🏷

Classifications

Harrison's Chapter

◆

Subtypes

7

dHMN2A (HSPB8-related)

Autosomal dominant distal hereditary motor neuropathy type II caused by heterozygous missense mutations in HSPB8 (HSP22), most recurrently at the K141 hot-spot residue. HSPB8 is a small heat-shock protein chaperone; mutant protein promotes intracellular aggregate formation and binds its partner HSPB1 abnormally.

Show evidence (1 reference)

PMID:15122253 SUPPORT Human Clinical

"In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22)."

Establishes heterozygous HSPB8 K141 mutations as the cause of dominant dHMN type II.

dHMN2B / CMT2F (HSPB1-related)

Autosomal dominant distal hereditary motor neuropathy / axonal CMT2F caused by heterozygous missense mutations in HSPB1 (HSP27), a small heat-shock protein chaperone. Mutant HSPB1 reduces neuronal viability and disrupts neurofilament assembly.

Show evidence (1 reference)

PMID:15122254 SUPPORT Human Clinical

"We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy."

Establishes HSPB1 mutations as a cause of dominant distal HMN (and CMT2F).

dHMN5 / Silver syndrome (BSCL2-related)

Autosomal dominant distal hereditary motor neuropathy type V and Silver syndrome caused by heterozygous BSCL2 missense mutations (N88S, S90L). BSCL2 encodes the endoplasmic-reticulum protein seipin; the substitutions impair seipin glycosylation and cause aggregate formation and neurodegeneration, with upper-limb predominant amyotrophy and variable lower-limb spasticity.

Show evidence (1 reference)

PMID:14981520 SUPPORT Human Clinical

"we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L."

Establishes heterozygous BSCL2 mutations as the cause of dominant dHMN-V / Silver syndrome.

dHMN5 / CMT2D (GARS1-related)

Autosomal dominant distal spinal muscular atrophy type V / CMT2D caused by heterozygous GARS1 (glycyl-tRNA synthetase) missense mutations, with upper-limb predominant distal weakness and atrophy. This was the first aminoacyl-tRNA synthetase implicated in a human inherited neuropathy.

Show evidence (1 reference)

PMID:12690580 SUPPORT Human Clinical

"we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V."

Establishes heterozygous GARS1 mutations as a cause of dominant dSMA-V / CMT2D.

dHMN7B (DCTN1-related)

Autosomal dominant lower motor neuron disease / distal hereditary motor neuropathy caused by a heterozygous DCTN1 (dynactin p150glued) mutation in the microtubule-binding CAP-Gly domain, impairing dynactin-mediated axonal transport; the original family had vocal-cord and facial weakness with distal limb atrophy.

Show evidence (1 reference)

PMID:12627231 SUPPORT Human Clinical

"Mutation analysis of a gene in this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is predicted to distort the folding of dynactin's microtubule-binding domain."

Establishes a heterozygous DCTN1 (dynactin) mutation as a cause of dominant lower motor neuron disease.

dHMN7A (SLC5A7-related)

Autosomal dominant distal hereditary motor neuropathy type VII caused by a dominantly segregating SLC5A7 mutation encoding the presynaptic choline transporter (CHT). The truncating mutation reduces choline uptake at the neuromuscular junction, linking dHMN to impaired NMJ transmission.

Show evidence (1 reference)

PMID:23141292 SUPPORT Human Clinical

"Using linkage analysis and whole-exome sequencing of DNA samples from subjects with distal hereditary motor neuropathy type VII, we identified a mutation in SLC5A7, which encodes the presynaptic choline transporter (CHT)"

Establishes a dominant SLC5A7 mutation as the cause of dHMN type VII.

Scapuloperoneal / congenital distal SMA (TRPV4-related)

Autosomal dominant congenital distal SMA, scapuloperoneal SMA, and HMSN2C caused by heterozygous TRPV4 missense mutations affecting the intracellular N-terminal ankyrin domain, with reduced surface localization of the mutant calcium-permeable cation channel.

Show evidence (1 reference)

PMID:20037588 SUPPORT Human Clinical

"we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families."

Establishes heterozygous TRPV4 ankyrin-domain mutations as a cause of dominant distal/scapuloperoneal SMA.

⚙

Pathophysiology

4

Motor Neuron and Distal Axon Gene Defect

Heterozygous (dominant) mutations in motor-neuron and distal-axon genes — small heat-shock protein chaperones (HSPB1, HSPB8), the ER protein seipin (BSCL2), glycyl-tRNA synthetase (GARS1), the dynactin axonal-transport adaptor (DCTN1), the choline transporter (SLC5A7), and the TRPV4 cation channel — impair the homeostatic functions that lower motor neurons require to build and maintain their long peripheral axons. Recurrent molecular consequences are protein misfolding/aggregation, impaired axonal transport, and defective tRNA charging.

motor neuron CL:0000100

Protein folding (chaperone function) GO:0006457 ↓ DECREASED

Downstream

Disrupted Proteostasis and Axonal Transport Mutant chaperone, ER, synthetase, and dynactin proteins disturb protein quality control and axonal transport within the motor neuron.

Show evidence (1 reference)

PMID:21902652 SUPPORT Other

"The mutated genes identified to-date in dHMN include HSPB1, HSPB8, HSPB3, DCTN1, GARS, PLEKHG5, BSCL2, SETX, IGHMBP2, ATP7A and"

Lists the dominant dHMN genes whose products converge on motor-neuron axon biology.

Disrupted Proteostasis and Axonal Transport

Mutant small heat-shock proteins (HSPB1, HSPB8) and seipin (BSCL2) form intracellular aggregates and impair protein quality control, while mutant dynactin (DCTN1) and tRNA-synthetase (GARS1) defects compromise axonal transport and local translation — collectively undermining maintenance of the long motor axon.

motor neuron CL:0000100

Axonal transport GO:0098930 ↓ DECREASED

Downstream

Length-Dependent Distal Motor Axonopathy Impaired proteostasis and axonal transport preferentially compromise the longest peripheral motor axons, producing a length-dependent distal motor axonopathy.

