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Inheritance

1

Autosomal recessive HP:0000007

Biallelic TECPR2 variants. The founder allele c.3416delT was identified homozygously in Jewish Bukharian families; subsequent patients from unrelated non-Bukharian families carry other alleles, so the disorder is not restricted to that population.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:36137062 SUPPORT Human Clinical

"TECPR2-HSAN with ID is inherited in an autosomal recessive manner."

GeneReviews states the inheritance pattern.

PMID:23176824 SUPPORT Human Clinical

"Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein."

The original homozygous founder allele establishing recessive inheritance.

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Discussions and Knowledge Gaps

2

Does TECPR2 loss block autophagosome formation or autophagosome clearance? The published readouts point in opposite directions, and the answer determines what a therapeutic readout should even measure.

KNOWLEDGE GAP tecpr2_autophagy_direction_conflict

Attached to

pathophysiology#Impaired Autophagosome Formation and Cargo Delivery pathophysiology#Endolysosomal Dysfunction and Impaired Microglial Clearance

The original patient-fibroblast study found reduced LC3-II and reduced SQSTM1/p62 with attenuated delivery of both to the lysosome - a pattern consistent with a defect at autophagosome formation, since a pure clearance block would make p62 accumulate. Every in vivo model reports the opposite: autophagosomes pile up in axonal spheroids in the Spanish Water Dog and in the medulla and dorsal columns of the Tecpr2 knockout mouse, and the mouse authors read this as compromised targeting to the lysosome. The mechanistic work adds a third strand, placing TECPR2 at ER exit sites where it would act upstream at formation. These are not obviously reconcilable. Possible explanations include a cell-type difference between fibroblasts and neurons, a difference between an early formation defect and a late accumulation of stalled structures over years of neuronal life, or an artefact of measuring steady-state levels rather than flux. A fourth possibility has since appeared and is the most economical of the set: that neither reading is the whole story because TECPR2 also has a HOPS-dependent role in endolysosome maintenance, curated here as its own node. A protein required both at ER exit sites and at endolysosomal tethering would produce formation-like readouts in one assay and clearance-like readouts in another without either being an artefact. This does not resolve the conflict - nobody has measured flux in a system where both functions are separable - but it reframes it, and it is the explanation a new experiment should be designed against. The practical consequence is unchanged and concrete: an ASO or other therapy would need a validated autophagy readout, and it is currently unclear whether increased or decreased LC3-II should count as rescue.

Show evidence (4 references)

PMID:23176824 SUPPORT In Vitro

"found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II)"

The patient-fibroblast finding - decreased, not accumulated, autophagy markers.

PMID:33218264 REFUTE Model Organism

"Age-dependent correlation with accumulation of autophagosomes suggests compromised targeting to lysosome."

Graded REFUTE against the formation-defect reading - the mouse shows accumulation and the authors interpret it as a clearance defect, the opposite direction.

PMID:26431026 SUPPORT In Vitro

"TECPR2 and LC3C are required for autophagosome formation, possibly through maintaining functional ERES."

Independent mechanistic support for a defect at formation rather than clearance.

+ 1 more reference

Should MONDO:0014016 continue to be labelled a hereditary spastic paraplegia when the accumulated phenotype data identify sensory-autonomic neuropathy with intellectual disability as the dominant burden and do not list spasticity among core manifestations?

KNOWLEDGE GAP tecpr2_disease_name_mismatch

Attached to

pathophysiology#Corticospinal Axonopathy phenotypes#Spastic Paraplegia

This is a nomenclature problem with clinical consequences, not a filing dispute. The SPG49 name came from a single five-patient founder family in 2012. Three independent lines of evidence since then point the other way: the authors of the second patient series proposed reclassification as a hereditary sensory-autonomic neuropathy; the largest phenotyping cohort's core manifestation list omits spasticity; and the canine TECPR2 model's spinal lesions spare the motor pathways. A clinician searching under a spastic paraplegia label may not think to monitor for central hypoventilation, and apnea is a leading cause of death here. What is genuinely unresolved is whether the corticospinal involvement is a real but minor component or an artefact of the founder cohort's particular presentation - answering that needs prospective natural history data with systematic pyramidal examination, which the largest cohort explicitly sets up but does not yet provide.

Show evidence (2 references)

PMID:26542466 SUPPORT Human Clinical

"We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy."

The explicit reclassification proposal from the second patient series.

PMID:33847017 SUPPORT Human Clinical

"This sets the stage for future prospective natural history studies."

The largest cohort identifies prospective natural history data as the missing piece, which is what would settle the weight of the corticospinal component.

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Pathophysiology

6

TECPR2 Loss of Function

Biallelic TECPR2 variants reduce or abolish the protein. The founder allele is a 1 bp frameshift deletion producing a premature stop codon and predicted protein degradation. Missense variants make up nearly half of the disease-associated alleles and cluster in the N- and C-terminal beta-propeller repeat regions, which is also why classifying them under ACMG criteria is difficult.

TECPR2 hgnc:19957

Downstream

Destabilised COPII Coat and ER Exit Site Failure

Impaired Autophagosome Formation and Cargo Delivery

Endolysosomal Dysfunction and Impaired Microglial Clearance

Show evidence (2 references)

PMID:23176824 SUPPORT Human Clinical

"a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein"

Establishes the founder allele as a predicted null.

PMID:33847017 SUPPORT Human Clinical

"Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing beta-propeller repeats."

Maps the missense allele spectrum onto the beta-propeller domains.

Destabilised COPII Coat and ER Exit Site Failure

TECPR2 binds trafficking components including the COPII coat protein SEC24D and is required to stabilise SEC24D protein levels and maintain functional endoplasmic reticulum exit sites. This is not an inference from cell lines alone - TECPR2-deficient patient cells show altered SEC24D abundance and reduced ER export efficiency. The dependence runs through lipidated LC3C, which is what makes TECPR2 a scaffold joining the early secretory pathway to autophagy rather than a component of either alone.

endoplasmic reticulum to Golgi vesicle-mediated transport GO:0006888 ↓ DECREASED COPII-coated vesicle budding GO:0090114 ↓ DECREASED

endoplasmic reticulum exit site GO:0070971

Downstream

Impaired Autophagosome Formation and Cargo Delivery

Show evidence (3 references)

PMID:26431026 SUPPORT In Vitro

"TECPR2 is required for stabilization of SEC24D protein levels, maintenance of functional ER exit sites (ERES), and efficient ER export in a manner dependent on binding to lipidated LC3C."

Defines the COPII/ERES arm of TECPR2 function and its LC3C dependence.

PMID:26431026 SUPPORT In Vitro

"TECPR2-deficient HSP patient cells display alterations in SEC24D abundance and ER export efficiency."

Confirms the defect in patient-derived cells, not only in knockdown models.

PMID:26431026 SUPPORT In Vitro

"these results reveal that TECPR2 functions as molecular scaffold linking early secretion pathway and autophagy"

States the scaffold role that couples this node to the autophagy node.

Impaired Autophagosome Formation and Cargo Delivery

TECPR2 is an ATG8-binding positive regulator of autophagy. Patient fibroblasts show reduced SQSTM1/p62 and MAP1LC3B, with a more pronounced fall in the lipidated LC3-II form, and attenuated delivery of both LC3B and p62 to the lysosome where they are normally degraded. siRNA knockdown reproduces the same changes. Note the direction: p62 falls rather than accumulating, which is not the pattern of a simple block in autophagosome-lysosome fusion and is consistent instead with a defect upstream, at autophagosome formation.

macroautophagy GO:0016236 ↓ DECREASED autophagosome assembly GO:0000045 ↓ DECREASED

autophagosome GO:0005776

Animal models

Tecpr2 CRISPR-Cas9 knockout mouse Mouse recapitulates Autophagosome accumulation in affected CNS regions, interpreted by the authors as compromised targeting of autophagosomes to the lysosome.

Spanish Water Dog TECPR2 neuroaxonal dystrophy Dog recapitulates Provides the tissue-level correlate that human patient fibroblast studies cannot: autophagosome accumulation within axonal spheroids in an intact nervous system.

Downstream

Sensory and Autonomic Neuron Degeneration

Corticospinal Axonopathy

Show evidence (6 references)

PMID:23176824 SUPPORT In Vitro

"found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II)"

The primary cellular autophagy phenotype in patient fibroblasts.

PMID:23176824 SUPPORT In Vitro

"siRNA knockdown of TECPR2 showed similar changes, consistent with aberrant autophagy."

Knockdown reproduces the patient-cell phenotype, supporting causality.

PMID:23439247 SUPPORT In Vitro

"an attenuated delivery of both LC3B and the cargo-recruiting protein SQSTM1/p62 to the lysosome where they are subject to degradation"

Specifies the delivery defect underlying the reduced autophagic flux.

+ 3 more references

Endolysosomal Dysfunction and Impaired Microglial Clearance

A 2025 knock-in mouse carrying a disease-associated nonsense mutation identifies a second TECPR2 function: it interacts with the HOPS tethering complex, and its loss gives endolysosomal dysfunction in neurons. This node is curated as a sibling of the autophagosome-formation node rather than downstream of it, and the topology is the claim. The paper establishes a distinct HOPS-dependent role in endolysosome maintenance; it does not show that this lesion is a consequence of failed autophagosome formation. Drawing the serial edge would assert a sequence the source does not support. If a study later shows the endolysosomal defect follows from the formation defect, the edge is the change to make. The same model adds a second cell type to the mechanism. Damage-associated microglia respond to the dying neurons but their capacity to clear the debris is itself attenuated, so the disease is not purely neuron-autonomous - a failure to remove degenerating material sits alongside the failure that produces it. The pathology is strikingly region-specific, concentrated in the medulla, which is where the fatal autonomic and respiratory phenotypes would be expected to originate. That regional restriction is curated as an observation rather than as an explanation; why a ubiquitously expressed protein produces a lesion confined to one brain region is the model's central unanswered question.

neuron CL:0000540 microglial cell CL:0000129

lysosomal transport GO:0007041 ↓ DECREASED

Animal models

Tecpr2 L1152Yfs knock-in mouse Mouse recapitulates The model that establishes this node. Neuronal and microglial readouts converge on a dysfunctional endolysosomal system, and the HOPS interaction supplies the molecular basis.

Downstream

Sensory and Autonomic Neuron Degeneration

Show evidence (4 references)

PMID:41173829 SUPPORT Model Organism

"Overall, neuronal and microglia phenotypes point to a dysfunctional endolysosomal system when TECPR2 is missing."

The authors' summary of the lesion this node names.

PMID:41173829 SUPPORT In Vitro

"This was confirmed in TECPR2 knockout cells and linked to TECPR2's interaction with the homotypic fusion and protein sorting (HOPS)-tethering complex."

The molecular interaction behind the phenotype, in knockout cells. Graded IN_VITRO because the confirmation quoted is a cell experiment, unlike the mouse observations cited alongside it.

PMID:41173829 SUPPORT Model Organism

"However, their capacity to clear neuronal debris seems attenuated."

The microglial half of the node, and the reason the mechanism is not purely neuron-autonomous.

+ 1 more reference

Sensory and Autonomic Neuron Degeneration

The dominant clinical burden. Sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait combines with autonomic failure - central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia and gastroesophageal reflux with recurrent aspiration. This is why the disorder is now classified as a hereditary sensory-autonomic neuropathy rather than as a spastic paraplegia, and why apnea and asphyxia are the leading causes of death.

sensory neuron CL:0000101

Animal models

Tecpr2 CRISPR-Cas9 knockout mouse Mouse partially recapitulates Degeneration is concentrated in the gracile and cuneate nuclei and dorsal columns - the sensory relay pathways - matching the sensory limb of the human disorder, and in the medulla, the site relevant to respiratory control.

Tecpr2 L1152Yfs knock-in mouse Mouse partially recapitulates Gait ataxia and medullary degeneration match the sensory and brainstem limb of the human disorder, in an allele of the type patients actually carry.

Spanish Water Dog TECPR2 neuroaxonal dystrophy Dog partially recapitulates The canine lesions involve the sensory pathways of the spinal cord, matching the sensory limb of the human disorder.

Downstream

Hyporeflexia

Ataxia

Abnormal Autonomic Nervous System Physiology

Central Hypoventilation

Apnea

Gastrointestinal Dysmotility

Dysphagia

Gastroesophageal Reflux

Show evidence (3 references)

PMID:36137062 SUPPORT Human Clinical

"neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration)"

GeneReviews definition of the sensory and autonomic core of the phenotype.

PMID:26542466 SUPPORT Human Clinical

"the main disabling feature of this unique disorder is autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events"

Identifies autonomic-sensory neuropathy, not spasticity, as the main disabling feature.

PMID:26542466 SUPPORT Human Clinical

"We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy."

The explicit reclassification proposal that the current disease name reflects.

Corticospinal Axonopathy

The feature the SPG49 name was built on. Hereditary spastic paraplegias are defined by axonopathy of the corticospinal motor neurons, and spasticity does evolve in patients. It is curated here as a real but secondary component: the largest phenotyping cohort does not list spasticity among the core manifestations, and the canine TECPR2 model's spinal cord lesions spare the motor pathways that most human HSPs involve.

motor neuron CL:0000100

corticospinal tract UBERON:0002707

Animal models

Spanish Water Dog TECPR2 neuroaxonal dystrophy Dog fails to recapitulate The canine disease does not reproduce the corticospinal motor involvement that the HSP classification of the human disorder asserts.

Downstream

Spastic Paraplegia

Show evidence (2 references)

PMID:26431026 SUPPORT Human Clinical

"Hereditary spastic paraplegias (HSPs) are a diverse group of neurodegenerative diseases that are characterized by axonopathy of the corticospinal motor neurons."

Defines the corticospinal lesion that the HSP classification asserts.

PMID:26542466 SUPPORT Human Clinical

"in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy"

Graded PARTIAL deliberately. It confirms spasticity is real and evolving, while subordinating it to the autonomic-sensory neuropathy - which is exactly the secondary status this node claims.

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Pathograph

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Phenotypes

15

Digestive 2

Gastroesophageal Reflux VERY_FREQUENT HP:0002020

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration"

GeneReviews describes reflux with aspiration as part of the autonomic dysfunction.

Dysphagia FREQUENT HP:0002015

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration"

GeneReviews lists dysphagia among the autonomic gastrointestinal features.

Immune 1

Recurrent Respiratory Infections VERY_FREQUENT HP:0002205

Show evidence (1 reference)

PMID:33847017 SUPPORT Human Clinical

"muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations"

Lists respiratory infections among the core manifestations.

Musculoskeletal 2

Muscular Hypotonia VERY_FREQUENT HP:0001252

Show evidence (1 reference)

PMID:33847017 SUPPORT Human Clinical

"global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations"

Lists muscular hypotonia among the core manifestations.

Spastic Paraplegia FREQUENT HP:0001258

Not listed among the core manifestations in PMID:33847017's 28-individual analysis. Graded FREQUENT rather than VERY_FREQUENT for that reason. The first reported Chinese patient (PMID:35130874) illustrates how far the phenotype can depart from the founder description: normal development until age 10, no reflux, and no abnormal breathing during sleep, with paroxysmal hyperthermia and seizures dominating instead.

