-
    Rehabilitation to maintain range of motion, prevent contractures, support
    positioning and seating, and provide mobility aids. Directed at the functional
    consequences of weakness, spasticity and ataxia; it does not modify the
    underlying neurodegeneration.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical and occupational therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  notes: >-
    No CONDCA-specific rehabilitation trial or outcome study exists. This entry
    records standard-of-care practice for a progressive childhood neuromuscular and
    cerebellar disorder and deliberately carries no evidence item, because no cited
    source makes a claim about rehabilitation efficacy in this disease.

- name: Gastrostomy and Nutritional Support
  description: >-
    Enteral feeding via gastrostomy when bulbar weakness produces unsafe swallow,
    aspiration risk or inadequate caloric intake.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy tube placement
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:30976113
    reference_title: >-
      Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are
      associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy"
    explanation: >-
      Documents the feeding difficulty this intervention addresses. Marked INDIRECT
      because the source establishes the indication, not the efficacy of
      gastrostomy in CONDCA specifically.

- name: Noninvasive Ventilation
  description: >-
    Respiratory support for neuromuscular respiratory insufficiency, with airway
    clearance and prompt treatment of respiratory infections.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: noninvasive mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency"
    explanation: >-
      Documents the respiratory insufficiency this intervention addresses. Marked
      INDIRECT because the source establishes the indication, not ventilation
      efficacy in CONDCA.

- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence counselling (25% per pregnancy for carrier
    couples), carrier testing of relatives, and discussion of prenatal diagnosis
    and preimplantation genetic testing once the familial variants are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33909173
    reference_title: >-
      A novel pathogenic variant in the 3' end of the AGTPBP1 gene gives rise to
      neurodegeneration without cerebellar atrophy: an expansion of the disease
      phenotype?
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted Sanger sequencing confirmed the variant in both affected children and in heterozygous form in the parents."
    explanation: >-
      Demonstrates the carrier-parent structure that recurrence counselling and
      cascade testing are built on. Marked INDIRECT because it establishes the
      genetic basis for counselling rather than a counselling outcome.

- name: AAV-Mediated AGTPBP1 Gene Replacement
  description: >-
    PRECLINICAL ONLY - no human study. Neonatal delivery of a
    blood-brain-barrier-penetrating AAV vector expressing an N-terminally truncated
    but catalytically active Ccp1 prevented Purkinje cell degeneration and partially
    improved motor function in Ccp1-deficient mice. This is the most direct
    mechanistic rescue strategy for a recessive loss-of-function disorder, but no
    clinical trial, safety data, or human dosing information exists, and the mouse
    result required intervention before Purkinje cell loss.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: CCP1 Deglutamylase Deficiency
    treatment_effect: RESTORES
    description: >-
      Restores deglutamylase activity by supplying a functional CCP1 transgene,
      acting at the initiating molecular lesion.
  evidence:
  - reference: PMID:40754822
    reference_title: >-
      AAV-based gene therapy ameliorates neurological deficits in a mouse model of
      childhood-onset neurodegeneration with cerebellar atrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Expression of the N-terminally truncated form of Ccp1 (Ccp1Δ1), which retains deglutamylase activity, in neurons of Ccp1-deficient neonatal mice via a blood-brain barrier-penetrating AAV vector strongly prevented Purkinje cell degeneration during postnatal development."
    explanation: >-
      Demonstrates preclinical efficacy of gene replacement on the central
      histopathological lesion in the mouse model.
  - reference: PMID:40754822
    reference_title: >-
      AAV-based gene therapy ameliorates neurological deficits in a mouse model of
      childhood-onset neurodegeneration with cerebellar atrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "gene therapy using Ccp1Δ1 partially, albeit significantly, improved motor functions in these mice, notably enhancing voluntary gait stability"
    explanation: >-
      Supports the functional-benefit claim in the treatment description while
      recording its stated limit: the motor improvement was partial rather than
      complete, even though histological rescue was strong.

- name: TTLL1-Directed Reduction of Tubulin Polyglutamylation
  description: >-
    PRECLINICAL TARGET VALIDATION ONLY - no drug, no human study. Genetic deletion
    of the glutamylase TTLL1 fully rescues degeneration of vulnerable neurons and
    of peripheral myelinated axons in CCP1-deficient mice, identifying TTLL1 as the
    best-validated target in the disorder. No selective TTLL1 inhibitor suitable for
    clinical use has been reported. `treatment_term` deliberately carries no
    `term:` - the only candidate action term, NCIT:C49236 Therapeutic Procedure, is
    far broader than the concept and would assert a clinical intervention that does
    not exist. Needs term / NTR: "tubulin polyglutamylase inhibition".
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: TTLL1-directed reduction of tubulin polyglutamylation
  target_mechanisms:
  - target: Tubulin Hyperglutamylation
    treatment_effect: INHIBITS
    description: >-
      Removing the writer enzyme that produces the pathological polyglutamate side
      chains normalises the glutamylation state without restoring CCP1 itself.
  evidence:
  - reference: PMID:30420556
    reference_title: >-
      Excessive tubulin polyglutamylation causes neurodegeneration and perturbs
      neuronal transport.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1."
    explanation: >-
      Complete genetic rescue establishes TTLL1 as a validated target, though as a
      germline knockout rather than a pharmacological intervention.
  - reference: PMID:34309047
    reference_title: >-
      Distinct roles of α- and β-tubulin polyglutamylation in controlling axonal transport and in neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deletion of TTLL1, but not of TTLL7, prevents degeneration of Purkinje cells and of myelinated axons in peripheral nerves in these mice"
    explanation: >-
      Confirms that the rescue is specific to TTLL1 and extends to the peripheral
      nerve arm of the disease, sharpening the target definition.
  - reference: PMID:35404950
    reference_title: >-
      TTLL1 and TTLL4 polyglutamylases are required for the neurodegenerative
      phenotypes in pcd mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ttll1 deficiency attenuates Purkinje cell loss and function and reduces olfactory bulb mitral cell death and retinal photoreceptor degeneration."
    explanation: >-
      A systematic survey across five TTLLs confirms TTLL1 as the dominant target
      but describes the protection as attenuating rather than absolute across all
      vulnerable populations, and identifies TTLL4 as a second contributor. This
      supports the target while showing the single-target picture is incomplete.

- name: Microtubule Depolymerizer (Glutamylation Rebalancing)
  description: >-
    PRECLINICAL ONLY - no human study. Treating pcd Purkinje neurons with a
    microtubule depolymerizer corrected the glutamylation/deglutamylation ratio and
    increased Purkinje neuron survival, acting on the glutamylation imbalance
    itself rather than on CCP1 or TTLL1 protein levels. The agent is not named in
    the cited abstract, no dosing or safety data exist, and microtubule-destabilising
    drugs are themselves neurotoxic, so this is a mechanistic proof of concept
    rather than a therapeutic candidate.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Tubulin Hyperglutamylation
    treatment_effect: MODULATES
    description: >-
      Shifts the glutamylation/deglutamylation balance back toward normal without
      restoring the missing deglutamylase.
  evidence:
  - reference: PMID:33004692
    reference_title: >-
      Nna1 gene deficiency triggers Purkinje neuron death by tubulin
      hyperglutamylation and ER dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "treatment with a microtubule depolymerizer corrected the glutamylation/deglutamylation ratio, increasing PN survival"
    explanation: >-
      Demonstrates that pharmacologically rebalancing the glutamylation state
      rescues Purkinje neuron survival in the CCP1-deficient mouse, which is the
      claim this treatment entry makes.
  notes: >-
    `therapeutic_agent` is deliberately absent: the cited abstract names only the
    drug class ("a microtubule depolymerizer"), not a specific compound, so binding
    a CHEBI agent would assert an identity the source does not give.

- name: Recombinant Human VEGF-B
  description: >-
    PRECLINICAL ONLY - no human study. Moderate-dose recombinant human VEGF-B was
    neuroprotective in the pcd mouse, increasing Purkinje cell survival and
    improving motor, cognitive and social behaviour, apparently by partial
    inhibition or delay of apoptosis. The dose-response was inverted-U: more
    frequent dosing was detrimental to Purkinje cell survival. Recombinant human
    IGF-1 tested in the same study showed no neuroprotective effect. No paediatric
    safety or efficacy data exist.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant human VEGF-B
      term:
        id: NCIT:C1272
        label: Recombinant Vascular Endothelial Growth Factor
  target_mechanisms:
  - target: Purkinje Neuron Degeneration
    treatment_effect: INHIBITS
    description: >-
      Acts downstream of the tubulin lesion as a neuroprotectant, delaying or
      partially inhibiting Purkinje cell apoptosis rather than correcting the
      glutamylation defect.
  evidence:
  - reference: PMID:39859255
    reference_title: >-
      Neuroprotective Effects of VEGF-B in a Murine Model of Aggressive Neuronal
      Loss with Childhood Onset.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice"
    explanation: >-
      Demonstrates preclinical neuroprotective efficacy in the established CONDCA
      mouse model. The quoted claim is about treated mice, not treated patients.
  - reference: PMID:39859255
    reference_title: >-
      Neuroprotective Effects of VEGF-B in a Murine Model of Aggressive Neuronal
      Loss with Childhood Onset.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "increasing the frequency of rhVEGF-B administration had a detrimental effect on Purkinje cell survival, suggesting an inverted U-shaped dose-response curve of this substance"
    explanation: >-
      Supports the inverted-U dose-response stated in the treatment description.
      This is a limiting finding: it establishes a narrow therapeutic window and
      shows that more frequent dosing is harmful.
  - reference: PMID:39859255
    reference_title: >-
      Neuroprotective Effects of VEGF-B in a Murine Model of Aggressive Neuronal
      Loss with Childhood Onset.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "treatment with rhIGF-1 did not demonstrate any neuroprotective effect"
    explanation: >-
      Supports the description's statement that the comparator neurotrophic factor
      rhIGF-1, tested in the same experiment, showed no benefit. This is a null
      result about a DIFFERENT agent, so it is not evidence against rhVEGF-B.
      Marked INDIRECT for that reason. Note it also conflicts with an earlier pcd
      report summarised in PMID:34572343, which describes IGF-1 as improving
      weight, survival and motor performance; the discrepancy is unresolved and is
      recorded in this treatment's `notes`.

- name: Lacosamide (CRMP2 Modulation)
  description: >-
    PRECLINICAL ONLY - no human study in CONDCA. AGTPBP1 knockout raises CRMP2
    expression and causes mitochondrial dysfunction in differentiated neurons;
    lacosamide, which modulates CRMP2, improved cell morphology and mitochondrial
    function in vitro and rescued brain volume and swimming performance in
    AGTPBP1-deficient zebrafish. Lacosamide is an approved antiseizure medication in
    other indications, but its use here rests entirely on cell and zebrafish data.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lacosamide
      term:
        id: CHEBI:135939
        label: lacosamide
  target_mechanisms:
  - target: Impaired Microtubule-Based Axonal Transport
    treatment_effect: MODULATES
    description: >-
      Proposed to act through CRMP2, which links cytoskeletal dynamics to
      mitochondrial function. The source measures CRMP2 levels, neurite outgrowth,
      mitochondrial function and dopaminergic state; it does NOT measure axonal
      transport, so the link to this node is inferred from the shared
      microtubule/mitochondrial substrate rather than demonstrated.
  evidence:
  - reference: PMID:40347376
    reference_title: >-
      Lacosamide Is a Novel Drug That Improves AGTPBP1 Knockout-Mediated Impairment
      of Neuronal and Dopaminergic Function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lacosamide treatment in vitro improved cell morphology and restored mitochondrial function"
    explanation: >-
      Cell-based arm: lacosamide restored mitochondrial function in
      AGTPBP1-knockout cells. Split from the in vivo arm below so each item
      carries a single `evidence_source`.
  - reference: PMID:40347376
    reference_title: >-
      Lacosamide Is a Novel Drug That Improves AGTPBP1 Knockout-Mediated Impairment
      of Neuronal and Dopaminergic Function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "it rescued brain volume deficits and enhanced swimming performance in AGTPBP1-deficient zebrafish"
    explanation: >-
      In vivo arm: lacosamide rescued brain volume and motor performance in
      AGTPBP1-deficient zebrafish. Split from the in vitro arm above.
  notes: >-
    A correction was published for this article (PMID:41317263). It corrects the
    reported morpholino sequence used for the zebrafish agtpbp1 knockdown; it is
    a reagent-methods correction, not a retraction, and the reported results are
    unchanged. Noted here so the reagent detail is not taken from the original
    text.