Show evidence (2 references)

PMID:14981520 SUPPORT In Vitro

"The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration."

Mutant seipin aggregation exemplifies the proteostasis defect driving motor-neuron degeneration.

PMID:12627231 SUPPORT In Vitro

"Binding assays show decreased binding of the mutant protein to microtubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease."

Mutant dynactin reduces microtubule binding, impairing axonal transport.

Length-Dependent Distal Motor Axonopathy

Progressive degeneration of the distal portions of the longest motor axons with chronic motor denervation, manifest as neurogenic changes on EMG and a motor axonal pattern on nerve conduction studies with preserved sensory responses.

motor neuron CL:0000100

Anterograde axonal transport GO:0008089 ↓ DECREASED

Downstream

Distal Muscle Weakness and Wasting Chronic motor denervation of distal muscles produces progressive distal weakness and atrophy, beginning in the lower (or, for some subtypes, upper) limbs.

Show evidence (1 reference)

PMID:15122253 SUPPORT Human Clinical

"Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles."

Documents the motor-predominant, distal, length-dependent axonopathy with sensory sparing.

Distal Muscle Weakness and Wasting

Clinically evident distal limb weakness and muscle atrophy, typically beginning in the feet and lower legs with foot drop and pes cavus, without prominent sensory loss; some subtypes (BSCL2/Silver syndrome, GARS1/CMT2D) have upper-limb predominant hand amyotrophy, and TRPV4-related forms have a scapuloperoneal distribution.

Show evidence (1 reference)

PMID:15122253 SUPPORT Human Clinical

"pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles"

Describes the distal weakness/wasting endpoint of dominant dHMN.

⬡

Pathograph

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

●

Phenotypes

7

Limbs 1

Pes cavus Pes cavus HP:0001761

Show evidence (1 reference)

PMID:14981520 SUPPORT Human Clinical

"characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs"

Distal motor-predominant degeneration underlies the foot deformities of dHMN.

Musculoskeletal 2

Distal muscle weakness Distal muscle weakness HP:0002460

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36445400 SUPPORT Human Clinical

"Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement."

Defines distal muscle weakness as the core feature of HMN/dHMN.

Spasticity Spasticity HP:0001257

Show evidence (1 reference)

PMID:14981520 SUPPORT Human Clinical

"Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands"

Leg spasticity with hand amyotrophy defines the BSCL2/Silver-syndrome dHMN-V subtype.

Nervous System 1

Gait disturbance Gait disturbance HP:0001288

Show evidence (1 reference)

PMID:36445400 SUPPORT Human Clinical

"length-dependent distal muscle weakness and atrophy"

The distal lower-limb weakness of dHMN produces a steppage / foot-drop gait disturbance.

Other 3

Distal amyotrophy Distal amyotrophy HP:0003693

Show evidence (1 reference)

PMID:15122253 SUPPORT Human Clinical

"pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles"

Severe distal muscle atrophy is a hallmark of dominant dHMN.

Motor axonal neuropathy Motor axonal neuropathy HP:0007002

Show evidence (1 reference)

PMID:21902652 SUPPORT Other

"The distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement."

Documents the pure-motor, axonal character of dHMN.

Foot drop Foot dorsiflexor weakness HP:0009027

Show evidence (1 reference)

PMID:36445400 SUPPORT Human Clinical

"length-dependent distal muscle weakness and atrophy"

Foot drop (ankle dorsiflexor weakness) is the cardinal lower-limb manifestation of the length-dependent distal motor weakness that defines dHMN.

🧬

Genetic Associations

7

HSPB8

Gene: HSPB8 hgnc:30171

Autosomal Dominant

Show evidence (1 reference)

PMID:15122253 SUPPORT Human Clinical

"we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22)."

HSPB8 K141 mutations cause dominant dHMN type II.

HSPB1

Gene: HSPB1 hgnc:5246

Autosomal Dominant

Show evidence (1 reference)

PMID:15122254 SUPPORT Human Clinical

"Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F."

HSPB1 mutations cause dominant distal HMN / CMT2F.

BSCL2

Gene: BSCL2 hgnc:15832

Autosomal Dominant

Show evidence (1 reference)

PMID:14981520 SUPPORT Human Clinical

"identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L."

Heterozygous BSCL2 mutations cause dominant dHMN-V / Silver syndrome.

GARS1

Gene: GARS1 hgnc:4162

Autosomal Dominant

Show evidence (1 reference)

PMID:12690580 SUPPORT Human Clinical

"we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V."

Heterozygous GARS1 mutations cause dominant dSMA-V / CMT2D.

DCTN1

Gene: DCTN1 hgnc:2711

Autosomal Dominant

Show evidence (1 reference)

PMID:12627231 SUPPORT Human Clinical

"Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease."

A heterozygous DCTN1 mutation causes dominant lower motor neuron disease.

SLC5A7

Gene: SLC5A7 hgnc:14025

Autosomal Dominant

Show evidence (1 reference)

PMID:23141292 SUPPORT Human Clinical

"This dominantly segregating SLC5A7 mutation truncates the encoded product just beyond the final transmembrane domain, eliminating cytosolic-C-terminus sequences known to regulate surface transporter trafficking."

A dominant SLC5A7 mutation causes dHMN type VII.

TRPV4

Gene: TRPV4 hgnc:18083

Autosomal Dominant

Show evidence (1 reference)

PMID:20037588 SUPPORT Human Clinical

"We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families."

Heterozygous TRPV4 ankyrin-domain mutations cause dominant distal/scapuloperoneal SMA.

💊

Medical Actions

3

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Counseling for autosomal dominant recurrence risk (50% to offspring) and predictive/cascade testing once a pathogenic variant is identified; the primary preventive strategy given the genetic etiology and frequent incomplete penetrance.

