Charcot-Marie-Tooth Disease-Hearing Loss-Intellectual Disability Syndrome

Genetic MONDO:0008960 Pathograph 6 Show in embeddings browser Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome, also described in the neurological literature as hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of (sensory) large myelinated fibers (HMSN-ADM), is a rare, presumably autosomal recessive hereditary motor and sensory neuropathy. It is defined by early-onset, slowly progressive distal muscle weakness and atrophy, sensorineural deafness, and mild intellectual disability, with the pathognomonic finding of absence of large myelinated fibers (with a preserved complement of small myelinated fibers) on sural nerve biopsy. Autopsy evidence indicates the peripheral fiber loss reflects a primary lack of large-caliber neurons in the dorsal root ganglia and spinal anterior horns — a neuronopathy — together with cerebellar dentate neuron loss; variable demyelinating features and, rarely, epilepsy have been reported. The disorder was delineated from a small number of families (notably from a single geographic area of southern Italy); its causal gene remains unidentified, with the SMN1 and PMP22 genes explicitly excluded in the autopsied case.

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1
Inheritance
3
Pathophys.
6
Phenotypes
1
Hypotheses
2
Gaps
6
Pathograph
3
Medical Actions
4
References
🏷

Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

1
Autosomal Recessive HP:0000007
The syndrome is transmitted as a presumed autosomal recessive trait, typically affecting siblings of unaffected parents.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:9475604 SUPPORT Human Clinical
"which is transmitted in families probably as an autosomal recessive trait."
Supports autosomal recessive inheritance for the entity.
◈

Mechanistic Hypotheses

1
Developmental faulty-growth with subsequent axonal atrophy
developmental_faulty_growth_model EMERGING
Evidence balance 1 support
The original description proposed that the selective absence of large myelinated fibers arises from a developmental abnormality with faulty neuronal growth followed by axonal atrophy, rather than a classic degenerative or demyelinating process. This remains a hypothesis: it is inferred from consecutive sural-nerve biopsies in the index sibship and is not molecularly established.
Pathograph links
Loss of Large-Caliber Neurons in Dorsal Root Ganglia and Anterior Horns -> Absence of Large Myelinated Nerve Fibers Loss of the large-caliber parent neurons removes the large myelinated axons they project into peripheral motor and sensory nerves.
Show evidence (1 reference)
PMID:1506851 SUPPORT Human Clinical
"We infer from our findings that a developmental abnormality with faulty growth and subsequent axonal atrophy may be responsible."
The original authors explicitly frame the developmental faulty-growth/axonal-atrophy model as an inference, i.e. a hypothesis.
?