animal_models:
- name: Purkinje cell degeneration (pcd) mouse
  species: Mus musculus
  genotype: Agtpbp1 (Nna1) loss-of-function; spontaneous alleles pcd, pcd2J, pcd3J, plus engineered knockouts
  publication: PMID:11884758
  category: Spontaneous and engineered loss-of-function
  description: >-
    The pcd mouse is the established genetic model of CONDCA and predates the human
    disease by decades. Homozygotes have a histologically normal cerebellum at
    postnatal day 14 and then lose almost all Purkinje cells within weeks, with
    ataxia from around P20. Retinal photoreceptors, olfactory bulb mitral cells,
    selected thalamic neurons and alpha-motor neurons also degenerate, and males are
    infertile. Peripheral nerve and spinal motor neuron degeneration were recognised
    only after the human disease was described, and they are what make the model a
    genuine phenocopy rather than a cerebellum-only model.
  genes:
  - preferred_term: AGTPBP1
    term:
      id: hgnc:17258
      label: AGTPBP1
  modeled_mechanisms:
  - target: Purkinje Neuron Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Near-complete Purkinje cell loss with the same molecular lesion (tubulin hyperglutamylation) as the human disease.
    limitations: >-
      Purkinje cell death in the mouse is temporally compressed into a few postnatal weeks, whereas human disease ranges from rapidly fatal infancy to survival into adolescence, so the therapeutic window observed in mice may not translate.
  - target: Lower Motor Neuron and Peripheral Motor Axon Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Peripheral nerve and spinal motor neuron degeneration in pcd mice was shown
      to reproduce the human motor neuronopathy.
  evidence:
  - reference: PMID:11884758
    reference_title: >-
      Purkinje cell degeneration (pcd) phenotypes caused by mutations in the
      axotomy-induced gene, Nna1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The classical recessive mouse mutant, Purkinje cell degeneration (pcd), exhibits adult-onset degeneration of cerebellar Purkinje neurons, retinal photoreceptors, olfactory bulb mitral neurons, and selected thalamic neurons, and has defective spermatogenesis."
    explanation: >-
      Defines the full pcd phenotype and identifies Nna1 (the AGTPBP1 ortholog) as
      the mutated gene.
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease."
    explanation: >-
      Establishes the fidelity of the model for the peripheral and motor neuron arm
      of the human disease.
  - reference: PMID:34572343
    reference_title: >-
      The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
      Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration
      Mouse as an Animal Model for the Study of this Human Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the AGTPBP1 gene."
    explanation: >-
      Review assessment that the human course matches the established mouse model.
      Evidence source is OTHER because this is a review's overall judgement rather
      than a primary result.
  notes: >-
    Mouse data must not be used as the sole support for any human phenotype in this
    entry. Every human phenotype recorded here carries at least one HUMAN_CLINICAL
    evidence item; MODEL_ORGANISM items are used for mechanism and for model
    fidelity only.

discussions:
- discussion_id: condca-subtype-structure
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Should the severe infantile and milder cerebellar-predominant presentations of
    AGTPBP1-related disease be modelled as named subtypes?
  attaches_to:
  - "genetic#Biallelic AGTPBP1 pathogenic variants"
  rationale: >-
    The foundational cohort described two phenotypic extremes - critically ill
    infants with profound impairment at one end and a 14-year-old with a
    spastic-ataxic movement disorder and only mild intellectual disability at the
    other - with an intermediate group between them. This entry deliberately does
    NOT use `has_subtypes`, because the literature describes a continuous severity
    spectrum with no named, delimited nosologic entities, and because the original
    authors explicitly cautioned that it is too early to claim a definitive
    genotype-phenotype correlation. Introducing subtype names here would invent
    boundaries the evidence does not draw, and would create foreign-key targets that
    no published case definition could be matched against. Revisit if an
    international registry or a natural-history cohort defines reproducible clinical
    subgroups.
  proposed_experiments:
  - experiment_id: exp_condca_natural_history_registry
    name: Prospective international natural-history registry
    description: >-
      Enrol genotype-confirmed AGTPBP1 patients internationally with uniform HPO
      phenotyping, serial brain MRI, and standardised motor and respiratory
      scales, to establish whether reproducible clinical subgroups exist.
  - experiment_id: exp_condca_allele_activity_assay
    name: Per-allele residual deglutamylase activity assay
    description: >-
      Systematically assay residual CCP1 deglutamylase activity for each reported
      allele and correlate it with survival and motor outcome, to test whether a
      quantitative activity threshold rather than variant class predicts severity.

- discussion_id: condca-frequency-data
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are the true frequencies of each phenotype in AGTPBP1-related disease?
  attaches_to:
  - "phenotypes#Cerebellar Atrophy"
  rationale: >-
    The available denominators are small, retrospective literature-series samples with variable severity and per-feature assessment. The review reports muscle atrophy in half of patients and reflex alterations in almost all, but the latter combines opposite reflex directions and the former does not require neurogenic verification. Neither aggregate is assigned to a narrower phenotype. Prospective consistently ascertained denominators are lacking.
  proposed_experiments:
  - experiment_id: exp_condca_frequency_registry
    name: Registry-based phenotype frequency estimation
    description: >-
      Collect uniformly phenotyped, consecutively ascertained AGTPBP1 cases so
      that per-phenotype frequencies have a common denominator rather than being
      pooled across severity-ascertained case reports.

  evidence:
  - reference: PMID:34572343
    reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle atrophy was found in half of the patients (Figure 3C,D), and other regularly detected clinical manifestations included feeding problems, eye movement abnormalities, respiratory insufficiency, spasticity, tongue fasciculations and dystonia.
    explanation: >-
      Clinical synthesis of published cases; the muscle-atrophy proportion does not establish the frequency of every listed feature or of biopsy-proven neurogenic atrophy.
  - reference: PMID:34572343
    reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alterations in tendon reflexes were observed in almost all individuals.
    explanation: >-
      This is an aggregate of altered reflexes, not a separate estimate for hyporeflexia, areflexia or hyperreflexia.
- discussion_id: condca-cardiac-involvement
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is cardiomyopathy part of the AGTPBP1 phenotype?
  attaches_to:
  - phenotypes#Dilated Cardiomyopathy
  rationale: >-
    Samur et al. reported reversible dilated cardiomyopathy in a single p.Gln816Pro patient. The observation is retained with case-level evidence, but a causal cardiac pathway from CCP1 deficiency has not been established. General cytoskeletal functions in cardiomyocytes do not establish that this patient's cardiomyopathy was caused by AGTPBP1.
  proposed_experiments:
  - experiment_id: exp_condca_cardiac_surveillance
    name: Baseline cardiac assessment in a prospective cohort
    description: >-
      Perform baseline echocardiography and ECG on prospectively enrolled AGTPBP1
      patients to establish whether the single reported dilated cardiomyopathy
      recurs at a rate that would justify surveillance.

  evidence:
  - reference: DOI:10.1055/s-0042-1749669
    reference_title: 'Childhood-Onset Neurodegeneration with Cerebellar Atrophy Syndrome: Severe Neuronal Degeneration and Cardiomyopathy with Loss of Tubulin Deglutamylase Cytosolic Carboxypeptidase 1'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a patient with a seizure, dystonia, dilated cardiomyopathy (DCM), and accompanying atrophy of caudate nuclei, putamen, and cerebellum.
    explanation: >-
      Single p.Gln816Pro case; the authors describe the cardiac finding as an expansion of the possible phenotype, not an established penetrant manifestation.
- discussion_id: condca-human-neuropathology-spectrum
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How representative is the first human autopsy of the regional pathology across AGTPBP1 genotypes and ages?
  attaches_to:
  - "pathophysiology#Purkinje Neuron Degeneration"
  rationale: >-
    The 2018 discovery series lacked postmortem examinations. The 2026 first autopsy now directly establishes Purkinje, granular and anterior horn-cell loss in one infant. It does not establish universal lobule X sparing, the complete mouse death pathway, or the same regional pathology in patients without cerebellar atrophy or lower motor-neuron signs. The remaining uncertainty concerns distribution and representativeness, not whether human Purkinje loss has ever been observed.
  proposed_experiments:
  - experiment_id: exp_condca_neuropathology
    name: Neuropathological examination of CONDCA cerebellum
    description: >-
      Compare additional genetically confirmed postmortem cases across ages and genotypes, quantifying regional neuronal loss and tubulin glutamylation against controls.
  - experiment_id: exp_condca_quantitative_mri
    name: Purkinje-layer-sensitive quantitative cerebellar MRI
    description: >-
      High-resolution cerebellar imaging in CONDCA patients to test whether the volume loss follows the lobular pattern of the mouse (near-complete loss with relative sparing of lobule X) rather than a diffuse pattern.

  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cerebellum showed normal-sized folia with a marked loss of Purkinje cells. There was a prominence of Bergmann glial cells.
    explanation: >-
      Direct human autopsy evidence supersedes the discovery-series absence of postmortem examinations.
- discussion_id: condca-human-mechanism-gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which downstream mechanisms established in pcd mice actually operate in human
    CONDCA neurons?
  attaches_to:
  - "pathophysiology#Purkinje Cell Endoplasmic Reticulum Stress"
  rationale: >-
    Human muscle hyperglutamylation and human Purkinje/anterior horn-cell loss are documented. The transport, mitochondrial-fusion and ER-stress routes nevertheless rest on model perturbations rather than direct human neuronal measurements. These supported candidate paths are represented with qualifications; the remaining gap is mediation and human translation, not absence of a modeled connection.
  proposed_experiments:
  - experiment_id: exp_condca_patient_ipsc_neurons
    name: Patient iPSC-derived neuronal model
    description: >-
      Differentiate patient iPSCs into Purkinje-like neurons and spinal motor
      neurons and assay glutamylation state, cargo transport, mitochondrial
      motility and UPR activation, to test which mouse-derived downstream steps
      operate in human cells.
  - experiment_id: exp_condca_glutamylation_biomarker
    name: Accessible-tissue polyglutamylation biomarker
    description: >-
      Develop a pharmacodynamic assay of tubulin polyglutamylation measurable in
      blood or skin, so that target engagement can be read out in a future trial.

- discussion_id: condca-therapeutic-window
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there a therapeutic window in humans, and where does it close?
  attaches_to:
  - "treatments#AAV-Mediated AGTPBP1 Gene Replacement"
  rationale: >-
    Every successful preclinical rescue - Ttll1 deletion, neonatal AAV Ccp1
    delivery, rhVEGF-B - was applied before or during the pre-degenerative phase in
    a mouse whose Purkinje cell death is compressed into a few postnatal weeks. It
    is unknown whether the corresponding human window is wider (because the human
    course is slower) or already closed by the time a child is diagnosed. This is
    the central translational uncertainty for the disorder.
  proposed_experiments:
  - experiment_id: exp_condca_delayed_dosing
    name: Delayed-onset AAV dosing arms in the pcd mouse
    description: >-
      Dose Ccp1-deficient mice at progressively later postnatal timepoints to map
      the point at which Purkinje cell rescue is no longer achievable.
  - experiment_id: exp_condca_imaging_window
    name: Natural-history imaging cohort
    description: >-
      Serially image AGTPBP1 patients to date the onset of measurable cerebellar
      volume loss relative to symptom onset, bounding the human treatment window.