Physical Therapy and Orthotic Support

Action: physical therapy MAXO:0000011

Supportive rehabilitation including physical therapy and ankle-foot orthoses to manage distal weakness, foot drop, and gait disturbance.

Target Phenotypes: Distal muscle weakness HP:0002460

Supportive and Multidisciplinary Care

Action: supportive care MAXO:0000950

No disease-modifying therapy is available; management is supportive and multidisciplinary, including orthopedic correction of foot deformity, occupational therapy for hand involvement, and monitoring for respiratory or vocal-cord involvement in DCTN1-related disease.

{ }

Source YAML

click to show

name: Distal Hereditary Motor Neuronopathy, Autosomal Dominant
creation_date: "2026-06-17T00:00:00Z"
category: Genetic
description: >
  Autosomal dominant distal hereditary motor neuronopathy (dHMN; also called
  autosomal dominant distal spinal muscular atrophy, dSMA) is a clinically and
  genetically heterogeneous group of inherited lower motor neuron disorders
  characterized by slowly progressive, length-dependent distal muscle weakness
  and atrophy with minimal or absent sensory involvement. Neurophysiology shows
  chronic neurogenic denervation on EMG with a motor axonal pattern on nerve
  conduction studies and preserved sensory responses, distinguishing dHMN from
  axonal Charcot-Marie-Tooth disease (CMT2). The autosomal dominant forms are
  caused by heterozygous mutations in genes affecting motor-neuron and
  distal-axon biology, prominently the small heat-shock protein chaperones HSPB1
  (dHMN2B / CMT2F) and HSPB8 (dHMN2A), the endoplasmic-reticulum protein seipin
  BSCL2 (dHMN5 / Silver syndrome), the aminoacyl-tRNA synthetase GARS1
  (dHMN5 / CMT2D spectrum), the axonal-transport motor adaptor DCTN1
  (dynactin), the presynaptic choline transporter SLC5A7 (dHMN7A), and the cation
  channel TRPV4 (scapuloperoneal/congenital distal SMA spectrum). Recurrent
  pathogenic mechanisms include disrupted protein quality control with
  aggregation, impaired axonal transport, defective tRNA charging/translation,
  and disturbed neuromuscular-junction transmission. The autosomal recessive
  forms (e.g., IGHMBP2/SMARD1, SIGMAR1, PLEKHG5) are a distinct sibling entry.
disease_term:
  preferred_term: autosomal dominant distal hereditary motor neuropathy
  term:
    id: MONDO:0015362
    label: neuronopathy, distal hereditary motor, autosomal dominant
parents:
- distal hereditary motor neuropathy
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
references:
- reference: PMID:36445400
  title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
- reference: PMID:21902652
  title: "Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies."
external_assertions:
- name: OMIM dHMN2A (HSPB8)
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:158590
  description: OMIM phenotype entry for distal hereditary motor neuronopathy type 2A (HSPB8-related).
- name: OMIM dHMN2B / CMT2F (HSPB1)
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:606595
  description: OMIM phenotype entry for distal hereditary motor neuronopathy type 2B / CMT2F (HSPB1-related).
- name: OMIM dHMN5 / Silver syndrome (BSCL2)
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:270685
  description: OMIM phenotype entry for Silver syndrome / distal hereditary motor neuropathy type V (BSCL2-related).
- name: OMIM dHMN5 / CMT2D (GARS1)
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:601472
  description: OMIM phenotype entry for distal spinal muscular atrophy type V / CMT2D (GARS1-related).
- name: OMIM dHMN7B (DCTN1)
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:607641
  description: OMIM phenotype entry for distal hereditary motor neuronopathy type 7B (DCTN1-related).
has_subtypes:
- name: dHMN2A
  display_name: dHMN2A (HSPB8-related)
  description: >
    Autosomal dominant distal hereditary motor neuropathy type II caused by
    heterozygous missense mutations in HSPB8 (HSP22), most recurrently at the
    K141 hot-spot residue. HSPB8 is a small heat-shock protein chaperone; mutant
    protein promotes intracellular aggregate formation and binds its partner
    HSPB1 abnormally.
  evidence:
  - reference: PMID:15122253
    reference_title: "Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22)."
    explanation: Establishes heterozygous HSPB8 K141 mutations as the cause of dominant dHMN type II.
- name: dHMN2B
  display_name: dHMN2B / CMT2F (HSPB1-related)
  description: >
    Autosomal dominant distal hereditary motor neuropathy / axonal CMT2F caused
    by heterozygous missense mutations in HSPB1 (HSP27), a small heat-shock
    protein chaperone. Mutant HSPB1 reduces neuronal viability and disrupts
    neurofilament assembly.
  evidence:
  - reference: PMID:15122254
    reference_title: "Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy."
    explanation: Establishes HSPB1 mutations as a cause of dominant distal HMN (and CMT2F).
- name: dHMN5
  display_name: dHMN5 / Silver syndrome (BSCL2-related)
  description: >
    Autosomal dominant distal hereditary motor neuropathy type V and Silver
    syndrome caused by heterozygous BSCL2 missense mutations (N88S, S90L). BSCL2
    encodes the endoplasmic-reticulum protein seipin; the substitutions impair
    seipin glycosylation and cause aggregate formation and neurodegeneration,
    with upper-limb predominant amyotrophy and variable lower-limb spasticity.
  evidence:
  - reference: PMID:14981520
    reference_title: "Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L."
    explanation: Establishes heterozygous BSCL2 mutations as the cause of dominant dHMN-V / Silver syndrome.
- name: dHMN5-GARS
  display_name: dHMN5 / CMT2D (GARS1-related)
  description: >
    Autosomal dominant distal spinal muscular atrophy type V / CMT2D caused by
    heterozygous GARS1 (glycyl-tRNA synthetase) missense mutations, with
    upper-limb predominant distal weakness and atrophy. This was the first
    aminoacyl-tRNA synthetase implicated in a human inherited neuropathy.
  evidence:
  - reference: PMID:12690580
    reference_title: "Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V."
    explanation: Establishes heterozygous GARS1 mutations as a cause of dominant dSMA-V / CMT2D.
- name: dHMN7B
  display_name: dHMN7B (DCTN1-related)
  description: >
    Autosomal dominant lower motor neuron disease / distal hereditary motor
    neuropathy caused by a heterozygous DCTN1 (dynactin p150glued) mutation in
    the microtubule-binding CAP-Gly domain, impairing dynactin-mediated axonal
    transport; the original family had vocal-cord and facial weakness with distal
    limb atrophy.
  evidence:
  - reference: PMID:12627231
    reference_title: "Mutant dynactin in motor neuron disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis of a gene in this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is predicted to distort the folding of dynactin's microtubule-binding domain."
    explanation: Establishes a heterozygous DCTN1 (dynactin) mutation as a cause of dominant lower motor neuron disease.
- name: dHMN7A
  display_name: dHMN7A (SLC5A7-related)
  description: >
    Autosomal dominant distal hereditary motor neuropathy type VII caused by a
    dominantly segregating SLC5A7 mutation encoding the presynaptic choline
    transporter (CHT). The truncating mutation reduces choline uptake at the