Show evidence (2 references)

PMID:23176824 SUPPORT Human Clinical

"We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis"

The original description on which the spastic paraplegia classification rests.

PMID:26542466 SUPPORT Human Clinical

"in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy"

Confirms spasticity while explicitly subordinating it, which is the basis for grading it below the sensory-autonomic features.

Nervous System 4

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:36137062 SUPPORT Human Clinical

"is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities"

GeneReviews states developmental delay and intellectual disability as defining features.

PMID:33847017 SUPPORT Human Clinical

"A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations."

Places developmental delay/intellectual disability first among core manifestations in the largest cohort.

Ataxia VERY_FREQUENT HP:0001251

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait"

GeneReviews describes the ataxic gait in the context of sensory neuropathy.

Atypical Behavior FREQUENT HP:0000708

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with..."

Behavioral abnormalities in the GeneReviews characterisation sentence, alongside the developmental and neurologic features.

Abnormal Autonomic Nervous System Physiology VERY_FREQUENT HP:0012332

Show evidence (1 reference)

PMID:26542466 SUPPORT Human Clinical

"autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events"

Documents paroxysmal autonomic events and chronic respiratory disease.

Respiratory 3

Central Hypoventilation VERY_FREQUENT HP:0007110

The original description quotes "gastresophageal" - a typographical error in the source abstract, preserved because snippets must be exact substrings of the cached reference.

Show evidence (2 references)

PMID:23176824 SUPPORT Human Clinical

"hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features"

Central hypoventilation in the original description of the disorder.

PMID:33847017 SUPPORT Human Clinical

"respiratory infections, and central/nocturnal hypopnea as core manifestations"

Confirms central/nocturnal hypopnea as a core manifestation in the largest cohort.

Apnea FREQUENT HP:0002104

Bound to Apnea (HP:0002104), not Sleep apnea (HP:0010535). The sources describe apnea as part of autonomic dysfunction and record wake apnea, so restricting the binding to the sleep-related child would assert a narrower claim than any of them makes. If a source is later found that separates sleep-related from wake apnea in this disorder, splitting into two phenotypes is the right move; asserting the split now would not be supported.

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"minimize risk for apnea and asphyxia, the two most common causes of death"

GeneReviews names apnea and asphyxia as the leading causes of death, establishing both the phenotype and its clinical weight.

Aspiration FREQUENT HP:0002835

Temporal: RECURRENT

Sequelae: Recurrent Respiratory Infections

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with..."

Recurrent aspiration named as a feature of the gastroesophageal reflux disease in the GeneReviews characterisation sentence.

Other 3

Hyporeflexia VERY_FREQUENT HP:0001265

Show evidence (2 references)

PMID:33847017 SUPPORT Human Clinical

"muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations"

Lists hyporeflexia among the core manifestations.

PMID:23176824 SUPPORT Human Clinical

"severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features"

Areflexia recorded in the original five-patient description.

Gastrointestinal Dysmotility FREQUENT HP:0002579

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with..."

Gastrointestinal dysmotility named in the autonomic-dysfunction list of the GeneReviews characterisation sentence.

Thin Corpus Callosum FREQUENT HP:0033725

Show evidence (1 reference)

PMID:33847017 SUPPORT Human Clinical

"A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%."

Quantifies the imaging finding at 52%, supporting the FREQUENT grading.

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Genetic Associations

1

TECPR2

Gene: TECPR2 hgnc:19957 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:23176824 SUPPORT Human Clinical

"The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis."

Original identification of TECPR2 as the causal gene.

PMID:33847017 SUPPORT Human Clinical

"Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging."

Documents the variant-interpretation difficulty central to diagnosing this disorder.

PMID:38436550 SUPPORT Human Clinical

"we reviewed previously published candidate TECPR2 missense variants to clarify clinical outcomes and variant classification using current approved guidelines, classifying a number of published variants as of uncertain significance"

Confirms that previously reported missense variants have been downgraded to VUS, which bears directly on how the literature's genotype claims should be read.

Variants (1)

c.3416delT

The founder frameshift allele identified homozygously in Jewish Bukharian families in the original 2012 description.

Show evidence (1 reference)

PMID:26542466 SUPPORT Human Clinical

"TECPR2 was first described as a disease causing gene when the c.3416delT frameshift mutation was found in five Jewish Bukharian patients with similar features."

Names the founder allele and its population of origin.

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Medical Actions

4

Multidisciplinary Supportive Care

Action: Supportive Care NCIT:C15747

There is no disease-modifying treatment. Management is supportive and explicitly aimed at reducing the risk of apnea and asphyxia, drawing on neurology, developmental and behavioural medicine, feeding, pulmonology, gastroenterology, orthopedics, ethics and medical genetics.

Show evidence (2 references)

PMID:36137062 SUPPORT Human Clinical

"Currently there are no specific disease-modifying treatments for TECPR2-HSAN with ID."

States the absence of disease-modifying therapy.

PMID:36137062 SUPPORT Human Clinical

"Supportive care can include multidisciplinary care by pediatric specialists in neurology, development, behavior, feeding, pulmonology, gastroenterology, orthopedics, ethics, and medical genetics."

Defines the composition of supportive care recommended by GeneReviews.

Genetic Counselling and Family Testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive counselling with a 25% recurrence risk for sibs, and carrier, prenatal or preimplantation testing once the familial variants are known. Counselling carries more weight in this disorder than the recurrence figure alone implies: the estimated carrier frequency in the Ashkenazi Jewish population is about 1 in 155, and unrelated non-founder patients have been identified as far afield as China, so the at-risk population is not confined to the families the disorder was first described in.

Show evidence (2 references)

PMID:36137062 SUPPORT Human Clinical

"If both parents are known to be heterozygous for a TECPR2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."

The recurrence risks that counselling communicates.

PMID:36137062 SUPPORT Human Clinical

"Once the TECPR2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."

The testing options counselling opens once the familial variants are known, which is what makes identifying them useful beyond the proband.

Avoidance of Respiratory Depressants

Action: Supportive Care NCIT:C15747

Drugs that cause decreased consciousness, hypopnea or CO2 retention - benzodiazepines and antihistamines are the named examples - are to be avoided, or used only at low doses with close monitoring. This follows directly from central hypoventilation being a core feature and apnea a leading cause of death.

Target Phenotypes: Central hypoventilation HP:0007110

Show evidence (1 reference)

PMID:36137062 SUPPORT Human Clinical

"Avoid drugs that cause decreased consciousness, hypopnea, and CO2 retention such as benzodiazepines or antihistamines; or if necessary, use at low doses with close monitoring."

GeneReviews Agents/Circumstances to Avoid, quoted directly.

TECPR2 Exon 8 Skipping Antisense Oligonucleotide (investigational)

Action: Pharmacotherapy NCIT:C15986

A preclinical, genotype-specific splice-modulation strategy - not an approved therapy. The c.1319delT (p.Leu440Argfs*19) frameshift creates a premature stop codon in exon 8. Because exon 8 encodes an unstructured 111-amino-acid region and is 333 nucleotides long, skipping it restores an in-frame TECPR2 retaining 1,300 of 1,411 residues. The lead candidate ASO-005-02 reached ~27 nM potency in patient fibroblasts, and the rescued protein kept the punctate neuronal distribution of full-length TECPR2 in iPSC-derived neurons - a surrogate for function, not a functional assay. A single 20 mg intrathecal dose in cynomolgus monkeys was tolerated with broad CNS distribution and detectable exon-8 skipping. Two limits are worth stating plainly. First, eligibility is narrow: the strategy only helps patients carrying an exon 8 mutation, which the authors estimate at up to a few hundred patients worldwide. Second, the chemistry recorded here (2'-O-methyl bases, phosphorothioate linkages) is what the source states for the initial 25-mer screening set; the optimized lead's final chemistry is not specified in the abstract or the quoted text, so treat the chemistry annotation as provisional.

Mechanism Target:

TECPR2 Loss of Function — Removes the premature termination codon by skipping the exon that contains it, restoring expression of a shortened but in-frame TECPR2 protein.

Show evidence (1 reference)

PMID:35860385 SUPPORT In Vitro

"TECPR2 exon 8 skipping restored in-frame expression of a TECPR2 protein variant (TECPR2ΔEx8) containing 1,300 of 1,411 amino acids."

Establishes that the ASO restores in-frame protein expression from the mutant allele.

Show evidence (4 references)

PMID:35860385 SUPPORT In Vitro

"Optimization of ASO sequences generated a lead candidate (ASO-005-02) with ∼27 nM potency in patient-derived fibroblasts."

Quantifies lead-candidate potency in patient-derived cells.

PMID:35860385 SUPPORT In Vitro

"we used iPSC-derived neurons to analyze the neuronal localization of TECPR2ΔEx8 and showed that this form of TECPR2 retains the distinct, punctate neuronal expression pattern of full-length TECPR2"

Graded PARTIAL - correct subcellular localization is a surrogate for function, not a demonstration that the truncated protein performs TECPR2's autophagy or ER-export role.

PMID:35860385 SUPPORT Model Organism

"ASO-005-02 had an acceptable tolerability profile in vivo following a single 20-mg intrathecal dose in cynomolgus monkeys, showing some transient non-adverse behavioral effects with no correlating histopathology"

Non-human primate tolerability and CNS delivery data supporting further development.

+ 1 more reference

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Diagnosis

1

Molecular genetic testing for biallelic TECPR2 variants

The diagnosis rests on biallelic pathogenic or likely pathogenic TECPR2 variants in a proband with suggestive findings. There is no biochemical or imaging test that establishes it. Two things make the molecular step harder than that sentence suggests: nearly half the disease-associated alleles are missense and cluster in the beta-propeller repeats, where ACMG classification is difficult, and the clinical picture overlaps familial dysautonomia closely enough that the disorder was originally described as a spastic paraplegia and later reclassified.

Show evidence (2 references)

PMID:36137062 SUPPORT Human Clinical

"The diagnosis of TECPR2-HSAN with ID is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TECPR2 identified by molecular genetic testing."

The GeneReviews diagnostic criterion.

PMID:33847017 SUPPORT Human Clinical

"Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing beta-propeller repeats."

Graded PARTIAL. It does not state a diagnostic criterion, but it identifies where the interpretive difficulty sits - a missense-heavy allele spectrum concentrated in two domains is exactly the situation in which variant classification, not variant detection, is the bottleneck.

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Prevalence

3

Worldwide (published cases)

Cases In Literature Ultra Rare

More than 30 individuals identified as of the GeneReviews chapter. The disorder was initially thought to be confined to Jewish Bukharian families, and the discovery of unrelated non-Bukharian patients suggests it is underdiagnosed rather than genuinely that restricted.

Show evidence (3 references)

PMID:36137062 SUPPORT Human Clinical

"To date, more than 30 individuals with TECPR2-HSAN with ID have been identified."

GeneReviews case count.

PMID:26542466 SUPPORT Human Clinical

"The discovery of additional mutations in non-Bukharian patients implies that this disease might be more common than previously appreciated"

Supports underdiagnosis rather than true restriction to one population.

PMID:35130874 SUPPORT Human Clinical

"The present case reports the first instance of HSP49 detected in China."

Extends the reported geographic range well beyond the founder population, consistent with underdiagnosis outside the populations where the disorder was first described.

Ashkenazi Jewish

Carrier Frequency 645.2 per 100,000 >1 in 1,000

Estimated pathogenic-variant carrier frequency of 1 in 155 in the Ashkenazi Jewish population, against 1 in 1221 in the general population. Note this is an estimate derived from variant data, not an observed carrier screen, and 1/155 is a strikingly high figure for a disorder with only ~30 reported patients - which is itself an argument that the condition is underdiagnosed or that some counted alleles are less penetrant than assumed. ABOVE_1_IN_1000 is the schema-correct band here, since 645.2 per 100,000 exceeds 100. See the general-population record below for the KB-wide question about whether disease-occurrence bands belong on carrier frequencies at all.

Show evidence (1 reference)

PMID:33847017 SUPPORT Human Clinical

"We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations."

Source of both carrier-frequency estimates.

General population

Carrier Frequency 81.9 per 100,000 1–9 per 10,000

Estimated pathogenic-variant carrier frequency of 1 in 1221 in the general population. Banded BAND_1_5_PER_10000, not ABOVE_1_IN_1000: 1 in 1221 is below 1 in 1000. Note the band name understates its range - PrevalenceClassEnum defines BAND_1_5_PER_10000 as 10-99 per 100,000, deliberately combining the Orphanet 1-5 and 6-9 classes so there is no gap between it and ABOVE_1_IN_1000, and _band_from_rate() buckets any rate at or above 10 into it. Read the enum description rather than the class name before concluding a rate falls between bands. A real question remains, and it is not specific to this entry: the Orphanet classes band disease occurrence, and a carrier frequency is not disease occurrence, so a reader filtering on the band will compare carrier rates against patient rates. That is a KB-wide convention question - 34 of 37 CARRIER_FREQUENCY records set a band - and it is not for one entry to answer by diverging. The band is set to the schema-correct value and the concern is recorded here.

Show evidence (1 reference)

PMID:33847017 SUPPORT Human Clinical

"We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations."

Source of the general-population carrier-frequency estimate.

🐁

Animal Models

3

Tecpr2 CRISPR-Cas9 knockout mouse

An engineered null model, complementing the naturally occurring canine missense model. It develops age-dependent neuroaxonal dystrophy concentrated in the gracile and cuneate nuclei of the medulla oblongata and the dorsal white matter column of the spinal cord, with autophagosome accumulation tracking the neurodegeneration.

Species

Mouse

Genotype

tecpr2-/- CRISPR-Cas9 knockout

Genes

TECPR2 hgnc:19957

Publication

PMID:33218264

Pathograph links

Impaired Autophagosome Formation and Cargo Delivery recapitulates fidelity: moderate Autophagosome accumulation in affected CNS regions, interpreted by the authors as compromised targeting of autophagosomes to the lysosome.

Limitations: The direction of the autophagy defect differs from the original patient-fibroblast report, which found decreased LC3-II and p62 rather than accumulation. Accumulation points to a downstream delivery or fusion block; depletion points to a defect at formation. The mouse cannot by itself settle which applies in human disease, and the two readings are not reconcilable as stated.

Readouts

Autophagosome accumulation in medulla oblongata and dorsal spinal tracts

Direction: INCREASED

Interpretation: Regional autophagosome accumulation co-localizing with neuroaxonal dystrophy.

Show evidence (1 reference)

PMID:33218264 SUPPORT Model Organism

"Age-dependent correlation with accumulation of autophagosomes suggests compromised targeting to lysosome."

The measurement and the authors' interpretation of it.

Show evidence (1 reference)

PMID:33218264 SUPPORT Model Organism

"our findings establish the tecpr2 knockout mouse as a potential model for SPG49 and ascribe a new role to TECPR2 in macroautophagy/autophagy-related neurodegenerative disorders"

The authors' claim that the model is informative for TECPR2-dependent autophagy.

Sensory and Autonomic Neuron Degeneration partially recapitulates fidelity: moderate Degeneration is concentrated in the gracile and cuneate nuclei and dorsal columns - the sensory relay pathways - matching the sensory limb of the human disorder, and in the medulla, the site relevant to respiratory control.