- discussion_id: condca-variable-anatomy
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which factors determine cerebellar and motor-system involvement?
  attaches_to:
  - phenotypes#Cerebellar Atrophy
  - phenotypes#Lower Motor Neuron Degeneration
  rationale: >-
    Two siblings with homozygous c.3293G>A had neither cerebellar atrophy on MRI nor lower motor-neuron findings. This is variable expression, not a disease-level negation of either phenotype. The autopsy case also illustrates that an apparently unremarkable cerebellar MRI does not exclude microscopic cell loss.
  evidence:
  - reference: PMID:33909173
    reference_title: "A novel pathogenic variant in the 3' end of the AGTPBP1 gene gives rise to neurodegeneration without cerebellar atrophy: an expansion of the disease phenotype?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in our patients, no signs of cerebellar atrophy in cranial MRI were present, so the acronym CONDCA is not applicable; lower motor neuron findings were also absent.
    explanation: >-
      The reported absence is scoped to these patients and does not export a disease-level HPOA NOT.
- discussion_id: condca-immune-attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Is thymic aplasia an AGTPBP1 manifestation?
  attaches_to:
  - pathophysiology#Absent Thymic Tissue
  - phenotypes#Thymic Aplasia
  - phenotypes#Lymphopenia
  rationale: >-
    A single homozygous nonsense case had absent thymus, persistent lymphopenia and fatal adenovirus infection. The authors report no other known immunodeficiency variants, but lymphocyte subsets were not obtained. The downstream thymic contribution to lymphopenia is represented provisionally; a causal gene-to-thymic-development pathway and recurrence in other patients remain unproven. Thymic aplasia names the same anatomical absence as the tissue node, so no causal arrow connects those two labels; the aplasia remains an explicitly unexplained clinical finding. Sepsis-associated hemophagocytosis, hepatic steatosis and pigment cast nephropathy are retained as terminal case findings rather than generalized primary CONDCA manifestations.
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lymphopenia suggests that the disorder may be causing a primary immunodeficiency (PID) in the affected children.
    explanation: >-
      The authors explicitly frame immunodeficiency attribution as a possibility.
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A lymphocyte subset analysis could not be performed as PID was not suspected during life. The whole exome sequencing also did not reveal any other genetic variants linked to known PIDs.
    explanation: >-
      Defines the limits of the immunological and alternative-genetic assessment.
- discussion_id: condca-callosal-origin
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What initiates callosal white-matter loss or dysplasia?
  attaches_to:
  - pathophysiology#Callosal White Matter Loss
  - phenotypes#Abnormal Corpus Callosum Morphology
  rationale: >-
    The autopsy establishes myelin loss underlying callosal thinning in one infant. It does not distinguish primary defective axonal development or myelination from secondary degeneration, nor show that earlier reports of dysplastic callosal morphology share this route. The tissue-loss-to-thinning edge is retained while its upstream cause remains unresolved.
  evidence:
  - reference: PMID:42358771
    reference_title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sections from the corpus callosum showed thinned out corpus callosum with marked loss of myelin.
    explanation: >-
      Direct human callosal histology; this does not establish the prenatal or postnatal origin of all callosal abnormalities.
- discussion_id: condca-regional-clinical-attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which neural regions account for the remaining movement, ocular and sensory manifestations?
  attaches_to:
  - phenotypes#Spasticity
  - phenotypes#Dystonia
  - phenotypes#Oculomotor Apraxia
  - phenotypes#Esotropia
  - phenotypes#Hand Tremor
  - phenotypes#Hearing Impairment
  - phenotypes#Seizures
  - phenotypes#Caudate Atrophy
  - phenotypes#Putaminal Atrophy
  - phenotypes#Microcephaly
  rationale: >-
    Spasticity indicates a central motor component, but the reviewed human studies do not establish the affected descending pathways. Dystonia and seizures coexist with caudate/putaminal atrophy in one case without demonstrating that this lesion causes either symptom. Hand tremor includes rest and action components, and the sporadic hearing loss is unlocalized. The broad eye-movement relation to weakness/cerebellar dysfunction is represented, while the specific origins of apraxia and esotropia are not separated. Microcephaly includes postnatal head-growth decline, but neither cerebellar loss nor peripheral motor-neuron loss alone has been shown to explain it; the first 2019 case also had a potentially contributing NCAPD3 variant. These gaps concern lesion or causal attribution, not simply absent pathway nodes.
  evidence:
  - reference: PMID:30420557
    reference_title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Additional constantly
      observed features were microcephaly, eye movement abnormali-
      ties, feeding difficulties, ataxia, spasticity, and dystonia.
    explanation: >-
      The human series lists these findings. The sentence supplies occurrence, not a per-feature population frequency.
  - reference: DOI:10.1055/s-0042-1749669
    reference_title: 'Childhood-Onset Neurodegeneration with Cerebellar Atrophy Syndrome: Severe Neuronal Degeneration and Cardiomyopathy with Loss of Tubulin Deglutamylase Cytosolic Carboxypeptidase 1'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a novel homozygous missense (NM_015239: c.2447A > C, p. Gln816Pro) variant in the AGTPBP1 gene that c.2447A > C variant has never been reported in a homozygous state in the Genome Aggregation (gnomAD; v2.1.1) database, identified by whole-exome sequencing in a patient with a seizure, dystonia, dilated cardiomyopathy (DCM), and accompanying atrophy of caudate nuclei, putamen, and cerebellum.
    explanation: >-
      The single p.Gln816Pro case documents caudate and putaminal atrophy alongside dystonia and seizures. Their co-occurrence does not establish which regional lesion causes either clinical manifestation or whether the basal-ganglia findings recur in other genotypes.
  - reference: PMID:34572343
    reference_title: 'The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other clinical features, such as bilateral hearing loss and hand tremors, were sporadically detected.
    explanation: >-
      Published human observations; no hearing-loss subtype or frequency band is inferred.
  - reference: PMID:30976113
    reference_title: Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We cannot
      rule out a potential contribution of this variant to the pheno-
      type although AGTPBP1 seems to be the main contributor.
    explanation: >-
      The NCAPD3 co-variant is a stated confound in the first patient; it is not assumed to explain every microcephaly case.
- discussion_id: condca-expanded-case-phenotypes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which unusual findings recur in genetically secure cases?
  attaches_to:
  - phenotypes#Abnormal Eye Movements
  - phenotypes#Oculomotor Apraxia
  rationale: >-
    The 2024 likely-pathogenic p.Thr884Pro patient had coarse facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips and large ears; arachnodactyly, interphalangeal hyperextensibility, low-inserted thumbs, toe camptodactyly, prominent heels, scoliosis and joint contractures were also described. Table 2 additionally records brisk reflexes, hypometric saccades and poor eye contact, and ERG showed retinal dysfunction. The extensor plantar response in the 4.5-month-old autopsy case is not separately treated as a pathological Babinski sign because that response can be physiological at this age. These are preserved as a case expansion whose individual causal attribution and recurrence are unresolved. The second AGTPBP1 patient carried p.Thr512Ala classified as a VUS and had strabismus, oculomotor apraxia, optic-nerve dysfunction and contractures; that case is not pooled as equally established genetic evidence. Mouse retinal degeneration is not substituted for these human observations.
  evidence:
  - reference: PMID:38153683
    reference_title: The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 3 presented with GDD, dysmorphic facial features “course facies, narrow forehead, thick eyebrows, broad bulbous nose, short philtrum, thick lips, and large ears,” oculomotor apraxia, and seizures.
    explanation: >-
      Patient 3 carried homozygous p.Thr884Pro, classified as likely pathogenic. The distinct patient 7 carried a VUS and is not pooled as equivalent genetic evidence.
  - reference: PMID:38153683
    reference_title: The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had multiple skeletal deformities “arachnodactyly, bilateral hyperextensibility of the interphalangeal joints, bilateral low inserted thumb, toes camptodactyly, bilateral prominent heel, severe scoliosis and joint contractures” and bilateral fungal infection of both feet (Fig. 3).
    explanation: >-
      The antecedent is patient 3, the likely-pathogenic AGTPBP1 case; these unusual observations remain explicitly case-scoped.
  - reference: PMID:38153683
    reference_title: The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 7 had a homozygous missense variant in the AGTPBP1 gene (c.1534A > G; p. (Thr512Ala) causing an amino acid change from Thr to Ala at position 512. It is classified as a variant of uncertain significance (class 3) according to the recommendations of Centogene and ACMG.
    explanation: >-
      Patient 7 is genetically less certain than patient 3.
notes: >-
  GeneReviews baseline: a PubMed search for a GeneReviews chapter covering AGTPBP1 or CONDCA ("AGTPBP1 GeneReviews[All Fields]" and a broader disease-name search) returned no results on 2026-08-31. No GeneReviews chapter exists for this disorder, so no GeneReviews-derived phenotype baseline was available and none is tagged in `references`.

  Childhood mortality is recorded under `progression`, not as a phenotype: the obvious HPO term (HP:0003819 Death in childhood) sits in the mortality/aging branch rather than under Phenotypic abnormality, so it is not a member of the PhenotypeTerm dynamic enum and cannot be bound in `phenotypes`.

  Scope decision on non-neurological AGTPBP1 phenotypes: biallelic AGTPBP1 missense variants have separately been linked to human teratozoospermia with sperm head and flagellar defects (PMID:37937809), consistent with the defective spermatogenesis of pcd mice. Those patients were ascertained for infertility, not neurodegeneration, and are not reported to have CONDCA. Male infertility is therefore not curated as a CONDCA phenotype in this entry; whether the two allelic presentations are one spectrum is unresolved.

  `evidence_source` grading rule used throughout this entry: the value describes what the QUOTED SENTENCE reports, not the study design of the paper as a whole. So a review's summary of published patient findings is HUMAN_CLINICAL, a review's description of the pcd mouse is MODEL_ORGANISM, and a review's own framing or overall judgement (a definitional statement, an assessment of model fidelity, a statement about the state of the treatment field) is OTHER. This matters most for PMID:34572343, which supplies clinical synthesis and model context.

  Module conformance: three pathophysiology nodes declare conformance to `cerebellar_purkinje_degeneration`. The module's amplifier node (Purkinje Cell Calcium and Proteostasis Dysregulation) is deliberately not claimed, because the amplifying step in CONDCA is a tubulin post-translational-modification and transport defect rather than a calcium-handling defect; the disorder-specific amplifier nodes (Tubulin Hyperglutamylation, Impaired Microtubule-Based Axonal Transport) occupy that position in the chain instead. The module's `Loss of Cerebellar Cortical Output` node is also not claimed: the human data establish neuronal loss and cerebellar atrophy, but do not directly measure Purkinje-to-deep-nuclei signalling. The redundant structural-atrophy node has been removed; neuronal loss remains upstream of the clinical atrophy and the qualified motor consequence. Conforming to an unmeasured human output node would overstate the available functional evidence.

  Deep research provenance: this entry used the Edison/falcon deep-research report at research/Neurodegeneration_Childhood-onset_With_Cerebellar_Atrophy-deep-research-falcon.md. Its own reference validation reported 9/9 references resolved with no confabulations, and its term validation 41/41 terms resolved with matching labels. Those numbers are narrower than they look, and are not why this entry is trustworthy. The report carries 38 citations but contains no PMIDs at all - it cites by author-year key - so only the 9 identifier-bearing citations were ever machine-checked, and the same frontmatter records `on_topic: 6` of those 9, with the remaining 3 undecided rather than cleared. The ~29 author-year citations were treated as unverified throughout. This review independently assessed the cited clinical sources and relevant mechanistic studies, restored the 2019 full text through the reference fetcher, added the DOI-keyed cardiac case and the 2026 human autopsy report, and verified every new quotation against generated caches. The report was generated with an empty mondo_id, so a Named Entity Confusion preflight against MONDO:0032650 was run explicitly; it returned a WARN because TTLL1 is mentioned frequently, but TTLL1 is the counteracting glutamylase central to this mechanism rather than a rival disease gene, and the report's OMIM ID (618276) matches the MONDO term. Every PMID, snippet and ontology CURIE used here was independently re-verified against the cached source.

references:
- reference: PMID:30420557
  title: Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.
- reference: PMID:34572343
  title: >-
    The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease
    Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an
    Animal Model for the Study of this Human Disease.
- reference: PMID:42358771
  title: 'Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.'

📚

References & Deep Research

References

3

PMID:30420557

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

No top-level findings curated for this source.

PMID:34572343

The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease.

No top-level findings curated for this source.

PMID:42358771

Autopsy Findings in AGTPBP1 Gene-Related Infantile Neurodegeneration: A Case Report and Review of Literature.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

GeneReviews baseline: a PubMed search for a GeneReviews chapter covering AGTPBP1 or CONDCA ("AGTPBP1 GeneReviews[All Fields]" and a broader disease-name search) returned no results on 2026-08-31. No GeneReviews chapter exists for this disorder, so no GeneReviews-derived phenotype baseline was available and none is tagged in `references`. Childhood mortality is recorded under `progression`, not as a phenotype: the obvious HPO term (HP:0003819 Death in childhood) sits in the mortality/aging branch rather than under Phenotypic abnormality, so it is not a member of the PhenotypeTerm dynamic enum and cannot be bound in `phenotypes`. Scope decision on non-neurological AGTPBP1 phenotypes: biallelic AGTPBP1 missense variants have separately been linked to human teratozoospermia with sperm head and flagellar defects (PMID:37937809), consistent with the defective spermatogenesis of pcd mice. Those patients were ascertained for infertility, not neurodegeneration, and are not reported to have CONDCA. Male infertility is therefore not curated as a CONDCA phenotype in this entry; whether the two allelic presentations are one spectrum is unresolved. `evidence_source` grading rule used throughout this entry: the value describes what the QUOTED SENTENCE reports, not the study design of the paper as a whole. So a review's summary of published patient findings is HUMAN_CLINICAL, a review's description of the pcd mouse is MODEL_ORGANISM, and a review's own framing or overall judgement (a definitional statement, an assessment of model fidelity, a statement about the state of the treatment field) is OTHER. This matters most for PMID:34572343, which supplies clinical synthesis and model context. Module conformance: three pathophysiology nodes declare conformance to `cerebellar_purkinje_degeneration`. The module's amplifier node (Purkinje Cell Calcium and Proteostasis Dysregulation) is deliberately not claimed, because the amplifying step in CONDCA is a tubulin post-translational-modification and transport defect rather than a calcium-handling defect; the disorder-specific amplifier nodes (Tubulin Hyperglutamylation, Impaired Microtubule-Based Axonal Transport) occupy that position in the chain instead. The module's `Loss of Cerebellar Cortical Output` node is also not claimed: the human data establish neuronal loss and cerebellar atrophy, but do not directly measure Purkinje-to-deep-nuclei signalling. The redundant structural-atrophy node has been removed; neuronal loss remains upstream of the clinical atrophy and the qualified motor consequence. Conforming to an unmeasured human output node would overstate the available functional evidence. Deep research provenance: this entry used the Edison/falcon deep-research report at research/Neurodegeneration_Childhood-onset_With_Cerebellar_Atrophy-deep-research-falcon.md. Its own reference validation reported 9/9 references resolved with no confabulations, and its term validation 41/41 terms resolved with matching labels. Those numbers are narrower than they look, and are not why this entry is trustworthy. The report carries 38 citations but contains no PMIDs at all - it cites by author-year key - so only the 9 identifier-bearing citations were ever machine-checked, and the same frontmatter records `on_topic: 6` of those 9, with the remaining 3 undecided rather than cleared. The ~29 author-year citations were treated as unverified throughout. This review independently assessed the cited clinical sources and relevant mechanistic studies, restored the 2019 full text through the reference fetcher, added the DOI-keyed cardiac case and the 2026 human autopsy report, and verified every new quotation against generated caches. The report was generated with an empty mondo_id, so a Named Entity Confusion preflight against MONDO:0032650 was run explicitly; it returned a WARN because TTLL1 is mentioned frequently, but TTLL1 is the counteracting glutamylase central to this mechanism rather than a rival disease gene, and the report's OMIM ID (618276) matches the MONDO term. Every PMID, snippet and ontology CURIE used here was independently re-verified against the cached source.

