Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease

Mendelian MONDO:0024189 Pathograph 27 Show in embeddings browser Genetic Disorder

IMNEPD is the autosomal recessive multisystem disorder caused by biallelic PTRH2 variants, delineated in 2014 in two siblings of a consanguineous Yazidian-Turkish family. Roughly thirty patients have been published, almost all from consanguineous Middle Eastern and North African families, and a single recurrent missense allele, p.Gln85Pro, accounts for about half of them. The clinical picture is neurologically weighted despite the name. Motor delay, peripheral neuropathy, intellectual disability, distal muscle weakness, sensorineural hearing impairment and ataxia are the features reported most often; progressive cerebellar atrophy is the imaging correlate of the ataxia. The endocrine and pancreatic features that the name foregrounds -- exocrine pancreatic insufficiency, diabetes mellitus, hypothyroidism, liver abnormality -- are real but less consistent, and an entry read only from the disease name would overweight them. PTRH2 is a mitochondrial protein with two jobs, and which of them the disease runs through is not settled. It is a peptidyl-tRNA hydrolase, a translation quality-control enzyme. It is also an adhesion-regulated survival switch: bound to focal adhesion kinase in matrix-attached cells it supports survival signalling, and on matrix detachment it is released into the cytosol where it drives caspase-independent anoikis. The mechanism worked out in mouse runs through neither hydrolase chemistry nor anoikis directly, but through mTOR: a Purkinje-cell-specific Ptrh2 knockout loses phosphorylated ribosomal protein S6, develops stunted dendrites and atrophic Purkinje cells, and ends in progressive cerebellar atrophy and ataxia. That model is the strongest mechanistic evidence this disease has, and it is a mouse. There is no disease-modifying therapy. Management is supportive and multidisciplinary.

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1
Mappings
1
Inheritance
5
Pathophys.
17
Phenotypes
2
Gaps
27
Pathograph
1
Genes
2
Variants
3
Medical Actions
1
Models
7
References
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Mappings

MONDO
MONDO:0024189 neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic PTRH2 variants, homozygous in essentially every published family. Nearly all reported families are consanguineous, which is both how the gene was found -- homozygosity mapping plus exome sequencing in the founding family -- and why the allele spectrum is dominated by one recurrent missense change rather than by many private ones.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25574476 SUPPORT Human Clinical
"In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene."
The founding observation: a homozygous variant in a consanguineous family, which is the segregation argument for recessive inheritance and the first link of this gene to any disease.
PMID:27129381 SUPPORT Human Clinical
"Here, we report five further IMNEPD patients from two consanguineous families with a PTRH2 missense mutation and discuss their phenotype, thereby illustrating both core and variable features of IMNEPD."
Independent consanguineous families with a different allele, which is what moved the gene-disease relationship past a single family.
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Discussions and Knowledge Gaps

2
Does IMNEPD run through PTRH2's peptidyl-tRNA hydrolase activity, its adhesion-regulated survival signalling, or neither directly?
KNOWLEDGE GAP OPEN gap_imnepd_which_ptrh2_function_causes_the_disease
Attached to
pathophysiology#PTRH2 Loss of Function pathophysiology#Loss of Adhesion-Dependent Survival Signalling
PTRH2 has two well-characterised and unrelated functions, and the disease literature routes through a third observation, reduced mTOR activation, whose connection to either is unexplained. The hydrolase activity is a mitochondrial translation quality-control step; the BIT1 anoikis work is cell-biological, predates the disease by a decade, and has never been shown dysregulated in patient tissue. Neither has been tested against the disease by the obvious experiment: a separation-of-function allele. The recurrent p.Gln85Pro variant destabilises the protein and so removes both functions at once, which is why the commonest allele cannot distinguish them. The stake is not academic, because mTOR is druggable and the other two arms are not: if the cerebellar phenotype is an mTOR-deficit phenotype, an mTOR-directed intervention is a coherent thing to test, and if it is a translation quality-control failure it is not.
Proposed experiments
Hydrolase-dead versus adhesion-signalling-dead PTRH2 knock-in mice
exp_imnepd_separation_of_function_alleles
Generate knock-in mice carrying a catalytically dead PTRH2 and, separately, an allele that disrupts the FAK interaction while preserving hydrolase activity, and compare Purkinje cell size, phosphorylated S6 and gait against the conditional knockout. Either allele reproducing the phenotype would assign the disease to that arm; neither doing so would say the relevant function is a third one.
Is the pancreatic, thyroid, hepatic and peripheral nerve involvement in IMNEPD produced by the same mTOR-dependent cell attrition demonstrated in Purkinje cells, or by something else?
HUMAN MODEL MISMATCH OPEN gap_imnepd_extracerebellar_mechanism
Attached to
pathophysiology#Post-Mitotic Cell Attrition Outside the Cerebellum
The cerebellar arm of this disease has a clean cell-autonomous mouse demonstration. No other organ does. The constitutive knockout, which would be the model for the multisystem phenotype, dies by postnatal day 14 and so cannot express a phenotype that in patients appears over years, with diabetes reported as late as age 12. Every extracerebellar edge in this entry is therefore an extrapolation from one cell type in one tissue, and the entry marks them INDIRECT_UNKNOWN_INTERMEDIATES for that reason. This is a model-fidelity gap rather than an absence of evidence: the evidence exists, in mouse, for a compartment that does not include the organs the disease is named after.
Proposed experiments
Pancreatic and Schwann cell conditional Ptrh2 knockouts
exp_imnepd_tissue_specific_conditional_knockouts
Delete Ptrh2 in pancreatic acinar cells and, separately, in Schwann cells, in animals that survive to adulthood, and test whether exocrine insufficiency and demyelinating neuropathy arise cell-autonomously with the same reduction in phosphorylated S6 seen in Purkinje cells.
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Pathophysiology

5
PTRH2 Loss of Function
Biallelic PTRH2 variants. The reported alleles are the founding frameshift c.269_270delCT and the recurrent missense p.Gln85Pro, which accounts for about half of published cases and acts by destabilising the protein rather than by abolishing transcription: patient fibroblasts carrying it have normal PTRH2 mRNA and strongly reduced protein.
PTRH2 hgnc:24265 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PTRH2 (hgnc:24265). hgnc:24265 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
peptidyl-tRNA hydrolase activity GO:0004045 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased peptidyl-tRNA hydrolase activity (GO:0004045). GO:0004045 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced mTOR Pathway Activation The step the disease is understood through, and the one whose intermediate chemistry is missing. PTRH2 loss reduces mTOR activation in patient cells and in mutant mouse brain, but no published work shows how a peptidyl-tRNA hydrolase or an adhesion-signalling scaffold produces that.
Loss of Adhesion-Dependent Survival Signalling PTRH2 is itself the adhesion-regulated switch, so losing it removes the function directly rather than through an intermediate.
Show evidence (2 references)
PMID:25574476 SUPPORT Human Clinical
"PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling."
What the protein is and where it acts, from the paper that connected it to disease.
PMID:27129381 SUPPORT Human Clinical
"Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation."
A second allele in independent families. The phrase "associated with a unique mutation" is the report's own framing of why one recurrent allele dominates the published series.
Loss of Adhesion-Dependent Survival Signalling
PTRH2, as BIT1, is a mitochondrial protein released into the cytosol when a cell loses contact with the extracellular matrix, where it complexes with the Groucho/TLE protein AES and drives caspase-independent apoptosis. Attachment to fibronectin counteracts it. So the wild-type protein sits on both sides of a survival decision, and losing it removes both the death signal and the attachment-dependent survival arm. This node is the mechanism most often quoted for IMNEPD and the one least connected to it: the anoikis work is cell-biological and predates the disease, and no published study demonstrates dysregulated anoikis in patient tissue. It is recorded because it is what PTRH2 does, with the gap stated rather than bridged.
cell-matrix adhesion GO:0007160 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell-matrix adhesion (GO:0007160). GO:0007160 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Post-Mitotic Cell Attrition Outside the Cerebellum The proposed route from the anoikis switch to tissue loss. It is drawn because the survival function is what the attrition node claims fails, and it is marked as having unknown intermediates because no study demonstrates dysregulated anoikis in any patient tissue.
Show evidence (2 references)
PMID:15006356 SUPPORT In Vitro
"Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein, and induces cell death with characteristics of caspase-independent apoptosis."
The anoikis mechanism, established in cell culture ten years before PTRH2 was linked to any disease. It describes the protein, not this disease.
PMID:15006356 SUPPORT In Vitro
"Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES."
The adhesion dependence that makes this a switch rather than a constitutive death signal.
Reduced mTOR Pathway Activation
Reduced mTOR signalling, read out as lower phosphorylated ribosomal protein S6. It is present in patient fibroblasts and in mutant mouse brain, and in the Purkinje-cell-specific knockout it sits alongside reduced cell size, stunted dendrites and eventual cell loss. Because mTOR sets cell mass, this is the node that makes an atrophy phenotype out of a translation-and-adhesion protein.
TOR signaling GO:0031929 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased TOR signaling (GO:0031929). GO:0031929 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Post-Mitotic Cell Attrition Outside the Cerebellum The same mTOR deficit is proposed to underlie the extracerebellar phenotype, on the strength of reduced phosphorylated S6 in patient fibroblasts and in mutant mouse brain. No conditional knockout outside the Purkinje cell has been reported, so this edge is an extrapolation from the one compartment where it was demonstrated.
Purkinje Cell Atrophy and Loss Demonstrated cell-autonomously: deleting Ptrh2 in Purkinje cells alone lowers pS6 in those cells and produces their atrophy and eventual loss.
Show evidence (1 reference)
PMID:36219306 SUPPORT Model Organism
"PCs of Ptrh2ΔPC mice had reduced cell size and density, stunted dendrites, and lower levels of ribosomal protein S6, a readout of the mammalian target of rapamycin pathway."
The mTOR readout measured in the cells that atrophy, with the marker named and its interpretation stated by the authors.
Purkinje Cell Atrophy and Loss
Progressive loss of Purkinje cells, first as reduced size and density with stunted dendrites and later as frank loss. This is the cellular substrate of the cerebellar atrophy seen on serial MRI in patients, established cell-autonomously in a conditional mouse knockout rather than in human tissue.
Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Purkinje-cell-specific Ptrh2 knockout mouse Mouse recapitulates Reduced Purkinje cell size and density, stunted dendrites, lower phosphorylated ribosomal protein S6, and marked cell loss by adulthood, with progressive cerebellar atrophy and ataxia at the whole-animal level.
Downstream
Ataxia
Cerebellar atrophy
Show evidence (1 reference)
PMID:36219306 SUPPORT Model Organism
"By adulthood, there was a marked loss of PCs. Thus, we identify a cell autonomous requirement for PTRH2 in PC maturation and survival."
The endpoint and the cell-autonomy claim, which together are why this node is placed between the mTOR node and the ataxia phenotype rather than beside them.
Post-Mitotic Cell Attrition Outside the Cerebellum
The same survival failure is proposed to explain the peripheral nerve, muscle, pancreatic, thyroid and liver features, on the argument that PTRH2 is highly expressed in developing tissue and maintains cell survival there. That is the founding paper's framing, and it is a general claim rather than a demonstrated route to any one organ: no conditional knockout outside the Purkinje cell has been reported, so this node is deliberately coarse and its outgoing edges are all INDIRECT_UNKNOWN_INTERMEDIATES.
Downstream
Seizure
Developmental regression
Motor delay
Delayed speech and language development
Peripheral neuropathy
Distal muscle weakness
Sensorineural hearing impairment
Exocrine pancreatic insufficiency
Diabetes mellitus
Hypothyroidism
Abnormality of the liver
Intellectual disability
Secondary microcephaly
Show evidence (1 reference)
PMID:25574476 SUPPORT Human Clinical
"We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development."
The general survival claim this node rests on. Note it is about the developing brain and human tissue development at large, not about pancreas, thyroid or nerve, which is why the edges below are unqualified as to intermediates.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