Limitations: The report describes behavioural pathologies and regional neurodegeneration but does not demonstrate the central hypoventilation or apnea that kill human patients. That medullary involvement is anatomically suggestive of a respiratory phenotype is an inference, not a measurement made here.

Show evidence (1 reference)

PMID:33218264 SUPPORT Model Organism

"manifested predominantly as neuroaxonal dystrophy in the gracile (GrN) and cuneate nuclei (CuN) of the medulla oblongata in the brainstem and dorsal white matter column of the spinal cord"

Localizes the degeneration to sensory relay and medullary structures; graded PARTIAL because no respiratory or autonomic function was measured.

Show evidence (1 reference)

PMID:33218264 SUPPORT Model Organism

"we report the generation of a novel CRISPR-Cas9 tecpr2 knockout (tecpr2-/-) mouse that exhibits behavioral pathologies observed in SPG49 patients"

Establishes the model and its claimed behavioural correspondence to patients.

Tecpr2 L1152Yfs knock-in mouse

A second, allele-specific mouse, generated to address a stated limitation of the knockout: a null cannot test whether a truncated mutant TECPR2 protein is itself toxic. The knock-in carries an HSAN9-associated nonsense allele rather than a deletion. It reproduces gait ataxia and the medullary axonal dystrophy seen in the knockout, and it is the source of the endolysosomal and microglial arm of this pathograph: proteomics and imaging of the affected medulla, damage-associated microglia with reduced clearance capacity, and a HOPS interaction mapped in TECPR2 knockout cells.

Species

Mouse

Genotype

Tecpr2 L1152Yfs homozygous knock-in (models human TECPR2 p.Leu1139Argfs*75)

Genes

TECPR2 hgnc:19957

Publication

PMID:41173829

Pathograph links

Endolysosomal Dysfunction and Impaired Microglial Clearance recapitulates fidelity: moderate The model that establishes this node. Neuronal and microglial readouts converge on a dysfunctional endolysosomal system, and the HOPS interaction supplies the molecular basis.

Limitations: Two limits bound what this model shows. The corresponding human lesion has been demonstrated only in patient fibroblasts and engineered knockout cells, not in patient nervous tissue, so the endolysosomal claim rests on a mouse plus human cell lines rather than on human neuropathology. And the design intent was only partly met: the knock-in was made so a truncated mutant protein could be tested for toxic gain-of-function, but TECPR2 was undetectable at the protein level, so functionally this remains a loss-of-expression model like the knockout.

Readouts

Medullary axonal swelling with regional neuronal loss

Direction: INCREASED

Interpretation: The anatomical lesion, restricted to the medulla, in which the altered organelle and protein homeostasis was measured.

Show evidence (1 reference)

PMID:41173829 SUPPORT Model Organism

"the presence of axonal swelling in a specific region of the medulla correlated with neuronal loss in this area"

Localizes the lesion and ties the swelling to actual neuronal loss.

Disease-associated microglia state with reduced endocytic capacity

Direction: ALTERED

Interpretation: Microglia respond to the neuronal damage but shift to a state with increased lysosomal protein content and decreased endocytosis - the reason this node treats clearance failure as part of the mechanism rather than as a reaction to it.

Show evidence (1 reference)

PMID:41173829 SUPPORT Model Organism

"The DAM state was confirmed by immunohistochemistry along with microglia proteomics and immunofluorescence which showed increased lysosomal proteins and a decrease in endocytic processes."

The measurements behind the microglial half of the node.

Show evidence (1 reference)

PMID:41173829 SUPPORT Model Organism

"Collectively, we uncovered a role of TECPR2 in endolysosome maintenance which seems relevant for healthy neurons in a particular brain region."

The authors' statement of what the model establishes.

Sensory and Autonomic Neuron Degeneration partially recapitulates fidelity: moderate Gait ataxia and medullary degeneration match the sensory and brainstem limb of the human disorder, in an allele of the type patients actually carry.

Limitations: The same gap as in the knockout: the medulla is the anatomically right place for the fatal respiratory phenotype, but no respiratory or autonomic function was measured, so the correspondence to central hypoventilation and apnea is inferred from location. The pathology is also strikingly region-restricted, and why a ubiquitously expressed protein produces a lesion confined to one region is unexplained by this model.

Readouts

Gait ataxia

Direction: ALTERED

Interpretation: The behavioural phenotype the authors match to the human presentation.

Show evidence (1 reference)

PMID:41173829 SUPPORT Model Organism

"Behavioral and phenotypic studies of these mice showed a gait ataxia phenotype as observed in HSAN9 patients and axonal dystrophy as observed in Tecpr2 KO mice."

Records the gait phenotype and its correspondence to patients.

Show evidence (1 reference)

PMID:41173829 SUPPORT Model Organism

"Mice show altered gait, highly region-specific axonal dystrophy, and extensive local gliosis."

Graded PARTIAL. The degeneration is real but its regional restriction is the model's own unexplained finding, so it supports the node without accounting for its distribution.

Show evidence (2 references)

PMID:41173829 SUPPORT Model Organism

"Here, we report a novel mouse model which harbors a HSAN9-associated nonsense mutation that causes loss of TECPR2 expression."

Establishes the model and what distinguishes it from the knockout - a patient-type nonsense allele rather than an engineered deletion.

PMID:41173829 SUPPORT Model Organism

"Tecpr2 KO mice do not faithfully recapitulate disease pathology induced by HSAN9-associated mutations since possible toxic gain-of-functions of TECPR2 mutant variants cannot be assessed in this model."

The authors' rationale for building this model, and the reason it is curated alongside the knockout rather than as a duplicate of it.

Spanish Water Dog TECPR2 neuroaxonal dystrophy

A naturally occurring, not engineered, juvenile-onset neuroaxonal dystrophy in Spanish Water Dogs, mapped to a homozygous TECPR2 missense variant at a highly conserved residue with autosomal recessive segregation. Histopathology shows spheroid formation in cerebral, cerebellar and brainstem grey matter and in the sensory pathways of the spinal cord, without iron accumulation, and the spheroids contain packed double-membraned vesicles identified as autophagosomes.

Species

Dog

Genotype

TECPR2 c.4009C>T (p.R1337W) homozygous

Genes

TECPR2 hgnc:19957

Publication

PMID:26555167

Pathograph links

Impaired Autophagosome Formation and Cargo Delivery recapitulates fidelity: moderate Provides the tissue-level correlate that human patient fibroblast studies cannot: autophagosome accumulation within axonal spheroids in an intact nervous system.

Limitations: A missense allele, not a null, so residual TECPR2 function is likely and the severity is not calibrated against human genotypes. The autophagosome identification is immunohistochemical and ultrastructural rather than a flux measurement, so it shows accumulation without establishing where in the pathway the block sits.

Readouts

Autophagosome content of axonal spheroids

Direction: INCREASED

Interpretation: Accumulated double-membraned vesicles within spheroids, consistent with disturbed autophagic turnover in vivo.

Show evidence (1 reference)

PMID:26555167 SUPPORT Model Organism

"Ultrastructurally spheroids contained predominantly closely packed vesicles with a double-layered membrane, which were characterized as autophagosomes using immunohistochemistry."

The ultrastructural and immunohistochemical basis for the readout.

Show evidence (1 reference)

PMID:26555167 SUPPORT Model Organism

"Immunohistochemistry and the ultrastructural findings further support the assumption, that TECPR2 regulates autophagosome accumulation in the autophagic pathways."

Supports the model as informative for TECPR2-dependent autophagy in vivo.

Sensory and Autonomic Neuron Degeneration partially recapitulates fidelity: moderate The canine lesions involve the sensory pathways of the spinal cord, matching the sensory limb of the human disorder.

Limitations: The published comparison notes the canine lesions spare the motor pathways that most human HSPs involve, and no autonomic phenotype - hypoventilation, apnea, GI dysmotility - is reported for the dogs. So the model covers the sensory limb of the human disease but not the autonomic one, which is the limb that drives human mortality.

Show evidence (1 reference)

PMID:26555167 SUPPORT Model Organism

"Histopathology demonstrated spheroid formation accentuated in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem and in the sensory pathways of the spinal cord."

Documents sensory pathway involvement, graded PARTIAL because the autonomic features of the human disease are not among the reported canine findings.

Corticospinal Axonopathy fails to recapitulate fidelity: low The canine disease does not reproduce the corticospinal motor involvement that the HSP classification of the human disorder asserts.

Limitations: The authors state directly that the canine lesions differ from most human HSPs in sparing the motor pathways. Note this cuts both ways as evidence: read as a model limitation it is a species difference, but read alongside the human cohort data showing spasticity is not a core manifestation, it is a point of agreement that the corticospinal component of this disorder is weaker than its SPG49 name implies.

Show evidence (1 reference)

PMID:26555167 SUPPORT Model Organism

"In contrast to the canine NAD, the spinal cord lesions in most types of human HSP involve the sensory and the motor pathways."

Explicit statement that the canine lesions do not involve the motor pathways.

Show evidence (2 references)

PMID:26555167 SUPPORT Model Organism

"a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W)"

Establishes the causal TECPR2 variant underlying the canine model.

PMID:26555167 SUPPORT Model Organism

"This canine NAD form displays etiologic parallels to an inherited TECPR2 associated type of human hereditary spastic paraparesis (HSP)."

The authors' own statement of the model's relevance to the human disorder.

{ }

Source YAML

click to show

name: Hereditary Spastic Paraplegia 49
category: Mendelian
creation_date: "2026-08-27T00:00:00Z"
synonyms:
- SPG49
- TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability
- TECPR2-HSAN with ID
- Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay
- HSAN9
- TECPR2 hereditary spastic paraplegia
- Autosomal recessive spastic paraplegia 49
description: >-
  Biallelic TECPR2 variants cause an autosomal recessive neurodevelopmental and
  neurodegenerative disorder first described in five Jewish Bukharian individuals in 2012
  and named spastic paraplegia 49 (SPG49). TECPR2 is a tectonin beta-propeller protein
  that binds ATG8-family proteins and scaffolds the early secretory pathway to autophagy:
  it stabilises the COPII coat protein SEC24D, maintains functional endoplasmic reticulum
  exit sites, and is required with LC3C for autophagosome formation. Loss of TECPR2 gives
  patient fibroblasts reduced LC3B and SQSTM1/p62 with attenuated delivery to the
  lysosome, placing the disease among the congenital disorders of autophagy.

  The name is a historical artefact and is the main thing to understand about this entry.
  As more non-Bukharian patients were found, the dominant clinical burden turned out to be
  sensory and autonomic neuropathy with intellectual disability - central hypoventilation
  and apnea, gastroesophageal reflux with recurrent aspiration, dysmotility, dysphagia,
  areflexia and ataxic gait - rather than corticospinal spasticity. The largest cohort
  (17 new plus 11 published individuals) lists developmental delay/intellectual
  disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and
  central/nocturnal hypopnea as the core manifestations, and spasticity is not among them.
  The field and GeneReviews now use "TECPR2-related hereditary sensory and autonomic
  neuropathy with intellectual disability"; MONDO:0014016 still carries the HSP label.
  This entry is bound to that MONDO term because that is the concept being curated, but a
  reader should not expect a pure spastic paraplegia phenotype.

  Apnea and asphyxia are the two most common causes of death, which is what makes the
  respiratory and autonomic features the management priority rather than the gait.
disease_term:
  preferred_term: hereditary spastic paraplegia 49
  term:
    id: MONDO:0014016
    label: hereditary spastic paraplegia 49
parents:
- Complex Hereditary Spastic Paraplegia
references:
- reference: PMID:36137062
  title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic TECPR2 variants. The founder allele c.3416delT was identified homozygously in
    Jewish Bukharian families; subsequent patients from unrelated non-Bukharian families
    carry other alleles, so the disorder is not restricted to that population.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TECPR2-HSAN with ID is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the inheritance pattern.
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein."
    explanation: The original homozygous founder allele establishing recessive inheritance.
pathophysiology:
- name: TECPR2 Loss of Function
  description: >-
    Biallelic TECPR2 variants reduce or abolish the protein. The founder allele is a 1 bp
    frameshift deletion producing a premature stop codon and predicted protein degradation.
    Missense variants make up nearly half of the disease-associated alleles and cluster in
    the N- and C-terminal beta-propeller repeat regions, which is also why classifying them
    under ACMG criteria is difficult.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TECPR2
    term:
      id: hgnc:19957
      label: TECPR2
  downstream:
  - target: Destabilised COPII Coat and ER Exit Site Failure
    causal_link_type: DIRECT
  - target: Impaired Autophagosome Formation and Cargo Delivery
    causal_link_type: DIRECT
  - target: Endolysosomal Dysfunction and Impaired Microglial Clearance
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein"
    explanation: Establishes the founder allele as a predicted null.
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing beta-propeller repeats."
    explanation: Maps the missense allele spectrum onto the beta-propeller domains.
- name: Destabilised COPII Coat and ER Exit Site Failure
  description: >-
    TECPR2 binds trafficking components including the COPII coat protein SEC24D and is
    required to stabilise SEC24D protein levels and maintain functional endoplasmic
    reticulum exit sites. This is not an inference from cell lines alone - TECPR2-deficient
    patient cells show altered SEC24D abundance and reduced ER export efficiency. The
    dependence runs through lipidated LC3C, which is what makes TECPR2 a scaffold joining
    the early secretory pathway to autophagy rather than a component of either alone.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: endoplasmic reticulum to Golgi vesicle-mediated transport
    modifier: DECREASED
    term:
      id: GO:0006888
      label: endoplasmic reticulum to Golgi vesicle-mediated transport
  - preferred_term: COPII-coated vesicle budding
    modifier: DECREASED
    term:
      id: GO:0090114
      label: COPII-coated vesicle budding
  cellular_components:
  - preferred_term: endoplasmic reticulum exit site
    term:
      id: GO:0070971
      label: endoplasmic reticulum exit site
  downstream:
  - target: Impaired Autophagosome Formation and Cargo Delivery
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26431026
    reference_title: "TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TECPR2 is required for stabilization of SEC24D protein levels, maintenance of functional ER exit sites (ERES), and efficient ER export in a manner dependent on binding to lipidated LC3C."
    explanation: Defines the COPII/ERES arm of TECPR2 function and its LC3C dependence.
  - reference: PMID:26431026
    reference_title: "TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TECPR2-deficient HSP patient cells display alterations in SEC24D abundance and ER export efficiency."
    explanation: Confirms the defect in patient-derived cells, not only in knockdown models.
  - reference: PMID:26431026
    reference_title: "TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these results reveal that TECPR2 functions as molecular scaffold linking early secretion pathway and autophagy"
    explanation: States the scaffold role that couples this node to the autophagy node.
- name: Impaired Autophagosome Formation and Cargo Delivery
  description: >-
    TECPR2 is an ATG8-binding positive regulator of autophagy. Patient fibroblasts show
    reduced SQSTM1/p62 and MAP1LC3B, with a more pronounced fall in the lipidated LC3-II
    form, and attenuated delivery of both LC3B and p62 to the lysosome where they are
    normally degraded. siRNA knockdown reproduces the same changes. Note the direction:
    p62 falls rather than accumulating, which is not the pattern of a simple block in
    autophagosome-lysosome fusion and is consistent instead with a defect upstream, at
    autophagosome formation.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: macroautophagy
    modifier: DECREASED
    term:
      id: GO:0016236
      label: macroautophagy
  - preferred_term: autophagosome assembly
    modifier: DECREASED
    term:
      id: GO:0000045
      label: autophagosome assembly
  cellular_components:
  - preferred_term: autophagosome
    term:
      id: GO:0005776
      label: autophagosome
  downstream:
  - target: Sensory and Autonomic Neuron Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Corticospinal Axonopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II)"
    explanation: The primary cellular autophagy phenotype in patient fibroblasts.
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "siRNA knockdown of TECPR2 showed similar changes, consistent with aberrant autophagy."
    explanation: Knockdown reproduces the patient-cell phenotype, supporting causality.
  - reference: PMID:23439247
    reference_title: "TECPR2: a new autophagy link for neurodegeneration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "an attenuated delivery of both LC3B and the cargo-recruiting protein SQSTM1/p62 to the lysosome where they are subject to degradation"
    explanation: Specifies the delivery defect underlying the reduced autophagic flux.
  - reference: PMID:26431026
    reference_title: "TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TECPR2 and LC3C are required for autophagosome formation, possibly through maintaining functional ERES."
    explanation: >-
      Links the autophagy defect mechanistically back to the ER exit site node rather than
      leaving the two as parallel observations.
  - reference: PMID:26715604
    reference_title: "Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations"
    explanation: >-
      The review that defines the congenital-disorders-of-autophagy class names SPG49/TECPR2
      as one of its founding members, which is the basis for the classification asserted in
      this entry's description. Graded OTHER because it is an expert synthesis rather than
      a study reporting its own data.
  - reference: PMID:34130600
    reference_title: "The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPG49-associated TECPR2 and BPAN-associated WDR45 linked to the phagophore/autophagosome formation stages"
    explanation: >-
      An independent review places TECPR2's lesion at the formation stage rather than at
      fusion or clearance, which is the step this node names.
- name: Endolysosomal Dysfunction and Impaired Microglial Clearance
  description: >-
    A 2025 knock-in mouse carrying a disease-associated nonsense mutation identifies a
    second TECPR2 function: it interacts with the HOPS tethering complex, and its loss gives
    endolysosomal dysfunction in neurons. This node is curated as a sibling of the
    autophagosome-formation node rather than downstream of it, and the topology is the
    claim. The paper establishes a distinct HOPS-dependent role in endolysosome maintenance;
    it does not show that this lesion is a consequence of failed autophagosome formation.
    Drawing the serial edge would assert a sequence the source does not support. If a study
    later shows the endolysosomal defect follows from the formation defect, the edge is the
    change to make. The same
    model adds a second cell type to the mechanism. Damage-associated microglia respond to
    the dying neurons but their capacity to clear the debris is itself attenuated, so the
    disease is not purely neuron-autonomous - a failure to remove degenerating material sits
    alongside the failure that produces it.