Create: Neurodegeneration_Childhood-onset_With_Cerebellar_Atrophy · 2026-09-01T03:14:40Z · View source

Created the CONDCA (AGTPBP1/CCP1) entry de novo from primary literature, using the Edison/falcon deep-research report at research/Neurodegeneration_Childhood-onset_With_Cerebellar_Atrophy-deep-research-falcon.md as leads only. GeneReviews baseline: searched PubMed for an AGTPBP1/CONDCA GeneReviews chapter ('AGTPBP1 GeneReviews[All Fields]' and a broader disease-name search); no chapter exists, so no GeneReviews phenotype baseline was available and none is tagged. Report handling: the falcon report was generated with an empty mondo_id, so a Named Entity Confusion preflight was run explicitly (just preflight-dr ... MONDO:0032650 --strict); it returned WARN only because TTLL1 is mentioned 10 times, but TTLL1 is the counteracting glutamylase central to this mechanism rather than a rival disease gene, and the report's OMIM ID 618276 matches the MONDO term, so the report is on-target. The report's own reference_validation reported 9/9 resolved and term_validation 41/41 resolved with matching labels, but the report carries 38 citations and contains ZERO PMIDs, so only 9 identifier-bearing citations were ever checked; the ~29 author-year-keyed citations were treated as unverified. Every DOI in the report was converted to a PMID via the PMC ID converter and re-fetched, so the entry cites 21 distinct PMIDs and NO DOI-keyed evidence at all -- every snippet is therefore covered by the gating CI validator, and no --unskip-prefix DOI run was needed. Content: 9-node causal pathophysiology chain (CCP1 deglutamylase deficiency -> tubulin hyperglutamylation -> impaired microtubule-based axonal transport and Purkinje cell ER stress -> Purkinje neuron degeneration and lower motor neuron/peripheral axon degeneration -> progressive cerebellar atrophy and motor neuronopathy -> cerebellar ataxia/movement disorder and progressive weakness), with edge-level evidence including the TTLL1 genetic rescue experiments. Three nodes declare conforms_to against cerebellar_purkinje_degeneration (#Cerebellar Neuron Insult, #Purkinje Neuron Degeneration, #Cerebellar Ataxia); the module's calcium/proteostasis amplifier node is deliberately NOT claimed because the CONDCA amplifier is a tubulin post-translational-modification and transport defect. 19 phenotypes, all with at least one HUMAN_CLINICAL evidence item (mouse data is never the sole support for a human phenotype). Deliberate omissions recorded in the file: has_subtypes is NOT used (the literature describes a continuous severity spectrum with no named nosologic entities, and Shashi et al. explicitly cautioned against a definitive genotype-phenotype correlation) -- recorded as discussion condca-subtype-structure; frequency: is omitted on all but one phenotype (neurogenic muscle atrophy, FREQUENT, from an explicit 'half of the patients' statement) because the published counts come from severity-ascertained case reports with differing denominators -- recorded as condca-frequency-data; the single 2023 dilated-cardiomyopathy case report is NOT curated as a phenotype because its journal has no PubMed record and no PMID-anchored snippet is possible -- recorded as condca-cardiac-involvement; childhood mortality is recorded under progression rather than phenotypes because HP:0003819 is outside the PhenotypeTerm dynamic enum; AGTPBP1-related teratozoospermia (PMID:37937809) is noted as out of scope. Five knowledge-gap discussions. Treatments: five supportive-care entries plus four clearly-labelled PRECLINICAL-ONLY investigational entries (AAV Ccp1 gene replacement, TTLL1-directed polyglutamylation reduction, rhVEGF-B, lacosamide/CRMP2), each with target_mechanisms linking to the pathograph. Treatment terms use NCIT throughout (MAXO is retired in this repo). No datasets block: just discover-datasets returned no GEO candidates, which is expected for an ultra-rare disorder. Validation: just validate passes (schema + terms + references, 107/107 snippets verified); check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length and check-snippet-grading all pass; compliance 86.3% global / 86.5% weighted. A red-team self-review (dismech-pr-review skill, run in a fresh-context subagent) was performed before opening the PR and found 6 critical and 11 important issues, all fixed in this same PR: three snippets truncated immediately before the clause carrying their claim (Nna1 deglutamatase, Delta2-tubulin, and the ataxia edge); two supports:REFUTE items pointed at objects they did not refute (the AGTPBP1 causal-gene entry, and a null result about a different drug attached to the rhVEGF-B entry); a bundled ataxia/spasticity/dystonia node whose causal attribution its own phenotype entry contradicted; two evidence items mixing IN_VITRO and MODEL_ORGANISM in one quote; a cultured-hippocampal-neuron result graded MODEL_ORGANISM; an inconsistent evidence_source policy for the PMID:34572343 review, now governed by an explicit rule recorded in notes (grade what the quoted sentence reports, not the paper's overall design); a cell-autonomy claim that wrongly excluded any glial contribution; and an ESTABLISHED confidence on a Purkinje-cell-degeneration node that no human study has ever confirmed. That last one produced the most substantive change: PMID:30420557 states outright that 'we could not yet obtain direct evidence for Purkinje cell degeneration in human patients as no postmortem examinations were conducted', so the node was downgraded to PROVISIONAL, that disclaimer was added as a supports:NO_EVIDENCE item, and a sixth discussion of kind HUMAN_MODEL_MISMATCH was added. The review also surfaced two content gaps now filled: a Tongue Fasciculations phenotype (HP:0001308) quotable from a snippet the entry already cited twice, and a microtubule-depolymerizer preclinical treatment from PMID:33004692. The frequency rationale was rewritten to state the real reason bands are mostly omitted (the counts sit in a table the reference cache does not capture as text, so no CI-verifiable snippet exists for them) rather than the post-hoc epistemic reason originally recorded.

Falcon ▸

Neurodegeneration, Childhood-Onset, with Cerebellar Atrophy (CONDCA): Disease-Characteristics Report

Edison Scientific Literature 38 citations 2026-08-31T20:54:54.510547

Neurodegeneration, Childhood-Onset, with Cerebellar Atrophy (CONDCA): Disease-Characteristics Report

Executive summary

CONDCA is an ultra-rare, usually infantile-onset, progressive autosomal-recessive neurodegenerative disorder caused by biallelic loss-of-function or damaging hypomorphic variants in AGTPBP1, which encodes cytosolic carboxypeptidase 1 (CCP1/NNA1). The best-established disease axis is cerebellar Purkinje-cell degeneration combined with spinal motor-neuron and peripheral motor-axon disease. The molecular lesion disrupts the neuronal “tubulin code”: loss of CCP1-mediated deglutamylation produces excessive, predominantly TTLL1-dependent tubulin polyglutamylation, reduced Δ2-tubulin formation, impaired axonal cargo transport, and selective neuronal degeneration. Human evidence remains limited to small case series and reports; no population prevalence, validated clinical criteria, approved disease-modifying therapy, or disease-specific interventional trial was identified. (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4, bodakuntla2021distinctrolesof pages 1-2, magiera2018excessivetubulinpolyglutamylation pages 1-2)