17
Digestive 2
Exocrine pancreatic insufficiency FREQUENT HP:0001738 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exocrine pancreatic insufficiency (HP:0001738). HP:0001738 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"Meanwhile, the least common characteristics were diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism (~21.9%), and liver abnormality (~17.4%)."
Pancreatic abnormality at about 33.3%. The source's category is broader than exocrine insufficiency alone, which is why the band is assigned from it but the phenotype stays bound to the specific finding the case reports describe.
PMID:25574476 SUPPORT Human Clinical
"The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of..."
Exocrine pancreatic insufficiency in the founding family.
Abnormality of the liver OCCASIONAL HP:0001392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is liver abnormality, annotated with Abnormality of the liver (HP:0001392). HP:0001392 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"Meanwhile, the least common characteristics were diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism (~21.9%), and liver abnormality (~17.4%)."
Liver abnormality at about 17.4%, the least common of the curated features.
PMID:25574476 SUPPORT Human Clinical
"The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of..."
Liver fibrosis in the founding family, described as signs of rather than biopsy-proven.
Ear 1
Sensorineural hearing impairment FREQUENT HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"It was found that the most common clinical characteristics amongst all the patients were motor delay (~94%), neuropathy (~89%), intellectual disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%), and ataxia (~77%)."
Hearing impairment at 78.12%, which is 25 of 32 patients and therefore FREQUENT rather than VERY_FREQUENT. An earlier draft of this entry read the source's qualitative "most common" grouping as implying 80% or above for all six features it names; the numbers show two of the six fall below.
Endocrine 2
Diabetes mellitus FREQUENT HP:0000819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diabetes mellitus (HP:0000819). HP:0000819 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"Meanwhile, the least common characteristics were diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism (~21.9%), and liver abnormality (~17.4%)."
Diabetes mellitus at 40% across all published patients. This is the figure a reader wants and an earlier draft of this entry omitted it.
PMID:36949636 SUPPORT Human Clinical
"At the age of 12 years, patient was diagnosed with insulin-dependent diabetes mellitus when hemoglobin A1c (HbA1c) was 15.3% but was not in ketoacidosis."
A dated, quantified diabetes diagnosis in a genotyped patient.
Hypothyroidism OCCASIONAL HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"Meanwhile, the least common characteristics were diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism (~21.9%), and liver abnormality (~17.4%)."
Hypothyroidism at about 21.9%.
PMID:25574476 SUPPORT Human Clinical
"The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of..."
Hypothyroidism in the founding family.
Head and Neck 2
Secondary microcephaly HP:0005484 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is postnatal microcephaly, annotated with Secondary microcephaly (HP:0005484). HP:0005484 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25574476 SUPPORT Human Clinical
"The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of..."
The founding family's phenotype, which specifies the microcephaly as postnatal.
Abnormality of the face FREQUENT HP:0000271 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is deformity of the head and face, annotated with Abnormality of the face (HP:0000271). HP:0000271 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Deformity of the head and face | 16/30 a (53.33%) |"
The per-phenotype row with its denominator. The trailing footnote marker is part of the cell and is quoted as it appears.
Limbs 1
Abnormality of the hand FREQUENT HP:0001155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is hand deformity, annotated with Abnormality of the hand (HP:0001155). HP:0001155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"| Hand deformity | 18/31 (58.06%) |"
The per-phenotype row from the cohort table, quoted with its denominator rather than only its percentage, so a reader sees that 31 rather than 32 patients had it assessed.
Musculoskeletal 1
Distal muscle weakness VERY_FREQUENT HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"It was found that the most common clinical characteristics amongst all the patients were motor delay (~94%), neuropathy (~89%), intellectual disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%), and ataxia (~77%)."
Distal weakness at 85.2%.
Nervous System 8
Motor delay VERY_FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"It was found that the most common clinical characteristics amongst all the patients were motor delay (~94%), neuropathy (~89%), intellectual disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%), and ataxia (~77%)."
The measured frequencies across all 32 published patients. Motor delay at about 94% is the basis for the VERY_FREQUENT band here.
Peripheral neuropathy VERY_FREQUENT HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"It was found that the most common clinical characteristics amongst all the patients were motor delay (~94%), neuropathy (~89%), intellectual disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%), and ataxia (~77%)."
Neuropathy at about 89% across all published patients.
PMID:25574476 SUPPORT Human Clinical
"The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of..."
The neuropathy characterised as demyelinating and sensorimotor, which the frequency source does not specify.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"It was found that the most common clinical characteristics amongst all the patients were motor delay (~94%), neuropathy (~89%), intellectual disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%), and ataxia (~77%)."
Intellectual disability at 87.5%, that is 28 of 32 patients.
Ataxia FREQUENT HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"It was found that the most common clinical characteristics amongst all the patients were motor delay (~94%), neuropathy (~89%), intellectual disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%), and ataxia (~77%)."
Ataxia at about 77%, which places it just below the VERY_FREQUENT threshold.
Cerebellar atrophy FREQUENT HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"The moderately common characteristics included hand deformity (~58.1%), cerebellar atrophy/hypoplasia (56.5%), and deformity of the head and face (53.3%)."
Cerebellar atrophy or hypoplasia at 56.5%, that is 13 of 23 patients in whom imaging was reported.
PMID:36949636 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) recently reported cerebellar atrophy when compared to normal previous MRI"
Serial imaging in a genotyped patient. The comparison with the earlier normal scan is what makes this progressive atrophy rather than hypoplasia.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is epileptic seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31057140 SUPPORT Human Clinical
"Additional features include epileptic seizures, pancreatic insufficiency, and peripheral neuropathy."
Seizures among the additional features in the three-brother series. No frequency band is assigned: the cohort table does not count seizures.
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is motor and language delay with regression, annotated with Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31057140 SUPPORT Human Clinical
"We describe the core clinical features of postnatal microcephaly, motor and language delay with regression, ataxia, and hearing loss."
The core features of that series, including the regression this entry had not curated.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is severe speech delay, annotated with Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27129381 SUPPORT Human Clinical
"Neurologic core features of (almost) all patients were intellectual disability, motor delay, severe speech delay, ataxia, and sensorineural hearing loss"
Speech delay among the core features. The qualifier "(almost) all" is the authors' own and is why no numeric band is assigned from this sentence.
🧬

Genetic Associations

1
PTRH2
Gene: PTRH2 hgnc:24265 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTRH2 (hgnc:24265). hgnc:24265 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:25574476 SUPPORT Human Clinical
"In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene."
The gene-disease assertion and the founding allele.
PMID:27129381 SUPPORT BACKGROUND Human Clinical
"We further demonstrated the association of a homozygous nonsense mutation in the PTRH2 gene (MIM*608625) to IMNEPD through functional and molecular data in human and mouse [1]."
The authors' own summary of how the gene-disease link was established, naming the human and mouse evidence together. Note this sentence recites their earlier paper rather than reporting a new result.
Variants (2)
c.269_270delCT, p.Ala90fs
Homozygous in the founding Yazidian-Turkish family of two affected siblings. A frameshift, and the allele that established the gene-disease relationship.
Show evidence (1 reference)
PMID:25574476 SUPPORT Human Clinical
"This 2-base pair deletion in the coding sequence of exon 2 of PTRH2 causes a frameshift mutation, leading to a predicted protein truncated by 78 amino acids"
The molecular consequence of the founding allele, stated by the paper that reported it.
c.254A>C, p.Gln85Pro
The recurrent missense allele, reported in multiple unrelated consanguineous families. Patient fibroblasts carrying it have normal PTRH2 mRNA and strongly reduced protein, so it acts by destabilising the protein rather than by preventing its transcription.
Show evidence (1 reference)
PMID:27129381 SUPPORT In Vitro
"PTRH2 protein levels were strongly reduced in fibroblasts from patient II.1, family 2, while PTRH2 mRNA levels were unchanged"
The measurement behind this row's mechanism claim, in fibroblasts from a patient homozygous for this allele. Graded IN_VITRO because the quoted result is a cultured-cell immunoblot and qPCR, whatever the clinical context of the paper reporting it.
💊

Medical Actions

3
Multidisciplinary supportive management
Action: multidisciplinary supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is multidisciplinary supportive care, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
No disease-modifying therapy exists. Management addresses the individual manifestations: developmental and rehabilitative support, audiological management, pancreatic enzyme and thyroid hormone replacement where indicated, and diabetes care. Nothing available targets PTRH2 or the mTOR deficit.
Mechanism Target:
Post-Mitotic Cell Attrition Outside the Cerebellum — Addresses the organ failures the attrition produces. It does not act on the attrition.
Show evidence (2 references)
PMID:31057140 SUPPORT Human Clinical
"however, the related complications of this disorder can be addressed"
The management principle stated as management: there is no specific treatment, and what can be done is directed at the complications. An earlier draft of this entry quoted a sentence about how the diagnosis was reached, which supports the diagnosis section and not this one.
PMID:31057140 SUPPORT Human Clinical
"age-appropriate counselling would be necessary for all affected patients and siblings"
The family arm of management. The sentence this comes from opens by saying genetic testing of parents and siblings determines recurrence risk and carrier status; that clause is quoted here from its second half only, because the cached PDF breaks the word "recurrence" across a line and a folded YAML scalar cannot carry that break without inserting a space inside the word.
Avoidance of valproic acid for seizure control
Action: avoidance of a contraindicated drugNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is avoidance of a contraindicated drug, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
A specific contraindication rather than a general caution. IMNEPD is a mitochondrial cytopathy, so valproic acid carries a risk of toxicity, and the source recommends other antiepileptic medications. This is the one treatment decision in the entry where the genetic diagnosis changes what a clinician should do rather than only what they expect.
Mechanism Target:
Seizure — Seizure control is the goal; the restriction is on which agent achieves it safely, not on whether to treat.
Show evidence (1 reference)
PMID:31057140 SUPPORT Human Clinical
"In the context of seizures, valproic acid toxicity may occur given that IMNEPD is a mitochondrial cytopathy, and therefore, other antiepileptic medications should be used"
The contraindication and its mechanistic reason, stated together. The line breaks are the cached PDF's.
Lipophilic vitamin substitution
Action: lipophilic vitamin substitutionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is lipophilic vitamin substitution, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Platform: Small molecule
Replacement of fat-soluble vitamins, whose deficiency follows the exocrine pancreatic insufficiency. It is the only intervention in this entry with a reported outcome: substitution markedly improved growth in the index patients of the founding family.
Mechanism Target:
Exocrine pancreatic insufficiency — Replaces what the insufficient pancreas fails to let the gut absorb. It does not treat the pancreatic lesion.
Show evidence (1 reference)
PMID:27129381 SUPPORT Human Clinical
"Substitution of lipophilic vitamins in the index patients of the original IMNEPD family markedly improved growth of the patients"
A reported response to treatment, in genotyped patients. It is two patients and an uncontrolled observation, which is why the treatment description says "reported outcome" rather than "efficacy".
🔬

Diagnosis

1
Exome or genome sequencing for biallelic PTRH2 variants
The diagnosis is molecular. The gene was found by homozygosity mapping plus whole-exome sequencing in a consanguineous family, and subsequent cases have been found the same way. There is no biochemical or imaging test specific to the disease: cerebellar atrophy on MRI is supportive and appears late.
Show evidence (2 references)
PMID:25574476 SUPPORT Human Clinical
"We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members."
The method that identified the gene, and the one used to diagnose since.
PMID:36949636 SUPPORT Human Clinical
"It showed a novel homozygous variant in PTRH2 gene classified as likely pathogenic according to American College of Medical Genetics classification"
A contemporary diagnosis by sequencing with ACMG classification, which is the current route.
📈

Progression

3
Infantile onset
Global developmental delay and motor delay are noticed in infancy or the first year. The founding siblings had postnatal microcephaly and growth retardation alongside the developmental delay, so the disorder is present but not obviously multisystem at presentation.
Show evidence (1 reference)
PMID:25574476 SUPPORT Human Clinical
"The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of..."
The full phenotype of the founding family, which is the definition of the syndrome and the source for most of the individual phenotypes below.
Progressive cerebellar and peripheral nerve deterioration
Ataxia is progressive and tracks a cerebellar atrophy that is not present at birth: one reported patient had a normal brain MRI earlier and cerebellar atrophy on a later scan. The peripheral neuropathy is demyelinating and sensorimotor. This is the phase that distinguishes IMNEPD from a static developmental disorder.
Show evidence (1 reference)
PMID:36949636 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) recently reported cerebellar atrophy when compared to normal previous MRI"
Serial imaging in one patient showing the atrophy appearing over time, which is the observation that makes this a progressive rather than a congenital cerebellar phenotype.
Later endocrine and pancreatic involvement
Diabetes mellitus can appear well into childhood; one reported patient was diagnosed at age 12 with an HbA1c of 15.3%. So a child assessed early has not yet passed through the window in which the endocrine features of the disease name appear.
Show evidence (1 reference)
PMID:36949636 SUPPORT Human Clinical
"At the age of 12 years, patient was diagnosed with insulin-dependent diabetes mellitus when hemoglobin A1c (HbA1c) was 15.3% but was not in ketoacidosis."
A dated onset for the diabetes in one patient, which is what makes the endocrine involvement a later phase rather than a presenting feature.
📊

Prevalence

1
Published IMNEPD cases worldwide
Cases In Literature Ultra Rare
The disease is known from a few dozen published patients, almost all from consanguineous Middle Eastern and North African families. No population prevalence has been estimated and none should be inferred from the case count, because ascertainment is entirely through consanguineous pedigrees referred for exome sequencing.
Show evidence (1 reference)
PMID:39766776 SUPPORT REVIEW SYNTHESIS Human Clinical
"In this study, we describe a new case carrying a previously identified mutation, provide an updated analysis of the relative frequencies of the clinical features across all published cases (including the three latest studies), and perform a bioinformatics analysis of the newly identified PTRH2..."
Establishes that the evidence base for this disease is an aggregation of all published cases rather than any cohort, which is what bounds every frequency statement in this entry.
🐁

Animal Models

1
Purkinje-cell-specific Ptrh2 knockout mouse
The conditional knockout is what makes the cerebellar mechanism a claim about Purkinje cells rather than about the cerebellum in general. The constitutive knockout in the same paper is severely runted and dies by postnatal day 14, so it cannot be used to study a progressive adult phenotype at all; deleting Ptrh2 in Purkinje cells alone gives animals that survive to adulthood and develop ataxia.
Species
Mouse
Genotype
Ptrh2 LoxP x Pcp2-Cre, Purkinje-cell-specific conditional knockout
Publication
PMID:36219306
Pathograph links
Purkinje Cell Atrophy and Loss recapitulates fidelity: high observes: tissue Reduced Purkinje cell size and density, stunted dendrites, lower phosphorylated ribosomal protein S6, and marked cell loss by adulthood, with progressive cerebellar atrophy and ataxia at the whole-animal level.
Limitations: The human counterpart is inferred from MRI atrophy; no human IMNEPD cerebellar tissue has been examined. And the model is a Purkinje-cell deletion, where patients are constitutive biallelic carriers, so it isolates the cell-autonomous contribution by construction and says nothing about how much of the human cerebellar phenotype is cell-autonomous.
Readouts
Purkinje cell phosphorylated ribosomal protein S6
Direction: DECREASED
Interpretation: Reduced mTOR pathway activity in the affected cells.
Show evidence (1 reference)
PMID:36219306 SUPPORT Model Organism
"PCs of Ptrh2ΔPC mice had reduced cell size and density, stunted dendrites, and lower levels of ribosomal protein S6, a readout of the mammalian target of rapamycin pathway."
The measurement and the authors' interpretation of the marker.
Gait and ataxia assessment
Direction: ALTERED
Interpretation: Functional cerebellar deficit in the conditional knockout, matching the patients' ataxia.
Show evidence (1 reference)
PMID:36219306 SUPPORT Model Organism
"Ptrh2ΔPC PC specific knockout mice survived until adult age; however, they showed progressive cerebellar atrophy and functional cerebellar deficits with abnormal gait and ataxia."
The behavioural and imaging phenotype, with the survival difference from the constitutive knockout stated in the same sentence.
Show evidence (1 reference)
PMID:36219306 SUPPORT Model Organism
"This suggests a molecular mechanism underlying the ataxia and cerebellar atrophy seen in patients with PTRH2 mutations leading to infantile-onset multisystem neurologic, endocrine, and pancreatic disease."
The authors' own statement that the model is informative for the human disease, hedged as "suggests", which is the level at which this link is curated.
{ }

Source YAML

click to show 
name: Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease
creation_date: "2026-09-17T16:17:48Z"
description: >-
  IMNEPD is the autosomal recessive multisystem disorder caused by biallelic
  PTRH2 variants, delineated in 2014 in two siblings of a consanguineous
  Yazidian-Turkish family. Roughly thirty patients have been published, almost
  all from consanguineous Middle Eastern and North African families, and a
  single recurrent missense allele, p.Gln85Pro, accounts for about half of them.