    The pathology is strikingly region-specific, concentrated in the medulla, which is
    where the fatal autonomic and respiratory phenotypes would be expected to originate.
    That regional restriction is curated as an observation rather than as an explanation;
    why a ubiquitously expressed protein produces a lesion confined to one brain region is
    the model's central unanswered question.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: lysosomal transport
    modifier: DECREASED
    term:
      id: GO:0007041
      label: lysosomal transport
  downstream:
  - target: Sensory and Autonomic Neuron Degeneration
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41173829
    reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, neuronal and microglia phenotypes point to a dysfunctional endolysosomal system when TECPR2 is missing."
    explanation: The authors' summary of the lesion this node names.
  - reference: PMID:41173829
    reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This was confirmed in TECPR2 knockout cells and linked to TECPR2's interaction with the homotypic fusion and protein sorting (HOPS)-tethering complex."
    explanation: >-
      The molecular interaction behind the phenotype, in knockout cells. Graded IN_VITRO
      because the confirmation quoted is a cell experiment, unlike the mouse observations
      cited alongside it.
  - reference: PMID:41173829
    reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, their capacity to clear neuronal debris seems attenuated."
    explanation: >-
      The microglial half of the node, and the reason the mechanism is not purely
      neuron-autonomous.
  - reference: PMID:41173829
    reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice show altered gait, highly region-specific axonal dystrophy, and extensive local gliosis."
    explanation: >-
      Graded PARTIAL. It establishes the in vivo phenotype but its most striking feature -
      that the axonal dystrophy is region-specific - is not explained by anything in this
      pathograph, and is recorded in the node description as an open question.
- name: Sensory and Autonomic Neuron Degeneration
  description: >-
    The dominant clinical burden. Sensory neuropathy with lower-limb hypo- or areflexia and
    ataxic gait combines with autonomic failure - central hypoventilation and apnea,
    gastrointestinal dysmotility, dysphagia and gastroesophageal reflux with recurrent
    aspiration. This is why the disorder is now classified as a hereditary
    sensory-autonomic neuropathy rather than as a spastic paraplegia, and why apnea and
    asphyxia are the leading causes of death.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  downstream:
  - target: Hyporeflexia
    causal_link_type: DIRECT
  - target: Ataxia
    causal_link_type: DIRECT
  - target: Abnormal Autonomic Nervous System Physiology
    causal_link_type: DIRECT
  - target: Central Hypoventilation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Apnea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Gastrointestinal Dysmotility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Dysphagia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Gastroesophageal Reflux
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration)"
    explanation: GeneReviews definition of the sensory and autonomic core of the phenotype.
  - reference: PMID:26542466
    reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the main disabling feature of this unique disorder is autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events"
    explanation: Identifies autonomic-sensory neuropathy, not spasticity, as the main disabling feature.
  - reference: PMID:26542466
    reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy."
    explanation: The explicit reclassification proposal that the current disease name reflects.
- name: Corticospinal Axonopathy
  description: >-
    The feature the SPG49 name was built on. Hereditary spastic paraplegias are defined by
    axonopathy of the corticospinal motor neurons, and spasticity does evolve in patients.
    It is curated here as a real but secondary component: the largest phenotyping cohort
    does not list spasticity among the core manifestations, and the canine TECPR2 model's
    spinal cord lesions spare the motor pathways that most human HSPs involve.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  locations:
  - preferred_term: corticospinal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
  downstream:
  - target: Spastic Paraplegia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26431026
    reference_title: "TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary spastic paraplegias (HSPs) are a diverse group of neurodegenerative diseases that are characterized by axonopathy of the corticospinal motor neurons."
    explanation: Defines the corticospinal lesion that the HSP classification asserts.
  - reference: PMID:26542466
    reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy"
    explanation: >-
      Graded PARTIAL deliberately. It confirms spasticity is real and evolving, while
      subordinating it to the autonomic-sensory neuropathy - which is exactly the
      secondary status this node claims.
phenotypes:
- name: Intellectual Disability
  category: Neurologic
  description: >-
    Developmental delay evolving into intellectual disability, present in essentially all
    reported individuals and one of the two features in the current disease name.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities"
    explanation: GeneReviews states developmental delay and intellectual disability as defining features.
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations."
    explanation: Places developmental delay/intellectual disability first among core manifestations in the largest cohort.
- name: Muscular Hypotonia
  category: Neurologic
  description: Generalized hypotonia, a core manifestation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations"
    explanation: Lists muscular hypotonia among the core manifestations.
- name: Ataxia
  category: Neurologic
  description: Ataxic gait, reflecting the sensory neuropathy as much as any cerebellar involvement.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait"
    explanation: GeneReviews describes the ataxic gait in the context of sensory neuropathy.
- name: Hyporeflexia
  category: Neurologic
  description: >-
    Lower-limb hypo- or areflexia. Worth noting as a discriminator: depressed reflexes are
    the opposite of the hyperreflexia expected in a pure corticospinal spastic paraplegia,
    and reflect the peripheral sensory neuropathy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations"
    explanation: Lists hyporeflexia among the core manifestations.
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features"
    explanation: Areflexia recorded in the original five-patient description.
- name: Central Hypoventilation
  category: Respiratory
  description: >-
    Fluctuating central hypoventilation and central/nocturnal hypopnea. Together with apnea
    this is the feature that drives mortality.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Central hypoventilation
    term:
      id: HP:0007110
      label: Central hypoventilation
  evidence:
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features"
    explanation: Central hypoventilation in the original description of the disorder.
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory infections, and central/nocturnal hypopnea as core manifestations"
    explanation: Confirms central/nocturnal hypopnea as a core manifestation in the largest cohort.
  notes: >-
    The original description quotes "gastresophageal" - a typographical error in the source
    abstract, preserved because snippets must be exact substrings of the cached reference.
- name: Apnea
  category: Respiratory
  description: >-
    Apnea, occurring in wakefulness as well as sleep, as part of the autonomic dysfunction.
    Apnea and asphyxia are the two most common causes of death, which sets the management
    priority for this disorder.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  notes: >-
    Bound to Apnea (HP:0002104), not Sleep apnea (HP:0010535). The sources describe apnea
    as part of autonomic dysfunction and record wake apnea, so restricting the binding to
    the sleep-related child would assert a narrower claim than any of them makes. If a
    source is later found that separates sleep-related from wake apnea in this disorder,
    splitting into two phenotypes is the right move; asserting the split now would not be
    supported.
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "minimize risk for apnea and asphyxia, the two most common causes of death"
    explanation: >-
      GeneReviews names apnea and asphyxia as the leading causes of death, establishing
      both the phenotype and its clinical weight.
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  description: Gastroesophageal reflux disease with recurrent aspiration.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration"
    explanation: GeneReviews describes reflux with aspiration as part of the autonomic dysfunction.
- name: Dysphagia
  category: Gastrointestinal
  description: Swallowing difficulty contributing to aspiration risk.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration"
    explanation: GeneReviews lists dysphagia among the autonomic gastrointestinal features.
- name: Recurrent Respiratory Infections
  category: Respiratory
  description: >-
    Recurrent respiratory infections, driven by aspiration from reflux and dysphagia
    together with hypoventilation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations"
    explanation: Lists respiratory infections among the core manifestations.
- name: Atypical Behavior
  category: Neurologic
  description: >-
    Behavioral abnormalities, listed among the defining features alongside developmental
    delay and intellectual disability. The GeneReviews management section names behaviour
    as one of the specialties multidisciplinary care should include, so it is a management
    problem in practice and not only a descriptive finding.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration)."
    explanation: >-
      Behavioral abnormalities in the GeneReviews characterisation sentence, alongside the
      developmental and neurologic features.
- name: Gastrointestinal Dysmotility
  category: Gastrointestinal
  description: >-
    Gastrointestinal dysmotility as part of the autonomic dysfunction. Curated separately
    from dysphagia and reflux because it is a distinct autonomic manifestation rather than
    a consequence of them.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gastrointestinal dysmotility
    term:
      id: HP:0002579
      label: Gastrointestinal dysmotility
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration)."
    explanation: >-
      Gastrointestinal dysmotility named in the autonomic-dysfunction list of the
      GeneReviews characterisation sentence.
- name: Aspiration
  category: Respiratory
  description: >-
    Recurrent aspiration, described as a consequence of gastroesophageal reflux disease.
    This is the link between the gastrointestinal and the respiratory phenotypes, and it is
    the mechanism behind the recurrent respiratory infections curated separately.
  frequency: FREQUENT
  sequelae:
  - target: Recurrent Respiratory Infections
    causal_link_type: DIRECT
    description: >-
      Aspirated gastric contents are the route by which the reflux becomes a respiratory
      problem. Encoded as a sequela rather than left in prose so the phenotype-to-phenotype
      step is machine-readable.
  phenotype_term:
    preferred_term: Aspiration
    term:
      id: HP:0002835
      label: Aspiration
    temporality: RECURRENT
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration)."
    explanation: >-
      Recurrent aspiration named as a feature of the gastroesophageal reflux disease in the
      GeneReviews characterisation sentence.
- name: Thin Corpus Callosum
  category: Neurologic
  description: Thin corpus callosum on brain MRI, in about half of individuals imaged.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%."
    explanation: Quantifies the imaging finding at 52%, supporting the FREQUENT grading.
- name: Spastic Paraplegia
  category: Neurologic
  description: >-
    Evolving lower-limb spasticity. It is the feature the SPG49 name was built on, but it
    is not among the core manifestations in the largest phenotyping cohort, so it is
    graded below the sensory-autonomic and developmental features rather than as the
    defining phenotype.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
  evidence:
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis"
    explanation: The original description on which the spastic paraplegia classification rests.
  - reference: PMID:26542466
    reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to intellectual disability and evolving spasticity the main disabling feature of this unique disorder is autonomic-sensory neuropathy"
    explanation: >-
      Confirms spasticity while explicitly subordinating it, which is the basis for
      grading it below the sensory-autonomic features.
  notes: >-
    Not listed among the core manifestations in PMID:33847017's 28-individual analysis.
    Graded FREQUENT rather than VERY_FREQUENT for that reason. The first reported Chinese
    patient (PMID:35130874) illustrates how far the phenotype can depart from the founder
    description: normal development until age 10, no reflux, and no abnormal breathing
    during sleep, with paroxysmal hyperthermia and seizures dominating instead.
- name: Abnormal Autonomic Nervous System Physiology
  category: Neurologic
  description: >-
    Autonomic dysfunction including paroxysmal autonomic events, dysmotility and
    respiratory dysregulation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:26542466
    reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events"
    explanation: Documents paroxysmal autonomic events and chronic respiratory disease.
genetic:
- name: TECPR2
  notes: >-
    TECPR2 encodes a tectonin beta-propeller repeat-containing ATG8-binding protein.
    Missense variants make up nearly half of the disease-associated alleles and cluster in
    the N- and C-terminal beta-propeller regions, and classifying them by ACMG criteria is
    explicitly noted as difficult - several previously published candidate missense
    variants have since been reclassified as of uncertain significance.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TECPR2
    term:
      id: hgnc:19957
      label: TECPR2
  evidence:
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis."
    explanation: Original identification of TECPR2 as the causal gene.
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging."
    explanation: Documents the variant-interpretation difficulty central to diagnosing this disorder.
  - reference: PMID:38436550
    reference_title: "TECPR2-related hereditary sensory and autonomic neuropathy in two siblings from Palestine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we reviewed previously published candidate TECPR2 missense variants to clarify clinical outcomes and variant classification using current approved guidelines, classifying a number of published variants as of uncertain significance"
    explanation: >-
      Confirms that previously reported missense variants have been downgraded to VUS,
      which bears directly on how the literature's genotype claims should be read.
  variants:
  - name: c.3416delT
    description: >-
      The founder frameshift allele identified homozygously in Jewish Bukharian families in
      the original 2012 description.
    evidence:
    - reference: PMID:26542466
      reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TECPR2 was first described as a disease causing gene when the c.3416delT frameshift mutation was found in five Jewish Bukharian patients with similar features."
      explanation: Names the founder allele and its population of origin.
prevalence:
- population: Worldwide (published cases)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    More than 30 individuals identified as of the GeneReviews chapter. The disorder was
    initially thought to be confined to Jewish Bukharian families, and the discovery of
    unrelated non-Bukharian patients suggests it is underdiagnosed rather than genuinely
    that restricted.
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, more than 30 individuals with TECPR2-HSAN with ID have been identified."
    explanation: GeneReviews case count.
  - reference: PMID:26542466
    reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The discovery of additional mutations in non-Bukharian patients implies that this disease might be more common than previously appreciated"
    explanation: Supports underdiagnosis rather than true restriction to one population.
  - reference: PMID:35130874
    reference_title: "Novel detection of mutation in the TECPR2 gene in a Chinese hereditary spastic paraplegia 49 patient: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present case reports the first instance of HSP49 detected in China."
    explanation: >-
      Extends the reported geographic range well beyond the founder population, consistent
      with underdiagnosis outside the populations where the disorder was first described.
- population: Ashkenazi Jewish
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 645.2
  notes: >-
    Estimated pathogenic-variant carrier frequency of 1 in 155 in the Ashkenazi Jewish
    population, against 1 in 1221 in the general population. Note this is an estimate
    derived from variant data, not an observed carrier screen, and 1/155 is a
    strikingly high figure for a disorder with only ~30 reported patients - which is
    itself an argument that the condition is underdiagnosed or that some counted alleles
    are less penetrant than assumed. ABOVE_1_IN_1000 is the schema-correct band here, since
    645.2 per 100,000 exceeds 100. See the general-population record below for the KB-wide
    question about whether disease-occurrence bands belong on carrier frequencies at all.
  evidence:
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations."
    explanation: Source of both carrier-frequency estimates.
- population: General population
  measure_type: CARRIER_FREQUENCY
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 81.9
  notes: >-
    Estimated pathogenic-variant carrier frequency of 1 in 1221 in the general population.
    Banded BAND_1_5_PER_10000, not ABOVE_1_IN_1000: 1 in 1221 is below 1 in 1000. Note the
    band name understates its range - PrevalenceClassEnum defines BAND_1_5_PER_10000 as
    10-99 per 100,000, deliberately combining the Orphanet 1-5 and 6-9 classes so there is
    no gap between it and ABOVE_1_IN_1000, and _band_from_rate() buckets any rate at or above
    10 into it. Read the enum description rather than the class name before concluding a
    rate falls between bands.