domain	best-supported finding	quantitative evidence	evidence type	key source/date
Identity / inheritance	CONDCA is a rare autosomal recessive neurodegenerative disease caused by biallelic AGTPBP1 (CCP1) variants; OMIM 618276	Foundational cohort: 13 affected individuals from 10 unrelated families; later summaries cite ~18-20 reported patients	Human clinical-genetic cohort; disease database association	Shashi et al., EMBO J 2018, published 2018-11-12, DOI: https://doi.org/10.15252/embj.2018100540, PMID 30420557 (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4); Open Targets EFO_0010256 (OpenTargets Search: Neurodegeneration childhood-onset with cerebellar atrophy)
Core phenotypes and frequencies	Early infantile/childhood-onset progressive neurologic disease with motor delay, hypotonia, weakness, cognitive impairment, cerebellar atrophy, and motor neuropathy/lower motor neuron involvement	Aggregated review of ~20 patients: motor delay 20/20; hypotonia 19/20; muscle weakness 16/18; cognitive delay 17/20; microcephaly 11/20; feeding difficulties 13/20; respiratory distress 9/20; cerebellar atrophy 18/20; corpus callosum dysplasia 6/20; muscle atrophy 9/18	Human case-series synthesis from primary reports/review	Baltanás et al., Biomedicines 2021, DOI: https://doi.org/10.3390/biomedicines9091157 (baltanas2021thechildhoodonsetneurodegeneration pages 7-9, baltanas2021thechildhoodonsetneurodegeneration pages 9-10)
Natural history / onset	Onset is usually from birth to 20 months with progressive worsening; disease can be severe and fatal in childhood, though milder survivors exist	In the 2018 cohort, 6/13 had a fatal course; one summarized review reports 7/18 deaths; patient ages at presentation ranged from 7 months to 14 years in one review summary	Human cohort and review synthesis	Shashi et al. 2018 (shashi2018lossoftubulin pages 1-2); Baltanás et al. 2021 (baltanas2021thechildhoodonsetneurodegeneration pages 9-10, baltanas2021thechildhoodonsetneurodegeneration pages 6-7)
MRI / neurodiagnostics	Brain MRI most consistently shows cerebellar atrophy; corpus callosum abnormalities and microcephaly are frequent co-findings	Cerebellar atrophy in 18/20 in aggregated review; severe or moderate cerebellar atrophy shown across many individuals in foundational cohort	Human imaging evidence	Shashi et al. 2018 (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4); Baltanás et al. 2021 (baltanas2021thechildhoodonsetneurodegeneration pages 7-9)
Electrophysiology / peripheral nerve	Disease affects cerebellum, spinal motor neurons, and peripheral nerves, typically with axonal motor neuropathy and denervation, while sensory involvement is less emphasized	Aggregated review: denervation 5/20, neurogenic changes 2/20, axonal motor neuropathy 5/20	Human neurophysiology and pathology	Shashi et al. 2018 (shashi2018lossoftubulin pages 1-2); Baltanás et al. 2021 (baltanas2021thechildhoodonsetneurodegeneration pages 9-10, baltanas2021thechildhoodonsetneurodegeneration pages 7-9)
Molecular mechanism	AGTPBP1/CCP1 loss causes defective tubulin deglutamylation, reduced D2-tubulin generation, and excess tubulin polyglutamylation, linking microtubule PTM dysregulation to neurodegeneration	Human muscle biopsy showed polyglutamylated tubulin accumulation; missense mutants lacked detectable catalytic activity for D2-tubulin generation in cell assays	Human molecular pathology; cell-based functional evidence	Shashi et al. 2018, DOI above (shashi2018lossoftubulin pages 2-4)
Mechanistic downstream effects	Excess polyglutamylation impairs neuronal transport and is sufficient to drive neuron-autonomous degeneration; TTLL1 is a major pathogenic counter-enzyme in CCP1 deficiency	In mouse models, simultaneous TTLL1 loss fully rescued degeneration of selected neurons; transport defects affected multiple cargo classes in hippocampal neurons	Mouse genetics; cultured neuron experiments	Magiera et al., EMBO J 2018, DOI: https://doi.org/10.15252/embj.2018100440 (magiera2018excessivetubulinpolyglutamylation pages 1-2); Bodakuntla et al., EMBO J 2021, published 2021-07-26, DOI: https://doi.org/10.15252/embj.2021108498 (bodakuntla2021distinctrolesof pages 1-2)
Diagnostics	Whole-exome sequencing is the key diagnostic approach because phenotype overlaps other pediatric neurodegenerative/cerebellar atrophy disorders; segregation testing is used for confirmation	2024 Egyptian WES cohort: 7 patients from 6 families overall; 2 AGTPBP1 cases identified; sequencing described at ~50x average coverage	Human diagnostic study	Ashaat et al., Molecular Neurobiology 2024, published online 2023-12-28, DOI: https://doi.org/10.1007/s12035-023-03866-y (ashaat2024thediagnosticvalue pages 1-2, ashaat2024thediagnosticvalue pages 7-10)
Variant spectrum	Reported AGTPBP1 disease variants include nonsense, frameshift, splice, deletion, and missense alleles; truncating genotypes trend more severe than some missense genotypes	Foundational cohort identified 6 loss-of-function and 6 missense variants; variants were absent or extremely rare in population databases (AF below 0.00005 in cited summary)	Human clinical-genetic and functional evidence	Shashi et al. 2018 (shashi2018lossoftubulin pages 2-4); Baltanás et al. 2021 (baltanas2021thechildhoodonsetneurodegeneration pages 6-7)
Expanded phenotypes	Phenotypic spectrum may extend beyond classic cerebellar atrophy/motor neuron disease to atypical imaging or systemic findings	2021 report described 2 siblings with homozygous c.3293G>A and neurodegeneration without cerebellar atrophy; 2023 case reported homozygous c.2447A>C (p.Gln816Pro) with seizures, dystonia, dilated cardiomyopathy, and caudate/putaminal/cerebellar atrophy	Human case reports	Türay et al., Neurogenetics 2021, DOI: https://doi.org/10.1007/s10048-021-00643-8 (turay2021anovelpathogenic pages 1-2); Samur et al., J Pediatr Neurol 2023, DOI: https://doi.org/10.1055/s-0042-1749669 (samur2023childhoodonsetneurodegenerationwith pages 1-2)
Recent 2024 human developments	New AGTPBP1 cases continue to expand mutational and phenotypic spectrum in consanguineous families	Ashaat 2024 reported 2 homozygous AGTPBP1 variants in Egyptian patients: novel c.2650A>C (p.Thr884Pro), likely pathogenic; and c.1534A>G (p.Thr512Ala), classified as VUS in that paper; cohort age range 1.5-18 years, all families consanguineous	Human WES cohort	Ashaat et al. 2024 (ashaat2024thediagnosticvalue pages 10-11, ashaat2024thediagnosticvalue pages 1-2, ashaat2024thediagnosticvalue pages 7-10)
Prognosis	Prognosis is generally poor with severe disability, progressive neurologic decline, and childhood mortality, but expressivity is variable	6/13 fatal in Shashi 2018; milder survivors included a 14-year-old with spastic-ataxic movement disorder and mild intellectual disability in the foundational cohort	Human cohort	Shashi et al. 2018 (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4)
Treatment status	No approved disease-modifying therapy or disease-specific clinical trial was identified; management is currently supportive and genetics-guided	Clinical trial search found no relevant registered interventional trial; supportive treatment reversed cardiomyopathy in one 2023 case report, but not the neurologic disease	Clinical trial landscape; case report	ClinicalTrials search result (OpenTargets Search: Neurodegeneration childhood-onset with cerebellar atrophy); Samur et al. 2023 (samur2023childhoodonsetneurodegenerationwith pages 1-2)
Preclinical therapy signals (2025)	In the PCD mouse model, rhVEGF-B showed neuroprotective benefit, whereas rhIGF-1 did not under tested conditions	Abstract reports rhVEGF-B at moderate dosage "stopped the process of neuronal death" and restored motor, cognitive, and social functions; increased dosing was detrimental; rhIGF-1 showed no neuroprotective effect	Mouse preclinical therapeutic study	Pérez-Revuelta et al., Int J Mol Sci 2025, published 2025-01-10, DOI: https://doi.org/10.3390/ijms26020538 (perezrevuelta2025neuroprotectiveeffectsof pages 1-2, perezrevuelta2025neuroprotectiveeffectsof pages 4-7, perezrevuelta2025neuroprotectiveeffectsof pages 10-12, perezrevuelta2025neuroprotectiveeffectsof pages 19-20)
Model organism	The Purkinje cell degeneration (pcd) mouse is the best-established model and recapitulates cerebellar atrophy plus broader neurodegeneration; sheep are cited as having lower motor neuron-like disease with AGTPBP1 involvement	Mouse model shows Purkinje cell loss, cerebellar atrophy, peripheral nerve pathology, reduced motor neurons, excess polyglutamylation, and decreased D2-tubulin; review also cites ovine lower motor neuron disease	Mouse and comparative-animal evidence	Shashi et al. 2018 (shashi2018lossoftubulin pages 6-7); Baltanás et al. 2021 (baltanas2021thechildhoodonsetneurodegeneration pages 19-21, baltanas2021thechildhoodonsetneurodegeneration pages 21-22)

Table: This table condenses the strongest available evidence for AGTPBP1-related childhood-onset neurodegeneration with cerebellar atrophy across clinical, molecular, diagnostic, prognostic, and model-system domains. It is useful as a quick-reference scaffold for a fuller disease knowledge-base entry.

1. Disease information

Definition and identifiers

Preferred name: Neurodegeneration, childhood-onset, with cerebellar atrophy.
Abbreviation: CONDCA.
OMIM: 618276.
Defining gene: AGTPBP1, also called CCP1 or NNA1; Open Targets/EFO maps the disorder as EFO:0010256 and identifies AGTPBP1 as the strongest associated target. The additional Open Targets association with ABHD12 reflects phenotypic/database overlap and should not be treated as a defining cause of AGTPBP1-related CONDCA. (OpenTargets Search: Neurodegeneration childhood-onset with cerebellar atrophy)
MONDO: A precise MONDO accession was not confirmed in the retrieved evidence; it should therefore be left unresolved rather than inferred from OMIM/EFO cross-mapping.
Orphanet, MeSH, ICD-10/ICD-11: No disease-specific codes were confirmed. Coding generally requires broader categories such as hereditary ataxia, neurodegenerative disease, cerebellar atrophy, or motor-neuron disease.
Synonyms: AGTPBP1-related neurodegeneration; CCP1 deficiency; infantile-onset neurodegeneration due to CCP1 loss; childhood-onset neurodegeneration with cerebellar atrophy syndrome; AGTPBP1-related cerebellar degeneration and motor neuropathy.

This entry is an aggregated disease-level synthesis, not an individual EHR record. Its principal evidence consists of published patients, family studies, functional assays, and animal models. The landmark study identified 13 affected individuals from 10 unrelated families. Its abstract states: “We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration.” (shashi2018lossoftubulin pages 1-2)

2. Etiology, risk, and protective factors

Causal factor

The established cause is biallelic germline AGTPBP1 dysfunction. Nonsense, frameshift, canonical splice, exon/gene-region deletion, and damaging missense alleles have been reported. Null alleles abolish functional CCP1; tested missense proteins were unstable and lacked detectable catalytic activity for Δ2-tubulin generation. This supports loss of function rather than gain of function or dominant-negative action. (shashi2018lossoftubulin pages 2-4)

Genetic risk

Having two pathogenic or likely pathogenic alleles is the principal risk factor.
Consanguinity increases the probability of homozygosity but is not required. An aggregated series reported consanguinity in 14/19 assessed patients; the 2024 Egyptian cohort was entirely consanguineous. (baltanas2021thechildhoodonsetneurodegeneration pages 7-9, ashaat2024thediagnosticvalue pages 1-2)
In the foundational series, disease alleles were absent or extremely rare in population databases, with reported allele frequencies below 0.00005. The probability of randomly observing the implicated biallelic genotypes from gnomAD frequencies was calculated as 3.08×10⁻⁶. (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4)
A preliminary genotype–phenotype trend suggests biallelic truncating alleles more often produce critically severe/fatal disease, whereas residual-function missense genotypes may be milder. Exceptions occur, so this is not a validated prognostic rule. (shashi2018lossoftubulin pages 2-4)

Environmental, infectious, and lifestyle factors

No toxin, infection, radiation, occupation, diet, smoking, alcohol exposure, or other environmental cause has been demonstrated. No validated gene–environment interaction is known. Environmental or lifestyle modifiers remain speculative, particularly because intrafamilial variability can occur. (ashaat2024thediagnosticvalue pages 10-11)

Protective factors

No protective human allele or environmental exposure has been established. Ttll1 deletion is strongly protective in CCP1-deficient mice, but this is an experimental genetic rescue, not a naturally occurring human protective factor. (bodakuntla2021distinctrolesof pages 1-2, magiera2018excessivetubulinpolyglutamylation pages 1-2)

3. Phenotypes

Reported frequencies vary because denominators combine small, incompletely phenotyped cohorts. The following estimates are best treated as provisional.

Phenotype	Characteristics and approximate frequency	Suggested HPO term
Global motor delay	Usually begins in infancy; progressive; 20/20 in an aggregated summary	Global developmental delay, HP:0001263; Motor delay, HP:0001270
Hypotonia	Early, usually severe and progressive; 19/20	Muscular hypotonia, HP:0001252
Muscle weakness/tetraparesis	16/18; often generalized and function-limiting	Muscle weakness, HP:0001324; Tetraparesis, HP:0002273
Cognitive/developmental impairment	17/20; ranges from mild intellectual disability to profound impairment or regression	Intellectual disability, HP:0001249; Developmental regression, HP:0002376
Cerebellar atrophy	Hallmark but not invariant; 18/20; may be early and progressive	Cerebellar atrophy, HP:0001272
Ataxia	Variable visibility because profound weakness may prevent walking	Cerebellar ataxia, HP:0001251; Gait ataxia, HP:0002066
Microcephaly	11/20	Microcephaly, HP:0000252
Feeding difficulty/failure to thrive	13/20; clinically important aspiration/nutrition risk	Feeding difficulties, HP:0011968; Failure to thrive, HP:0001508
Respiratory insufficiency/distress	9/20; likely related to neuromuscular weakness in severe disease	Respiratory insufficiency, HP:0002093
Muscle atrophy	9/18; neurogenic pathology documented	Muscular atrophy, HP:0003202
Motor neuropathy/denervation	Axonal motor neuropathy 5/20; denervation 5/20; sensory involvement generally absent	Motor axonal neuropathy, HP:0007002; Areflexia, HP:0001284
Abnormal eye movements	Oculomotor apraxia, hypometric saccades, strabismus, or poor fixation; frequent but not universal	Oculomotor apraxia, HP:0000657; Abnormality of eye movement, HP:0000496
Spasticity/dystonia/tremor	Variable mixed upper- and lower-motor/cerebellar movement disorder	Spasticity, HP:0001257; Dystonia, HP:0001332; Tremor, HP:0001337
Corpus-callosum abnormality	Dysplasia/hypoplasia in approximately 6/20	Abnormal corpus callosum morphology, HP:0001273
Seizures	Not a defining feature, but reported in expanded cases	Seizure, HP:0001250
Cardiomyopathy	One 2023 case had reversible dilated cardiomyopathy; association requires replication	Dilated cardiomyopathy, HP:0001644

These frequencies derive from a synthesis in which motor delay was 20/20, hypotonia 19/20, weakness 16/18, cognitive delay 17/20, microcephaly 11/20, feeding difficulty 13/20, respiratory distress 9/20, cerebellar atrophy 18/20, and callosal dysplasia 6/20. (baltanas2021thechildhoodonsetneurodegeneration pages 7-9)

Quality of life has not been measured with EQ-5D, SF-36, PROMIS, or a CONDCA-specific instrument. Nevertheless, inability to walk independently, tetraparesis, feeding and respiratory dependence, visual/oculomotor impairment, contractures, and profound cognitive disability indicate major effects on mobility, self-care, communication, schooling, and caregiver burden. This is clinical inference from functional manifestations, not formal patient-reported-outcome evidence. (baltanas2021thechildhoodonsetneurodegeneration pages 9-10, ashaat2024thediagnosticvalue pages 7-10)

4. Genetic and molecular information

Gene and protein

AGTPBP1 lies at chromosome 9q21 and encodes CCP1, a cytosolic metallocarboxypeptidase. CCP1 removes glutamate residues from polyglutamate side chains on α/β-tubulin and removes gene-encoded C-terminal glutamates from detyrosinated α-tubulin to generate Δ2/Δ3 tubulin. Suggested annotations include GO:0008237 metallopeptidase activity, GO:0006508 proteolysis, GO:0070507 regulation of microtubule cytoskeleton organization, and tubulin deglutamylation as the specific biological process. (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4)