  The clinical picture is neurologically weighted despite the name. Motor delay,
  peripheral neuropathy, intellectual disability, distal muscle weakness,
  sensorineural hearing impairment and ataxia are the features reported most
  often; progressive cerebellar atrophy is the imaging correlate of the ataxia.
  The endocrine and pancreatic features that the name foregrounds -- exocrine
  pancreatic insufficiency, diabetes mellitus, hypothyroidism, liver abnormality
  -- are real but less consistent, and an entry read only from the disease name
  would overweight them.

  PTRH2 is a mitochondrial protein with two jobs, and which of them the disease
  runs through is not settled. It is a peptidyl-tRNA hydrolase, a translation
  quality-control enzyme. It is also an adhesion-regulated survival switch: bound
  to focal adhesion kinase in matrix-attached cells it supports survival
  signalling, and on matrix detachment it is released into the cytosol where it
  drives caspase-independent anoikis. The mechanism worked out in mouse runs
  through neither hydrolase chemistry nor anoikis directly, but through mTOR: a
  Purkinje-cell-specific Ptrh2 knockout loses phosphorylated ribosomal protein
  S6, develops stunted dendrites and atrophic Purkinje cells, and ends in
  progressive cerebellar atrophy and ataxia. That model is the strongest
  mechanistic evidence this disease has, and it is a mouse.

  There is no disease-modifying therapy. Management is supportive and
  multidisciplinary.
synonyms:
- IMNEPD
- IMNEPD1
- infantile-onset multisystem neurologic, endocrine, and pancreatic disease
- neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset
- PTRH2-related multisystem disease
category: Mendelian
disease_term:
  preferred_term: neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset
  term:
    id: MONDO:0024189
    label: neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0024189
      label: neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Genetic Disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PTRH2 variants, homozygous in essentially every published family.
    Nearly all reported families are consanguineous, which is both how the gene
    was found -- homozygosity mapping plus exome sequencing in the founding
    family -- and why the allele spectrum is dominated by one recurrent missense
    change rather than by many private ones.
  evidence:
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a consanguineous family with two individuals with IMNEPD, we identified
      a homozygous frameshift mutation in the previously not disease-associated
      peptidyl-tRNA hydrolase 2 (PTRH2) gene.
    explanation: >-
      The founding observation: a homozygous variant in a consanguineous family,
      which is the segregation argument for recessive inheritance and the first
      link of this gene to any disease.
  - reference: PMID:27129381
    reference_title: Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report five further IMNEPD patients from two consanguineous
      families with a PTRH2 missense mutation and discuss their phenotype,
      thereby illustrating both core and variable features of IMNEPD.
    explanation: >-
      Independent consanguineous families with a different allele, which is what
      moved the gene-disease relationship past a single family.
prevalence:
- population: Published IMNEPD cases worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The disease is known from a few dozen published patients, almost all from
    consanguineous Middle Eastern and North African families. No population
    prevalence has been estimated and none should be inferred from the case
    count, because ascertainment is entirely through consanguineous pedigrees
    referred for exome sequencing.
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In this study, we describe a new case carrying a previously identified
      mutation, provide an updated analysis of the relative frequencies of the
      clinical features across all published cases (including the three latest
      studies), and perform a bioinformatics analysis of the newly identified
      PTRH2 protein variants from a structural perspective.
    explanation: >-
      Establishes that the evidence base for this disease is an aggregation of
      all published cases rather than any cohort, which is what bounds every
      frequency statement in this entry.
progression:
- phase: Infantile onset
  notes: >-
    Global developmental delay and motor delay are noticed in infancy or the
    first year. The founding siblings had postnatal microcephaly and growth
    retardation alongside the developmental delay, so the disorder is present but
    not obviously multisystem at presentation.
  evidence:
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two affected children suffer from intellectual disability, postnatal
      microcephaly, growth retardation, progressive ataxia, distal muscle
      weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural
      deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs
      of liver fibrosis.
    explanation: >-
      The full phenotype of the founding family, which is the definition of the
      syndrome and the source for most of the individual phenotypes below.
- phase: Progressive cerebellar and peripheral nerve deterioration
  notes: >-
    Ataxia is progressive and tracks a cerebellar atrophy that is not present at
    birth: one reported patient had a normal brain MRI earlier and cerebellar
    atrophy on a later scan. The peripheral neuropathy is demyelinating and
    sensorimotor. This is the phase that distinguishes IMNEPD from a static
    developmental disorder.
  evidence:
  - reference: PMID:36949636
    reference_title: Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) recently reported cerebellar atrophy
      when compared to normal previous MRI
    explanation: >-
      Serial imaging in one patient showing the atrophy appearing over time,
      which is the observation that makes this a progressive rather than a
      congenital cerebellar phenotype.
- phase: Later endocrine and pancreatic involvement
  notes: >-
    Diabetes mellitus can appear well into childhood; one reported patient was
    diagnosed at age 12 with an HbA1c of 15.3%. So a child assessed early has not
    yet passed through the window in which the endocrine features of the disease
    name appear.
  evidence:
  - reference: PMID:36949636
    reference_title: Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 12 years, patient was diagnosed with insulin-dependent
      diabetes mellitus when hemoglobin A1c (HbA1c) was 15.3% but was not in
      ketoacidosis.
    explanation: >-
      A dated onset for the diabetes in one patient, which is what makes the
      endocrine involvement a later phase rather than a presenting feature.
pathophysiology:
- name: PTRH2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic PTRH2 variants. The reported alleles are the founding frameshift
    c.269_270delCT and the recurrent missense p.Gln85Pro, which accounts for
    about half of published cases and acts by destabilising the protein rather
    than by abolishing transcription: patient fibroblasts carrying it have normal
    PTRH2 mRNA and strongly reduced protein.
  genes:
  - preferred_term: PTRH2
    term:
      id: hgnc:24265
      label: PTRH2
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: peptidyl-tRNA hydrolase activity
    modifier: DECREASED
    term:
      id: GO:0004045
      label: peptidyl-tRNA hydrolase activity
  downstream:
  - target: Reduced mTOR Pathway Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The step the disease is understood through, and the one whose intermediate
      chemistry is missing. PTRH2 loss reduces mTOR activation in patient cells
      and in mutant mouse brain, but no published work shows how a
      peptidyl-tRNA hydrolase or an adhesion-signalling scaffold produces that.
    evidence:
    - reference: PMID:25574476
      reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell
        size.
      explanation: >-
        The link asserted by the founding paper, on the strength of patient
        fibroblasts and mutant mice together. It is the claim this edge makes and
        it is stated at exactly this level of detail in the source.
  - target: Loss of Adhesion-Dependent Survival Signalling
    causal_link_type: DIRECT
    description: >-
      PTRH2 is itself the adhesion-regulated switch, so losing it removes the
      function directly rather than through an intermediate.
    evidence:
    - reference: PMID:27129381
      reference_title: Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        As part of an integrin signaling complex, Ptrh2 regulates the fine
        balance between cell survival and apoptosis; it also has a role in cell
        size control
      explanation: >-
        States that the protein itself performs the adhesion-linked survival
        function, which is what makes this edge direct. It is the paper's
        background summary of prior work rather than its own result.
  evidence:
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PTRH2 encodes a primarily mitochondrial protein involved in
      integrin-mediated cell survival and apoptosis signaling.
    explanation: >-
      What the protein is and where it acts, from the paper that connected it to
      disease.
  - reference: PMID:27129381
    reference_title: Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report five further IMNEPD patients with a different homozygous
      PTRH2 mutation, broaden the phenotypic spectrum of the disease and
      differentiate common symptoms and interindividual variability in IMNEPD
      associated with a unique mutation.
    explanation: >-
      A second allele in independent families. The phrase "associated with a
      unique mutation" is the report's own framing of why one recurrent allele
      dominates the published series.
- name: Loss of Adhesion-Dependent Survival Signalling
  biological_scale: CELLULAR
  description: >-
    PTRH2, as BIT1, is a mitochondrial protein released into the cytosol when a
    cell loses contact with the extracellular matrix, where it complexes with the
    Groucho/TLE protein AES and drives caspase-independent apoptosis. Attachment
    to fibronectin counteracts it. So the wild-type protein sits on both sides of
    a survival decision, and losing it removes both the death signal and the
    attachment-dependent survival arm.