Discussions and Knowledge Gaps

2
What is the causal gene of the Charcot-Marie-Tooth disease-hearing-loss-intellectual-disability syndrome (HMSN-ADM)? The entity was delineated clinically and pathologically from a small number of families but remains genetically unsolved.
KNOWLEDGE GAP OPEN gap_unknown_causal_gene
Attached to
pathophysiology#Loss of Large-Caliber Neurons in Dorsal Root Ganglia and Anterior Horns
The disorder was defined as a distinct clinicopathological entity in the 1990s from a small number of (mostly southern Italian) families and is presumed autosomal recessive, but no causal gene has been identified. In the only autopsied case, targeted molecular analysis explicitly excluded the survival motor neuron gene (SMN1) and PMP22. Modern exome/genome sequencing of the reported pedigrees (or newly ascertained families) is needed to resolve the molecular basis.
Proposed experiments
Exome/genome sequencing of HMSN-ADM pedigrees
exp_wgs_hmsn_adm_pedigrees
Perform trio or affected-sib-pair whole-exome/whole-genome sequencing on the originally reported families and any newly ascertained cases to identify the recessive causal variant, leveraging the shared geographic origin to test for a founder allele.
Show evidence (1 reference)
PMID:11442171 SUPPORT Human Clinical
"Molecular genetic analyses in our case revealed neither genetic alterations in the survival motor neuron gene nor in the PMP-22 gene."
Documents that the two obvious candidate genes (SMN1 and PMP22) were excluded, and the causal gene remains unknown.
What is the pathomechanism linking the underlying (still genetically unsolved) neurodegenerative process to the CNS features of this syndrome — the sensorineural deafness and mild intellectual disability that (with the neuropathy) define it, and the epilepsy reported in the autopsied case?
KNOWLEDGE GAP OPEN gap_deafness_id_pathomechanism
Attached to
pathophysiology#Loss of Large-Caliber Neurons in Dorsal Root Ganglia and Anterior Horns pathophysiology#Cerebellar Dentate Nucleus Neuron Loss
Sensorineural deafness and mild intellectual disability are two of the three defining features of the entity, and epilepsy occurred in the autopsied case, but the literature does not establish the mechanistic basis of these CNS features: it is unknown whether the deafness is cochlear or a central/auditory-neuron (retrocochlear) lesion, the neuroanatomical basis of the intellectual disability is uncharacterised, and the dentate/cerebellar lesion has no established clinical correlate. These phenotypes are therefore deliberately left without an upstream causal edge and recorded as an explicit, auditable knowledge gap rather than linked by a fabricated mechanism. Resolving the causal gene and obtaining audiologic (ABR/OAE) and neuroimaging characterisation would clarify these arms.
Proposed experiments
Audiologic and neuroimaging characterisation of HMSN-ADM
exp_audiologic_neuroimaging_characterisation
Perform auditory brainstem response / otoacoustic emission testing to localise the deafness (cochlear vs auditory-neuropathy) and structural/ functional brain imaging to characterise the substrate of the intellectual disability in affected individuals.
⚙