    A real question remains, and it is not specific to this entry: the Orphanet classes band
    disease occurrence, and a carrier frequency is not disease occurrence, so a reader
    filtering on the band will compare carrier rates against patient rates. That is a
    KB-wide convention question - 34 of 37 CARRIER_FREQUENCY records set a band - and it is
    not for one entry to answer by diverging. The band is set to the schema-correct value
    and the concern is recorded here.
  evidence:
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations."
    explanation: Source of the general-population carrier-frequency estimate.
diagnosis:
- name: Molecular genetic testing for biallelic TECPR2 variants
  description: >-
    The diagnosis rests on biallelic pathogenic or likely pathogenic TECPR2 variants in a
    proband with suggestive findings. There is no biochemical or imaging test that
    establishes it. Two things make the molecular step harder than that sentence suggests:
    nearly half the disease-associated alleles are missense and cluster in the
    beta-propeller repeats, where ACMG classification is difficult, and the clinical
    picture overlaps familial dysautonomia closely enough that the disorder was originally
    described as a spastic paraplegia and later reclassified.
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of TECPR2-HSAN with ID is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TECPR2 identified by molecular genetic testing."
    explanation: The GeneReviews diagnostic criterion.
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing beta-propeller repeats."
    explanation: >-
      Graded PARTIAL. It does not state a diagnostic criterion, but it identifies where the
      interpretive difficulty sits - a missense-heavy allele spectrum concentrated in two
      domains is exactly the situation in which variant classification, not variant
      detection, is the bottleneck.
treatments:
- name: Multidisciplinary Supportive Care
  description: >-
    There is no disease-modifying treatment. Management is supportive and explicitly aimed
    at reducing the risk of apnea and asphyxia, drawing on neurology, developmental and
    behavioural medicine, feeding, pulmonology, gastroenterology, orthopedics, ethics and
    medical genetics.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently there are no specific disease-modifying treatments for TECPR2-HSAN with ID."
    explanation: States the absence of disease-modifying therapy.
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive care can include multidisciplinary care by pediatric specialists in neurology, development, behavior, feeding, pulmonology, gastroenterology, orthopedics, ethics, and medical genetics."
    explanation: Defines the composition of supportive care recommended by GeneReviews.
- name: Genetic Counselling and Family Testing
  description: >-
    Autosomal recessive counselling with a 25% recurrence risk for sibs, and carrier,
    prenatal or preimplantation testing once the familial variants are known. Counselling
    carries more weight in this disorder than the recurrence figure alone implies: the
    estimated carrier frequency in the Ashkenazi Jewish population is about 1 in 155, and
    unrelated non-founder patients have been identified as far afield as China, so the
    at-risk population is not confined to the families the disorder was first described in.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If both parents are known to be heterozygous for a TECPR2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."
    explanation: The recurrence risks that counselling communicates.
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the TECPR2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
    explanation: >-
      The testing options counselling opens once the familial variants are known, which is
      what makes identifying them useful beyond the proband.
- name: Avoidance of Respiratory Depressants
  description: >-
    Drugs that cause decreased consciousness, hypopnea or CO2 retention - benzodiazepines
    and antihistamines are the named examples - are to be avoided, or used only at low
    doses with close monitoring. This follows directly from central hypoventilation being a
    core feature and apnea a leading cause of death.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Central hypoventilation
    term:
      id: HP:0007110
      label: Central hypoventilation
  evidence:
  - reference: PMID:36137062
    reference_title: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Avoid drugs that cause decreased consciousness, hypopnea, and CO2 retention such as benzodiazepines or antihistamines; or if necessary, use at low doses with close monitoring."
    explanation: GeneReviews Agents/Circumstances to Avoid, quoted directly.
- name: TECPR2 Exon 8 Skipping Antisense Oligonucleotide (investigational)
  description: >-
    A preclinical, genotype-specific splice-modulation strategy - not an approved therapy.
    The c.1319delT (p.Leu440Argfs*19) frameshift creates a premature stop codon in exon 8.
    Because exon 8 encodes an unstructured 111-amino-acid region and is 333 nucleotides
    long, skipping it restores an in-frame TECPR2 retaining 1,300 of 1,411 residues. The
    lead candidate ASO-005-02 reached ~27 nM potency in patient fibroblasts, and the
    rescued protein kept the punctate neuronal distribution of full-length TECPR2 in
    iPSC-derived neurons - a surrogate for function, not a functional assay. A single 20 mg
    intrathecal dose in cynomolgus monkeys was tolerated with broad CNS distribution and
    detectable exon-8 skipping.

    Two limits are worth stating plainly. First, eligibility is narrow: the strategy only
    helps patients carrying an exon 8 mutation, which the authors estimate at up to a few
    hundred patients worldwide. Second, the chemistry recorded here (2'-O-methyl bases,
    phosphorothioate linkages) is what the source states for the initial 25-mer screening
    set; the optimized lead's final chemistry is not specified in the abstract or the
    quoted text, so treat the chemistry annotation as provisional.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: SPLICE_MODULATION_EXON_SKIPPING
    target_gene:
      preferred_term: TECPR2
      term:
        id: hgnc:19957
        label: TECPR2
    target_transcript: TECPR2 mRNA
    target_exon: exon 8
    conjugation: UNCONJUGATED
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: TECPR2 Loss of Function
    description: >-
      Removes the premature termination codon by skipping the exon that contains it,
      restoring expression of a shortened but in-frame TECPR2 protein.
    evidence:
    - reference: PMID:35860385
      reference_title: "Developing antisense oligonucleotides for a TECPR2 mutation-induced, ultra-rare neurological disorder using patient-derived cellular models."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "TECPR2 exon 8 skipping restored in-frame expression of a TECPR2 protein variant (TECPR2ΔEx8) containing 1,300 of 1,411 amino acids."
      explanation: Establishes that the ASO restores in-frame protein expression from the mutant allele.
  evidence:
  - reference: PMID:35860385
    reference_title: "Developing antisense oligonucleotides for a TECPR2 mutation-induced, ultra-rare neurological disorder using patient-derived cellular models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Optimization of ASO sequences generated a lead candidate (ASO-005-02) with ∼27 nM potency in patient-derived fibroblasts."
    explanation: Quantifies lead-candidate potency in patient-derived cells.
  - reference: PMID:35860385
    reference_title: "Developing antisense oligonucleotides for a TECPR2 mutation-induced, ultra-rare neurological disorder using patient-derived cellular models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we used iPSC-derived neurons to analyze the neuronal localization of TECPR2ΔEx8 and showed that this form of TECPR2 retains the distinct, punctate neuronal expression pattern of full-length TECPR2"
    explanation: >-
      Graded PARTIAL - correct subcellular localization is a surrogate for function, not a
      demonstration that the truncated protein performs TECPR2's autophagy or ER-export role.
  - reference: PMID:35860385
    reference_title: "Developing antisense oligonucleotides for a TECPR2 mutation-induced, ultra-rare neurological disorder using patient-derived cellular models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ASO-005-02 had an acceptable tolerability profile in vivo following a single 20-mg intrathecal dose in cynomolgus monkeys, showing some transient non-adverse behavioral effects with no correlating histopathology"
    explanation: Non-human primate tolerability and CNS delivery data supporting further development.
  - reference: PMID:35860385
    reference_title: "Developing antisense oligonucleotides for a TECPR2 mutation-induced, ultra-rare neurological disorder using patient-derived cellular models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there are currently no available disease-modifying therapies for this disease"
    explanation: >-
      Confirms the investigational status - this ASO is preclinical, and nothing
      disease-modifying is currently available to patients.
animal_models:
- name: Tecpr2 CRISPR-Cas9 knockout mouse
  species: Mouse
  genotype: tecpr2-/- CRISPR-Cas9 knockout
  publication: PMID:33218264
  description: >-
    An engineered null model, complementing the naturally occurring canine missense model.
    It develops age-dependent neuroaxonal dystrophy concentrated in the gracile and cuneate
    nuclei of the medulla oblongata and the dorsal white matter column of the spinal cord,
    with autophagosome accumulation tracking the neurodegeneration.
  genes:
  - preferred_term: TECPR2
    term:
      id: hgnc:19957
      label: TECPR2
  modeled_mechanisms:
  - target: Impaired Autophagosome Formation and Cargo Delivery
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Autophagosome accumulation in affected CNS regions, interpreted by the authors as
      compromised targeting of autophagosomes to the lysosome.
    limitations: >-
      The direction of the autophagy defect differs from the original patient-fibroblast
      report, which found decreased LC3-II and p62 rather than accumulation. Accumulation
      points to a downstream delivery or fusion block; depletion points to a defect at
      formation. The mouse cannot by itself settle which applies in human disease, and the
      two readings are not reconcilable as stated.
    readouts:
    - name: Autophagosome accumulation in medulla oblongata and dorsal spinal tracts
      target: Impaired Autophagosome Formation and Cargo Delivery
      direction: INCREASED
      interpretation: Regional autophagosome accumulation co-localizing with neuroaxonal dystrophy.
      evidence:
      - reference: PMID:33218264
        reference_title: "A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophy associated with autophagosome accumulation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Age-dependent correlation with accumulation of autophagosomes suggests compromised targeting to lysosome."
        explanation: The measurement and the authors' interpretation of it.
    evidence:
    - reference: PMID:33218264
      reference_title: "A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophy associated with autophagosome accumulation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "our findings establish the tecpr2 knockout mouse as a potential model for SPG49 and ascribe a new role to TECPR2 in macroautophagy/autophagy-related neurodegenerative disorders"
      explanation: The authors' claim that the model is informative for TECPR2-dependent autophagy.
  - target: Sensory and Autonomic Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Degeneration is concentrated in the gracile and cuneate nuclei and dorsal columns -
      the sensory relay pathways - matching the sensory limb of the human disorder, and in
      the medulla, the site relevant to respiratory control.
    limitations: >-
      The report describes behavioural pathologies and regional neurodegeneration but does
      not demonstrate the central hypoventilation or apnea that kill human patients. That
      medullary involvement is anatomically suggestive of a respiratory phenotype is an
      inference, not a measurement made here.
    evidence:
    - reference: PMID:33218264
      reference_title: "A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophy associated with autophagosome accumulation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "manifested predominantly as neuroaxonal dystrophy in the gracile (GrN) and cuneate nuclei (CuN) of the medulla oblongata in the brainstem and dorsal white matter column of the spinal cord"
      explanation: >-
        Localizes the degeneration to sensory relay and medullary structures; graded PARTIAL
        because no respiratory or autonomic function was measured.
  evidence:
  - reference: PMID:33218264
    reference_title: "A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophy associated with autophagosome accumulation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we report the generation of a novel CRISPR-Cas9 tecpr2 knockout (tecpr2-/-) mouse that exhibits behavioral pathologies observed in SPG49 patients"
    explanation: Establishes the model and its claimed behavioural correspondence to patients.
- name: Tecpr2 L1152Yfs knock-in mouse
  species: Mouse
  genotype: Tecpr2 L1152Yfs homozygous knock-in (models human TECPR2 p.Leu1139Argfs*75)
  publication: PMID:41173829
  description: >-
    A second, allele-specific mouse, generated to address a stated limitation of the
    knockout: a null cannot test whether a truncated mutant TECPR2 protein is itself toxic.
    The knock-in carries an HSAN9-associated nonsense allele rather than a deletion. It
    reproduces gait ataxia and the medullary axonal dystrophy seen in the knockout, and it
    is the source of the endolysosomal and microglial arm of this pathograph: proteomics
    and imaging of the affected medulla, damage-associated microglia with reduced clearance
    capacity, and a HOPS interaction mapped in TECPR2 knockout cells.
  genes:
  - preferred_term: TECPR2
    term:
      id: hgnc:19957
      label: TECPR2
  modeled_mechanisms:
  - target: Endolysosomal Dysfunction and Impaired Microglial Clearance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model that establishes this node. Neuronal and microglial readouts converge on a
      dysfunctional endolysosomal system, and the HOPS interaction supplies the molecular
      basis.
    limitations: >-
      Two limits bound what this model shows. The corresponding human lesion has been
      demonstrated only in patient fibroblasts and engineered knockout cells, not in patient
      nervous tissue, so the endolysosomal claim rests on a mouse plus human cell lines
      rather than on human neuropathology. And the design intent was only partly met: the
      knock-in was made so a truncated mutant protein could be tested for toxic
      gain-of-function, but TECPR2 was undetectable at the protein level, so functionally
      this remains a loss-of-expression model like the knockout.
    readouts:
    - name: Medullary axonal swelling with regional neuronal loss
      target: Endolysosomal Dysfunction and Impaired Microglial Clearance
      direction: INCREASED
      interpretation: >-
        The anatomical lesion, restricted to the medulla, in which the altered organelle and
        protein homeostasis was measured.
      evidence:
      - reference: PMID:41173829
        reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "the presence of axonal swelling in a specific region of the medulla correlated with neuronal loss in this area"
        explanation: Localizes the lesion and ties the swelling to actual neuronal loss.
    - name: Disease-associated microglia state with reduced endocytic capacity
      target: Endolysosomal Dysfunction and Impaired Microglial Clearance
      direction: ALTERED
      interpretation: >-
        Microglia respond to the neuronal damage but shift to a state with increased
        lysosomal protein content and decreased endocytosis - the reason this node treats
        clearance failure as part of the mechanism rather than as a reaction to it.
      evidence:
      - reference: PMID:41173829
        reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The DAM state was confirmed by immunohistochemistry along with microglia proteomics and immunofluorescence which showed increased lysosomal proteins and a decrease in endocytic processes."
        explanation: The measurements behind the microglial half of the node.
    evidence:
    - reference: PMID:41173829
      reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Collectively, we uncovered a role of TECPR2 in endolysosome maintenance which seems relevant for healthy neurons in a particular brain region."
      explanation: The authors' statement of what the model establishes.
  - target: Sensory and Autonomic Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Gait ataxia and medullary degeneration match the sensory and brainstem limb of the
      human disorder, in an allele of the type patients actually carry.
    limitations: >-
      The same gap as in the knockout: the medulla is the anatomically right place for the
      fatal respiratory phenotype, but no respiratory or autonomic function was measured, so
      the correspondence to central hypoventilation and apnea is inferred from location. The
      pathology is also strikingly region-restricted, and why a ubiquitously expressed
      protein produces a lesion confined to one region is unexplained by this model.
    readouts:
    - name: Gait ataxia
      target: Sensory and Autonomic Neuron Degeneration
      direction: ALTERED
      interpretation: The behavioural phenotype the authors match to the human presentation.
      evidence:
      - reference: PMID:41173829
        reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Behavioral and phenotypic studies of these mice showed a gait ataxia phenotype as observed in HSAN9 patients and axonal dystrophy as observed in Tecpr2 KO mice."
        explanation: Records the gait phenotype and its correspondence to patients.
    evidence:
    - reference: PMID:41173829
      reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice show altered gait, highly region-specific axonal dystrophy, and extensive local gliosis."
      explanation: >-
        Graded PARTIAL. The degeneration is real but its regional restriction is the model's
        own unexplained finding, so it supports the node without accounting for its
        distribution.
  evidence:
  - reference: PMID:41173829
    reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report a novel mouse model which harbors a HSAN9-associated nonsense mutation that causes loss of TECPR2 expression."
    explanation: >-
      Establishes the model and what distinguishes it from the knockout - a patient-type
      nonsense allele rather than an engineered deletion.
  - reference: PMID:41173829
    reference_title: "Neuropathy-associated Tecpr2 mutation knock-in mice reveal endolysosomal loss of function phenotypes in neurons and microglia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tecpr2 KO mice do not faithfully recapitulate disease pathology induced by HSAN9-associated mutations since possible toxic gain-of-functions of TECPR2 mutant variants cannot be assessed in this model."
    explanation: >-
      The authors' rationale for building this model, and the reason it is curated alongside
      the knockout rather than as a duplicate of it.
- name: Spanish Water Dog TECPR2 neuroaxonal dystrophy
  species: Dog
  genotype: TECPR2 c.4009C>T (p.R1337W) homozygous
  publication: PMID:26555167
  description: >-
    A naturally occurring, not engineered, juvenile-onset neuroaxonal dystrophy in Spanish
    Water Dogs, mapped to a homozygous TECPR2 missense variant at a highly conserved
    residue with autosomal recessive segregation. Histopathology shows spheroid formation
    in cerebral, cerebellar and brainstem grey matter and in the sensory pathways of the
    spinal cord, without iron accumulation, and the spheroids contain packed
    double-membraned vesicles identified as autophagosomes.
  genes:
  - preferred_term: TECPR2
    term:
      id: hgnc:19957
      label: TECPR2
  modeled_mechanisms:
  - target: Impaired Autophagosome Formation and Cargo Delivery
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Provides the tissue-level correlate that human patient fibroblast studies cannot:
      autophagosome accumulation within axonal spheroids in an intact nervous system.
    limitations: >-
      A missense allele, not a null, so residual TECPR2 function is likely and the severity
      is not calibrated against human genotypes. The autophagosome identification is
      immunohistochemical and ultrastructural rather than a flux measurement, so it shows
      accumulation without establishing where in the pathway the block sits.
    readouts:
    - name: Autophagosome content of axonal spheroids
      target: Impaired Autophagosome Formation and Cargo Delivery
      direction: INCREASED
      interpretation: >-
        Accumulated double-membraned vesicles within spheroids, consistent with disturbed
        autophagic turnover in vivo.
      evidence:
      - reference: PMID:26555167
        reference_title: "TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Ultrastructurally spheroids contained predominantly closely packed vesicles with a double-layered membrane, which were characterized as autophagosomes using immunohistochemistry."
        explanation: The ultrastructural and immunohistochemical basis for the readout.
    evidence:
    - reference: PMID:26555167
      reference_title: "TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Immunohistochemistry and the ultrastructural findings further support the assumption, that TECPR2 regulates autophagosome accumulation in the autophagic pathways."
      explanation: Supports the model as informative for TECPR2-dependent autophagy in vivo.
  - target: Sensory and Autonomic Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The canine lesions involve the sensory pathways of the spinal cord, matching the
      sensory limb of the human disorder.
    limitations: >-
      The published comparison notes the canine lesions spare the motor pathways that most
      human HSPs involve, and no autonomic phenotype - hypoventilation, apnea, GI
      dysmotility - is reported for the dogs. So the model covers the sensory limb of the
      human disease but not the autonomic one, which is the limb that drives human
      mortality.
    evidence:
    - reference: PMID:26555167
      reference_title: "TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Histopathology demonstrated spheroid formation accentuated in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem and in the sensory pathways of the spinal cord."
      explanation: >-
        Documents sensory pathway involvement, graded PARTIAL because the autonomic
        features of the human disease are not among the reported canine findings.
  - target: Corticospinal Axonopathy
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The canine disease does not reproduce the corticospinal motor involvement that the
      HSP classification of the human disorder asserts.
    limitations: >-
      The authors state directly that the canine lesions differ from most human HSPs in
      sparing the motor pathways. Note this cuts both ways as evidence: read as a model
      limitation it is a species difference, but read alongside the human cohort data
      showing spasticity is not a core manifestation, it is a point of agreement that the
      corticospinal component of this disorder is weaker than its SPG49 name implies.
    evidence:
    - reference: PMID:26555167
      reference_title: "TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast to the canine NAD, the spinal cord lesions in most types of human HSP involve the sensory and the motor pathways."
      explanation: Explicit statement that the canine lesions do not involve the motor pathways.
  evidence:
  - reference: PMID:26555167
    reference_title: "TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W)"
    explanation: Establishes the causal TECPR2 variant underlying the canine model.
  - reference: PMID:26555167
    reference_title: "TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This canine NAD form displays etiologic parallels to an inherited TECPR2 associated type of human hereditary spastic paraparesis (HSP)."
    explanation: The authors' own statement of the model's relevance to the human disorder.
discussions:
- discussion_id: tecpr2_autophagy_direction_conflict
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does TECPR2 loss block autophagosome formation or autophagosome clearance? The
    published readouts point in opposite directions, and the answer determines what a
    therapeutic readout should even measure.
  attaches_to:
  - pathophysiology#Impaired Autophagosome Formation and Cargo Delivery
  - pathophysiology#Endolysosomal Dysfunction and Impaired Microglial Clearance
  rationale: >-
    The original patient-fibroblast study found reduced LC3-II and reduced SQSTM1/p62 with
    attenuated delivery of both to the lysosome - a pattern consistent with a defect at
    autophagosome formation, since a pure clearance block would make p62 accumulate.
    Every in vivo model reports the opposite: autophagosomes pile up in axonal spheroids
    in the Spanish Water Dog and in the medulla and dorsal columns of the Tecpr2 knockout
    mouse, and the mouse authors read this as compromised targeting to the lysosome. The
    mechanistic work adds a third strand, placing TECPR2 at ER exit sites where it would
    act upstream at formation. These are not obviously reconcilable. Possible explanations
    include a cell-type difference between fibroblasts and neurons, a difference between
    an early formation defect and a late accumulation of stalled structures over years of
    neuronal life, or an artefact of measuring steady-state levels rather than flux.