    neuromuscular junction, linking dHMN to impaired NMJ transmission.
  evidence:
  - reference: PMID:23141292
    reference_title: "Defective presynaptic choline transport underlies hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using linkage analysis and whole-exome sequencing of DNA samples from subjects with distal hereditary motor neuropathy type VII, we identified a mutation in SLC5A7, which encodes the presynaptic choline transporter (CHT)"
    explanation: Establishes a dominant SLC5A7 mutation as the cause of dHMN type VII.
- name: dHMN-TRPV4
  display_name: Scapuloperoneal / congenital distal SMA (TRPV4-related)
  description: >
    Autosomal dominant congenital distal SMA, scapuloperoneal SMA, and
    HMSN2C caused by heterozygous TRPV4 missense mutations affecting the
    intracellular N-terminal ankyrin domain, with reduced surface localization
    of the mutant calcium-permeable cation channel.
  evidence:
  - reference: PMID:20037588
    reference_title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families."
    explanation: Establishes heterozygous TRPV4 ankyrin-domain mutations as a cause of dominant distal/scapuloperoneal SMA.
pathophysiology:
- name: Motor Neuron and Distal Axon Gene Defect
  description: >
    Heterozygous (dominant) mutations in motor-neuron and distal-axon genes —
    small heat-shock protein chaperones (HSPB1, HSPB8), the ER protein seipin
    (BSCL2), glycyl-tRNA synthetase (GARS1), the dynactin axonal-transport
    adaptor (DCTN1), the choline transporter (SLC5A7), and the TRPV4 cation
    channel — impair the homeostatic functions that lower motor neurons require
    to build and maintain their long peripheral axons. Recurrent molecular
    consequences are protein misfolding/aggregation, impaired axonal transport,
    and defective tRNA charging.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Protein folding (chaperone function)
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  evidence:
  - reference: PMID:21902652
    reference_title: "Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mutated genes identified to-date in dHMN include HSPB1, HSPB8, HSPB3, DCTN1, GARS, PLEKHG5, BSCL2, SETX, IGHMBP2, ATP7A and"
    explanation: Lists the dominant dHMN genes whose products converge on motor-neuron axon biology.
  downstream:
  - target: Disrupted Proteostasis and Axonal Transport
    description: >
      Mutant chaperone, ER, synthetase, and dynactin proteins disturb protein
      quality control and axonal transport within the motor neuron.
    causal_link_type: DIRECT
- name: Disrupted Proteostasis and Axonal Transport
  description: >
    Mutant small heat-shock proteins (HSPB1, HSPB8) and seipin (BSCL2) form
    intracellular aggregates and impair protein quality control, while mutant
    dynactin (DCTN1) and tRNA-synthetase (GARS1) defects compromise axonal
    transport and local translation — collectively undermining maintenance of
    the long motor axon.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Axonal transport
    term:
      id: GO:0098930
      label: axonal transport
    modifier: DECREASED
  evidence:
  - reference: PMID:14981520
    reference_title: "Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration."
    explanation: Mutant seipin aggregation exemplifies the proteostasis defect driving motor-neuron degeneration.
  - reference: PMID:12627231
    reference_title: "Mutant dynactin in motor neuron disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Binding assays show decreased binding of the mutant protein to microtubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease."
    explanation: Mutant dynactin reduces microtubule binding, impairing axonal transport.
  downstream:
  - target: Length-Dependent Distal Motor Axonopathy
    description: >
      Impaired proteostasis and axonal transport preferentially compromise the
      longest peripheral motor axons, producing a length-dependent distal motor
      axonopathy.
    causal_link_type: DIRECT
- name: Length-Dependent Distal Motor Axonopathy
  description: >
    Progressive degeneration of the distal portions of the longest motor axons
    with chronic motor denervation, manifest as neurogenic changes on EMG and a
    motor axonal pattern on nerve conduction studies with preserved sensory
    responses.
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Anterograde axonal transport
    term:
      id: GO:0008089
      label: anterograde axonal transport
    modifier: DECREASED
  evidence:
  - reference: PMID:15122253
    reference_title: "Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles."
    explanation: Documents the motor-predominant, distal, length-dependent axonopathy with sensory sparing.
  downstream:
  - target: Distal Muscle Weakness and Wasting
    description: >
      Chronic motor denervation of distal muscles produces progressive distal
      weakness and atrophy, beginning in the lower (or, for some subtypes, upper)
      limbs.
    causal_link_type: DIRECT
- name: Distal Muscle Weakness and Wasting
  description: >
    Clinically evident distal limb weakness and muscle atrophy, typically
    beginning in the feet and lower legs with foot drop and pes cavus, without
    prominent sensory loss; some subtypes (BSCL2/Silver syndrome, GARS1/CMT2D)
    have upper-limb predominant hand amyotrophy, and TRPV4-related forms have a
    scapuloperoneal distribution.
  evidence:
  - reference: PMID:15122253
    reference_title: "Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles"
    explanation: Describes the distal weakness/wasting endpoint of dominant dHMN.
phenotypes:
- category: Phenotypic
  name: Distal muscle weakness
  description: Progressive weakness of distal limb muscles, typically beginning in the lower limbs.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement."
    explanation: Defines distal muscle weakness as the core feature of HMN/dHMN.
- category: Phenotypic
  name: Distal amyotrophy
  description: Wasting of distal limb muscles.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: PMID:15122253
    reference_title: "Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles"
    explanation: Severe distal muscle atrophy is a hallmark of dominant dHMN.
- category: Phenotypic
  name: Motor axonal neuropathy
  description: Pure motor axonal involvement on nerve conduction studies with preserved sensory responses.
  phenotype_term:
    preferred_term: Motor axonal neuropathy
    term:
      id: HP:0007002
      label: Motor axonal neuropathy
  evidence:
  - reference: PMID:21902652
    reference_title: "Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement."
    explanation: Documents the pure-motor, axonal character of dHMN.
- category: Phenotypic
  name: Pes cavus
  description: High-arched foot deformity secondary to chronic distal denervation.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:14981520
    reference_title: "Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs"
    explanation: Distal motor-predominant degeneration underlies the foot deformities of dHMN.
- category: Phenotypic
  name: Spasticity
  description: >
    Lower-limb spasticity in BSCL2/Silver syndrome (a hereditary spastic
    paraparesis-overlap phenotype) reflecting additional upper motor neuron
    involvement in some dominant subtypes.