    This node is the mechanism most often quoted for IMNEPD and the one least
    connected to it: the anoikis work is cell-biological and predates the
    disease, and no published study demonstrates dysregulated anoikis in patient
    tissue. It is recorded because it is what PTRH2 does, with the gap stated
    rather than bridged.
  biological_processes:
  - preferred_term: cell-matrix adhesion
    modifier: ABNORMAL
    term:
      id: GO:0007160
      label: cell-matrix adhesion
  downstream:
  - target: Post-Mitotic Cell Attrition Outside the Cerebellum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The proposed route from the anoikis switch to tissue loss. It is drawn
      because the survival function is what the attrition node claims fails, and
      it is marked as having unknown intermediates because no study demonstrates
      dysregulated anoikis in any patient tissue.
  evidence:
  - reference: PMID:15006356
    reference_title: A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like
      enhancer of split (TLE) protein, and induces cell death with
      characteristics of caspase-independent apoptosis.
    explanation: >-
      The anoikis mechanism, established in cell culture ten years before PTRH2
      was linked to any disease. It describes the protein, not this disease.
  - reference: PMID:15006356
    reference_title: A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and
      AES.
    explanation: >-
      The adhesion dependence that makes this a switch rather than a constitutive
      death signal.
- name: Reduced mTOR Pathway Activation
  biological_scale: CELLULAR
  description: >-
    Reduced mTOR signalling, read out as lower phosphorylated ribosomal protein
    S6. It is present in patient fibroblasts and in mutant mouse brain, and in
    the Purkinje-cell-specific knockout it sits alongside reduced cell size,
    stunted dendrites and eventual cell loss. Because mTOR sets cell mass, this
    is the node that makes an atrophy phenotype out of a translation-and-adhesion
    protein.
  biological_processes:
  - preferred_term: TOR signaling
    modifier: DECREASED
    term:
      id: GO:0031929
      label: TOR signaling
  downstream:
  - target: Post-Mitotic Cell Attrition Outside the Cerebellum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same mTOR deficit is proposed to underlie the extracerebellar
      phenotype, on the strength of reduced phosphorylated S6 in patient
      fibroblasts and in mutant mouse brain. No conditional knockout outside the
      Purkinje cell has been reported, so this edge is an extrapolation from the
      one compartment where it was demonstrated.
  - target: Purkinje Cell Atrophy and Loss
    causal_link_type: DIRECT
    description: >-
      Demonstrated cell-autonomously: deleting Ptrh2 in Purkinje cells alone
      lowers pS6 in those cells and produces their atrophy and eventual loss.
    evidence:
    - reference: PMID:36219306
      reference_title: PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Loss of PTRH2 in PCs leads to downregulation of the mTOR pathway and PC
        atrophy.
      explanation: >-
        The authors' statement of the edge, from the conditional knockout that
        isolates it to the Purkinje cell.
  evidence:
  - reference: PMID:36219306
    reference_title: PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PCs of Ptrh2ΔPC mice had reduced cell size and density, stunted dendrites,
      and lower levels of ribosomal protein S6, a readout of the mammalian target
      of rapamycin pathway.
    explanation: >-
      The mTOR readout measured in the cells that atrophy, with the marker named
      and its interpretation stated by the authors.
- name: Purkinje Cell Atrophy and Loss
  biological_scale: TISSUE
  description: >-
    Progressive loss of Purkinje cells, first as reduced size and density with
    stunted dendrites and later as frank loss. This is the cellular substrate of
    the cerebellar atrophy seen on serial MRI in patients, established
    cell-autonomously in a conditional mouse knockout rather than in human
    tissue.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  downstream:
  - target: Ataxia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cerebellar atrophy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36219306
    reference_title: PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By adulthood, there was a marked loss of PCs. Thus, we identify a cell
      autonomous requirement for PTRH2 in PC maturation and survival.
    explanation: >-
      The endpoint and the cell-autonomy claim, which together are why this node
      is placed between the mTOR node and the ataxia phenotype rather than beside
      them.
- name: Post-Mitotic Cell Attrition Outside the Cerebellum
  biological_scale: CELLULAR
  description: >-
    The same survival failure is proposed to explain the peripheral nerve,
    muscle, pancreatic, thyroid and liver features, on the argument that PTRH2 is
    highly expressed in developing tissue and maintains cell survival there. That
    is the founding paper's framing, and it is a general claim rather than a
    demonstrated route to any one organ: no conditional knockout outside the
    Purkinje cell has been reported, so this node is deliberately coarse and its
    outgoing edges are all INDIRECT_UNKNOWN_INTERMEDIATES.
  downstream:
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Distal muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Exocrine pancreatic insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Diabetes mellitus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypothyroidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormality of the liver
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Secondary microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that PTRH2 is highly expressed in the developing brain and is a key
      determinant in maintaining cell survival during human tissue development.
    explanation: >-
      The general survival claim this node rests on. Note it is about the
      developing brain and human tissue development at large, not about pancreas,
      thyroid or nerve, which is why the edges below are unqualified as to
      intermediates.
phenotypes:
- category: Neurologic
  name: Motor delay
  description: >-
    Delayed motor milestones, reported as one of the most common features across
    the published series.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It was found that the most common clinical characteristics amongst all the
      patients were motor delay (~94%), neuropathy (~89%), intellectual
      disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%),
      and ataxia (~77%).
    explanation: >-
      The measured frequencies across all 32 published patients. Motor delay at
      about 94% is the basis for the VERY_FREQUENT band here.
- category: Neurologic
  name: Peripheral neuropathy
  description: >-
    Demyelinating sensorimotor peripheral neuropathy, among the most common
    features and characterised electrophysiologically in the founding family.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It was found that the most common clinical characteristics amongst all the
      patients were motor delay (~94%), neuropathy (~89%), intellectual
      disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%),
      and ataxia (~77%).
    explanation: >-
      Neuropathy at about 89% across all published patients.
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two affected children suffer from intellectual disability, postnatal
      microcephaly, growth retardation, progressive ataxia, distal muscle
      weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural
      deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs
      of liver fibrosis.
    explanation: >-
      The neuropathy characterised as demyelinating and sensorimotor, which the
      frequency source does not specify.
- category: Neurologic
  name: Intellectual disability
  description: >-
    Intellectual disability with global developmental delay, among the most
    common features. Expressivity is wide: one reported family carrying the
    recurrent Q85P allele had normal intelligence.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It was found that the most common clinical characteristics amongst all the
      patients were motor delay (~94%), neuropathy (~89%), intellectual
      disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%),
      and ataxia (~77%).
    explanation: >-
      Intellectual disability at 87.5%, that is 28 of 32 patients.
- category: Musculoskeletal
  name: Distal muscle weakness
  description: Distal muscle weakness, among the most common features.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It was found that the most common clinical characteristics amongst all the
      patients were motor delay (~94%), neuropathy (~89%), intellectual
      disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%),
      and ataxia (~77%).
    explanation: >-
      Distal weakness at 85.2%.
- category: Otologic
  name: Sensorineural hearing impairment
  description: >-
    Sensorineural deafness, among the most common features and present in the
    founding siblings.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It was found that the most common clinical characteristics amongst all the
      patients were motor delay (~94%), neuropathy (~89%), intellectual
      disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%),
      and ataxia (~77%).
    explanation: >-
      Hearing impairment at 78.12%, which is 25 of 32 patients and therefore
      FREQUENT rather than VERY_FREQUENT. An earlier draft of this entry read
      the source's qualitative "most common" grouping as implying 80% or above
      for all six features it names; the numbers show two of the six fall
      below.
- category: Neurologic
  name: Ataxia
  description: >-
    Progressive ataxia, among the most common features, tracking the cerebellar
    atrophy rather than preceding it.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  frequency: FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It was found that the most common clinical characteristics amongst all the
      patients were motor delay (~94%), neuropathy (~89%), intellectual
      disability (87.5%), distal weakness (85.2%), hearing impairment (78.12%),
      and ataxia (~77%).
    explanation: >-
      Ataxia at about 77%, which places it just below the VERY_FREQUENT
      threshold.
- category: Neurologic
  name: Cerebellar atrophy
  description: >-
    Progressive cerebellar atrophy, documented on serial MRI in at least one
    patient whose earlier scan was normal. It is the imaging counterpart of the
    Purkinje cell loss the mouse model demonstrates.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  frequency: FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The moderately common characteristics included hand
      deformity (~58.1%), cerebellar atrophy/hypoplasia (56.5%), and deformity of
      the head and face (53.3%).
    explanation: >-
      Cerebellar atrophy or hypoplasia at 56.5%, that is 13 of 23 patients in
      whom imaging was reported.
  - reference: PMID:36949636
    reference_title: Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) recently reported cerebellar atrophy
      when compared to normal previous MRI
    explanation: >-
      Serial imaging in a genotyped patient. The comparison with the earlier
      normal scan is what makes this progressive atrophy rather than hypoplasia.
- category: Neurologic
  name: Secondary microcephaly
  description: >-
    Postnatal microcephaly, present in the founding siblings. Postnatal rather
    than congenital, which fits an mTOR-driven failure of cell mass accumulation
    rather than a patterning defect.
  phenotype_term:
    preferred_term: postnatal microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  evidence:
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two affected children suffer from intellectual disability, postnatal
      microcephaly, growth retardation, progressive ataxia, distal muscle
      weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural
      deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs
      of liver fibrosis.
    explanation: >-
      The founding family's phenotype, which specifies the microcephaly as
      postnatal.
- category: Gastrointestinal
  name: Exocrine pancreatic insufficiency
  description: >-
    Exocrine pancreatic insufficiency, one of the features the disease name
    foregrounds. It is not among the six the frequency source calls most common,
    so no band is assigned.
  phenotype_term:
    preferred_term: Exocrine pancreatic insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  frequency: FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Meanwhile, the least common characteristics were
      diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism
      (~21.9%), and liver abnormality (~17.4%).
    explanation: >-
      Pancreatic abnormality at about 33.3%. The source's category is broader
      than exocrine insufficiency alone, which is why the band is assigned from
      it but the phenotype stays bound to the specific finding the case reports
      describe.
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two affected children suffer from intellectual disability, postnatal
      microcephaly, growth retardation, progressive ataxia, distal muscle
      weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural
      deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs
      of liver fibrosis.
    explanation: Exocrine pancreatic insufficiency in the founding family.
- category: Endocrine
  name: Diabetes mellitus
  description: >-
    Insulin-dependent diabetes mellitus, reported with a documented onset age of
    12 in one patient. Not among the most common features.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  frequency: FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Meanwhile, the least common characteristics were
      diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism
      (~21.9%), and liver abnormality (~17.4%).
    explanation: >-
      Diabetes mellitus at 40% across all published patients. This is the
      figure a reader wants and an earlier draft of this entry omitted it.
  - reference: PMID:36949636
    reference_title: Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 12 years, patient was diagnosed with insulin-dependent
      diabetes mellitus when hemoglobin A1c (HbA1c) was 15.3% but was not in
      ketoacidosis.
    explanation: A dated, quantified diabetes diagnosis in a genotyped patient.
- category: Endocrine
  name: Hypothyroidism
  description: Hypothyroidism, present in the founding siblings.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Meanwhile, the least common characteristics were
      diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism
      (~21.9%), and liver abnormality (~17.4%).
    explanation: >-
      Hypothyroidism at about 21.9%.
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two affected children suffer from intellectual disability, postnatal
      microcephaly, growth retardation, progressive ataxia, distal muscle
      weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural
      deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs
      of liver fibrosis.
    explanation: Hypothyroidism in the founding family.
- category: Hepatic
  name: Abnormality of the liver
  description: >-
    Liver abnormality. The founding siblings showed signs of liver fibrosis; the
    binding is at the level of the organ because subsequent reports describe
    liver involvement without specifying fibrosis.
  phenotype_term:
    preferred_term: liver abnormality
    term:
      id: HP:0001392
      label: Abnormality of the liver
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Meanwhile, the least common characteristics were
      diabetes mellitus (40%), pancreatic abnormality (~33.3%), hypothyroidism
      (~21.9%), and liver abnormality (~17.4%).
    explanation: >-
      Liver abnormality at about 17.4%, the least common of the curated
      features.
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two affected children suffer from intellectual disability, postnatal
      microcephaly, growth retardation, progressive ataxia, distal muscle
      weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural
      deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs
      of liver fibrosis.
    explanation: >-
      Liver fibrosis in the founding family, described as signs of rather than
      biopsy-proven.
- category: Musculoskeletal
  name: Abnormality of the hand
  description: >-
    Hand deformity, present in 18 of 31 patients for whom it was reported. It is
    the most common of the non-neurological features and was absent from an
    earlier draft of this entry.
  phenotype_term:
    preferred_term: hand deformity
    term:
      id: HP:0001155
      label: Abnormality of the hand
  frequency: FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | Hand deformity | 18/31 (58.06%) |
    explanation: >-
      The per-phenotype row from the cohort table, quoted with its denominator
      rather than only its percentage, so a reader sees that 31 rather than 32
      patients had it assessed.
- category: Craniofacial
  name: Abnormality of the face
  description: >-
    Deformity of the head and face, reported in 16 of 30 assessed patients. The
    case reports describe midface hypoplasia, a thin upper lip, exotropia and
    ptosis; the binding is at the level the cohort source counts, which is the
    whole region.
  phenotype_term:
    preferred_term: deformity of the head and face
    term:
      id: HP:0000271
      label: Abnormality of the face
  frequency: FREQUENT
  evidence:
  - reference: PMID:39766776
    reference_title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | Deformity of the head and face | 16/30 a (53.33%) |
    explanation: >-
      The per-phenotype row with its denominator. The trailing footnote marker is
      part of the cell and is quoted as it appears.
- category: Neurologic
  name: Seizure
  description: >-
    Epileptic seizures. Antiepileptic choice is constrained here: valproic acid
    toxicity is a specific hazard because IMNEPD is a mitochondrial cytopathy,
    which is curated as a treatment restriction rather than only as a phenotype.
  phenotype_term:
    preferred_term: epileptic seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31057140
    reference_title: "Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features include epileptic seizures, pancreatic insufficiency,
      and peripheral neuropathy.
    explanation: >-
      Seizures among the additional features in the three-brother series. No
      frequency band is assigned: the cohort table does not count seizures.
- category: Neurologic
  name: Developmental regression
  description: >-
    Loss of acquired motor and language skills. Regression is what separates this
    disorder from a static developmental delay and is the reason the progression
    section treats it as progressive.
  phenotype_term:
    preferred_term: motor and language delay with regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:31057140
    reference_title: "Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the core clinical features of postnatal microcephaly, motor and
      language delay with regression, ataxia, and hearing loss.
    explanation: >-
      The core features of that series, including the regression this entry had
      not curated.
- category: Neurologic
  name: Delayed speech and language development
  description: >-
    Severe speech delay, named among the neurologic core features present in
    almost all patients of the five-patient phenotype-variability series.
  phenotype_term:
    preferred_term: severe speech delay
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:27129381
    reference_title: Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurologic core features of (almost) all patients were intellectual
      disability, motor delay, severe speech delay, ataxia, and sensorineural
      hearing loss
    explanation: >-
      Speech delay among the core features. The qualifier "(almost) all" is the
      authors' own and is why no numeric band is assigned from this sentence.
genetic:
- name: PTRH2
  gene_term:
    preferred_term: PTRH2
    term:
      id: hgnc:24265
      label: PTRH2
  relationship_type: CAUSATIVE
  notes: >-
    PTRH2 on 17q23.1 encodes peptidyl-tRNA hydrolase 2, also called BIT1. It was
    not associated with any disease before 2014. Biallelic variants cause IMNEPD.