    A fourth possibility has since appeared and is the most economical of the set: that
    neither reading is the whole story because TECPR2 also has a HOPS-dependent role in
    endolysosome maintenance, curated here as its own node. A protein required both at ER
    exit sites and at endolysosomal tethering would produce formation-like readouts in one
    assay and clearance-like readouts in another without either being an artefact. This does
    not resolve the conflict - nobody has measured flux in a system where both functions are
    separable - but it reframes it, and it is the explanation a new experiment should be
    designed against.

    The practical consequence is unchanged and concrete: an ASO or other therapy would need
    a validated autophagy readout, and it is currently unclear whether increased or decreased
    LC3-II should count as rescue.
  evidence:
  - reference: PMID:23176824
    reference_title: "Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II)"
    explanation: The patient-fibroblast finding - decreased, not accumulated, autophagy markers.
  - reference: PMID:33218264
    reference_title: "A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophy associated with autophagosome accumulation."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Age-dependent correlation with accumulation of autophagosomes suggests compromised targeting to lysosome."
    explanation: >-
      Graded REFUTE against the formation-defect reading - the mouse shows accumulation and
      the authors interpret it as a clearance defect, the opposite direction.
  - reference: PMID:26431026
    reference_title: "TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TECPR2 and LC3C are required for autophagosome formation, possibly through maintaining functional ERES."
    explanation: Independent mechanistic support for a defect at formation rather than clearance.
  - reference: PMID:34130600
    reference_title: "The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The role of defective TECPR2 implicated in SPG49 is not fully resolved but may involve impairment of early autophagosome generation due to reduced scaffolding at ER membrane exit sites"
    explanation: >-
      A review of the whole autophagy-disorder class states the TECPR2 mechanism is still
      open, which is the gap this discussion records. It is external confirmation that the
      conflict is a genuine state of the field rather than a curation artefact.
- discussion_id: tecpr2_disease_name_mismatch
  kind: KNOWLEDGE_GAP
  prompt: >-
    Should MONDO:0014016 continue to be labelled a hereditary spastic paraplegia when the
    accumulated phenotype data identify sensory-autonomic neuropathy with intellectual
    disability as the dominant burden and do not list spasticity among core manifestations?
  attaches_to:
  - pathophysiology#Corticospinal Axonopathy
  - phenotypes#Spastic Paraplegia
  rationale: >-
    This is a nomenclature problem with clinical consequences, not a filing dispute. The
    SPG49 name came from a single five-patient founder family in 2012. Three independent
    lines of evidence since then point the other way: the authors of the second patient
    series proposed reclassification as a hereditary sensory-autonomic neuropathy;
    the largest phenotyping cohort's core manifestation list omits spasticity;
    and the canine TECPR2 model's spinal lesions spare the motor pathways. A clinician
    searching under a spastic paraplegia label may not think to monitor for central
    hypoventilation, and apnea is a leading cause of death here. What is genuinely
    unresolved is whether the corticospinal involvement is a real but minor component or
    an artefact of the founder cohort's particular presentation - answering that needs
    prospective natural history data with systematic pyramidal examination, which the
    largest cohort explicitly sets up but does not yet provide.
  evidence:
  - reference: PMID:26542466
    reference_title: "TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that the disease should therefore be classified as a new subtype of hereditary sensory-autonomic neuropathy."
    explanation: The explicit reclassification proposal from the second patient series.
  - reference: PMID:33847017
    reference_title: "Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This sets the stage for future prospective natural history studies."
    explanation: >-
      The largest cohort identifies prospective natural history data as the missing piece,
      which is what would settle the weight of the corticospinal component.

📚

References & Deep Research

References

1

PMID:36137062

TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Hereditary Spastic Paraplegia 49 (SPG49) / TECPR2-Related Disorder — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-08-27T14:15:26.309045

Hereditary Spastic Paraplegia 49 (SPG49) / TECPR2-Related Disorder — Comprehensive Research Report

1. Disease Information

Overview. Hereditary Spastic Paraplegia 49 (SPG49) is an ultra-rare, autosomal recessive, complex neurodevelopmental and neurodegenerative disorder caused by biallelic loss-of-function variants in TECPR2 (tectonin beta-propeller repeat containing 2), a gene on chromosome 14q32.31 that regulates autophagosome–lysosome fusion and, separately, COPII-dependent ER export. It was first described in 2012 in five Bukharian Jewish patients as an autosomal-recessive complicated hereditary spastic paraplegia (Oz-Levi et al. 2012, Am J Hum Genet, PMID:23176824). Subsequent characterization of larger cohorts showed the phenotype is broader than isolated spasticity — a multisystem sensory, autonomic, and developmental disorder — leading to reclassification as Hereditary Sensory and Autonomic Neuropathy type IX (HSAN9), sometimes written "TECPR2-related HSAN with intellectual disability." Both names (SPG49 and HSAN9) are used interchangeably in the literature and databases for the same gene-disease pair.

Key identifiers: - OMIM disease: #615031, Spastic Paraplegia 49, Autosomal Recessive; OMIM gene: 615000, TECPR2 (OMIM) - MONDO: MONDO:0014016 - Orphanet: ORPHA:320385, Hereditary sensory and autonomic neuropathy due to TECPR2 mutation (Orphanet) - ICD-10: G11.4 (hereditary spastic paraplegia); relatedly G60.- for hereditary/idiopathic neuropathy - Gene: TECPR2; HGNC:19957 (note: some secondary sources list HGNC:30346 — HGNC:19957 is the authoritative current ID); UniProt O15040; NCBI Gene ID 9895 - GeneReviews: "TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability" (NBK584409) - MedGen: C3542549

Synonyms/alternative names: Spastic paraplegia 49, autosomal recessive; SPG49; Hereditary sensory and autonomic neuropathy type IX (HSAN9); HSAN9 with developmental delay; TECPR2-related neurodevelopmental disorder; complicated autosomal-recessive HSP with TECPR2 mutation.

Source of information. Nearly all clinical characterization derives from aggregated disease-level resources — case series and cohort reports pooled by international collaborators — rather than large EHR datasets, reflecting the disorder's ultra-rarity (>30–40 reported individuals worldwide as of the most recent cohort study).

2. Etiology

Disease causal factor: SPG49/HSAN9 is a purely monogenic, autosomal-recessive Mendelian disorder. There is no described environmental, infectious, or multifactorial contribution to primary disease causation — all reported cases carry biallelic pathogenic TECPR2 variants.

Genetic risk factors: - Causal variants: biallelic (homozygous or compound heterozygous) loss-of-function variants in TECPR2 — nonsense, frameshift, canonical splice-site, and a smaller fraction of missense variants clustered in the N-terminal WD/beta-propeller and C-terminal TECPR-repeat domains (Neuser et al. 2021, Hum Mutat, PMID:33847017). - Population founder variants (act as genetic risk factors in specific ancestries — see §9): - Bukharian Jewish: c.3416delT, p.Leu1139ArgfsTer75 (original founder allele; PMID:23176824) - Ashkenazi Jewish: c.1319delT, p.Leu440ArgfsTer19 (PMID:26542466, Heimer et al. 2016) - Heterozygous (monoallelic) TECPR2 variants have separately been reported to cause a distinct, milder, presumably dominant-negative or haploinsufficiency phenotype of progressive cerebellar atrophy with global developmental delay — genetically and mechanistically distinct from the classic biallelic HSAN9/SPG49 syndrome (Ramsey et al. 2022, Mol Genet Genomic Med, PMID:34994087). - No modifier genes have been formally established, though phenotypic variability among individuals homozygous for the same founder allele is documented.