Pathophysiology

3
Loss of Large-Caliber Neurons in Dorsal Root Ganglia and Anterior Horns
The primary lesion is a lack of large-caliber neurons in the dorsal root ganglia (large sensory neurons) and the spinal anterior horns (large motor neurons), demonstrated at autopsy. A developmental abnormality with faulty neuronal growth, followed by axonal atrophy, is the proposed (still hypothetical) basis for the selective loss of the large-fiber population.
Developmental faulty-growth with subsequent axonal atrophy
Anterior horn motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Anterior horn motor neuron, annotated with motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. Dorsal root ganglion sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Dorsal root ganglion sensory neuron, annotated with sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Neuron development GO:0048666 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Neuron development (GO:0048666). GO:0048666 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Absence of Large Myelinated Nerve Fibers Loss of the large-caliber parent neurons removes the large myelinated axons they project into peripheral motor and sensory nerves. Developmental faulty-growth with subsequent axonal atrophy
Cerebellar Dentate Nucleus Neuron Loss The same large-caliber neuronal degeneration extends centrally to the cerebellar dentate nucleus, demonstrated at autopsy.
Show evidence (2 references)
PMID:11442171 SUPPORT Human Clinical
"The autopsy showed complete absence of large myelinated fibers in peripheral motor and sensory nerves corresponding to a lack of large neurons in dorsal root ganglia and anterior horns of the spinal cord, moderate neurogenic muscle atrophy, and nearly complete absence of neurons in the dentate..."
Autopsy evidence that absence of large myelinated peripheral fibers reflects a primary lack of large neurons in the dorsal root ganglia and anterior horns (a neuronopathy), with additional cerebellar dentate neuron loss.
PMID:1506851 SUPPORT Human Clinical
"We infer from our findings that a developmental abnormality with faulty growth and subsequent axonal atrophy may be responsible."
Original description proposes a developmental abnormality with faulty neuronal growth and subsequent axonal atrophy as the mechanism.
Absence of Large Myelinated Nerve Fibers
Sural nerve biopsy shows a selective absence of large myelinated fibers with a normal density/complement of small myelinated fibers and, in most cases, no primary axonal degeneration; overt demyelinating change is variable and has been seen only in some (younger) patients. This selective large-fiber deficit is the diagnostic pathological hallmark of the entity.
Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Downstream
Decreased Number of Large Peripheral Myelinated Nerve Fibers The tissue-level deficit is observed directly as the pathognomonic sural nerve biopsy finding.
Distal Muscle Weakness
Peripheral Neuropathy
Show evidence (2 references)
PMID:9475604 SUPPORT Human Clinical
"Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration."
Sural nerve biopsy in two affected brothers shows the selective absence of large myelinated fibers with preserved small fibers and no axonal degeneration.
PMID:9475604 SUPPORT Human Clinical
"Signs of demyelination were found only in the younger patient."
Demyelinating change is variable across affected individuals, supporting a primary large-fiber neuronopathy rather than a uniform demyelinating process.
Cerebellar Dentate Nucleus Neuron Loss
The neurodegenerative process extends centrally: autopsy showed nearly complete absence of neurons in the dentate nucleus of the cerebellum, a documented CNS lesion of the entity beyond the peripheral large-neuron loss.
Cerebellar dentate nucleus neuron CL:1001611 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cerebellar dentate nucleus neuron, annotated with cerebellar neuron (CL:1001611). CL:1001611 is a cell type from the Cell Ontology.
Neuron development GO:0048666 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Neuron development (GO:0048666). GO:0048666 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:11442171 SUPPORT Human Clinical
"nearly complete absence of neurons in the dentate nucleus of the cerebellum."
Autopsy documents near-complete cerebellar dentate nucleus neuron loss as a central component of the neurodegeneration.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Charcot-Marie-Tooth Disease-Hearing Loss-Intellectual Disability Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Ear 1
Sensorineural Hearing Impairment VERY_FREQUENT HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural deafness, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9475604 SUPPORT Human Clinical
"with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation."
Deafness is a defining component of the entity in affected brothers.
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), qualified as course progressive; childhood onset. HP:0002460 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Onset: CHILDHOOD
Show evidence (2 references)
PMID:1506851 SUPPORT Human Clinical
"Two brothers with a presumably hereditary motor and sensory polyneuropathy"
The motor-sensory polyneuropathy (with its distal motor component) is the defining, consistently present feature of the entity across reported siblings.
PMID:11442171 SUPPORT Human Clinical
"moderate neurogenic muscle atrophy"
Autopsy documents neurogenic muscle atrophy, the substrate of the distal motor weakness/wasting.
Nervous System 3
Peripheral Neuropathy OBLIGATE HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830), qualified as childhood onset. HP:0009830 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (1 reference)
PMID:9475604 SUPPORT Human Clinical
"We describe two brothers, 11 and 13 years old, respectively, with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation."
Establishes the early-onset hereditary motor and sensory neuropathy as the core clinical feature.
Mild Intellectual Disability VERY_FREQUENT HP:0001256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild intellectual disability (HP:0001256). HP:0001256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9475604 SUPPORT Human Clinical
"with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation."
Intellectual disability (mental retardation) is a defining component of the entity.
Seizures VERY_RARE HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11442171 SUPPORT Human Clinical
"a girl of non-consanguineous parents with a presumably autosomal recessive type of motor and sensory neuropathy clinically associated with deafness, mental retardation, and epilepsy."
The autopsied case is described as having motor and sensory neuropathy clinically associated with deafness, mental retardation, and epilepsy — documenting epilepsy as a rare associated feature.
Other 1
Decreased Number of Large Peripheral Myelinated Nerve Fibers OBLIGATE HP:0003387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased number of large peripheral myelinated nerve fibers (HP:0003387). HP:0003387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9475604 SUPPORT Human Clinical
"Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration."
Documents the selective large-myelinated-fiber deficit that defines the entity.
💊

Medical Actions

3
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Supportive physiotherapy and rehabilitation to maintain strength, mobility, and function; no disease-modifying therapy exists.
Hearing Rehabilitation
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management of sensorineural deafness with hearing aids or cochlear implantation and early auditory-verbal support to aid communication.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling for autosomal recessive recurrence risk; the causal gene is not yet identified, so molecular carrier testing is not currently available.
🔬