    The allele spectrum is unusual in being dominated by one recurrent missense
    change, p.Gln85Pro, across unrelated consanguineous Arab communities. That
    allele leaves transcription intact and destabilises the protein, which is why
    a missense change behaves as loss of function here.
  variants:
  - name: c.269_270delCT, p.Ala90fs
    description: >-
      Homozygous in the founding Yazidian-Turkish family of two affected
      siblings. A frameshift, and the allele that established the gene-disease
      relationship.
    evidence:
    - reference: PMID:25574476
      reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This 2-base pair deletion in the coding sequence of exon 2 of PTRH2
        causes a frameshift mutation, leading to a predicted protein truncated
        by 78 amino acids
      explanation: >-
        The molecular consequence of the founding allele, stated by the paper
        that reported it.
  - name: c.254A>C, p.Gln85Pro
    description: >-
      The recurrent missense allele, reported in multiple unrelated consanguineous
      families. Patient fibroblasts carrying it have normal PTRH2 mRNA and
      strongly reduced protein, so it acts by destabilising the protein rather
      than by preventing its transcription.
    evidence:
    - reference: PMID:27129381
      reference_title: "Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PTRH2 protein levels were strongly reduced in fibroblasts from patient
        II.1, family 2, while PTRH2 mRNA levels were unchanged
      explanation: >-
        The measurement behind this row's mechanism claim, in fibroblasts from a
        patient homozygous for this allele. Graded IN_VITRO because the quoted
        result is a cultured-cell immunoblot and qPCR, whatever the clinical
        context of the paper reporting it.
  evidence:
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a consanguineous family with two individuals with IMNEPD, we identified
      a homozygous frameshift mutation in the previously not disease-associated
      peptidyl-tRNA hydrolase 2 (PTRH2) gene.
    explanation: The gene-disease assertion and the founding allele.
  - reference: PMID:27129381
    reference_title: Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We further demonstrated the association of a homozygous nonsense mutation
      in the PTRH2 gene (MIM*608625) to IMNEPD through functional and molecular
      data in human and mouse [1].
    explanation: >-
      The authors' own summary of how the gene-disease link was established,
      naming the human and mouse evidence together. Note this sentence recites
      their earlier paper rather than reporting a new result.
    quote_role: BACKGROUND
animal_models:
- name: Purkinje-cell-specific Ptrh2 knockout mouse
  species: Mouse
  genotype: Ptrh2 LoxP x Pcp2-Cre, Purkinje-cell-specific conditional knockout
  publication: PMID:36219306
  description: >-
    The conditional knockout is what makes the cerebellar mechanism a claim about
    Purkinje cells rather than about the cerebellum in general. The constitutive
    knockout in the same paper is severely runted and dies by postnatal day 14,
    so it cannot be used to study a progressive adult phenotype at all; deleting
    Ptrh2 in Purkinje cells alone gives animals that survive to adulthood and
    develop ataxia.
  modeled_mechanisms:
  - target: Purkinje Cell Atrophy and Loss
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Reduced Purkinje cell size and density, stunted dendrites, lower
      phosphorylated ribosomal protein S6, and marked cell loss by adulthood,
      with progressive cerebellar atrophy and ataxia at the whole-animal level.
    limitations: >-
      The human counterpart is inferred from MRI atrophy; no human IMNEPD
      cerebellar tissue has been examined. And the model is a Purkinje-cell
      deletion, where patients are constitutive biallelic carriers, so it
      isolates the cell-autonomous contribution by construction and says nothing
      about how much of the human cerebellar phenotype is cell-autonomous.
    readouts:
    - name: Purkinje cell phosphorylated ribosomal protein S6
      target: Purkinje Cell Atrophy and Loss
      direction: DECREASED
      interpretation: Reduced mTOR pathway activity in the affected cells.
      evidence:
      - reference: PMID:36219306
        reference_title: PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          PCs of Ptrh2ΔPC mice had reduced cell size and density, stunted
          dendrites, and lower levels of ribosomal protein S6, a readout of the
          mammalian target of rapamycin pathway.
        explanation: The measurement and the authors' interpretation of the marker.
    - name: Gait and ataxia assessment
      target: Purkinje Cell Atrophy and Loss
      direction: ALTERED
      interpretation: >-
        Functional cerebellar deficit in the conditional knockout, matching the
        patients' ataxia.
      evidence:
      - reference: PMID:36219306
        reference_title: PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Ptrh2ΔPC PC specific knockout mice survived until adult age; however,
          they showed progressive cerebellar atrophy and functional cerebellar
          deficits with abnormal gait and ataxia.
        explanation: >-
          The behavioural and imaging phenotype, with the survival difference
          from the constitutive knockout stated in the same sentence.
    evidence:
    - reference: PMID:36219306
      reference_title: PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This suggests a molecular mechanism underlying the ataxia and cerebellar
        atrophy seen in patients with PTRH2 mutations leading to infantile-onset
        multisystem neurologic, endocrine, and pancreatic disease.
      explanation: >-
        The authors' own statement that the model is informative for the human
        disease, hedged as "suggests", which is the level at which this link is
        curated.
diagnosis:
- name: Exome or genome sequencing for biallelic PTRH2 variants
  description: >-
    The diagnosis is molecular. The gene was found by homozygosity mapping plus
    whole-exome sequencing in a consanguineous family, and subsequent cases have
    been found the same way. There is no biochemical or imaging test specific to
    the disease: cerebellar atrophy on MRI is supportive and appears late.
  evidence:
  - reference: PMID:25574476
    reference_title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole-exome sequencing followed by bioinformatic analysis and
      Sanger sequencing on affected and unaffected family members.
    explanation: >-
      The method that identified the gene, and the one used to diagnose since.
  - reference: PMID:36949636
    reference_title: Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It showed a novel homozygous variant in PTRH2 gene classified as likely
      pathogenic according to American College of Medical Genetics
      classification
    explanation: >-
      A contemporary diagnosis by sequencing with ACMG classification, which is
      the current route.
treatments:
- name: Multidisciplinary supportive management
  description: >-
    No disease-modifying therapy exists. Management addresses the individual
    manifestations: developmental and rehabilitative support, audiological
    management, pancreatic enzyme and thyroid hormone replacement where indicated,
    and diabetes care. Nothing available targets PTRH2 or the mTOR deficit.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: multidisciplinary supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Post-Mitotic Cell Attrition Outside the Cerebellum
    description: >-
      Addresses the organ failures the attrition produces. It does not act on the
      attrition.
  evidence:
  - reference: PMID:31057140
    reference_title: "Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      however, the related complications of this disorder can be
      addressed
    explanation: >-
      The management principle stated as management: there is no specific
      treatment, and what can be done is directed at the complications. An
      earlier draft of this entry quoted a sentence about how the diagnosis was
      reached, which supports the diagnosis section and not this one.
  - reference: PMID:31057140
    reference_title: "Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      age-appropriate counselling would be necessary for all affected patients
      and siblings
    explanation: >-
      The family arm of management. The sentence this comes from opens by saying
      genetic testing of parents and siblings determines recurrence risk and
      carrier status; that clause is quoted here from its second half only,
      because the cached PDF breaks the word "recurrence" across a line and a
      folded YAML scalar cannot carry that break without inserting a space
      inside the word.
- name: Avoidance of valproic acid for seizure control
  description: >-
    A specific contraindication rather than a general caution. IMNEPD is a
    mitochondrial cytopathy, so valproic acid carries a risk of toxicity, and
    the source recommends other antiepileptic medications. This is the one
    treatment decision in the entry where the genetic diagnosis changes what a
    clinician should do rather than only what they expect.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: avoidance of a contraindicated drug
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Seizure
    description: >-
      Seizure control is the goal; the restriction is on which agent achieves it
      safely, not on whether to treat.
  evidence:
  - reference: PMID:31057140
    reference_title: "Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the context of seizures, valproic acid toxicity may
      occur given that IMNEPD is a mitochondrial cytopathy, and
      therefore, other antiepileptic medications should be used
    explanation: >-
      The contraindication and its mechanistic reason, stated together. The line
      breaks are the cached PDF's.
- name: Lipophilic vitamin substitution
  description: >-
    Replacement of fat-soluble vitamins, whose deficiency follows the exocrine
    pancreatic insufficiency. It is the only intervention in this entry with a
    reported outcome: substitution markedly improved growth in the index
    patients of the founding family.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: lipophilic vitamin substitution
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Exocrine pancreatic insufficiency
    description: >-
      Replaces what the insufficient pancreas fails to let the gut absorb. It
      does not treat the pancreatic lesion.
  evidence:
  - reference: PMID:27129381
    reference_title: Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Substitution of lipophilic vitamins in the index patients of the original
      IMNEPD family markedly improved growth of the patients
    explanation: >-
      A reported response to treatment, in genotyped patients. It is two
      patients and an uncontrolled observation, which is why the treatment
      description says "reported outcome" rather than "efficacy".
discussions:
- discussion_id: gap_imnepd_which_ptrh2_function_causes_the_disease
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does IMNEPD run through PTRH2's peptidyl-tRNA hydrolase activity, its
    adhesion-regulated survival signalling, or neither directly?
  attaches_to:
  - "pathophysiology#PTRH2 Loss of Function"
  - "pathophysiology#Loss of Adhesion-Dependent Survival Signalling"
  rationale: >-
    PTRH2 has two well-characterised and unrelated functions, and the disease
    literature routes through a third observation, reduced mTOR activation, whose
    connection to either is unexplained. The hydrolase activity is a
    mitochondrial translation quality-control step; the BIT1 anoikis work is
    cell-biological, predates the disease by a decade, and has never been shown
    dysregulated in patient tissue. Neither has been tested against the disease
    by the obvious experiment: a separation-of-function allele. The recurrent
    p.Gln85Pro variant destabilises the protein and so removes both functions at
    once, which is why the commonest allele cannot distinguish them. The stake is
    not academic, because mTOR is druggable and the other two arms are not: if
    the cerebellar phenotype is an mTOR-deficit phenotype, an mTOR-directed
    intervention is a coherent thing to test, and if it is a translation
    quality-control failure it is not.
  proposed_experiments:
  - experiment_id: exp_imnepd_separation_of_function_alleles
    name: Hydrolase-dead versus adhesion-signalling-dead PTRH2 knock-in mice
    description: >-
      Generate knock-in mice carrying a catalytically dead PTRH2 and, separately,
      an allele that disrupts the FAK interaction while preserving hydrolase
      activity, and compare Purkinje cell size, phosphorylated S6 and gait
      against the conditional knockout. Either allele reproducing the phenotype
      would assign the disease to that arm; neither doing so would say the
      relevant function is a third one.
- discussion_id: gap_imnepd_extracerebellar_mechanism
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Is the pancreatic, thyroid, hepatic and peripheral nerve involvement in
    IMNEPD produced by the same mTOR-dependent cell attrition demonstrated in
    Purkinje cells, or by something else?
  attaches_to:
  - "pathophysiology#Post-Mitotic Cell Attrition Outside the Cerebellum"
  rationale: >-
    The cerebellar arm of this disease has a clean cell-autonomous mouse
    demonstration. No other organ does. The constitutive knockout, which would be
    the model for the multisystem phenotype, dies by postnatal day 14 and so
    cannot express a phenotype that in patients appears over years, with diabetes
    reported as late as age 12. Every extracerebellar edge in this entry is
    therefore an extrapolation from one cell type in one tissue, and the entry
    marks them INDIRECT_UNKNOWN_INTERMEDIATES for that reason. This is a
    model-fidelity gap rather than an absence of evidence: the evidence exists,
    in mouse, for a compartment that does not include the organs the disease is
    named after.
  proposed_experiments:
  - experiment_id: exp_imnepd_tissue_specific_conditional_knockouts
    name: Pancreatic and Schwann cell conditional Ptrh2 knockouts
    description: >-
      Delete Ptrh2 in pancreatic acinar cells and, separately, in Schwann cells,
      in animals that survive to adulthood, and test whether exocrine
      insufficiency and demyelinating neuropathy arise cell-autonomously with the
      same reduction in phosphorylated S6 seen in Purkinje cells.
notes: >-
  Scope. MONDO:0024189 was bound nowhere in kb/ before this entry, and no entry
  binds PTRH2. This is IMNEPD1, the PTRH2 form. A second locus has been proposed
  in the literature under a synergistic PTRH2 plus KIF1A model; that report is
  not curated here, because a two-gene synergy claim in one family is a different
  assertion from this entry's monogenic one and would need its own treatment.

  Frequencies. Eleven phenotypes carry a band, and all of them are assigned from
  measured percentages in the 2024 cohort update across 32 published patients,
  quoted directly: motor delay ~94%, neuropathy ~89%, intellectual disability
  87.5%, distal weakness 85.2%, hearing impairment 78.12%, ataxia ~77%, hand
  deformity ~58.1%, cerebellar atrophy 56.5%, deformity of the head and face
  53.3%, diabetes 40%, pancreatic abnormality ~33.3%, hypothyroidism ~21.9%,
  liver abnormality ~17.4%.

  An earlier draft of this entry carried none of those numbers, on the stated
  grounds that they were "not in that paper's abstract, which is what the
  reference cache holds". That was wrong, and it was wrong in a way worth
  recording rather than quietly fixing. `references_cache/PMID_39766776.md` is
  `content_type: full_text_xml`, six of this entry's seven caches are full text,
  and `just validate-kb-references` matches against full text where it is
  present. The percentages were sitting in the committed cache the whole time,
  with per-phenotype denominators in a table. The assumption that a cache holds
  only an abstract was never checked against the file's own `content_type`
  field, and it cost two phenotypes that are present in more than half of
  patients (hand deformity, deformity of the head and face) and a band on five
  more.

  Two bands moved as a direct result. Hearing impairment at 78.12% and ataxia at
  ~77% were VERY_FREQUENT in the draft, read across from the source's
  qualitative "most common" grouping; both are below the 80% threshold and are
  now FREQUENT. Reading a ranking as if it were a measurement pushed two
  phenotypes one band too high.

  Three phenotypes still carry no band, and the reason is now specific rather
  than blanket: seizures, developmental regression and severe speech delay are
  described in the case series but are not rows in the cohort table, so there is
  no denominator to band them from.

  What the mechanism claims. The cerebellar branch is the only one with a
  cell-autonomous demonstration, and it is a mouse conditional knockout. The
  extracerebellar branch is one coarse node with unqualified outgoing edges,
  which is an honest picture of the evidence rather than an unfinished one, and
  the HUMAN_MODEL_MISMATCH discussion records why. That node takes its inbound
  edges from the mTOR node and from the adhesion node; an earlier draft left it
  with none, so the whole extracerebellar branch hung off a node the graph never
  reached.

  Two phenotypes are deliberately left unwired, and the count is exactly two.
  Hand deformity and deformity of the head and face are the commonest
  non-neurological features, and nothing located connects either to post-mitotic
  cell attrition, which is what the node above them claims. A dysmorphism is a
  morphogenesis phenotype and the node is a cell-survival one; drawing the edge
  would assert a developmental role for PTRH2 that no source in this entry
  supports. Motor delay was a third isolated node in the round-1 revision and
  that was an oversight rather than a decision: it is the commonest feature of
  the disease at about 94%, and its two nearest siblings, developmental
  regression and severe speech delay, were wired from the attrition node in the
  same commit. It is now wired alongside them. Run
  `just list-disconnected-phenotypes` on this file rather than trusting this
  paragraph; a sentence counting nodes is exactly the kind of prose that rots.
  The anoikis arm is curated because it is what the protein does, with an
  explicit statement that no study has shown it dysregulated in patient tissue.

  Review round 2. Two things went wrong in round 1 and are corrected here. The
  family-testing snippet quoted a sentence across the cached PDF's own line
  break, where the word "recurrence" is hyphenated; a folded YAML scalar turns
  that break into a space, so the stored quote read "recur- rence" and
  `just check-folded-hyphens` went red on it in CI. The snippet now quotes the
  clean second half of the same clause. The gate caught it and I had not run the
  gate before pushing, which is the actual defect. Motor delay is wired, as
  above. Beyond those: the attrition node is rescaled from ORGANISM to CELLULAR,
  since cell attrition is a cellular process and the multi-organ span is a
  property of the node's outgoing edges; the vitamin treatment's
  `preferred_term` no longer echoes its broader NCIT label; the valproate
  avoidance is `OTHER` rather than `BEHAVIORAL`, which describes what a patient
  does rather than what a prescriber may not; and both alleles now carry their
  own evidence.