  subtype: dHMN5
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:14981520
    reference_title: "Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands"
    explanation: Leg spasticity with hand amyotrophy defines the BSCL2/Silver-syndrome dHMN-V subtype.
- category: Phenotypic
  name: Foot drop
  description: >
    Bilateral foot drop (ankle dorsiflexor weakness) is a cardinal early lower-limb
    manifestation of the length-dependent distal motor weakness of dHMN.
  phenotype_term:
    preferred_term: Foot drop
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "length-dependent distal muscle weakness and atrophy"
    explanation: Foot drop (ankle dorsiflexor weakness) is the cardinal lower-limb manifestation of the length-dependent distal motor weakness that defines dHMN.
- category: Phenotypic
  name: Gait disturbance
  description: >
    A steppage / foot-drop gait results from distal lower-limb weakness and is a
    common presenting feature of dHMN.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "length-dependent distal muscle weakness and atrophy"
    explanation: The distal lower-limb weakness of dHMN produces a steppage / foot-drop gait disturbance.
genetic:
- name: HSPB8
  gene_term:
    preferred_term: HSPB8
    term:
      id: hgnc:30171
      label: HSPB8
  inheritance:
  - name: Autosomal Dominant
  subtype: dHMN2A
  notes: >
    Heterozygous HSPB8 (HSP22) K141 hot-spot missense mutations cause dominant
    dHMN type II; mutant protein forms intracellular aggregates.
  evidence:
  - reference: PMID:15122253
    reference_title: "Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22)."
    explanation: HSPB8 K141 mutations cause dominant dHMN type II.
- name: HSPB1
  gene_term:
    preferred_term: HSPB1
    term:
      id: hgnc:5246
      label: HSPB1
  inheritance:
  - name: Autosomal Dominant
  subtype: dHMN2B
  notes: >
    Heterozygous HSPB1 (HSP27) missense mutations cause dominant distal HMN and
    axonal CMT2F.
  evidence:
  - reference: PMID:15122254
    reference_title: "Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F."
    explanation: HSPB1 mutations cause dominant distal HMN / CMT2F.
- name: BSCL2
  gene_term:
    preferred_term: BSCL2
    term:
      id: hgnc:15832
      label: BSCL2
  inheritance:
  - name: Autosomal Dominant
  subtype: dHMN5
  notes: >
    Heterozygous BSCL2 (seipin) N88S/S90L missense mutations cause dominant
    dHMN-V and Silver syndrome via impaired glycosylation and aggregation.
  evidence:
  - reference: PMID:14981520
    reference_title: "Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L."
    explanation: Heterozygous BSCL2 mutations cause dominant dHMN-V / Silver syndrome.
- name: GARS1
  gene_term:
    preferred_term: GARS1
    term:
      id: hgnc:4162
      label: GARS1
  inheritance:
  - name: Autosomal Dominant
  subtype: dHMN5-GARS
  notes: >
    Heterozygous GARS1 (glycyl-tRNA synthetase) missense mutations cause dominant
    dSMA-V / CMT2D; first aminoacyl-tRNA synthetase implicated in inherited
    neuropathy.
  evidence:
  - reference: PMID:12690580
    reference_title: "Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V."
    explanation: Heterozygous GARS1 mutations cause dominant dSMA-V / CMT2D.
- name: DCTN1
  gene_term:
    preferred_term: DCTN1
    term:
      id: hgnc:2711
      label: DCTN1
  inheritance:
  - name: Autosomal Dominant
  subtype: dHMN7B
  notes: >
    Heterozygous DCTN1 (dynactin p150glued) CAP-Gly-domain mutation causes
    dominant lower motor neuron disease with impaired axonal transport.
  evidence:
  - reference: PMID:12627231
    reference_title: "Mutant dynactin in motor neuron disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease."
    explanation: A heterozygous DCTN1 mutation causes dominant lower motor neuron disease.
- name: SLC5A7
  gene_term:
    preferred_term: SLC5A7
    term:
      id: hgnc:14025
      label: SLC5A7
  inheritance:
  - name: Autosomal Dominant
  subtype: dHMN7A
  notes: >
    Dominantly segregating SLC5A7 (presynaptic choline transporter) mutation
    causes dHMN type VII via reduced choline uptake at the neuromuscular junction.
  evidence:
  - reference: PMID:23141292
    reference_title: "Defective presynaptic choline transport underlies hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This dominantly segregating SLC5A7 mutation truncates the encoded product just beyond the final transmembrane domain, eliminating cytosolic-C-terminus sequences known to regulate surface transporter trafficking."
    explanation: A dominant SLC5A7 mutation causes dHMN type VII.
- name: TRPV4
  gene_term:
    preferred_term: TRPV4
    term:
      id: hgnc:18083
      label: TRPV4
  inheritance:
  - name: Autosomal Dominant
  subtype: dHMN-TRPV4
  notes: >
    Heterozygous TRPV4 ankyrin-domain missense mutations cause dominant
    congenital distal SMA, scapuloperoneal SMA, and HMSN2C.
  evidence:
  - reference: PMID:20037588
    reference_title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families."
    explanation: Heterozygous TRPV4 ankyrin-domain mutations cause dominant distal/scapuloperoneal SMA.
prevalence:
- population: general (pooled HMN estimate)
  notes: >
    Cumulative estimated prevalence of hereditary motor neuropathies is 2.14 per
    100,000; a dHMN cohort study reported a minimum prevalence of 2.3 per 100,000.
    Most dominant dHMN families carry mutations in HSPB1, GARS1, BICD2, or DNAJB2.
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their cumulative estimated prevalence is 2.14/100 000 and, to date, around 30 causative genes have been identified with autosomal dominant, recessive,and X-linked inheritance."
    explanation: Provides the pooled HMN prevalence estimate and notes dominant inheritance among causes.
  - reference: PMID:33369814
    reference_title: "Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals."
    explanation: Provides a population-specific minimum dHMN prevalence.
- population: dHMN cohort (gene frequencies)
  notes: >
    In a genetically screened dHMN cohort, the most frequent causes were
    dominant-acting HSPB1 and GARS1 mutations.
  evidence:
  - reference: PMID:33369814
    reference_title: "Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes."
    explanation: HSPB1 and GARS1 are the most frequent (dominant) dHMN genes.
treatments:
- name: Genetic counseling
  description: >
    Counseling for autosomal dominant recurrence risk (50% to offspring) and
    predictive/cascade testing once a pathogenic variant is identified; the
    primary preventive strategy given the genetic etiology and frequent
    incomplete penetrance.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Physical Therapy and Orthotic Support
  description: >
    Supportive rehabilitation including physical therapy and ankle-foot orthoses
    to manage distal weakness, foot drop, and gait disturbance.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
- name: Supportive and Multidisciplinary Care
  description: >
    No disease-modifying therapy is available; management is supportive and
    multidisciplinary, including orthopedic correction of foot deformity,
    occupational therapy for hand involvement, and monitoring for respiratory or
    vocal-cord involvement in DCTN1-related disease.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
datasets: []