Diagnosis

1
Electrophysiology and Sural Nerve Biopsy
Nerve conduction studies show marked reduction of motor and sensory conduction velocity with absent sensory nerve action potentials; sural nerve biopsy shows the characteristic absence of large myelinated fibers with preserved small fibers, which is the diagnostic hallmark.
Show evidence (1 reference)
PMID:9475604 SUPPORT Human Clinical
"Electrophysiological studies showed marked reduction of motor and sensory conduction velocity and absence of sensory action potentials."
Describes the electrophysiological findings that, with the biopsy, support the diagnosis.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease-Hearing Loss-Intellectual Disability Syndrome
creation_date: "2026-07-31T00:00:00Z"
category: Genetic
description: >
  Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome,
  also described in the neurological literature as hereditary motor and sensory
  neuropathy with deafness, mental retardation, and absence of (sensory) large
  myelinated fibers (HMSN-ADM), is a rare, presumably autosomal recessive
  hereditary motor and sensory neuropathy. It is defined by early-onset,
  slowly progressive distal muscle weakness and atrophy, sensorineural
  deafness, and mild intellectual disability, with the pathognomonic finding
  of absence of large myelinated fibers (with a preserved complement of small
  myelinated fibers) on sural nerve biopsy. Autopsy evidence indicates the
  peripheral fiber loss reflects a primary lack of large-caliber neurons in the
  dorsal root ganglia and spinal anterior horns — a neuronopathy — together
  with cerebellar dentate neuron loss; variable demyelinating features and,
  rarely, epilepsy have been reported. The disorder was delineated from a small
  number of families (notably from a single geographic area of southern Italy);
  its causal gene remains unidentified, with the SMN1 and PMP22 genes
  explicitly excluded in the autopsied case.
disease_term:
  preferred_term: Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome
  term:
    id: MONDO:0008960
    label: Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome
parents:
- Charcot-Marie-Tooth Disease
synonyms:
- HMSN-ADM
- Hereditary motor and sensory neuropathy with deafness, intellectual disability and absent sensory large myelinated fibers
- Charcot-Marie-Tooth disease-deafness-intellectual disability syndrome

classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Hereditary motor and sensory neuropathy (with sensorineural deafness and
      intellectual disability) — a neurologic / neuromuscular disorder.

pathophysiology:
- name: Loss of Large-Caliber Neurons in Dorsal Root Ganglia and Anterior Horns
  biological_scale: CELLULAR
  description: >
    The primary lesion is a lack of large-caliber neurons in the dorsal root
    ganglia (large sensory neurons) and the spinal anterior horns (large motor
    neurons), demonstrated at autopsy. A developmental abnormality with faulty
    neuronal growth, followed by axonal atrophy, is the proposed (still
    hypothetical) basis for the selective loss of the large-fiber population.
  cell_types:
  - preferred_term: Anterior horn motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: Dorsal root ganglion sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Neuron development
    term:
      id: GO:0048666
      label: neuron development
    modifier: ABNORMAL
  downstream:
  - target: Absence of Large Myelinated Nerve Fibers
    description: >
      Loss of the large-caliber parent neurons removes the large myelinated
      axons they project into peripheral motor and sensory nerves.
    hypothesis_groups:
    - developmental_faulty_growth_model
  - target: Cerebellar Dentate Nucleus Neuron Loss
    description: >
      The same large-caliber neuronal degeneration extends centrally to the
      cerebellar dentate nucleus, demonstrated at autopsy.
  evidence:
  - reference: PMID:11442171
    reference_title: "Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autopsy showed complete absence of large myelinated fibers in peripheral motor and sensory nerves corresponding to a lack of large neurons in dorsal root ganglia and anterior horns of the spinal cord, moderate neurogenic muscle atrophy, and nearly complete absence of neurons in the dentate nucleus of the cerebellum."
    explanation: Autopsy evidence that absence of large myelinated peripheral fibers reflects a primary lack of large neurons in the dorsal root ganglia and anterior horns (a neuronopathy), with additional cerebellar dentate neuron loss.
  - reference: PMID:1506851
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We infer from our findings that a developmental abnormality with faulty growth and subsequent axonal atrophy may be responsible."
    explanation: Original description proposes a developmental abnormality with faulty neuronal growth and subsequent axonal atrophy as the mechanism.