Variant classes and selected variants

The foundational cohort identified six loss-of-function and six distinct missense alleles, including a deletion of upstream/N-terminal exons and the splice variant c.2336-1G>T, which activated a cryptic splice site, removed 29 nucleotides, and caused p.Met780fs. Variant segregation supported autosomal-recessive inheritance. (shashi2018lossoftubulin pages 2-4)

Additional reported variants include:

c.3293G>A, p.Ser1098Asn: homozygous in two siblings with neurodegeneration but reportedly no cerebellar atrophy or lower-motor-neuron findings, illustrating phenotypic expansion. (turay2021anovelpathogenic pages 1-2)
c.2447A>C, p.Gln816Pro: novel homozygous missense variant reported in 2023 with seizures, dystonia, dilated cardiomyopathy, and caudate, putaminal, and cerebellar atrophy; no homozygotes were reported in gnomAD v2.1.1. (samur2023childhoodonsetneurodegenerationwith pages 1-2)
c.2650A>C, p.Thr884Pro: novel homozygous missense variant, classified likely pathogenic by the 2024 authors. (ashaat2024thediagnosticvalue pages 7-10)
c.1534A>G, p.Thr512Ala: homozygous missense variant, classified as a VUS in the 2024 report; it should not be upgraded without additional evidence. (ashaat2024thediagnosticvalue pages 7-10)

The Ashaat paper contains an internal transcript/variant-label inconsistency elsewhere, describing p.Gly884Arg under another nucleotide representation. For knowledge-base curation, the original sequencing files/LOVD submission should be checked before harmonizing that record. (ashaat2024thediagnosticvalue pages 10-11, ashaat2024thediagnosticvalue pages 7-10)

All known disease-causing alleles are germline. No somatic CONDCA mechanism, pathogenic repeat expansion, mitochondrial-DNA lesion, recurrent aneuploidy, translocation, or inversion is established. The foundational series did include a homozygous genomic deletion, so copy-number analysis remains relevant. No validated modifier gene or disease-associated epigenetic signature has been reported.

5. Environmental information

CONDCA is a monogenic disorder. No causal toxin, pollutant, occupational exposure, radiation, dietary deficiency, infection, or lifestyle factor is known. Routine vaccination has no disease-specific preventive role, although standard immunization remains important because respiratory weakness may increase complications of infection. Evidence for environmental modulation is presently absent.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic damaging AGTPBP1 variants lead to absent, unstable, truncated, or catalytically inactive CCP1 protein. (shashi2018lossoftubulin pages 2-4)
Loss of CCP1 activity leads to failure to shorten tubulin polyglutamate side chains and reduced conversion of detyrosinated α-tubulin to Δ2/Δ3 tubulin. (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 6-7)
Continued TTLL-family glutamylase activity—especially TTLL1 on α-tubulin—leads to excessive neuronal microtubule polyglutamylation. TTLL7 mainly modifies β-tubulin and does not drive the same CCP1-deficient degeneration. (bodakuntla2021distinctrolesof pages 1-2)
Hyperglutamylated microtubules lead to reduced axonal transport efficiency for mitochondria, lysosomes, LAMP1-positive endosomes, and BDNF vesicles; direct evidence comes from cultured neurons and mouse models, whereas its quantitative contribution in human neurons is inferred. (magiera2018excessivetubulinpolyglutamylation pages 1-2, baltanas2021thechildhoodonsetneurodegeneration pages 1-2)
Transport failure and microtubule dysfunction lead to impaired neuronal maintenance, organelle/axoplasmic disorganization, mitochondrial stress, and ultimately cell-autonomous degeneration. The exact death-signaling sequence in human CONDCA remains incompletely defined. (magiera2018excessivetubulinpolyglutamylation pages 1-2)
Selective vulnerability leads to early Purkinje-cell loss and later/parallel injury to spinal α-motor neurons and peripheral myelinated motor axons; other vulnerable populations in pcd mice include olfactory mitral, thalamic, retinal photoreceptor, and inferior olivary neurons. (baltanas2021thechildhoodonsetneurodegeneration pages 1-2, baltanas2021thechildhoodonsetneurodegeneration pages 9-10)
Purkinje-cell loss leads to cerebellar atrophy, ataxia, impaired motor learning, and likely cognitive/social cerebellar dysfunction. (perezrevuelta2025neuroprotectiveeffectsof pages 1-2)
Motor-neuron and peripheral-axon loss leads to hypotonia, weakness, areflexia, neurogenic muscle atrophy, contractures, tetraparesis, feeding difficulty, and respiratory compromise. (baltanas2021thechildhoodonsetneurodegeneration pages 9-10, shashi2018lossoftubulin pages 6-7)
Axonal/myelin degeneration leads to secondary macrophage/microglial activation and debris clearance; inflammation appears downstream rather than the initiating lesion. (shashi2018lossoftubulin pages 6-7)

Evidence strength and rescue experiments

Human muscle biopsy demonstrated accumulation of polyglutamylated tubulin, and transfected patient missense proteins failed to generate detectable Δ2-tubulin. Thus, defective enzymatic activity is demonstrated in human-derived material/cell assays. (shashi2018lossoftubulin pages 2-4)

Causality of hyperglutamylation is strongest in mice: Purkinje-specific CCP1 loss caused cell-intrinsic degeneration, while simultaneous Ttll1 deletion preserved Purkinje cells for up to 18 months. A later study showed that TTLL1, but not TTLL7, deletion prevented Purkinje-cell and peripheral myelinated-axon degeneration and increased mitochondrial motility. The primary study summarized its conclusion as: “Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1.” (bodakuntla2021distinctrolesof pages 1-2, magiera2018excessivetubulinpolyglutamylation pages 1-2)

Suggested process terms include microtubule-based transport (GO:0099111), axonal transport (GO:0098930), regulation of microtubule polymerization/depolymerization, mitochondrial transport, neuron apoptotic process (GO:0051402), and neuroinflammatory response. Suggested cell types include Purkinje neuron (CL:0000121), motor neuron (CL:0000100), retinal photoreceptor (CL:0000210), skeletal muscle cell (CL:0000188), macrophage (CL:0000235), and microglial cell (CL:0000129).

Omics and advanced technologies

No validated patient transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omics signature was identified. Current profiling is principally targeted immunoblotting, immunohistology, cell biology, and mouse genetics. Accordingly, omics biomarkers should be marked unavailable.

7. Anatomical structures affected

The primary system is the nervous system, involving both central and peripheral compartments.

Cerebellum, especially Purkinje-cell layer and cerebellar vermis: suggested UBERON:0002037 and Purkinje-cell layer term; disease is usually bilateral/diffuse rather than unilateral.
Spinal cord ventral horn and α-motor neurons: suggested UBERON:0002240 and ventral-horn annotation.
Peripheral motor nerves/myelinated axons: reduced axon number and caliber, disorganized axoplasm, and secondary myelin abnormalities are demonstrated in mice. (shashi2018lossoftubulin pages 6-7)
Skeletal muscle: secondary neurogenic atrophy with grouped fiber atrophy and fatty replacement, not a primary myopathy. (shashi2018lossoftubulin pages 2-4)
Corpus callosum/cerebrum/basal ganglia: variably involved on MRI; caudate and putaminal atrophy were reported in the 2023 expanded case. (samur2023childhoodonsetneurodegenerationwith pages 1-2)
Retina/optic system: photoreceptor degeneration is prominent in pcd mice; visual/optic dysfunction occurs in some human cases, but systematic prevalence is unknown. (baltanas2021thechildhoodonsetneurodegeneration pages 21-22, ashaat2024thediagnosticvalue pages 7-10)
Heart: dilated cardiomyopathy is currently an isolated expanded-phenotype observation, not established routine organ involvement. (samur2023childhoodonsetneurodegenerationwith pages 1-2)

At the subcellular level, the principal compartment is the microtubule cytoskeleton (GO:0015630), with secondary involvement of axons, mitochondria, lysosomes/endosomes, Golgi apparatus, and vesicular-transport machinery. (magiera2018excessivetubulinpolyglutamylation pages 1-2, baltanas2021thechildhoodonsetneurodegeneration pages 18-19)

8. Temporal development

Onset is usually congenital-to-infantile, between birth and approximately 20 months, and is typically insidious rather than acute. Early hypotonia, delayed motor acquisition, abnormal eye movements, feeding difficulty, or microcephaly is followed by progressive weakness, cerebellar atrophy, neuropathy, spasticity/dystonia, contractures, respiratory impairment, and severe disability. (baltanas2021thechildhoodonsetneurodegeneration pages 9-10, baltanas2021thechildhoodonsetneurodegeneration pages 7-9)

There is no validated staging system. A practical descriptive framework is:

Early/presymptomatic-developmental phase: normal or mildly delayed initial development in some children.
Early symptomatic phase: hypotonia, motor delay, feeding or oculomotor abnormalities, emerging cerebellar atrophy.
Progressive multisystem neurologic phase: ataxia, weakness, motor neuropathy, regression, muscle wasting, spasticity/dystonia.
Advanced phase: loss/non-acquisition of ambulation, tetraparesis, contractures, nutritional and respiratory complications.

The course is chronic and usually progressive, not episodic or relapsing-remitting. Spontaneous neurologic remission has not been documented. The pcd mouse suggests an early pre-degenerative therapeutic window before Purkinje-cell death: cellular changes appear around postnatal days 15–18, with overt death from day 18 and very few Purkinje cells outside lobule X by day 40. Translation of that interval to humans is unknown. (perezrevuelta2025neuroprotectiveeffectsof pages 1-2)

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy has a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of a non-carrier. Both sexes are affected; no convincing sex bias is evident. One synthesis contained approximately equal numbers of females and males. (baltanas2021thechildhoodonsetneurodegeneration pages 6-7, baltanas2021thechildhoodonsetneurodegeneration pages 7-9)

Penetrance for clearly pathogenic biallelic null alleles appears high, but cannot be formally estimated. Expressivity is marked: the foundational cohort ranged from critically ill infants to a 14-year-old with spastic-ataxic movement disorder and mild intellectual disability. Anticipation is not expected, and no founder allele, germline-mosaicism rate, carrier frequency, ethnic predominance, incidence, or prevalence has been established. (shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4)

Published families originate from multiple regions, including Europe, the Middle East, North Africa, and Turkey, but this reflects ascertainment and consanguinity rather than established geographic enrichment. Reported case counts—roughly 20 in early syntheses plus subsequent reports—are too small to calculate cases per 100,000. (baltanas2021thechildhoodonsetneurodegeneration pages 6-7, ashaat2024thediagnosticvalue pages 1-2)

10. Diagnostics

Clinical and laboratory evaluation

There are no consensus diagnostic criteria. Suspect CONDCA in an infant or child with progressive hypotonia/weakness, developmental delay or regression, cerebellar atrophy, areflexia or axonal motor neuropathy, especially after spinal muscular atrophy testing is negative or when upper-motor/cerebellar signs coexist.

Recommended work-up includes:

Brain MRI with attention to cerebellum, vermis, corpus callosum, cerebral volume, and basal ganglia.
Nerve conduction studies and EMG to identify predominantly axonal motor neuropathy/denervation.
Swallowing, nutrition, respiratory function, and sleep assessment.
Ophthalmology with ocular-motor examination; ERG/VEP when vision is impaired.
EEG when seizures or regression occur.
Echocardiography/ECG at baseline may be reasonable because cardiomyopathy has been reported, although evidence is insufficient for a formal surveillance guideline. (samur2023childhoodonsetneurodegenerationwith pages 1-2)
CK and routine metabolic testing are mainly useful to exclude mimics; no diagnostic blood/urine metabolite or enzyme assay is validated.
Muscle biopsy can show chronic denervation and tubulin hyperglutamylation, but is invasive and unnecessary when molecular diagnosis is available. (shashi2018lossoftubulin pages 2-4)

Genetic testing strategy

First tier: trio WES or WGS, or a comprehensive childhood-onset ataxia/neurodegeneration/motor-neuropathy panel including AGTPBP1.
Confirm candidate variants by Sanger sequencing and parental segregation.
Ensure copy-number calling; if negative despite strong suspicion, use genome sequencing, exome-array CNV analysis, or targeted deletion/duplication testing because an AGTPBP1 genomic deletion is known.
RNA studies can clarify splice variants or deep-intronic candidates.
Reanalyse VUS periodically and do not diagnose from a single heterozygous allele without a second pathogenic allele or compelling functional evidence.