📚

References & Deep Research

References

2

PMID:36445400

Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases.

No top-level findings curated for this source.

PMID:21902652

Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Distal Hereditary Motor Neuronopathy, Autosomal Dominant (AD-dHMN) — Comprehensive Disease Characteristics Report

Edison Scientific Literature 37 citations 2026-06-17T21:27:50.272290

Distal Hereditary Motor Neuronopathy, Autosomal Dominant (AD-dHMN) — Comprehensive Disease Characteristics Report

Target disease

Disease name: Distal hereditary motor neuronopathy / distal hereditary motor neuropathy, autosomal dominant (often abbreviated AD-dHMN) (xie2020geneticandclinical pages 1-2, frasquet2021distalhereditarymotor pages 1-2, bansagi2017clinicalandgenetic pages 58-62).
Category: Rare inherited lower motor neuron / motor-predominant peripheral neuropathy (“hereditary motor neuropathy”, HMN) (zambon2023earlyonsethereditary pages 1-2, frasquet2021distalhereditarymotor pages 1-2).
Synonyms and related terms: distal hereditary motor neuropathy (dHMN), hereditary motor neuropathy (HMN), distal spinal muscular atrophy (dSMA), “motor CMT2”/axonal Charcot–Marie–Tooth overlap spectrum (frasquet2021distalhereditarymotor pages 1-2, bansagi2017clinicalandgenetic pages 58-62, zambon2023earlyonsethereditary pages 1-1).

Ontology/identifier note (important limitation): In the retrieved evidence set, authoritative cross-references for a single umbrella concept “autosomal dominant distal hereditary motor neuronopathy” (e.g., MONDO, Orphanet, OMIM, ICD-10/ICD-11, MeSH) were not directly available. The literature instead commonly uses (i) dHMN subtype designations (e.g., dHMN-I/II/V/VII) and/or (ii) gene-labelled entities (e.g., AD-dHMN-HSPB1, AD-dHMN-GARS) (xie2020geneticandclinical pages 1-2, carroll2019inheritedneuropathies pages 11-12). A knowledge base entry typically needs to treat AD-dHMN as a genetically heterogeneous group rather than a single gene-defined disorder (zambon2023earlyonsethereditary pages 1-2, parmar2024geneticsofinherited pages 1-1).

1. Disease information (current understanding)

What is the disease?

Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuromuscular disorders characterized by slowly progressive distal limb weakness and atrophy with minimal or no sensory involvement, reflecting predominant degeneration/dysfunction of motor neurons/axons (xie2020geneticandclinical pages 1-2, frasquet2021distalhereditarymotor pages 1-2, bansagi2017clinicalandgenetic pages 58-62). HMNs/dHMNs are classically described as lower motor neuron disorders with length-dependent distal weakness/atrophy, chronic denervation on needle EMG, and relatively preserved motor conduction velocities compared with demyelinating neuropathies (zambon2023earlyonsethereditary pages 1-2, zambon2023earlyonsethereditary pages 1-1).

Key concepts/definitions

“Pure motor” neuropathy / neuronopathy: preserved sensory nerve action potentials (SNAPs) with abnormalities predominantly in motor studies and neurogenic EMG changes; mild sensory abnormalities can occur and may shift classification toward motor CMT2 (bansagi2017clinicalandgenetic pages 58-62, bansagi2017clinicalandgenetica pages 62-73).
Continuum/overlap: There is substantial clinical and genetic overlap between dHMN and axonal CMT2, SMA-LED, juvenile ALS, and other lower motor neuron disorders; the same gene may produce different phenotypes (zambon2023earlyonsethereditary pages 1-1, bansagi2017clinicalandgenetic pages 58-62).