- name: Absence of Large Myelinated Nerve Fibers
  biological_scale: TISSUE
  description: >
    Sural nerve biopsy shows a selective absence of large myelinated fibers
    with a normal density/complement of small myelinated fibers and, in most
    cases, no primary axonal degeneration; overt demyelinating change is
    variable and has been seen only in some (younger) patients. This selective
    large-fiber deficit is the diagnostic pathological hallmark of the entity.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  downstream:
  - target: Decreased Number of Large Peripheral Myelinated Nerve Fibers
    description: >
      The tissue-level deficit is observed directly as the pathognomonic sural
      nerve biopsy finding.
  - target: Distal Muscle Weakness
  - target: Peripheral Neuropathy
  evidence:
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration."
    explanation: Sural nerve biopsy in two affected brothers shows the selective absence of large myelinated fibers with preserved small fibers and no axonal degeneration.
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs of demyelination were found only in the younger patient."
    explanation: Demyelinating change is variable across affected individuals, supporting a primary large-fiber neuronopathy rather than a uniform demyelinating process.
  notes: >-
    Deliberate modeling divergence: the Orphanet/MONDO definition glosses this
    entity as a "demyelinating" HMSN, but the primary literature (autopsy
    PMID:11442171; biopsy PMID:9475604 with demyelination in only the younger
    patient) shows the large-fiber deficit reflects loss of large-caliber parent
    neurons, not a uniform demyelinating process. The neuronopathy model follows
    the primary evidence and is intentionally not "corrected" back to the
    ontology gloss.

- name: Cerebellar Dentate Nucleus Neuron Loss
  biological_scale: CELLULAR
  description: >
    The neurodegenerative process extends centrally: autopsy showed nearly
    complete absence of neurons in the dentate nucleus of the cerebellum, a
    documented CNS lesion of the entity beyond the peripheral large-neuron loss.
  cell_types:
  - preferred_term: Cerebellar dentate nucleus neuron
    term:
      id: CL:1001611
      label: cerebellar neuron
  biological_processes:
  - preferred_term: Neuron development
    term:
      id: GO:0048666
      label: neuron development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:11442171
    reference_title: "Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nearly complete absence of neurons in the dentate nucleus of the cerebellum."
    explanation: Autopsy documents near-complete cerebellar dentate nucleus neuron loss as a central component of the neurodegeneration.

phenotypes:
- name: Peripheral Neuropathy
  category: Neurological
  frequency: OBLIGATE
  description: >
    An early-onset, slowly progressive hereditary motor and sensory
    (poly)neuropathy is the defining clinical feature, with marked slowing of
    motor and sensory conduction and absent sensory action potentials on
    electrophysiology.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
    onset:
      onset_category: CHILDHOOD
      notes: Early-onset; reported affected siblings presented in the first-to-second decade.
  evidence:
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two brothers, 11 and 13 years old, respectively, with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation."
    explanation: Establishes the early-onset hereditary motor and sensory neuropathy as the core clinical feature.

- name: Decreased Number of Large Peripheral Myelinated Nerve Fibers
  category: Neurological
  frequency: OBLIGATE
  description: >
    The pathognomonic sural nerve biopsy finding: selective absence/marked
    reduction of large myelinated nerve fibers with preserved small fibers.
  phenotype_term:
    preferred_term: Decreased number of large peripheral myelinated nerve fibers
    term:
      id: HP:0003387
      label: Decreased number of large peripheral myelinated nerve fibers
  evidence:
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration."
    explanation: Documents the selective large-myelinated-fiber deficit that defines the entity.