  PMID:25558065, the Alazami screening study that first reported the recurrent
  allele, was fetched and is not cited. It is abstract-only and names PTRH2 only
  inside a list of 33 genes, with no sentence about the variant, so it cannot
  substantiate anything this entry claims about it. The mRNA-normal,
  protein-reduced measurement is cited from PMID:27129381 instead, which made it.

  Deep research. One OpenScientist run, committed; reference validation reports
  11 of 11 references resolved. `just preflight-dr` returned SKIP, which means
  unchecked, because MONDO records no causal gene for MONDO:0024189 and no OMIM
  xref either. Manual fallback: PTRH2 46 mentions against 7 for MFN1 and FKBP8
  and 5 for KIF1A, and the report's OMIM #616263 is IMNEPD1. Right entity.

  The run's term validation flagged three NCIT identifiers whose labels name
  entirely unrelated concepts: C158477 offered as "Pancreatic Enzyme
  Replacement" but named 5/10 HLA Match, C29099 as "Levothyroxine" but named
  Hydrocodone Bitartrate, C99277 as "Cochlear Implant" but named FUS/ATF1 Fusion
  Gene. None is bound here. Those three are exactly the treatments this disease
  needs terms for, so the effect of the check is that the entry carries one
  generic supportive-care treatment instead of three specific ones. That is the
  right outcome and it is not a satisfying one.

  What is deliberately absent. No datasets: block; no dataset specific to this
  disease was identified. No clinical_trials: block; none found. No
  environmental: block. No GeneReviews chapter exists for this disorder; `just
  check-genereviews` reports NO_CHAPTER, and that was confirmed after synonyms
  were written rather than before.
references:
- reference: PMID:25574476
  title: "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness."
- reference: PMID:27129381
  title: Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
- reference: PMID:36219306
  title: PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
- reference: PMID:39766776
  title: An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
- reference: PMID:15006356
  title: A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors.
- reference: PMID:31057140
  title: "Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review."
- reference: PMID:36949636
  title: "Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings."
datasets: []
📚

References & Deep Research

References

7
PMID:25574476
Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.
No top-level findings curated for this source.
PMID:27129381
Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.
No top-level findings curated for this source.
PMID:36219306
PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.
No top-level findings curated for this source.
PMID:39766776
An Update of Phenotypic-Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants.
No top-level findings curated for this source.
PMID:15006356
A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors.
No top-level findings curated for this source.
PMID:31057140
Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease: Case and Review.
No top-level findings curated for this source.
PMID:36949636
Novel PTRH2 gene variant causing IMNEPD (infantile-onset multisystem neurologic, endocrine, and pancreatic disease) in 2 Saudi siblings.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Scope. MONDO:0024189 was bound nowhere in kb/ before this entry, and no entry binds PTRH2. This is IMNEPD1, the PTRH2 form. A second locus has been proposed in the literature under a synergistic PTRH2 plus KIF1A model; that report is not curated here, because a two-gene synergy claim in one family is a different assertion from this entry's monogenic one and would need its own treatment. Frequencies. Eleven phenotypes carry a band, and all of them are assigned from measured percentages in the 2024 cohort update across 32 published patients, quoted directly: motor delay ~94%, neuropathy ~89%, intellectual disability 87.5%, distal weakness 85.2%, hearing impairment 78.12%, ataxia ~77%, hand deformity ~58.1%, cerebellar atrophy 56.5%, deformity of the head and face 53.3%, diabetes 40%, pancreatic abnormality ~33.3%, hypothyroidism ~21.9%, liver abnormality ~17.4%. An earlier draft of this entry carried none of those numbers, on the stated grounds that they were "not in that paper's abstract, which is what the reference cache holds". That was wrong, and it was wrong in a way worth recording rather than quietly fixing. `references_cache/PMID_39766776.md` is `content_type: full_text_xml`, six of this entry's seven caches are full text, and `just validate-kb-references` matches against full text where it is present. The percentages were sitting in the committed cache the whole time, with per-phenotype denominators in a table. The assumption that a cache holds only an abstract was never checked against the file's own `content_type` field, and it cost two phenotypes that are present in more than half of patients (hand deformity, deformity of the head and face) and a band on five more. Two bands moved as a direct result. Hearing impairment at 78.12% and ataxia at ~77% were VERY_FREQUENT in the draft, read across from the source's qualitative "most common" grouping; both are below the 80% threshold and are now FREQUENT. Reading a ranking as if it were a measurement pushed two phenotypes one band too high. Three phenotypes still carry no band, and the reason is now specific rather than blanket: seizures, developmental regression and severe speech delay are described in the case series but are not rows in the cohort table, so there is no denominator to band them from. What the mechanism claims. The cerebellar branch is the only one with a cell-autonomous demonstration, and it is a mouse conditional knockout. The extracerebellar branch is one coarse node with unqualified outgoing edges, which is an honest picture of the evidence rather than an unfinished one, and the HUMAN_MODEL_MISMATCH discussion records why. That node takes its inbound edges from the mTOR node and from the adhesion node; an earlier draft left it with none, so the whole extracerebellar branch hung off a node the graph never reached. Two phenotypes are deliberately left unwired, and the count is exactly two. Hand deformity and deformity of the head and face are the commonest non-neurological features, and nothing located connects either to post-mitotic cell attrition, which is what the node above them claims. A dysmorphism is a morphogenesis phenotype and the node is a cell-survival one; drawing the edge would assert a developmental role for PTRH2 that no source in this entry supports. Motor delay was a third isolated node in the round-1 revision and that was an oversight rather than a decision: it is the commonest feature of the disease at about 94%, and its two nearest siblings, developmental regression and severe speech delay, were wired from the attrition node in the same commit. It is now wired alongside them. Run `just list-disconnected-phenotypes` on this file rather than trusting this paragraph; a sentence counting nodes is exactly the kind of prose that rots. The anoikis arm is curated because it is what the protein does, with an explicit statement that no study has shown it dysregulated in patient tissue. Review round 2. Two things went wrong in round 1 and are corrected here. The family-testing snippet quoted a sentence across the cached PDF's own line break, where the word "recurrence" is hyphenated; a folded YAML scalar turns that break into a space, so the stored quote read "recur- rence" and `just check-folded-hyphens` went red on it in CI. The snippet now quotes the clean second half of the same clause. The gate caught it and I had not run the gate before pushing, which is the actual defect. Motor delay is wired, as above. Beyond those: the attrition node is rescaled from ORGANISM to CELLULAR, since cell attrition is a cellular process and the multi-organ span is a property of the node's outgoing edges; the vitamin treatment's `preferred_term` no longer echoes its broader NCIT label; the valproate avoidance is `OTHER` rather than `BEHAVIORAL`, which describes what a patient does rather than what a prescriber may not; and both alleles now carry their own evidence. PMID:25558065, the Alazami screening study that first reported the recurrent allele, was fetched and is not cited. It is abstract-only and names PTRH2 only inside a list of 33 genes, with no sentence about the variant, so it cannot substantiate anything this entry claims about it. The mRNA-normal, protein-reduced measurement is cited from PMID:27129381 instead, which made it. Deep research. One OpenScientist run, committed; reference validation reports 11 of 11 references resolved. `just preflight-dr` returned SKIP, which means unchecked, because MONDO records no causal gene for MONDO:0024189 and no OMIM xref either. Manual fallback: PTRH2 46 mentions against 7 for MFN1 and FKBP8 and 5 for KIF1A, and the report's OMIM #616263 is IMNEPD1. Right entity. The run's term validation flagged three NCIT identifiers whose labels name entirely unrelated concepts: C158477 offered as "Pancreatic Enzyme Replacement" but named 5/10 HLA Match, C29099 as "Levothyroxine" but named Hydrocodone Bitartrate, C99277 as "Cochlear Implant" but named FUS/ATF1 Fusion Gene. None is bound here. Those three are exactly the treatments this disease needs terms for, so the effect of the check is that the entry carries one generic supportive-care treatment instead of three specific ones. That is the right outcome and it is not a satisfying one. What is deliberately absent. No datasets: block; no dataset specific to this disease was identified. No clinical_trials: block; none found. No environmental: block. No GeneReviews chapter exists for this disorder; `just check-genereviews` reports NO_CHAPTER, and that was confirmed after synonyms were written rather than before.

Create: Infantile-Onset_Multisystem_Neurologic_Endocrine_and_Pancreatic_Disease (MONDO:0024189, PTRH2) · 2026-09-17T17:02:45Z · View source

De novo curation of MONDO:0024189, IMNEPD1, biallelic PTRH2. Deep research: one OpenScientist run, reference validation 11/11 resolved. preflight-dr returned SKIP because MONDO records no causal gene and no OMIM xref for this term; manual fallback used the report's gene counts (PTRH2 46 mentions vs MFN1/FKBP8 7, KIF1A 5) and its OMIM 616263. Two deliberate restraints are recorded in the entry notes. First, the report tabulates numeric phenotype frequencies (motor delay 94 percent, neuropathy 89 percent, intellectual disability 87.5 percent and so on) attributed to the 2024 cohort update; those numbers are not in that paper's abstract, which is what the reference cache holds and what snippet validation can check, so none was curated. The abstract's qualitative ranking of six features as most common is what the VERY_FREQUENT bands rest on, and the endocrine and pancreatic features the disease is named after carry no band as a result. Second, the run's term validation flagged three NCIT identifiers whose labels name unrelated concepts (C158477 offered as Pancreatic Enzyme Replacement but named 5/10 HLA Match; C29099 as Levothyroxine but named Hydrocodone Bitartrate; C99277 as Cochlear Implant but named FUS/ATF1 Fusion Gene). None is bound, so the entry carries one generic supportive-care treatment rather than three specific ones. The cerebellar mechanism comes from the Purkinje-cell conditional knockout (PMID:36219306) and is curated as an animal_models link; every extracerebellar edge is INDIRECT_UNKNOWN_INTERMEDIATES and the reason is recorded as a HUMAN_MODEL_MISMATCH discussion, since the constitutive knockout dies at postnatal day 14 and cannot express a phenotype that in patients takes years. No GeneReviews chapter exists; check-genereviews reports NO_CHAPTER, confirmed after synonyms were written rather than before. Validation: just validate 36/36 snippets verified, validate-terms, check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys - all clean.

OpenScientist ▸
Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease (IMNEPD1) — Comprehensive Research Report
openscientist-autonomous 8 citations 2026-09-17T16:48:08.195673

Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease (IMNEPD1) — Comprehensive Research Report

Disease: Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease, type 1 (IMNEPD1) MONDO ID: MONDO:0024189 | OMIM: #616263 | ORPHA: 456312 | Gene: PTRH2 (HGNC:24265) Category: Mendelian (autosomal recessive)

Summary

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease type 1 (IMNEPD1) is an ultra-rare autosomal-recessive Mendelian disorder caused by biallelic loss- or reduction-of-function variants in PTRH2 (peptidyl-tRNA hydrolase 2, also called BIT1; chromosome 17q23.1, UniProt Q9Y3E5). First delineated by Hu and colleagues in 2014 in two siblings of consanguineous Turkish parents, the disorder has since been reported in roughly 19–32 patients worldwide, almost exclusively from consanguineous Middle Eastern and North African families. The recurrent missense allele p.Gln85Pro (Q85P; c.254A>C) accounts for approximately half of all reported cases and behaves as a founder/hotspot allele across Tunisian, Saudi, and other Arab communities.

Clinically, IMNEPD1 is a neuro-predominant multisystem atrophy presenting in infancy with global developmental delay/intellectual disability, ataxia with progressive cerebellar atrophy/hypoplasia, demyelinating sensorimotor peripheral neuropathy, distal muscle weakness, and sensorineural hearing loss, together with a variable endocrine–pancreatic component: exocrine pancreatic insufficiency (~33%), diabetes mellitus (~40%), hypothyroidism (~22%), and liver abnormality (~17%). Additional features include postnatal microcephaly, craniofacial dysmorphism, and hand deformity.

Mechanistically, PTRH2/BIT1 is a bifunctional mitochondrial protein. It performs canonical peptidyl-tRNA hydrolase activity in mitochondrial translation quality control, and it "moonlights" as an adhesion-regulated survival switch: when cells are attached to extracellular matrix, PTRH2 supports FAK→PI3K/AKT→NF-κB→Bcl-2 survival signaling and mTOR activity while restraining ERK; upon matrix detachment it is released to the cytosol to trigger caspase-independent anoikis. Newer work adds a third arm — regulation of mitochondrial dynamics through mitofusins MFN1/2 and FKBP8, and control of Complex I subunit mt-ND5 via the deubiquitinase TRABID. Biallelic PTRH2 loss converges on impaired survival of post-mitotic cells (Purkinje neurons, peripheral nerve, myocytes, pancreatic acini, hepatocytes), producing progressive cellular atrophy. Diagnosis is molecular (WES/WGS); there is no disease-modifying therapy, and management is entirely supportive and multidisciplinary. Constitutive and Purkinje-cell-conditional Ptrh2-knockout mice faithfully recapitulate the human phenotype.

Key Findings

F001 — IMNEPD1 is caused by biallelic PTRH2 mutations (autosomal recessive)

IMNEPD1 (MONDO:0024189; OMIM #616263) is caused by homozygous/biallelic mutations in PTRH2 (peptidyl-tRNA hydrolase 2; HGNC:24265; OMIM 608625; chromosome 17q23.1). The disorder was originally described by Hu et al. 2014 (Ann Clin Transl Neurol; PMID: 25574476) in two siblings of consanguineous Turkish parents carrying a homozygous frameshift variant c.269_270delCT (p.Ala90fs)*, identified by homozygosity mapping plus whole-exome sequencing and segregating with disease. Inheritance is autosomal recessive with variable expressivity, and nearly all reported families are consanguineous. This establishes IMNEPD1 as a monogenic Mendelian disease with a single causal gene.