Common subtype nomenclature

A commonly used clinical classification partitions autosomal dominant dHMN into subtypes such as dHMN-I (childhood onset), dHMN-II (adult onset), dHMN-V (upper-limb predominance), and dHMN-VII (vocal cord palsy) (xie2020geneticandclinical pages 1-2). A gene-based nomenclature is also used (e.g., AD-dHMN-HSPB1, AD-dHMN-HSPB8, AD-dHMN-GARS, AD-dHMN-REEP1, AD-dHMN-BSCL2) (carroll2019inheritedneuropathies pages 11-12).

2. Etiology

Primary causes

Genetic etiology dominates: dHMN/HMN has autosomal dominant, autosomal recessive, and X-linked forms, with ~30 causative genes summarized in a 2023 review focused on early-onset motor neuronopathies/HMN (zambon2023earlyonsethereditary pages 1-2). In a cohort context, autosomal dominant inheritance can comprise the majority of genetically confirmed cases (e.g., 60% AD among genetically confirmed cases in one Spanish catchment cohort summary) (rossor2021broadeningthegenetic pages 1-3).

Risk factors

Family history is a strong predictor of achieving a genetic diagnosis: one cohort summary reported 67.4% diagnostic yield in familial index cases vs 12.3% in sporadic cases (rossor2021broadeningthegenetic pages 1-3).
Other non-genetic risk factors are not well-established in the retrieved evidence; the disorder is typically considered Mendelian with phenotype-modifying influences possible but not well-quantified in these sources (gregianin2014identificationandcharacterisation pages 27-29).

Protective factors / gene–environment interactions

No robust protective factors or gene–environment interaction data specific to AD-dHMN were identified in the retrieved evidence set.

3. Phenotypes

Core phenotype (human clinical)

Across cohort and review sources, typical features include: * Distal muscle weakness and atrophy (often length-dependent, lower-limb predominant, but can be upper-limb predominant in dHMN-V) (xie2020geneticandclinical pages 1-2, frasquet2021distalhereditarymotor pages 1-2).
Foot deformities such as pes cavus and toe clawing are commonly described (bansagi2017clinicalandgenetic pages 58-62).
Minimal/no sensory involvement by history and examination; sensory NCS are typically preserved (xie2020geneticandclinical pages 1-2, bansagi2017clinicalandgenetic pages 58-62).

Onset and progression

Onset can be childhood to adulthood depending on subtype (xie2020geneticandclinical pages 1-2, frasquet2021distalhereditarymotor pages 1-2).
In a Spanish cohort, the most frequent age at onset was 2–10 years (28.8%) (frasquet2021distalhereditarymotor pages 1-2).
The course is generally slowly progressive (frasquet2021distalhereditarymotor pages 1-2, zambon2023earlyonsethereditary pages 1-2).

Electrophysiology and pathology

HMN/dHMN are associated with chronic denervation on needle EMG and relatively preserved motor nerve conduction velocities; classification frameworks emphasize preserved sensory nerve studies (zambon2023earlyonsethereditary pages 1-2, bansagi2017clinicalandgenetic pages 58-62).
In a regional clinic cohort, standardized nerve conduction plus EMG/motor unit potential (MUP) analysis were used for classification; authors note overlap and occasional minor sensory abnormalities (bansagi2017clinicalandgenetica pages 62-73).

Functional impact / real-world functional measurement

A dedicated observational study in adults with dHMN used objective outcomes that reflect real-world impairment: * MRI 3-point Dixon fat fraction (primary), * 3D gait analysis (kinematics/kinetics), and * isokinetic dynamometry for strength, along with clinical gait speed/endurance and other measures (NCT04193228 chunk 1, NCT04193228 chunk 2).

Suggested HPO terms (not exhaustive; ontology suggestions)

Distal muscle weakness (HP:0002460), Muscle atrophy (HP:0003202), Foot deformity (HP:0001760), Pes cavus (HP:0001761), Claw toes (HP:0001778), Gait abnormality (HP:0001288), Lower limb muscle weakness (HP:0007340), Hand muscle weakness (HP:0002463), Motor neuropathy (HP:0003431).

Phenotype frequency/QoL limitation

The retrieved evidence contains limited per-phenotype frequency and no disease-specific QoL instrument results for AD-dHMN; most quantitative data are cohort-level (age of onset distribution, diagnostic yield, etc.) (frasquet2021distalhereditarymotor pages 1-2, rossor2021broadeningthegenetic pages 1-3).

4. Genetic / molecular information

Causal genes (with emphasis on AD-dHMN)

Autosomal dominant dHMN is genetically heterogeneous. In the available evidence, key AD-dHMN-associated gene groups include: * Small heat shock proteins / chaperones (proteostasis): HSPB1, HSPB3, HSPB8 are classified as autosomal dominant dHMN genes, and chaperone dysfunction is a major mechanistic theme (lupo2016chaperonopathiesspotlighton pages 1-2, carroll2019inheritedneuropathies pages 11-12).
Aminoacyl-tRNA synthetases (ARS): GARS1 is a canonical AD-dHMN gene (carroll2019inheritedneuropathies pages 11-12), and ARS genes were suggested as frequent causes of autosomal dominant dHMN in a Chinese family cohort (xie2020geneticandclinical pages 1-2).
ER shaping / overlap with spasticity: REEP1 is classified as an AD-dHMN gene and is associated with pyramidal signs in at least some cases (carroll2019inheritedneuropathies pages 11-12, wu2022geneticspectrumin pages 5-6).
Other AD-dHMN genes in classification frameworks: BSCL2 (Silver syndrome/CMT overlap) (carroll2019inheritedneuropathies pages 11-12).
Axonal transport pathway genes appear in HMN gene tables (e.g., DCTN1) (zambon2023earlyonsethereditary pages 1-2).