Environmental risk factors: None identified as causal; secondary environmental risk factors (e.g., aspiration risk from dysphagia, hypoventilation exacerbated by sedatives) act on disease complications rather than disease initiation (see §12, drugs to avoid).

Protective factors: None described in the literature; this is a fully penetrant recessive loss-of-function disorder with no known protective alleles or environmental modifiers.

Gene-environment interactions: Not applicable/not reported — the disorder is monogenic with no established GxE interaction.

3. Phenotypes

Frequencies below are drawn from the largest published cohort (28 individuals: 17 new + 11 previously reported; Neuser et al. 2021, PMID:33847017) and GeneReviews (NBK584409).

Developmental/cognitive: - Global developmental delay / intellectual disability — 100% (universal; often severe, many nonverbal) — HP:0001263 (Developmental delay), HP:0001249 (Intellectual disability) - Speech delay, frequently absent expressive speech — HP:0000750 (Delayed speech and language development) - Behavioral abnormalities (autism-spectrum features, stereotypies) — ~62.5% — HP:0000708 (Behavioral abnormality)

Neurological/motor: - Muscular hypotonia (infantile onset) — 100% — HP:0001252 (Hypotonia) - Gait ataxia — 100% — HP:0002066 (Gait ataxia) - Spastic paraparesis/lower-limb spasticity (emerging later, in childhood/adolescence) — HP:0001258 (Spasticity), HP:0007256 (Progressive spasticity) - Lower-limb hypo/areflexia — ~85% — HP:0002522 (Areflexia) - Dysarthria — ~87.5% — HP:0001260 (Dysarthria) - Decreased pain and temperature sensitivity — ~50% — HP:0002829 (Impaired pain sensation) - Dystonia and Parkinsonian features can emerge in late childhood/adolescence — HP:0001332 (Dystonia)

Autonomic: - Central hypoventilation/apnea (nocturnal) — ~82% — HP:0004926 (Central sleep apnea) - Gastroesophageal reflux disease — ~94% — HP:0002020 (Gastroesophageal reflux) - Dysphagia — ~53%; recurrent aspiration — ~71% — HP:0002015 (Dysphagia), HP:0002835 (Recurrent aspiration pneumonia) - Gastrointestinal dysmotility — HP:0002579 (Intestinal pseudo-obstruction/dysmotility spectrum)

Dysmorphic/growth: - Mild brachycephalic microcephaly — ~59% — HP:0000252 (Microcephaly), HP:0000248 (Brachycephaly) - Short stature — ~58% — HP:0004322 - Short/broad neck, low anterior hairline, retrocollis posture — ~52% — HP:0000470 (Short neck) - Coarse facial features — HP:0000280

Onset/severity/progression characteristics: - Age of onset: infancy (motor delay, hypotonia typically noted in the first year) - Severity: variable but generally severe; most patients never achieve independent ambulation or full expressive speech - Progression: progressive/neurodegenerative course — possible regression in the second decade with loss of previously acquired ambulation; not static like cerebral palsy - Course pattern: chronic progressive, punctuated by acute respiratory/aspiration crises

Quality-of-life impact: Severe — near-universal loss of independent mobility and communication, lifelong dependence for feeding (often gastrostomy) and respiratory support (noninvasive ventilation), and premature mortality (see §11). No formal EQ-5D/SF-36 studies exist for this ultra-rare disorder; QoL data are qualitative, from natural-history/clinical cohort descriptions.

4. Genetic/Molecular Information

Causal gene: TECPR2 (Tectonin Beta-Propeller Repeat Containing 2), chr14q32.31; OMIM *615000; HGNC:19957; NCBI Gene 9895; Ensembl ENSG00000122986; UniProt O15040 (GeneCards; UniProt).

Variant classes (ClinVar/GeneReviews): predominantly frameshift, nonsense, and canonical splice-site variants producing a truncated/degraded protein (loss-of-function mechanism); a substantial minority (~half of reported alleles) are missense variants, clustering in the N-terminal WD/beta-propeller domain and the C-terminal six-TECPR-repeat domain — but ACMG/AMP classification of these missense alleles remains challenging due to limited functional-assay throughput (PMID:33847017). Sequence analysis (panel/exome/genome) detects essentially all reported pathogenic variants; larger structural deletions/duplications are rare but should be tested if sequencing is negative.

Representative pathogenic variants: - c.3416delT, p.Leu1139ArgfsTer75 — Bukharian Jewish founder (PMID:23176824) - c.1319delT, p.Leu440ArgfsTer19 — Ashkenazi Jewish founder (PMID:26542466), later used as the target of a splice-modulating antisense oligonucleotide (see §12) - c.2578+2T>C (splice donor variant) — reported in ClinVar for HSP49 - c.2599G>T, p.Glu867Ter — nonsense variant (ClinVar) - Additional missense and truncating alleles reported in a Chinese patient (PMID:35130874) and other worldwide cases, confirming genetic heterogeneity beyond the two founder populations.

Allele frequency in population databases: TECPR2 is a loss-of-function-intolerant gene in gnomAD (constrained; specific LOEUF/pLI value not independently confirmed in this search but the gene shows depletion of predicted-LoF variants consistent with recessive-disease constraint). Carrier frequency estimates from founder populations: ~1.33% in Bukharian Jews, ≥0.65% in Ashkenazi Jews (GeneReviews NBK584409). Estimated disease incidence ranges from ~1:22,500 in the Bukharian Jewish population to ~1:5,961,640 in the general population.

Somatic vs. germline: All reported variants are germline; there is no somatic/mosaic or cancer association.

Functional consequence: Loss of function predominates — nonsense/frameshift alleles cause nonsense-mediated decay or produce a truncated, non-functional protein; missense alleles are hypothesized to destabilize the WD/beta-propeller or TECPR domains. No gain-of-function or dominant-negative mechanism has been established for the classic biallelic disease, though the separately-described heterozygous cerebellar-atrophy phenotype (PMID:34994087) raises the possibility of haploinsufficiency or dominant-negative effects for a subset of heterozygous variants.

Modifier genes: None formally established.

Epigenetic information: No disease-specific DNA methylation, histone modification, or chromatin studies have been reported for TECPR2-related disease.

Chromosomal abnormalities: Not a contiguous-gene/CNV disorder in the classic sense; disease is driven by point mutations/small indels within TECPR2, not large chromosomal rearrangements (though large deletion/duplication testing is part of the standard diagnostic algorithm when sequencing is uninformative).

5. Environmental Information

No environmental toxins, occupational exposures, radiation, or lifestyle factors are implicated in causing SPG49/HSAN9 — it is a fully penetrant monogenic recessive disorder. No infectious triggers or pathogens are causally implicated (though recurrent respiratory infections/pneumonia are a major complication, not a cause, driven by aspiration secondary to dysphagia and hypotonia). No CTD/TOXNET or CDC/WHO environmental-exposure signal was identified for this gene-disease pair.

6. Mechanism / Pathophysiology

Core molecular lesion — autophagosome–lysosome fusion defect. TECPR2 is a large multidomain protein: an N-terminal WD/beta-propeller domain, a middle unstructured region, and a C-terminal domain of six TECPR repeats followed by an LC3-interacting region (LIR) motif. TECPR2 was identified as a human ATG8-family (LC3) interactor and positive regulator of autophagy, functioning specifically in targeting of autophagosomes to lysosomes via its C-terminal TECPR domain (UniProt O15040; PMID:23176824). Loss of TECPR2 causes decreased levels of autophagy markers SQSTM1/p62 and lipidated LC3-II in patient fibroblasts, and — in mouse and dog models — progressive, age-dependent accumulation of undegraded autophagosomes in neurons.

Second, distinct mechanism — ER exit site (ERES)/COPII secretory defect. TECPR2 also cooperates with the ATG8-family protein LC3C to regulate COPII-dependent ER export: it associates with the COPII coat protein SEC24D, stabilizing SEC24D levels and maintaining functional ER exit sites; TECPR2-deficient patient cells show altered SEC24D abundance and impaired ER export efficiency (Stadel et al. 2015, Mol Cell, PMID:26431026; confirmed and extended by spatial proteomics in Nature Communications 2023). This links TECPR2 loss to a broader secretory-pathway disturbance, not autophagy alone.

Endolysosomal maturation defect (most recent mechanistic advance, 2025). A newly published TECPR2 nonsense knock-in mouse model shows that TECPR2 interacts with the HOPS (homotypic fusion and protein sorting) tethering complex through its middle region and TECPR domain, and that loss of TECPR2 produces a broader dysfunctional endolysosomal system in both neurons and microglia — not merely blocked autophagosome-lysosome fusion. Affected axons accumulate swollen mitochondria, enlarged ER, autophagosomes, glycogen granules, and protein aggregates; microglia adopt a disease-associated phenotype with enlarged lysosomes but reduced capacity to clear neuronal debris, implicating impaired neuroimmune clearance in disease progression ([Cell Death & Disease, 2025, PMID:41173829, DOI:10.1038/s41419-025-08168-w]).

Causal chain (upstream → downstream): 1. Biallelic LoF TECPR2 variants → loss of TECPR domain-mediated autophagosome-lysosome tethering and SEC24D/COPII stabilization (molecular) 2. → Impaired autophagic flux (LC3-II/p62 dysregulation) + impaired ER export/secretory pathway function + impaired HOPS-mediated endolysosomal maturation (cellular) 3. → Progressive accumulation of undegraded autophagosomes, protein aggregates, and organellar damage (swollen mitochondria, enlarged ER) selectively in long axons of sensory/autonomic pathways — particularly the dorsal column nuclei (gracile and cuneate nuclei) and corticospinal tracts (tissue/cellular) 4. → Neuroaxonal dystrophy with axonal spheroid formation, age-dependent neurodegeneration, and secondary microglial dysfunction/disease-associated gliosis that fails to clear debris (tissue) 5. → Clinical phenotype: progressive spastic-ataxic gait disorder, sensory neuropathy, autonomic dysfunction (central hypoventilation, dysmotility), developmental delay, and premature death from respiratory/aspiration complications (organism level)

Suggested ontology terms: - GO (biological process): GO:0000045 (autophagosome assembly), GO:0000422 (autophagy of mitochondrion / mitophagy), GO:0016237 (lysosomal microautophagy) — most specifically GO:0061908 (autophagosome-lysosome fusion, note: verify exact ID against OAK) or the closest reachable macroautophagy child term; GO:0048208 (COPII vesicle coating); GO:0006888 (ER to Golgi vesicle-mediated transport) - GO (cellular component): GO:0005776 (autophagosome), GO:0005764 (lysosome), GO:0070081 (ER exit site — verify against OAK), GO:0030904 (HOPS complex if bindable) - CL (cell type): CL:0000540 (neuron), CL:0000031 (central nervous system neuron — sensory dorsal-column neuron), CL:0000129 (microglial cell) - UBERON: UBERON:0002771 (nucleus gracilis / dorsal column nuclei — verify exact term), UBERON:0002298 (dorsal column of spinal cord), UBERON:0001851 (corticospinal tract)

Immune involvement: Secondary — disease-associated microglial activation with impaired debris clearance (2025 knock-in mouse data), not primary autoimmunity.

Molecular profiling data available: Spatial proteomics of the secretory pathway in TECPR2-deficient cells (Nature Communications 2023); transcriptomic/proteomic/electron-microscopy characterization of the 2025 knock-in mouse model. No published human transcriptomic/GEO datasets specific to patient tissue were identified in this search.

7. Anatomical Structures Affected

Organ level: - Primary: central and peripheral nervous system (brain, spinal cord — especially dorsal columns/gracile and cuneate nuclei, corticospinal tracts, cerebellum), autonomic nervous system - Secondary: respiratory system (recurrent aspiration pneumonia, chronic lung disease from hypoventilation), gastrointestinal tract (dysmotility, reflux) - Body systems: nervous system (primary), respiratory system, digestive system, musculoskeletal system (contractures secondary to spasticity)

Tissue/cell level: - Long-tract sensory and motor axons (corticospinal tract, dorsal column pathways) — the primary site of neuroaxonal dystrophy - Cerebellum — progressive cerebellar atrophy (particularly documented in the heterozygous phenotype, PMID:34994087, and as an MRI feature in some biallelic patients) - Microglia — CNS resident immune cells implicated in the 2025 mechanistic model - Cell Ontology: CL:0000540 (neuron), CL:0000129 (microglial cell), CL:11000015 (or nearest CL term for dorsal column/gracile nucleus neuron)

Subcellular level: autophagosomes (GO:0005776), lysosomes (GO:0005764), ER exit sites/COPII vesicles (GO:0070081), mitochondria (swollen/dysmorphic in affected axons per 2025 model)

Localization/lateralization: Bilateral, symmetric involvement — consistent with a metabolic/degenerative rather than focal-lesion process. Neuroimaging shows thin/dysplastic corpus callosum (~52% in the Neuser 2021 cohort), mild ventriculomegaly, delayed myelination, and cerebral/cerebellar atrophy.

8. Temporal Development

Onset: Infancy — hypotonia and motor developmental delay are typically the presenting features, with delayed acquisition of independent walking (insidious, not acute onset).
Progression: Neurodegenerative and progressive rather than static. Course: hypotonia in infancy → spastic-ataxic gait pattern emerging in childhood → possible regression in the second decade with loss of previously achieved independent ambulation → lower-limb spasticity, dystonia, and Parkinsonian features can emerge in late childhood/adolescence.
Disease stages: no formal staging system exists (unlike cancer); natural-history descriptions divide the course into early developmental-delay phase, a plateau/functional phase, and a later regressive phase.
Rate: variable but generally described as slowly-to-moderately progressive over years to a decade or more.
Duration/outcome: chronic, lifelong, generally fatal in childhood/adolescence (see §11).
Remission: none described — this is a monogenic neurodegenerative disorder without a relapsing-remitting pattern.
Critical periods: early intervention (physical/occupational/speech therapy, early respiratory and nutritional surveillance) is emphasized in management guidance, though no data show a defined "window" that alters the underlying neurodegenerative trajectory.

9. Inheritance and Population

Epidemiology: - Prevalence: <1 per 1,000,000 (Orphanet ORPHA:320385) — an ultra-rare disease with >30–40 reported affected individuals in the literature to date. - Incidence estimates: ~1:22,500 in the Bukharian Jewish population vs. ~1:5,961,640 in the general population (GeneReviews NBK584409), reflecting the founder-effect concentration of disease in specific communities.

Inheritance pattern: Autosomal recessive for the classic biallelic SPG49/HSAN9 phenotype. A separately reported heterozygous (monoallelic) TECPR2 variant phenotype causes progressive cerebellar atrophy with developmental delay — a milder, likely dominantly-acting or haploinsufficient presentation, genetically distinct from the recessive syndrome (PMID:34994087).

Penetrance: Complete/full penetrance reported for biallelic pathogenic variants (all identified biallelic carriers to date are symptomatic); carriers of a single pathogenic allele in the recessive form are asymptomatic.