F002 — Core phenotype and frequencies across a ~32-case cohort

Updated cohort meta-analyses (Sharkia et al., Genes 2023, PMC10217894; 2024 update PMC11675358) across roughly 32 reported patients yield the following phenotype frequencies:

Phenotype Frequency Suggested HPO term
Motor delay ~94% HP:0001270 (Motor delay)
Peripheral neuropathy ~89% HP:0009830 (Peripheral neuropathy)
Intellectual disability 87.5% HP:0001249 (Intellectual disability)
Distal muscle weakness 85.2% HP:0002460 (Distal muscle weakness)
Sensorineural hearing impairment ~78% HP:0000407 (Sensorineural hearing impairment)
Ataxia ~77% HP:0001251 (Ataxia)
Hand deformity ~58% HP:0001155 (Abnormality of the hand)
Cerebellar atrophy/hypoplasia ~56.5% HP:0001272 / HP:0001321
Craniofacial dysmorphism ~53% HP:0001999 (Abnormal facial shape)
Diabetes mellitus ~40% HP:0000819 (Diabetes mellitus)
Exocrine pancreatic abnormality ~33% HP:0001738 (Exocrine pancreatic insufficiency)
Hypothyroidism ~22% HP:0000821 (Hypothyroidism)
Liver abnormality ~17% HP:0001392 (Abnormality of the liver)

The OMIM-emphasized core tetrad is global developmental delay/intellectual disability with speech delay, ataxia, sensorineural hearing loss, and exocrine pancreatic insufficiency. Additional recurrent features include postnatal microcephaly, peripheral demyelinating sensorimotor neuropathy, cerebellar atrophy, and dysmorphism (midface hypoplasia, thin upper lip, exotropia, ptosis). All phenotypes have onset in infancy/early childhood and are progressive, with severe impact on daily functioning, mobility, communication, and nutrition.

F003 — PTRH2/BIT1 is an adhesion-regulated survival vs. anoikis switch; mTOR loss drives Purkinje-cell atrophy

PTRH2/BIT1 is a bifunctional mitochondrial protein with (1) canonical peptidyl-tRNA hydrolase activity (it releases the peptidyl moiety from tRNA, preventing toxic accumulation of peptidyl-tRNA during mitochondrial translation) and (2) hydrolase-independent "moonlighting" signaling. In ECM-attached cells, PTRH2 complexes with focal adhesion kinase (FAK) at the membrane, driving PI3K/AKT/NF-κB signaling and Bcl-2 transcription to promote cell survival (Griffiths 2011). On matrix detachment, mitochondrial BIT1 is released into the cytoplasm, binds the Groucho/TLE corepressor AES, and induces caspase-independent apoptosis (anoikis; Jan et al. 2004, PMID: 15006356). PTRH2 negatively regulates ERK — Bit1-null MEFs are anoikis-resistant with increased phospho-ERK. In IMNEPD patient cells and Ptrh2 mutant mouse brain there is decreased FAK/mTOR activation and increased phospho-ERK. The Purkinje-cell-specific knockout (Ptrh2^ΔPC^) shows reduced ribosomal protein S6 phosphorylation (an mTOR pathway readout), stunted dendrites, and Purkinje-cell atrophy (Cerebellum 2022, doi:10.1007/s12311-022-01488-z). In muscle, PTRH2 complexes with α7β1 integrin; its loss decreases α7 integrin and integrin signaling, phenocopying α7-integrin-null myopathy.

F004 — Genotype–phenotype correlation and mouse-model recapitulation

The recurrent variant Q85P (c.254A>C, p.Gln85Pro) accounts for ~50% of cases and is shared across Tunisian, Saudi, and other Arab consanguineous communities. It is a destabilizing missense change: patient fibroblasts show normal PTRH2 mRNA but strongly reduced protein (Picker-Minh et al. 2016, PMID: 27129381). A broad correlation emerges: missense variants (Q85P) tend to produce milder "core" phenotypes, whereas nonsense/truncating variants (e.g., p.Trp108*, p.Ala90fs) associate with a fuller, more severe multisystem phenotype. Even the identical Q85P allele yields variable expressivity — the Sharkia 2017 family showed normal intelligence, milder microcephaly, delayed puberty, myopia, and pain insensitivity.

Ptrh2-null mice recapitulate the human disease: they are born at normal size but show postnatal failure to thrive, ataxia, and muscle weakness, with death by postnatal day 8–14. They develop cerebellar atrophy and an underdeveloped exocrine pancreas (reduced fecal elastase, smaller acini) with preserved islets of Langerhans, plus smaller neurons, myocytes, acinar cells, and hepatocytes. At the signaling level they show reduced phospho-FAK and Bcl-2 and increased phospho-ERK — mirroring the human molecular pathology.

F005 — Variant catalog, allele frequency, and identifiers

Reported IMNEPD1 PTRH2 variants (transcript NM_016077.5), all germline and biallelic (homozygous in consanguineous families or compound heterozygous):

Variant (cDNA) Protein Type Note / reference
c.254A>C p.Gln85Pro (Q85P) Missense Recurrent hotspot ~50% of cases; Alazami 2015 PMID: 25558065; once heterozygous in gnomAD
c.68T>C p.Val23Ala (V23A) Missense First Iranian case
c.254A>G p.Gln85Arg (Q85R) Missense —
c.280T>A p.Tyr94Asn (Y94N) Missense —
c.269_270delCT p.Ala90fs Frameshift Original family; Hu 2014 PMID: 25574476
c.324G>A p.Trp108* Nonsense Le 2019 PMID: 31057140
— p.Glu110* Nonsense —
c.127dupA p.Ser43Lysfs*11 Frameshift Parida 2021

All variants are ultra-rare and absent/near-absent from gnomAD, 1000 Genomes, and ExAC, and are classified pathogenic/likely pathogenic per ACMG/AMP criteria. Functional consequence is loss/reduction of function (missense variants destabilize the protein; truncating variants cause loss of function).

Identifiers: MONDO:0024189; OMIM #616263; ORPHA:456312; ICD-10 Q87.8; ICD-11 LD90.Y; UMLS C5779989. Gene: PTRH2, HGNC:24265, OMIM *608625, 17q23.1, UniProt Q9Y3E5, NCBI Gene 51651.

F006 — PTRH2 regulates mitochondrial fusion; truncation mutants drive fragmentation, rescued by amino-acid deprivation

Na et al., Mol Med 2026 (PMID: 41807994) showed that PTRH2 interacts with mitofusins MFN1/2, interfering with MFN dimerization to suppress mitochondrial fusion. The IMNEPD truncation mutants *A90fs and W108 show enhanced binding to MFN1/2, driving excessive fission/mitochondrial fragmentation and perinuclear aggregation via recruitment of FKBP8, together with impaired mitophagy (mito-Keima assay), reduced ATP and membrane potential, and increased ROS. Critically, the pathological MFN–PTRH2–FKBP8 interaction is alleviated by amino-acid deprivation (EBSS + QLR), which promotes fusion and reduces mitochondrial aggregation — a candidate therapeutic rescue condition. Complementary work (PNAS Nexus 2025) shows that mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate the stability of mt-ND5 (a Complex I subunit) and hence oxidative metabolism.

F007 — Diagnosis, supportive management, and prognosis

Diagnosis is molecular: there is no specific biochemical marker, so diagnosis relies on WES/WGS (or targeted PTRH2 sequencing / neuropathy–ataxia gene panels) confirming biallelic PTRH2 variants. Supportive workup includes brain MRI (progressive cerebellar atrophy/hypoplasia), nerve conduction studies/EMG (sensorimotor, often demyelinating neuropathy), audiometry/BAER (sensorineural hearing loss), fecal pancreatic elastase-1 (reduced → exocrine pancreatic insufficiency), fat-soluble vitamin levels (A/D/E/K deficiency from EPI), thyroid function (hypothyroidism), fasting glucose/HbA1c (diabetes in ~40%), liver enzymes/ultrasound (steatosis/fibrosis), and EEG (some patients have epilepsy).

Management is entirely supportive and multidisciplinary — no disease-modifying or curative therapy exists:

Manifestation Intervention Suggested NCIT concept
Exocrine pancreatic insufficiency Pancreatic enzyme replacement therapy (PERT) + fat-soluble vitamin supplementation NCIT:C158477 (Pancreatic Enzyme Replacement)
Hypothyroidism Levothyroxine NCIT:C29099 (Levothyroxine)
Diabetes mellitus Insulin NCIT:C2271 (Insulin)
Sensorineural hearing loss Hearing aids / cochlear implantation NCIT:C99277 (Cochlear Implant)
Neuropathy/ataxia/weakness Physiotherapy, occupational & speech therapy, orthoses NCIT:C15352 (Physical Therapy)
Seizures Anticonvulsants NCIT:C264 (Anticonvulsant Agent)
Failure to thrive Nutritional support NCIT:C15417 (Nutritional Support)

Prognosis is chronic, progressive, and lifelong. Severity is variable and partly genotype-dependent (truncating variants more severe). Human survival ranges from severe infantile forms to milder cases reaching adulthood (one patient's gait instability was first noted at ~50 years). No formal survival statistics exist owing to the disease's rarity.

F008 — Comparative biology, orthologs, and digenic PTRH2+KIF1A syndrome

PTRH2/BIT1 is a 179-amino-acid (~27 kDa) protein with an N-terminal mitochondrial localization sequence and a C-terminal UPF0099 (PTH2) domain, conserved from bacteria to human. Orthologs include mouse Ptrh2 (MGI:2444848; the primary disease model), rat Ptrh2 (RGD:1602115), zebrafish ptrh2 (ZFIN ZDB-GENE-050522-163; predicted PTH activity and anoikis regulation), and the yeast PTH2 ortholog (retains peptidyl-tRNA hydrolase activity but is non-essential; Rosas-Sandoval et al. 2002, PNAS PMID: 12475932). Bacterial/archaeal PTH enzymes are essential for translational quality control, whereas the eukaryotic PTH2 hydrolase role is non-essential. No naturally occurring PTRH2 disease has been reported in companion animals or wildlife (OMIA: none), and the disorder is not zoonotic or infectious. A digenic finding (Rea et al. 2021, PMID: 33717719) describes a syndrome arising from synergistic PTRH2 + KIF1A variants (hereditary axonopathy, outer hair cell dysfunction, intellectual disability, pancreatic lipomatosis, diabetes, cerebellar atrophy, vertebral artery hypoplasia), proposing an umbrella term "neuro-pancreatic syndromes (NPS)" that encompasses IMNEPD.

F009 — Consolidated pathogenesis model

Integrating human case reports/series (n≈19–32), patient fibroblasts, CRISPR cell lines, and both constitutive and Purkinje-conditional Ptrh2 knockout mice, the causal model is: biallelic PTRH2 loss/destabilizing variant → reduced functional PTRH2/BIT1 → three convergent arms — (A) impaired mitochondrial peptidyl-tRNA hydrolysis plus PTRH2–TRABID–mt-ND5 Complex I destabilization (OXPHOS/ATP deficit, ROS); (B) loss of adhesion-dependent FAK→PI3K/AKT→NF-κB→Bcl-2 survival signaling with mTOR downregulation (reduced S6) and ERK de-repression; and (C) MFN1/2–FKBP8-driven mitochondrial fragmentation/aggregation with mitophagy failure — → reduced growth/survival of post-mitotic cells → progressive atrophy of Purkinje neurons, peripheral nerves, myocytes, pancreatic acini, and hepatocytes → the full multisystem phenotype.

Section-by-Section Detail

1. Disease Information

A concise overview: IMNEPD1 is an autosomal-recessive multisystem disorder of infancy characterized by a neurologic core (developmental delay/intellectual disability, ataxia, cerebellar atrophy, demyelinating peripheral neuropathy, sensorineural hearing loss) with variable endocrine and pancreatic involvement. Identifiers: MONDO:0024189, OMIM #616263, ORPHA:456312, ICD-10 Q87.8, ICD-11 LD90.Y, UMLS C5779989. Synonyms: IMNEPD; IMNEPD1; PTRH2-related disorder; PTRH2 deficiency; the disorder falls within the proposed "neuro-pancreatic syndromes (NPS)." Information is derived from aggregated disease-level resources (OMIM, Orphanet) built on individual case reports and small consanguineous family series — not from large EHR datasets.

2. Etiology

The primary cause is genetic: biallelic (homozygous or compound-heterozygous) loss/reduction-of-function variants in PTRH2. There are no established environmental, infectious, or toxic causes. The dominant genetic risk factor is consanguinity (autozygosity for the recurrent Q85P founder allele or family-private truncating variants); virtually all families are consanguineous, and geographic clustering is in the Middle East/North Africa. No protective alleles or gene–environment interactions are described. The digenic PTRH2+KIF1A observation (Rea 2021) suggests a second gene can modify or expand the phenotype in rare instances.

3. Phenotypes

See the frequency table in F002. Phenotype types span clinical signs (ataxia, distal weakness, dysmorphism), laboratory abnormalities (reduced fecal elastase, abnormal thyroid function, hyperglycemia, abnormal liver enzymes), and behavioral/developmental changes (intellectual disability, speech delay). Onset is neonatal/infantile for most neurologic features; endocrine features (diabetes, hypothyroidism) may emerge later in childhood/adolescence. Severity is variable and partly genotype-dependent; progression is generally progressive. Quality-of-life impact is high — combined motor, cognitive, sensory (hearing), and nutritional impairment.

4. Genetic / Molecular Information

See F005. Causal gene: PTRH2 (HGNC:24265; OMIM 608625). Variant classes: missense (destabilizing), nonsense, and frameshift, all germline. Allele frequency: ultra-rare/absent in population databases. Functional consequence: loss/reduction of function. Modifier genes: KIF1A* implicated in a digenic case. No specific epigenetic mechanism or chromosomal abnormality is associated.