- name: Distal Muscle Weakness
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: >
    Early-onset, slowly progressive distal limb weakness and wasting from the
    motor component of the neuropathy / anterior horn large-neuron loss. Distal
    muscular weakness and atrophy is the leading defining feature of the entity
    and is present across the reported patients.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
    onset:
      onset_category: CHILDHOOD
      notes: Early-onset; affected brothers reported at ages 11 and 13.
  evidence:
  - reference: PMID:1506851
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two brothers with a presumably hereditary motor and sensory polyneuropathy"
    explanation: The motor-sensory polyneuropathy (with its distal motor component) is the defining, consistently present feature of the entity across reported siblings.
  - reference: PMID:11442171
    reference_title: "Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "moderate neurogenic muscle atrophy"
    explanation: Autopsy documents neurogenic muscle atrophy, the substrate of the distal motor weakness/wasting.

- name: Sensorineural Hearing Impairment
  category: Neurological
  frequency: VERY_FREQUENT
  description: >
    Sensorineural deafness is a constant component of the syndrome, present
    across the reported families together with the neuropathy and intellectual
    disability.
  phenotype_term:
    preferred_term: Sensorineural deafness
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation."
    explanation: Deafness is a defining component of the entity in affected brothers.

- name: Mild Intellectual Disability
  category: Neurological
  frequency: VERY_FREQUENT
  description: >
    Mild intellectual disability (historically termed mental retardation) is a
    consistent feature, with impaired speech development.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation."
    explanation: Intellectual disability (mental retardation) is a defining component of the entity.

- name: Seizures
  category: Neurological
  frequency: VERY_RARE
  description: >
    Epilepsy has been reported in a single autopsied case, representing a rare
    extension of the phenotype.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:11442171
    reference_title: "Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a girl of non-consanguineous parents with a presumably autosomal recessive type of motor and sensory neuropathy clinically associated with deafness, mental retardation, and epilepsy."
    explanation: The autopsied case is described as having motor and sensory neuropathy clinically associated with deafness, mental retardation, and epilepsy — documenting epilepsy as a rare associated feature.

discussions:
- discussion_id: gap_unknown_causal_gene
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the causal gene of the Charcot-Marie-Tooth
    disease-hearing-loss-intellectual-disability syndrome (HMSN-ADM)? The entity was delineated
    clinically and pathologically from a small number of families but remains
    genetically unsolved.
  attaches_to:
  - pathophysiology#Loss of Large-Caliber Neurons in Dorsal Root Ganglia and Anterior Horns
  rationale: >-
    The disorder was defined as a distinct clinicopathological entity in the
    1990s from a small number of (mostly southern Italian) families and is
    presumed autosomal recessive, but no causal gene has been identified. In the
    only autopsied case, targeted molecular analysis explicitly excluded the
    survival motor neuron gene (SMN1) and PMP22. Modern exome/genome sequencing
    of the reported pedigrees (or newly ascertained families) is needed to
    resolve the molecular basis.
  proposed_experiments:
  - experiment_id: exp_wgs_hmsn_adm_pedigrees
    name: Exome/genome sequencing of HMSN-ADM pedigrees
    description: >-
      Perform trio or affected-sib-pair whole-exome/whole-genome sequencing on
      the originally reported families and any newly ascertained cases to
      identify the recessive causal variant, leveraging the shared geographic
      origin to test for a founder allele.
  evidence:
  - reference: PMID:11442171
    reference_title: "Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular genetic analyses in our case revealed neither genetic alterations in the survival motor neuron gene nor in the PMP-22 gene."
    explanation: Documents that the two obvious candidate genes (SMN1 and PMP22) were excluded, and the causal gene remains unknown.