WES was particularly useful in the 2024 Egyptian series because clinical and MRI features overlapped several neurodegenerative disorders. The study sequenced seven patients from six families at approximately 50× mean coverage and found two homozygous AGTPBP1 genotypes. Its abstract reports: “Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX.” Published online 28 December 2023; 2024 volume; DOI: https://doi.org/10.1007/s12035-023-03866-y. (ashaat2024thediagnosticvalue pages 4-5, ashaat2024thediagnosticvalue pages 1-2, ashaat2024thediagnosticvalue pages 7-10)

CMA/karyotype/FISH are not routine first-line tests for classic CONDCA but may detect large deletions or alternative diagnoses. Mitochondrial-DNA and repeat-expansion testing are differential-diagnosis tools, not specific AGTPBP1 tests. No newborn screening assay is available.

Differential diagnosis

Important alternatives include PCH-spectrum disorders, EXOSC3/VRK1/ASAH1-related motor-neuron disorders, SMA, PLA2G6-associated neurodegeneration, COASY/FA2H disorders, mitochondrial disease, congenital disorders of glycosylation, neuronal ceroid lipofuscinosis, AOA1/APTX, PNKP-related disease, and other hereditary ataxias/complex neuropathies. Cerebellar atrophy after postnatal degeneration, combined with motor neuropathy and biallelic AGTPBP1 variants, favors CONDCA over primary cerebellar hypoplasia. (ashaat2024thediagnosticvalue pages 10-11)

11. Outcome and prognosis

Prognosis is frequently poor but variable. Six of the 13 foundational patients had a fatal course; a later 18-patient synthesis recorded seven deaths. Severe truncating genotypes were enriched among critically ill/fatal cases, whereas some missense genotypes survived longer with less cognitive impairment. These observations are preliminary and not suitable for individual survival prediction. (baltanas2021thechildhoodonsetneurodegeneration pages 9-10, shashi2018lossoftubulin pages 1-2, shashi2018lossoftubulin pages 2-4)

No 5-year/10-year survival curves, median life expectancy, standardized mortality rate, or validated prognostic biomarker exists. Major morbidity includes severe motor disability, non-ambulation, feeding/aspiration problems, respiratory insufficiency, contractures/scoliosis, communication and cognitive impairment, and caregiver dependence. Recovery of lost neurologic function has not been demonstrated. Quality-of-life instruments have not been reported.

Potential adverse prognostic indicators are very early onset, biallelic truncating alleles, rapid regression, severe respiratory or bulbar involvement, and profound early cerebellar atrophy; all require validation.

12. Treatment and current applications

Current care

No approved disease-modifying treatment exists. Management is multidisciplinary and supportive:

Physical and occupational therapy, mobility aids, contracture prevention, orthoses, and scoliosis surveillance.
Speech/augmentative communication and feeding therapy.
Caloric support, swallow-safety management, and gastrostomy when indicated.
Airway clearance, non-invasive ventilation, vaccination, and prompt respiratory-infection treatment.
Standard antiseizure therapy when seizures occur; treatment should be phenotype- and EEG-guided.
Standard management of dystonia/spasticity, pain, sleep disturbance, visual impairment, and cardiomyopathy.
Palliative-care involvement for advanced disease.

Suggested NCIT intervention concepts include Physical Therapy, Occupational Therapy, Speech Therapy, Gastrostomy, Noninvasive Ventilation, Anticonvulsant Therapy, Genetic Counseling, and Palliative Care. Exact NCIT codes should be assigned from the current NCIT release rather than inferred.

Experimental approaches

Reducing TTLL1-mediated polyglutamylation: strongest target-validation evidence. Ttll1 deletion rescues Purkinje cells and peripheral axons in CCP1-deficient mice. No selective clinical TTLL1 inhibitor or human efficacy evidence is available. (bodakuntla2021distinctrolesof pages 1-2, magiera2018excessivetubulinpolyglutamylation pages 1-2)
rhVEGF-B: a mouse study received 7 November 2024 and was published 10 January 2025. Moderate dosing improved motor behavior, normalized recognition memory and social preference, increased Purkinje-cell density, and delayed/partially inhibited apoptosis. Higher-frequency dosing was detrimental, indicating a narrow, inverted-U exposure response. These findings are preclinical and do not establish pediatric safety or efficacy. DOI: https://doi.org/10.3390/ijms26020538. The abstract states that moderate rhVEGF-B “stopped the process of neuronal death and restored motor, cognitive, and social functions,” but this wording refers to the PCD mouse, not treated patients. (perezrevuelta2025neuroprotectiveeffectsof pages 1-2, perezrevuelta2025neuroprotectiveeffectsof pages 10-12)
rhIGF-1: daily P20–P30 administration did not improve motor, memory, social, or Purkinje-cell survival outcomes in the same model. Earlier schedules remain untested in that experiment. (perezrevuelta2025neuroprotectiveeffectsof pages 4-7, perezrevuelta2025neuroprotectiveeffectsof pages 19-20)
Minocycline, NMDA antagonism, cerebellar grafts, and bone-marrow-derived cells: explored historically in pcd mice, with limited or surrogate effects; none is established for human CONDCA. (baltanas2021thechildhoodonsetneurodegeneration pages 18-19, baltanas2021thechildhoodonsetneurodegeneration pages 19-21)
Gene replacement/editing/RNA therapy: biologically plausible for a recessive loss-of-function disorder but no human trial was identified in the searches used for this report.

No disease-specific ClinicalTrials.gov interventional study or NCT identifier was found. No CONDCA pharmacogenomic guideline, CPIC recommendation, combination regimen, response rate, or disease-specific adverse-event dataset exists.

13. Prevention

There is no lifestyle, vaccine, environmental, or drug-based primary prevention for a de novo family diagnosis. Effective genetic prevention options are:

Carrier testing of relatives after familial variants are established.
Cascade screening and reproductive genetic counseling.
Prenatal diagnosis by chorionic-villus or amniotic-fluid testing.
Preimplantation genetic testing for monogenic disease.
Partner testing where a pathogenic AGTPBP1 allele is known.

Secondary prevention consists of early molecular diagnosis and prospective surveillance for feeding, respiratory, orthopedic, visual, seizure, and possibly cardiac complications. Tertiary prevention includes aspiration precautions, respiratory support, nutrition, rehabilitation, positioning, and contracture/scoliosis management. Population newborn screening is not justified because prevalence, screening performance, and effective presymptomatic therapy are unknown.

14. Other species and natural disease

Mouse, Mus musculus (NCBI Taxon 10090): spontaneous or engineered Agtpbp1-deficient pcd alleles cause ataxia, Purkinje-cell degeneration, cerebellar atrophy, retinal degeneration, peripheral neuropathy, motor-neuron loss, and infertility. (shashi2018lossoftubulin pages 6-7)
Sheep, Ovis aries (NCBI Taxon 9940): AGTPBP1 defects have been linked to a naturally occurring lower-motor-neuron-like disease, supporting evolutionary conservation of motor-neuron vulnerability. (baltanas2021thechildhoodonsetneurodegeneration pages 21-22)
Drosophila melanogaster (Taxon 7227), Caenorhabditis elegans (Taxon 6239), and zebrafish, Danio rerio (Taxon 7955): ortholog perturbation has been used to study mitochondrial, ciliary, neuronal, or drug-response biology; these are models rather than confirmed naturally occurring veterinary CONDCA. (baltanas2021thechildhoodonsetneurodegeneration pages 21-22)

There is no zoonotic potential or cross-species transmission: CONDCA is inherited, not infectious. A veterinary breed-ontology identifier or breed-specific prevalence was not established.

15. Model organisms

The pcd mouse is the principal disease model. It reproduces the causal gene defect, tubulin hyperglutamylation, reduced Δ2-tubulin, cerebellar atrophy, Purkinje-cell loss, peripheral myelinated-axon degeneration, and spinal motor-neuron loss. It also permits temporal and cell-specific genetic manipulation. (shashi2018lossoftubulin pages 6-7)

Key model applications include:

Testing cell autonomy with Purkinje-specific conditional knockout.
Dissecting the tubulin code through Ccp1/Ttll1/Ttll7 compound mutants.
Measuring transport of mitochondria and vesicular cargo in cultured neurons.
Testing neuroprotective compounds and intervention timing.
Studying downstream macrophage/microglial responses.

Limitations are substantial. Mouse Purkinje-cell degeneration is temporally compressed; human patients show wider genetic and clinical heterogeneity; respiratory, cognitive, and systemic manifestations are incompletely reproduced; dosing and blood–brain-barrier behavior differ; and rescue of mouse histology does not establish developmental recovery in children. The model is therefore highly informative mechanistically but only partially predictive therapeutically. (perezrevuelta2025neuroprotectiveeffectsof pages 1-2, magiera2018excessivetubulinpolyglutamylation pages 1-2)

Recent developments and authoritative interpretation

The most important 2023–2024 developments were not new therapies, but phenotypic and diagnostic expansion. The 2023 report added a homozygous p.Gln816Pro case with basal-ganglia atrophy, seizures, dystonia, and reversible dilated cardiomyopathy. The 2024 Egyptian WES study added two homozygous AGTPBP1 genotypes and emphasized exome sequencing for phenotypically overlapping childhood cerebellar-atrophy syndromes. These reports strengthen the argument for broad sequencing rather than relying on a rigid “classic” phenotype. (samur2023childhoodonsetneurodegenerationwith pages 1-2, ashaat2024thediagnosticvalue pages 1-2, ashaat2024thediagnosticvalue pages 7-10)

Mechanistically, authoritative experimental work supports tubulin hyperglutamylation—not nonspecific neuroinflammation—as the upstream actionable lesion. Magiera and colleagues concluded that excessive polyglutamylation is a “cell-autonomous mechanism for neurodegeneration,” while the Shashi cohort linked this directly to human CCP1 deficiency. The most rational therapeutic directions are therefore early AGTPBP1 replacement or controlled reduction of TTLL1-dependent glutamylation. Both remain experimental, and intervention may need to precede irreversible Purkinje-cell and motor-neuron loss. (magiera2018excessivetubulinpolyglutamylation pages 1-2, shashi2018lossoftubulin pages 1-2)

Evidence and data gaps

Reliable prevalence/incidence, longitudinal natural-history curves, complete variant penetrance, carrier frequencies, formal genotype–phenotype models, standardized quality-of-life outcomes, fluid biomarkers, patient omics, validated staging criteria, clinical guidelines, and controlled treatment studies are unavailable. Exact phenotype frequencies should be updated through an international registry using uniform HPO phenotyping, serial MRI, motor/respiratory scales, and centralized variant curation. The most urgent translational needs are a prospective natural-history cohort, pharmacodynamic biomarkers of tubulin polyglutamylation, and safety studies for gene replacement or TTLL1-directed therapy.