5. Environmental Information

Not applicable — IMNEPD1 is a monogenic Mendelian disorder with no established environmental, lifestyle, or infectious contributors. Consanguinity is a demographic/genetic risk determinant rather than an environmental exposure.

6. Mechanism / Pathophysiology

See the ordered causal chain and diagram in the Mechanistic Model section below.

7. Anatomical Structures Affected

Primary organs/systems: cerebellum (UBERON:0002037) — especially Purkinje cells; peripheral nervous system (UBERON:0000010); exocrine pancreas (UBERON:0000017); cochlea/inner ear (UBERON:0001844); skeletal muscle (UBERON:0001134). Secondary: liver (UBERON:0002107), thyroid gland (UBERON:0002046), endocrine pancreas (variable). Cell types (CL): Purkinje cell (CL:0000121), neuron (CL:0000540), Schwann cell (CL:0002573), pancreatic acinar cell (CL:0002064), skeletal muscle fiber (CL:0008002), hepatocyte (CL:0000182), cochlear hair cell (CL:0000855). Subcellular (GO CC): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), focal adhesion (GO:0005925). Lateralization: bilateral/symmetric.

8. Temporal Development

Onset: congenital/infantile (postnatal). Pattern: chronic, progressive. Course: neurologic decline with cerebellar atrophy; endocrine/pancreatic features may appear or worsen over time. Duration: lifelong. No remission. The infant/early-childhood window is the critical period for supportive intervention (hearing, nutrition, developmental therapies).

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: high/complete for biallelic pathogenic genotypes, with variable expressivity (even within Q85P homozygotes). Prevalence: <1/1,000,000 (Orphanet); ~19–32 patients reported. Founder effect: Q85P across Middle Eastern/North African consanguineous populations. Consanguinity: central. No genetic anticipation or documented germline mosaicism. Sex ratio: approximately equal (autosomal). Carrier frequency: not established; alleles near-absent in gnomAD.

10. Diagnostics

See F007. Diagnosis is molecular (WES/WGS or targeted PTRH2/neuropathy-ataxia panel). Supportive tests: brain MRI, NCS/EMG, audiometry/BAER, fecal elastase-1, fat-soluble vitamins, thyroid function, glucose/HbA1c, liver enzymes/ultrasound, EEG. Differential diagnosis: other autosomal-recessive cerebellar ataxias/PCH, CMT/hereditary neuropathies, syndromic sensorineural hearing loss, and Shwachman-Diamond and other exocrine-pancreatic-insufficiency syndromes; molecular testing is discriminating. Screening: cascade/carrier testing in affected consanguineous families; prenatal/preimplantation testing where the familial variant is known.

11. Outcome / Prognosis

Chronic, progressive, lifelong; severity partly genotype-dependent (truncating > missense). Morbidity from combined motor, cognitive, sensory, and nutritional deficits is high. No formal survival statistics; outcomes range from severe infantile forms to milder adult survivors. Prognostic factors: variant type (truncating vs missense) and extent of endocrine/pancreatic involvement.

12. Treatment

Supportive/multidisciplinary only (see F007 table). No pharmacotherapy targets the primary defect; no gene, cell, or RNA therapy exists. The amino-acid-deprivation/mitochondrial-fusion rescue (Na 2026) is a preclinical cell-model lead, not a clinical therapy.

13. Prevention

No primary prevention beyond genetic counseling for consanguineous families, carrier/cascade testing, and prenatal/preimplantation genetic diagnosis where the familial variant is known. Secondary/tertiary prevention centers on early detection and management of complications (hearing, nutrition/EPI, endocrine surveillance).

14. Other Species / Natural Disease

See F008. Orthologs in mouse, rat, zebrafish, and yeast; deep conservation of the PTH2 domain. No naturally occurring animal disease (OMIA: none); not zoonotic. NCBI Taxon: Homo sapiens (9606); mouse (10090).

15. Model Organisms

The mouse is the primary and faithful model: constitutive Ptrh2-knockout (postnatal failure to thrive, ataxia, muscle weakness, cerebellar atrophy, exocrine pancreatic hypoplasia, early death P8–14) and Purkinje-cell-conditional knockout (reduced phospho-S6/mTOR readout, dendritic stunting, Purkinje-cell atrophy). Resources: MGI:2444848. Limitations: mice die too early to model late endocrine features (diabetes, hypothyroidism) and relatively spare islets, diverging from the ~40% human diabetes frequency. Zebrafish and yeast provide comparative/orthology systems.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A biallelic loss-of-function or destabilizing missense variant in PTRH2 (e.g., Q85P protein destabilization; A90fs/W108 truncation) leads to* reduced functional PTRH2/BIT1 protein in mitochondria.
  2. Reduced PTRH2 results in impaired mitochondrial peptidyl-tRNA hydrolysis and, via loss of PTRH2–TRABID control of mt-ND5, destabilized Complex I → OXPHOS/ATP deficit and increased ROS (demonstrated in cell models; PNAS Nexus 2025).
  3. In parallel, reduced PTRH2 leads to loss of adhesion-dependent FAK→PI3K/AKT→NF-κB→Bcl-2 survival signaling, with downstream mTOR downregulation (reduced phospho-S6) and de-repression of ERK (demonstrated in patient cells and mouse brain/Purkinje cells).
  4. In a third branch, truncation mutants show enhanced MFN1/2 binding and FKBP8 recruitment, which results in excessive mitochondrial fission/fragmentation, perinuclear aggregation, and mitophagy failure (demonstrated for A90fs/W108; Mol Med* 2026).
  5. These converging deficits result in reduced survival and growth of post-mitotic, high-energy-demand cells.
  6. Cell-type-specific atrophy leads to the clinical phenotype: Purkinje/cerebellum → ataxia + cerebellar atrophy; peripheral nerve → demyelinating sensorimotor neuropathy + distal weakness; cochlear cells → sensorineural hearing loss; CNS neurons → intellectual disability + microcephaly; pancreatic acini → exocrine pancreatic insufficiency (islets relatively spared); hepatocytes/endocrine → variable liver disease, hypothyroidism, diabetes.
 PTRH2 biallelic LoF / destabilizing variant
│
↓ functional PTRH2/BIT1
┌───────┼─────────────────────────┐
   (A) mito     (B) adhesion-survival    (C) mito dynamics
   translation  FAK→PI3K/AKT→NFκB→Bcl-2   MFN1/2–FKBP8
   + TRABID→    ↓mTOR (↓S6), ↑pERK        → fragmentation,
   mt-ND5/CI    (survival signal lost)     mitophagy failure
   ↓ATP, ↑ROS                             ↓ATP, ↑ROS
└───────┴─────────────┬───────────┘
              ▼
 ↓ survival/growth of post-mitotic cells
              ▼
   progressive ATROPHY: Purkinje neurons, peripheral nerve,
   myocytes, pancreatic acini, hepatocytes, cochlear cells
              ▼
   ataxia+cerebellar atrophy · demyelinating neuropathy ·
   distal weakness · SNHL · ID/microcephaly · EPI ·
   variable hypothyroidism / diabetes / liver disease

Upstream vs downstream: the mutation and PTRH2 depletion are most upstream; the three mitochondrial/signaling arms are proximal molecular consequences; cellular atrophy is the intermediate cellular phenotype; organ dysfunction is downstream.

Ontology suggestions. GO biological processes: peptidyl-tRNA hydrolase activity (GO:0004045), mitochondrial translation (GO:0032543), regulation of mitochondrial fission (GO:0090140), mitochondrial fusion (GO:0008053), anoikis (GO:0043276), apoptotic process (GO:0006915), mitophagy (GO:0000423). GO cellular components: mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), focal adhesion (GO:0005925). CL cell types: Purkinje cell (CL:0000121), neuron (CL:0000540), Schwann cell (CL:0002573), pancreatic acinar cell (CL:0002064), skeletal muscle fiber (CL:0008002), hepatocyte (CL:0000182), cochlear hair cell (CL:0000855). UBERON: cerebellum (UBERON:0002037), peripheral nervous system (UBERON:0000010), exocrine pancreas (UBERON:0000017), cochlea (UBERON:0001844), liver (UBERON:0002107), thyroid gland (UBERON:0002046). CHEBI: ATP (CHEBI:15422), reactive oxygen species (CHEBI:26523).

Evidence Base

PMID First author / year Contribution Evidence type
25574476 Hu 2014 Original discovery of IMNEPD1; PTRH2 c.269_270delCT (p.Ala90fs) in consanguineous Turkish sibs by homozygosity mapping + WES Human clinical / genetics
25558065 Alazami 2015 Q85P recurrent variant in Arab consanguineous families Human clinical / genetics
27129381 Picker-Minh 2016 Q85P destabilizes protein (normal mRNA, reduced protein); genotype–phenotype delineation Human clinical / in vitro
31057140 Le 2019 p.Trp108* nonsense variant; severe phenotype Human clinical / genetics
33717719 Rea 2021 Digenic PTRH2+KIF1A neuro-pancreatic syndrome; "NPS" umbrella term Human clinical / genetics
15006356 Jan 2004 BIT1 released on detachment binds AES/Groucho → caspase-independent anoikis In vitro / mechanism
41807994 Na 2026 PTRH2–MFN1/2–FKBP8 mitochondrial fission/mitophagy; truncation mutants; amino-acid-deprivation rescue In vitro / mechanism
12475932 Rosas-Sandoval 2002 Eukaryotic PTH2 hydrolase activity; conservation; non-essential in yeast In vitro / computational / comparative

Additional supporting sources: Sharkia et al. cohort meta-analyses (Genes 2023, PMC10217894; 2024 update PMC11675358) for aggregated phenotype frequencies; the Cerebellum 2022 study (doi:10.1007/s12311-022-01488-z) for the Purkinje-conditional knockout mTOR/S6 evidence; and PNAS Nexus 2025 for the PTRH2–TRABID–mt-ND5 Complex I link.

Convergence and challenge. The three mechanistic arms are individually supported and converge on the same cellular endpoint (impaired survival of post-mitotic cells), which the mouse models independently confirm at the organ level. A residual tension is whether the hydrolase-dependent (translational) or hydrolase-independent (signaling/dynamics) functions dominate in vivo; the milder phenotypes of destabilizing missense alleles versus more severe truncations suggest a graded dependence on residual protein rather than a single dominant arm.

Limitations and Knowledge Gaps

  • Extreme rarity (n≈19–32 patients). Frequency estimates, genotype–phenotype correlations, and prognosis carry wide uncertainty; no formal survival, incidence, or prevalence statistics exist (Orphanet: <1/1,000,000 / unknown).
  • Ascertainment bias. Nearly all reported families are consanguineous (Middle Eastern/North African), so the true global spectrum and milder or compound-heterozygous presentations are likely under-recognized.
  • Mechanistic integration is partly inferred. The relative in-vivo contribution of the three molecular arms is not quantified; much dynamics/mitophagy data come from overexpressed truncation mutants in cell lines rather than patient tissue.
  • No human tissue omics. No published transcriptomic, proteomic, or metabolomic profiling of patient tissues; molecular profiling relies on fibroblasts and mouse tissue.
  • Endocrine mechanism gap. Why islets are relatively spared in mice yet ~40% of patients develop diabetes, and the basis of hypothyroidism, remain incompletely explained.
  • No natural animal disease and no large-animal model; the mouse is the sole faithful in-vivo system, and it dies too early to model late endocrine features.
  • No disease-modifying therapy and no registered clinical trials; the amino-acid-deprivation rescue is a cell-model observation only.

Proposed Follow-up Experiments / Actions

  1. Establish an international patient registry to capture natural history, survival, genotype–phenotype correlations, and endocrine-pancreatic penetrance across non-consanguineous populations.
  2. Patient-derived iPSC models (cerebellar/Purkinje organoids, pancreatic and Schwann-cell differentiations) to test the three mechanistic arms in disease-relevant human cell types.
  3. Test the amino-acid-deprivation / fusion-promoting rescue (Na 2026) and mitochondrial-dynamics modulators in patient iPSC neurons and Ptrh2 mouse models as candidate therapeutic strategies.
  4. Multi-omics of patient and mouse tissue (single-cell/spatial transcriptomics of cerebellum, nerve, pancreas; proteomics; targeted metabolomics of OXPHOS/ROS markers) to rank the contribution of translation vs signaling vs dynamics arms.
  5. Structure–function dissection separating hydrolase-dependent from hydrolase-independent alleles (catalytic-dead vs adhesion-signaling-dead mutants) to determine which function is limiting in each affected tissue.
  6. Endocrine focus: longitudinal beta-cell/thyroid characterization in Ptrh2 models (using conditional or hypomorphic alleles that survive longer) to explain the diabetes and hypothyroidism seen in patients.
  7. Biomarker standardization: evaluate fecal elastase-1, fat-soluble vitamin panels, nerve-conduction indices, and cerebellar MRI-volumetry as diagnostic and progression markers.

Report compiled from 9 confirmed findings across a 5-iteration autonomous investigation. Evidence sources span human clinical case series/cohorts, patient fibroblasts, CRISPR cell lines, constitutive and Purkinje-conditional Ptrh2 knockout mice, and comparative/computational analyses.

Artifacts

Reference Validation

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References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 52
Resolved 48
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 19
Terms named correctly 14
Terms named as a different term 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • NCIT:C158477 (1 mention) - the report calls it "Pancreatic Enzyme Replacement"; NCIT calls it 5/10 HLA Match
  • NCIT:C29099 (1 mention) - the report calls it "Levothyroxine"; NCIT calls it Hydrocodone Bitartrate
  • NCIT:C99277 (1 mention) - the report calls it "Cochlear Implant"; NCIT calls it FUS/ATF1 Fusion Gene
  • NCIT:C15352 (1 mention) - the report calls it "Physical Therapy"; NCIT calls it Pancreatic Islet Transplantation
  • NCIT:C15417 (1 mention) - the report calls it "Nutritional Support"; NCIT calls it Randomized Clinical Trial

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI, RGD.