Expressivity: Variable — even individuals homozygous for the same founder allele show a range of severity in developmental, respiratory, and orthopedic manifestations.

Genetic anticipation: Not reported/not applicable (not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented in the literature reviewed.

Founder effects (population-specific mutations): - Bukharian Jewish: c.3416delT, p.Leu1139ArgfsTer75 — carrier frequency ~1.33% - Ashkenazi Jewish: c.1319delT, p.Leu440ArgfsTer19 — carrier frequency ≥0.65%

Consanguinity: A substantial contributor — approximately half of affected individuals are born to consanguineous parents (GeneReviews), consistent with an autosomal recessive ultra-rare disease outside the two known founder populations.

Carrier frequency: See founder effects above; carrier screening panels for Ashkenazi and Bukharian Jewish populations increasingly include TECPR2.

Affected populations / geographic distribution: Original description in Bukharian Jewish families (Israel/Central Asian Jewish diaspora); Ashkenazi Jewish founder variant subsequently described; sporadic cases reported worldwide including a Chinese patient (PMID:35130874) and other non-founder populations reported in the 2021 international cohort (PMID:33847017), indicating global but very low-frequency occurrence outside founder populations.

Sex ratio: No sex predilection reported (autosomal gene).

Age distribution: Pediatric-onset disease; the affected population by definition skews toward children and adolescents given reduced life expectancy.

10. Diagnostics

Establishing the diagnosis requires identification of biallelic pathogenic/likely pathogenic TECPR2 variants in an individual with the compatible phenotype (GeneReviews NBK584409).

Molecular/genetic testing approaches: - Targeted founder-variant testing — first-line in Ashkenazi or Bukharian Jewish ancestry (c.1319delT / c.3416delT) - Multigene panels for hereditary spastic paraplegia or hereditary sensory/autonomic neuropathy - Exome or genome sequencing — comprehensive approach for non-founder-population or panel-negative cases; sequence analysis detects an estimated ~100% of reported pathogenic variant types (missense, nonsense, splice-site, small indels) - Deletion/duplication (CNV) analysis — reserved for cases where sequencing is uninformative, since large structural variants are rare in this gene

Neuroimaging (MRI) findings supporting diagnosis: thin/dysplastic corpus callosum (~52%), mild ventriculomegaly, delayed myelination, cerebral and/or cerebellar atrophy, flattening of the pons (particularly noted in the heterozygous cerebellar-atrophy phenotype, PMID:34994087).

Clinical/biochemical testing: No specific validated biomarker or enzyme assay exists; diagnosis is clinical + molecular. Research-grade autophagy-flux assays (LC3-II, p62 immunoblotting in patient fibroblasts) were used investigationally in the original description but are not a standard diagnostic test.

Differential diagnosis (per GeneReviews): - HSAN3 (familial dysautonomia, ELP1/IKBKAP) — usually milder intellectual disability; distinguishing features include alacrima and decreased fungiform tongue papillae - HSAN4 (NTRK1) — painless deformities and anhidrosis with episodic fevers - HSAN5 (NGF) — painless deformities; borderline/mild intellectual disability - Cerebral palsy — excluded by absence of perinatal risk factors and by the progressive course of SPG49/HSAN9 versus the static course of CP - Other complex/AR hereditary spastic paraplegias in the broader SPG differential

Screening: No population newborn-screening program exists (ultra-rare disease); however, targeted carrier screening for the Ashkenazi and Bukharian Jewish founder variants is increasingly incorporated into expanded Jewish genetic disease panels, and prenatal/preimplantation genetic testing is available once familial variants are identified.

11. Outcome/Prognosis

Prognosis is poor. GeneReviews explicitly notes "reduced life expectancy," with deaths occurring in the first or second decade of life in a substantial proportion of reported cases.

Leading causes of mortality: - Asphyxia from aspiration of solid foods - Nocturnal central apnea - Complications of chronic, progressive lung disease (recurrent aspiration pneumonia, respiratory failure)

Morbidity/functional outcomes: - Progressive loss of independent ambulation (many patients regress and lose walking ability in the second decade) - Persistent severe intellectual disability; many individuals remain nonverbal lifelong - Chronic respiratory disease requiring long-term noninvasive ventilation in a majority of patients - Feeding dependence (gastrostomy) common given the high rates of dysphagia (53%) and reflux (94%) - Orthopedic complications (contractures) from progressive spasticity

Recovery potential: None — this is a progressive neurodegenerative disorder; there is no reported spontaneous improvement, and no disease-modifying therapy currently exists to alter the trajectory (see §12).

Prognostic factors: No formal validated prognostic scoring system exists; qualitatively, earlier/more severe respiratory and bulbar (dysphagia) involvement correlates with worse outcomes, consistent with the mortality causes above.

12. Treatment

No curative or disease-modifying therapy is currently approved. Management is entirely supportive and multidisciplinary (GeneReviews NBK584409):

Respiratory: polysomnography for central hypoventilation/apnea surveillance, noninvasive ventilation, oxygen monitoring — NCIT:C15747 (Supportive Care); relevant NCIT concept for noninvasive ventilation/respiratory support
Gastroenterology/nutrition: swallow evaluation, feeding adaptations, consideration of gastrostomy, reflux management — NCIT:C15447 (Dietary Intervention); NCIT:C15986 (Pharmacotherapy, for anti-reflux medication such as proton-pump inhibitors)
Orthopedic/rehabilitative: bracing, physical therapy to prevent contractures — NCIT:C15302 (Physical Therapy), NCIT:C16186 (Orthopedic Surgical Procedure)
Behavioral: applied behavior analysis for autism-spectrum features — NCIT:C181743 (Behavioral Counseling) or nearest behavioral-intervention term
Developmental: early intervention services, special education, speech-language pathology — NCIT:C159273 (Speech Therapy)
Genetic counseling: NCIT:C15240 (Genetic Counseling), given autosomal recessive inheritance and available carrier/prenatal testing

Drugs to avoid: Benzodiazepines and antihistamines are explicitly flagged because they risk decreased consciousness, hypopnea, and CO₂ retention in a population already prone to central hypoventilation.

Experimental/investigational therapy — antisense oligonucleotide (ASO) exon-skipping: A 2022 study developed an ASO exon-skipping strategy targeting the Ashkenazi founder variant TECPR2 c.1319delT (p.Leu440Argfs19), which causes a premature stop codon within exon 8 (Molecular Therapy Nucleic Acids, PMID:35860385): - Patient-derived fibroblasts and iPSC-derived neurons homozygous for this variant were used as disease models, both showing complete absence of TECPR2 protein. - Lead candidate ASO-005-02 achieved ~27 nM potency in patient fibroblasts, inducing skipping of exon 8 to restore an in-frame, partially functional TECPR2ΔEx8 protein that retained the characteristic punctate neuronal localization of wild-type TECPR2 in iPSC-derived neurons. - In vivo testing in cynomolgus monkeys (single 20 mg intrathecal dose) showed an acceptable tolerability profile with broad CNS distribution and confirmed exon-8 skipping across multiple CNS tissues — representing a preclinical proof-of-concept for a precision, genotype-specific splice-modulation therapy* (therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE; aso_mechanism: SPLICE_MODULATION_EXON_SKIPPING; target_gene: TECPR2 (hgnc — verify correct lowercase HGNC numeric ID); target_exon: exon 8).

This ASO has not, to my knowledge from this search, progressed to a registered human clinical trial (no NCT identifier found); it remains at the primate/preclinical stage as of the most recent identified publication (2022).

No approved gene therapy, cell therapy, small-molecule, or targeted pharmacotherapy exists for the underlying TECPR2 autophagy/secretory defect.

13. Prevention

Primary prevention: genetic counseling and carrier screening in at-risk populations (Ashkenazi and Bukharian Jewish communities) to inform reproductive decision-making; the disease itself cannot be prevented once biallelic pathogenic genotype is present.
Secondary prevention: prenatal diagnosis and preimplantation genetic testing (PGT) are available once familial pathogenic variants are identified, allowing at-risk couples to avoid transmission or to prepare for early postnatal management.
Tertiary prevention (preventing complications in affected individuals): proactive respiratory surveillance (polysomnography, timely initiation of noninvasive ventilation) and aspiration-risk management (swallow studies, feeding modification/gastrostomy) are the most clinically consequential preventive measures, since aspiration and central apnea are the leading causes of death.
Immunization: no disease-specific vaccine strategy; standard respiratory-pathogen vaccination (influenza, pneumococcal, RSV prophylaxis where age-appropriate) is prudent given the high burden of recurrent aspiration pneumonia, though this is general supportive practice rather than a TECPR2-specific published recommendation.
Screening programs: no population-based newborn screening exists for this ultra-rare disorder; screening is limited to targeted carrier testing in founder populations.
Behavioral/public health interventions: not applicable beyond genetic counseling, given the purely monogenic etiology.

14. Other Species / Natural Disease

Naturally occurring TECPR2-related disease in animals — Spanish Water Dog neuroaxonal dystrophy: A naturally occurring, homologous disease was described in Spanish Water Dogs (Canis lupus familiaris, NCBITaxon:9615): four dogs presented with slowly progressive neurological signs (gait abnormalities, behavioral deficits) beginning at 6–11 months of age, segregating in an autosomal recessive pattern. Whole-genome/exome analysis identified a single, perfectly associated non-synonymous canine TECPR2 variant, c.4009C>T (p.R1337W) (Hahn et al. 2015, PLOS ONE, PMID:26555167). Histopathology showed axonal spheroid formation concentrated in the grey matter of cerebral hemispheres, cerebellum, brainstem, and spinal cord sensory pathways — with no iron accumulation — and ultrastructurally the spheroids contained densely packed double-membraned vesicles characterized as autophagosomes, closely mirroring the human disease mechanism. This is catalogued in OMIA as OMIA:001975-9615 (Neuroaxonal dystrophy, TECPR2-related, in dog). Commercial genetic panels (e.g., Paw Print Genetics) now offer this as a breed-specific test, giving it real veterinary screening relevance for Spanish Water Dog breeding programs.

Comparative biology: The dog phenotype (progressive neuroaxonal dystrophy with autophagosome accumulation in sensory/motor long tracts) closely parallels both the human disease and the engineered mouse models, supporting deep evolutionary conservation of TECPR2's role in axonal autophagosome clearance across mammals.

Zoonotic potential/transmission: Not applicable — this is a purely genetic, non-infectious, non-transmissible disorder.

15. Model Organisms

Mouse models (Mus musculus, NCBITaxon:10090; MGI:2144865, Tecpr2):

CRISPR-Cas9 Tecpr2⁻/⁻ knockout mouse (Tamim-Yecheskel et al. 2021, Autophagy; also referenced as PMID:33218264 in GeneReviews):
Recapitulates behavioral pathology seen in SPG49 patients.
Develops age-dependent neuroaxonal dystrophy, predominantly in the gracile (GrN) and cuneate nuclei (CuN) of the medulla oblongata and the dorsal white matter column of the spinal cord — anatomically matching the human dorsal-column sensory pathway involvement.
Shows age-dependent accumulation of autophagosomes, consistent with a defect in autophagosome-to-lysosome targeting.
Limitation: a knockout (complete null) model may not fully recapitulate the partial loss-of-function seen with some human missense alleles, and mice do not model the severe intellectual disability/speech phenotype central to the human disease (behavioral correlates in rodents are necessarily indirect).
TECPR2 nonsense knock-in mouse (2025) (Cell Death & Disease, PMID:41173829):
Carries the HSAN9-associated nonsense mutation directly (more genetically faithful than a full knockout).
Exhibits gait ataxia, axonal spheroids in sensory medullary regions, and progressive neuronal loss in dorsal column nuclei.
Reveals broader endolysosomal dysfunction beyond autophagosome-lysosome fusion, including TECPR2–HOPS complex interaction, organellar damage (swollen mitochondria, enlarged ER) in affected axons, and a maladaptive microglial disease-associated phenotype with enlarged lysosomes but reduced neuronal-debris clearance capacity.
This is the most mechanistically comprehensive model to date, integrating proteomics, transcriptomics, and electron microscopy.
Applications: studying endolysosomal/autophagy-microglia crosstalk in neurodegeneration; a platform for testing autophagy-enhancing or endolysosomal-targeted small molecules.

Naturally occurring large-animal model: The Spanish Water Dog (see §14) functions as a spontaneous, naturally occurring genetic model complementing the engineered mouse lines, valuable because it arises from an endogenous missense variant (p.R1337W) rather than an engineered null allele.

Cellular models: - Patient-derived dermal fibroblasts — used in the original 2012 description to demonstrate reduced LC3-II/p62 (autophagy flux defect), and subsequently in the 2022 ASO study. - Patient-derived iPSC-derived neurons (homozygous for c.1319delT) — used to confirm absence of TECPR2 protein and to validate ASO-induced exon-skipping and restoration of the characteristic punctate neuronal TECPR2 localization pattern (Molecular Therapy Nucleic Acids, PMID:35860385).

Resources: MGI (Tecpr2, MGI:2144865) for mouse strain/allele information; OMIA:001975-9615 for the canine model.

Summary of Key Ontology-Term Suggestions for KB Curation

Category	Suggested term(s)
Disease	MONDO:0014016; OMIM:615031; ORPHA:320385
Gene	HGNC:19957 (TECPR2) — verify exact numeric HGNC ID against the local `hgnc` OAK adapter before curating
Core phenotypes (HP)	HP:0001263 (Developmental delay), HP:0001249 (Intellectual disability), HP:0001252 (Hypotonia), HP:0002066 (Gait ataxia), HP:0001258 (Spasticity), HP:0002522 (Areflexia), HP:0001260 (Dysarthria), HP:0002829 (Impaired pain sensation), HP:0004926 (Central sleep apnea), HP:0002020 (Gastroesophageal reflux), HP:0002015 (Dysphagia), HP:0002835 (Recurrent aspiration pneumonia), HP:0000252 (Microcephaly), HP:0000708 (Behavioral abnormality)
Biological process (GO)	macroautophagy / autophagosome maturation and fusion with lysosome, COPII vesicle coating, ER-to-Golgi transport
Cellular component (GO)	autophagosome (GO:0005776), lysosome (GO:0005764), ER exit site
Cell types (CL)	neuron (CL:0000540), microglial cell (CL:0000129)
Anatomy (UBERON)	dorsal column of spinal cord, gracile/cuneate nuclei, cerebellum, corticospinal tract
Treatment (NCIT)	C15747 (Supportive Care), C15302 (Physical Therapy), C15240 (Genetic Counseling), C15447 (Dietary Intervention)
Inheritance	HP:0000007 (Autosomal recessive inheritance)

Note on curation caveats: Every ontology CURIE above should be verified against the dismech OAK adapters (just validate-terms) before use, since several (exact HGNC numeric ID, exact GO autophagosome-lysosome-fusion child term, exact UBERON dorsal-column-nucleus term) were not independently cross-checked against a live ontology lookup in this research pass and are offered as strong candidates rather than confirmed bindings.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	14
On topic	10
Off topic	0

All extracted references resolved successfully.

Hereditary Spastic Paraplegia 49

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Hereditary Spastic Paraplegia 49 (SPG49) / TECPR2-Related Disorder — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

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15. Model Organisms

Summary of Key Ontology-Term Suggestions for KB Curation

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