References

(shashi2018lossoftubulin pages 1-2): Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik‐Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, Luca Bartesaghi, Patrizia De Marco, Ahmed A Alfares, Ronit Marom, Stefan T Arold, Francisco J Guzmán‐Vega, Loren DM Pena, Edward C Smith, Maja Steinlin, Mohamed OE Babiker, Payam Mohassel, A Reghan Foley, Sandra Donkervoort, Rupleen Kaur, Partha S Ghosh, Valentina Stanley, Damir Musaev, Caroline Nava, Cyril Mignot, Boris Keren, Marcello Scala, Elisa Tassano, Paolo Picco, Paola Doneda, Chiara Fiorillo, Mahmoud Y Issa, Ali Alassiri, Ahmed Alahmad, Amanda Gerard, Pengfei Liu, Yaping Yang, Birgit Ertl‐Wagner, Peter G Kranz, Ingrid M Wentzensen, Rolf Stucka, Nicholas Stong, Andrew S Allen, David B Goldstein, Benedikt Schoser, Kai M Rösler, Majid Alfadhel, Valeria Capra, Roman Chrast, Tim M Strom, Erik‐Jan Kamsteeg, Carsten G Bönnemann, Joseph G Gleeson, Rudolf Martini, Carsten Janke, and Jan Senderek. Loss of tubulin deglutamylase ccp1 causes infantile‐onset neurodegeneration. The EMBO Journal, Nov 2018. URL: https://doi.org/10.15252/embj.2018100540, doi:10.15252/embj.2018100540. This article has 152 citations.
(shashi2018lossoftubulin pages 2-4): Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik‐Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, Luca Bartesaghi, Patrizia De Marco, Ahmed A Alfares, Ronit Marom, Stefan T Arold, Francisco J Guzmán‐Vega, Loren DM Pena, Edward C Smith, Maja Steinlin, Mohamed OE Babiker, Payam Mohassel, A Reghan Foley, Sandra Donkervoort, Rupleen Kaur, Partha S Ghosh, Valentina Stanley, Damir Musaev, Caroline Nava, Cyril Mignot, Boris Keren, Marcello Scala, Elisa Tassano, Paolo Picco, Paola Doneda, Chiara Fiorillo, Mahmoud Y Issa, Ali Alassiri, Ahmed Alahmad, Amanda Gerard, Pengfei Liu, Yaping Yang, Birgit Ertl‐Wagner, Peter G Kranz, Ingrid M Wentzensen, Rolf Stucka, Nicholas Stong, Andrew S Allen, David B Goldstein, Benedikt Schoser, Kai M Rösler, Majid Alfadhel, Valeria Capra, Roman Chrast, Tim M Strom, Erik‐Jan Kamsteeg, Carsten G Bönnemann, Joseph G Gleeson, Rudolf Martini, Carsten Janke, and Jan Senderek. Loss of tubulin deglutamylase ccp1 causes infantile‐onset neurodegeneration. The EMBO Journal, Nov 2018. URL: https://doi.org/10.15252/embj.2018100540, doi:10.15252/embj.2018100540. This article has 152 citations.
(bodakuntla2021distinctrolesof pages 1-2): Satish Bodakuntla, Xidi Yuan, Mariya Genova, Sudarshan Gadadhar, Sophie Leboucher, Marie‐Christine Birling, Dennis Klein, Rudolf Martini, Carsten Janke, and Maria M Magiera. Distinct roles of α‐ and β‐tubulin polyglutamylation in controlling axonal transport and in neurodegeneration. The EMBO Journal, Jul 2021. URL: https://doi.org/10.15252/embj.2021108498, doi:10.15252/embj.2021108498. This article has 70 citations.
(magiera2018excessivetubulinpolyglutamylation pages 1-2): Maria M Magiera, Satish Bodakuntla, Jakub Žiak, Sabrina Lacomme, Patricia Marques Sousa, Sophie Leboucher, Torben J Hausrat, Christophe Bosc, Annie Andrieux, Matthias Kneussel, Marc Landry, André Calas, Martin Balastik, and Carsten Janke. Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport. The EMBO Journal, Nov 2018. URL: https://doi.org/10.15252/embj.2018100440, doi:10.15252/embj.2018100440. This article has 183 citations.
(OpenTargets Search: Neurodegeneration childhood-onset with cerebellar atrophy): Open Targets Query (Neurodegeneration childhood-onset with cerebellar atrophy, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(baltanas2021thechildhoodonsetneurodegeneration pages 7-9): F Calvo Baltanás, MT Berciano, E Santos, and M Lafarga. The childhood-onset neurodegeneration with cerebellar atrophy (condca) disease caused by agtpbp1 gene mutations: the purkinje cell degeneration …. Unknown journal, 2021.
(baltanas2021thechildhoodonsetneurodegeneration pages 9-10): F Calvo Baltanás, MT Berciano, E Santos, and M Lafarga. The childhood-onset neurodegeneration with cerebellar atrophy (condca) disease caused by agtpbp1 gene mutations: the purkinje cell degeneration …. Unknown journal, 2021.
(baltanas2021thechildhoodonsetneurodegeneration pages 6-7): F Calvo Baltanás, MT Berciano, E Santos, and M Lafarga. The childhood-onset neurodegeneration with cerebellar atrophy (condca) disease caused by agtpbp1 gene mutations: the purkinje cell degeneration …. Unknown journal, 2021.
(ashaat2024thediagnosticvalue pages 1-2): Engy A. Ashaat, Hoda A. Ahmed, Nesma M. Elaraby, Alaaeldin Fayez, Ammal M. Metwally, Mona K. Mekkawy, Dalia Farouk Hussen, Neveen A. Ashaat, Rasha M. Elhossini, Heba Ahmed ElAwady, Randa H. A. Abdelgawad, Mona El Gammal, Mohamed Ahmed Al Kersh, and Dina Amin Saleh. The diagnostic value of whole-exome sequencing in a spectrum of rare neurological disorders associated with cerebellar atrophy. Molecular Neurobiology, 61:4949-4961, Dec 2024. URL: https://doi.org/10.1007/s12035-023-03866-y, doi:10.1007/s12035-023-03866-y. This article has 5 citations and is from a peer-reviewed journal.
(ashaat2024thediagnosticvalue pages 7-10): Engy A. Ashaat, Hoda A. Ahmed, Nesma M. Elaraby, Alaaeldin Fayez, Ammal M. Metwally, Mona K. Mekkawy, Dalia Farouk Hussen, Neveen A. Ashaat, Rasha M. Elhossini, Heba Ahmed ElAwady, Randa H. A. Abdelgawad, Mona El Gammal, Mohamed Ahmed Al Kersh, and Dina Amin Saleh. The diagnostic value of whole-exome sequencing in a spectrum of rare neurological disorders associated with cerebellar atrophy. Molecular Neurobiology, 61:4949-4961, Dec 2024. URL: https://doi.org/10.1007/s12035-023-03866-y, doi:10.1007/s12035-023-03866-y. This article has 5 citations and is from a peer-reviewed journal.
(turay2021anovelpathogenic pages 1-2): Sevim Türay, Recep Eröz, and A. Nazlı Başak. A novel pathogenic variant in the 3ʹ end of the agtpbp1 gene gives rise to neurodegeneration without cerebellar atrophy: an expansion of the disease phenotype? neurogenetics, 22:127-132, Apr 2021. URL: https://doi.org/10.1007/s10048-021-00643-8, doi:10.1007/s10048-021-00643-8. This article has 16 citations and is from a peer-reviewed journal.
(samur2023childhoodonsetneurodegenerationwith pages 1-2): Bahadir M. Samur, Gulhan A. Ercan-Sencicek, Ahmet Okay Caglayan, Huseyin Per, Hakan Gumus, Gulsum Gumus, and Ali Baykan. Childhood-onset neurodegeneration with cerebellar atrophy syndrome: severe neuronal degeneration and cardiomyopathy with loss of tubulin deglutamylase cytosolic carboxypeptidase 1. Aug 2023. URL: https://doi.org/10.1055/s-0042-1749669, doi:10.1055/s-0042-1749669. This article has 1 citations and is from a peer-reviewed journal.
(ashaat2024thediagnosticvalue pages 10-11): Engy A. Ashaat, Hoda A. Ahmed, Nesma M. Elaraby, Alaaeldin Fayez, Ammal M. Metwally, Mona K. Mekkawy, Dalia Farouk Hussen, Neveen A. Ashaat, Rasha M. Elhossini, Heba Ahmed ElAwady, Randa H. A. Abdelgawad, Mona El Gammal, Mohamed Ahmed Al Kersh, and Dina Amin Saleh. The diagnostic value of whole-exome sequencing in a spectrum of rare neurological disorders associated with cerebellar atrophy. Molecular Neurobiology, 61:4949-4961, Dec 2024. URL: https://doi.org/10.1007/s12035-023-03866-y, doi:10.1007/s12035-023-03866-y. This article has 5 citations and is from a peer-reviewed journal.
(perezrevuelta2025neuroprotectiveeffectsof pages 1-2): Laura Pérez-Revuelta, David Pérez-Boyero, Ester Pérez-Martín, Valeria Lorena Cabedo, Pablo González Téllez de Meneses, Eduardo Weruaga, David Díaz, and José Ramón Alonso. Neuroprotective effects of vegf-b in a murine model of aggressive neuronal loss with childhood onset. Jan 2025. URL: https://doi.org/10.3390/ijms26020538, doi:10.3390/ijms26020538. This article has 4 citations.
(perezrevuelta2025neuroprotectiveeffectsof pages 4-7): Laura Pérez-Revuelta, David Pérez-Boyero, Ester Pérez-Martín, Valeria Lorena Cabedo, Pablo González Téllez de Meneses, Eduardo Weruaga, David Díaz, and José Ramón Alonso. Neuroprotective effects of vegf-b in a murine model of aggressive neuronal loss with childhood onset. Jan 2025. URL: https://doi.org/10.3390/ijms26020538, doi:10.3390/ijms26020538. This article has 4 citations.
(perezrevuelta2025neuroprotectiveeffectsof pages 10-12): Laura Pérez-Revuelta, David Pérez-Boyero, Ester Pérez-Martín, Valeria Lorena Cabedo, Pablo González Téllez de Meneses, Eduardo Weruaga, David Díaz, and José Ramón Alonso. Neuroprotective effects of vegf-b in a murine model of aggressive neuronal loss with childhood onset. Jan 2025. URL: https://doi.org/10.3390/ijms26020538, doi:10.3390/ijms26020538. This article has 4 citations.
(perezrevuelta2025neuroprotectiveeffectsof pages 19-20): Laura Pérez-Revuelta, David Pérez-Boyero, Ester Pérez-Martín, Valeria Lorena Cabedo, Pablo González Téllez de Meneses, Eduardo Weruaga, David Díaz, and José Ramón Alonso. Neuroprotective effects of vegf-b in a murine model of aggressive neuronal loss with childhood onset. Jan 2025. URL: https://doi.org/10.3390/ijms26020538, doi:10.3390/ijms26020538. This article has 4 citations.
(shashi2018lossoftubulin pages 6-7): Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik‐Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, Luca Bartesaghi, Patrizia De Marco, Ahmed A Alfares, Ronit Marom, Stefan T Arold, Francisco J Guzmán‐Vega, Loren DM Pena, Edward C Smith, Maja Steinlin, Mohamed OE Babiker, Payam Mohassel, A Reghan Foley, Sandra Donkervoort, Rupleen Kaur, Partha S Ghosh, Valentina Stanley, Damir Musaev, Caroline Nava, Cyril Mignot, Boris Keren, Marcello Scala, Elisa Tassano, Paolo Picco, Paola Doneda, Chiara Fiorillo, Mahmoud Y Issa, Ali Alassiri, Ahmed Alahmad, Amanda Gerard, Pengfei Liu, Yaping Yang, Birgit Ertl‐Wagner, Peter G Kranz, Ingrid M Wentzensen, Rolf Stucka, Nicholas Stong, Andrew S Allen, David B Goldstein, Benedikt Schoser, Kai M Rösler, Majid Alfadhel, Valeria Capra, Roman Chrast, Tim M Strom, Erik‐Jan Kamsteeg, Carsten G Bönnemann, Joseph G Gleeson, Rudolf Martini, Carsten Janke, and Jan Senderek. Loss of tubulin deglutamylase ccp1 causes infantile‐onset neurodegeneration. The EMBO Journal, Nov 2018. URL: https://doi.org/10.15252/embj.2018100540, doi:10.15252/embj.2018100540. This article has 152 citations.
(baltanas2021thechildhoodonsetneurodegeneration pages 19-21): F Calvo Baltanás, MT Berciano, E Santos, and M Lafarga. The childhood-onset neurodegeneration with cerebellar atrophy (condca) disease caused by agtpbp1 gene mutations: the purkinje cell degeneration …. Unknown journal, 2021.
(baltanas2021thechildhoodonsetneurodegeneration pages 21-22): F Calvo Baltanás, MT Berciano, E Santos, and M Lafarga. The childhood-onset neurodegeneration with cerebellar atrophy (condca) disease caused by agtpbp1 gene mutations: the purkinje cell degeneration …. Unknown journal, 2021.
(baltanas2021thechildhoodonsetneurodegeneration pages 1-2): F Calvo Baltanás, MT Berciano, E Santos, and M Lafarga. The childhood-onset neurodegeneration with cerebellar atrophy (condca) disease caused by agtpbp1 gene mutations: the purkinje cell degeneration …. Unknown journal, 2021.
(baltanas2021thechildhoodonsetneurodegeneration pages 18-19): F Calvo Baltanás, MT Berciano, E Santos, and M Lafarga. The childhood-onset neurodegeneration with cerebellar atrophy (condca) disease caused by agtpbp1 gene mutations: the purkinje cell degeneration …. Unknown journal, 2021.
(ashaat2024thediagnosticvalue pages 4-5): Engy A. Ashaat, Hoda A. Ahmed, Nesma M. Elaraby, Alaaeldin Fayez, Ammal M. Metwally, Mona K. Mekkawy, Dalia Farouk Hussen, Neveen A. Ashaat, Rasha M. Elhossini, Heba Ahmed ElAwady, Randa H. A. Abdelgawad, Mona El Gammal, Mohamed Ahmed Al Kersh, and Dina Amin Saleh. The diagnostic value of whole-exome sequencing in a spectrum of rare neurological disorders associated with cerebellar atrophy. Molecular Neurobiology, 61:4949-4961, Dec 2024. URL: https://doi.org/10.1007/s12035-023-03866-y, doi:10.1007/s12035-023-03866-y. This article has 5 citations and is from a peer-reviewed journal.

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References weighed for topical relevance	9
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Neurodegeneration, Childhood-Onset, with Cerebellar Atrophy (CONDCA): Disease-Characteristics Report

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