- discussion_id: gap_deafness_id_pathomechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the pathomechanism linking the underlying (still genetically
    unsolved) neurodegenerative process to the CNS features of this syndrome —
    the sensorineural deafness and mild intellectual disability that (with the
    neuropathy) define it, and the epilepsy reported in the autopsied case?
  attaches_to:
  - pathophysiology#Loss of Large-Caliber Neurons in Dorsal Root Ganglia and Anterior Horns
  - pathophysiology#Cerebellar Dentate Nucleus Neuron Loss
  rationale: >-
    Sensorineural deafness and mild intellectual disability are two of the three
    defining features of the entity, and epilepsy occurred in the autopsied
    case, but the literature does not establish the mechanistic basis of these
    CNS features: it is unknown whether the deafness is cochlear or a
    central/auditory-neuron (retrocochlear) lesion, the neuroanatomical basis of
    the intellectual disability is uncharacterised, and the dentate/cerebellar
    lesion has no established clinical correlate. These phenotypes are therefore
    deliberately left without an upstream causal edge and recorded as an
    explicit, auditable knowledge gap rather than linked by a fabricated
    mechanism. Resolving the causal gene and obtaining audiologic (ABR/OAE) and
    neuroimaging characterisation would clarify these arms.
  proposed_experiments:
  - experiment_id: exp_audiologic_neuroimaging_characterisation
    name: Audiologic and neuroimaging characterisation of HMSN-ADM
    description: >-
      Perform auditory brainstem response / otoacoustic emission testing to
      localise the deafness (cochlear vs auditory-neuropathy) and structural/
      functional brain imaging to characterise the substrate of the intellectual
      disability in affected individuals.

mechanistic_hypotheses:
- hypothesis_group_id: developmental_faulty_growth_model
  hypothesis_label: Developmental faulty-growth with subsequent axonal atrophy
  status: EMERGING
  description: >-
    The original description proposed that the selective absence of large
    myelinated fibers arises from a developmental abnormality with faulty
    neuronal growth followed by axonal atrophy, rather than a classic
    degenerative or demyelinating process. This remains a hypothesis: it is
    inferred from consecutive sural-nerve biopsies in the index sibship and is
    not molecularly established.
  evidence:
  - reference: PMID:1506851
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We infer from our findings that a developmental abnormality with faulty growth and subsequent axonal atrophy may be responsible."
    explanation: The original authors explicitly frame the developmental faulty-growth/axonal-atrophy model as an inference, i.e. a hypothesis.

inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    The syndrome is transmitted as a presumed autosomal recessive trait,
    typically affecting siblings of unaffected parents.
  evidence:
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which is transmitted in families probably as an autosomal recessive trait."
    explanation: Supports autosomal recessive inheritance for the entity.

diagnosis:
- name: Electrophysiology and Sural Nerve Biopsy
  description: >
    Nerve conduction studies show marked reduction of motor and sensory
    conduction velocity with absent sensory nerve action potentials; sural
    nerve biopsy shows the characteristic absence of large myelinated fibers
    with preserved small fibers, which is the diagnostic hallmark.
  evidence:
  - reference: PMID:9475604
    reference_title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiological studies showed marked reduction of motor and sensory conduction velocity and absence of sensory action potentials."
    explanation: Describes the electrophysiological findings that, with the biopsy, support the diagnosis.

treatments:
- name: Physical Therapy and Rehabilitation
  description: >
    Supportive physiotherapy and rehabilitation to maintain strength, mobility,
    and function; no disease-modifying therapy exists.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy

- name: Hearing Rehabilitation
  description: >
    Management of sensorineural deafness with hearing aids or cochlear
    implantation and early auditory-verbal support to aid communication.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care

- name: Genetic Counseling
  description: >
    Genetic counseling for autosomal recessive recurrence risk; the causal gene
    is not yet identified, so molecular carrier testing is not currently
    available.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling

references:
- reference: PMID:1506851
  title: "Hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibers."
- reference: PMID:9475604
  title: "Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity."
- reference: PMID:9591228
  title: "A second family with hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibres, detected in the same geographic area as the first family."
- reference: PMID:11442171
  title: "Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM)."

datasets: []
📚

References & Deep Research

References

4
PMID:1506851
Hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibers.
No top-level findings curated for this source.
PMID:9475604
Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity.
No top-level findings curated for this source.
PMID:9591228
A second family with hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibres, detected in the same geographic area as the first family.
No top-level findings curated for this source.
PMID:11442171
Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM).
No top-level findings curated for this source.