The following figure/table from a 2023 Brain review provides a consolidated view of HMN genes, inheritance patterns, and mechanistic categories, supporting the breadth of implicated biology in dHMN (zambon2023earlyonsethereditary media 8b9ba4e3, zambon2023earlyonsethereditary media 85f57af2).

Example recent (2024) dominant variant and functional consequence

A 2024 report described a novel heterozygous NARS1 variant (c.1555G>C; p.Gly519Arg) segregating with dominant dHMN, absent from population databases and supported by loss-of-function in yeast complementation assays (theuriet2024apreviouslyunreported pages 1-3). This provides a concrete example of gene/variant expansion in the AD-dHMN spectrum using WGS plus functional validation (theuriet2024apreviouslyunreported pages 1-3).

Mechanistic categories (molecular pathways; current synthesis)

A 2023 review and accompanying gene table classify HMN/dHMN genes into recurrent mechanistic themes, including unfolded protein response/proteostasis, aminoacyl-tRNA synthetase dysfunction, impaired axonal transport, and mitochondrial dysfunction/ER–mitochondria interactions (zambon2023earlyonsethereditary pages 1-2, zambon2023earlyonsethereditary media 8b9ba4e3).

Suggested GO/CL/UBERON terms (ontology suggestions)

GO biological processes: axon transport (GO:0007411), protein folding (GO:0006457), response to unfolded protein (GO:0006986), translation (GO:0006412), mitochondrial organization (GO:0007005).
Cell types (CL): alpha motor neuron (CL:0000578), Schwann cell (CL:0000218) (noting that dHMN is motor-predominant but nerve-supporting cells may be secondarily involved).
Anatomy (UBERON): peripheral nerve (UBERON:0001021), spinal cord anterior horn (UBERON:0001883), skeletal muscle (UBERON:0001134).

5. Environmental information

No specific environmental, lifestyle, toxin, or infectious triggers were identified as established contributors to AD-dHMN in the retrieved evidence, consistent with a primarily genetic etiology (zambon2023earlyonsethereditary pages 1-2, frasquet2021distalhereditarymotor pages 1-2).

6. Mechanism / pathophysiology (causal chain)

Causal chain (generalized)

Pathogenic variants in genes governing proteostasis (chaperones), aminoacyl-tRNA synthetase function, axonal transport, and organelle homeostasis lead to motor neuron/peripheral motor axon dysfunction, producing length-dependent denervation and chronic reinnervation changes on EMG, culminating in distal muscle weakness/atrophy and foot/hand deformities over time (zambon2023earlyonsethereditary pages 1-2, zambon2023earlyonsethereditary pages 1-1, lupo2016chaperonopathiesspotlighton pages 1-2, theuriet2024apreviouslyunreported pages 1-3).

Upstream vs downstream

Upstream: gene/variant-driven molecular dysfunction in chaperoning/protein quality control or translation/enzymatic ARS activity, axonal transport machinery, and mitochondrial/ER homeostasis (lupo2016chaperonopathiesspotlighton pages 1-2, theuriet2024apreviouslyunreported pages 1-3, zambon2023earlyonsethereditary pages 1-2).
Downstream: axonal degeneration/denervation (electrophysiologic neurogenic changes), muscle atrophy, gait impairment, orthopedic deformities (zambon2023earlyonsethereditary pages 1-2, bansagi2017clinicalandgenetic pages 58-62, NCT04193228 chunk 1).

7. Anatomical structures affected

Primary: peripheral motor nerves/axons and motor neuron cell bodies (lower motor neuron system) (zambon2023earlyonsethereditary pages 1-2, zambon2023earlyonsethereditary pages 1-1).
Secondary: distal skeletal muscles (especially intrinsic foot muscles/peroneal compartment; can include hand muscles in dHMN-V) and related musculoskeletal structures through chronic weakness and imbalance (bansagi2017clinicalandgenetic pages 58-62, xie2020geneticandclinical pages 1-2).

8. Temporal development

Onset: childhood through adulthood depending on subtype; common childhood onset reported in cohorts (e.g., 2–10 years most frequent onset in one cohort) (frasquet2021distalhereditarymotor pages 1-2).
Progression: typically slow and chronic; adult patients in one NARS1 family remained ambulatory, suggesting relatively slowly progressive disease in that genotype (theuriet2024apreviouslyunreported pages 1-3).

9. Inheritance and population

Inheritance

By definition here, autosomal dominant dHMN includes families with heterozygous segregating variants; however, dHMN overall includes AD/AR/X-linked cases (zambon2023earlyonsethereditary pages 1-2, xie2020geneticandclinical pages 1-2). In a North-East England clinic cohort, 16/40 dHMN families were dominant, with many additional isolated cases (bansagi2017clinicalandgenetic pages 62-73).

Epidemiology (recently summarized quantitative metrics)

Prevalence estimates across studies/reviews converge in the range of ~2 per 100,000 (though methodology and case ascertainment differ): * Pooled HMN prevalence estimate: 2.14/100,000 (zambon2023earlyonsethereditary pages 1-2).
Minimum prevalence in a Spanish dHMN cohort: 2.3/100,000 (frasquet2021distalhereditarymotor pages 1-2).
North-East England dHMN prevalence: 2.14/100,000 (95% CI 1.62–2.66) (bansagi2017clinicalandgenetic pages 62-73).
A Spanish catchment cohort summary reported prevalence ~1 in 50,000* (equivalent to 2/100,000) (rossor2021broadeningthegenetic pages 1-3).

A comparative summary of key prevalence, AD proportion, and diagnostic-yield statistics is provided in the table below.

Study (year)	Population/setting	Sample size	Key metrics	Notes
Zambon et al. (2023)	Review of hereditary motor neuropathies (HMN), including dHMN; pooled literature estimate	Not stated in snippet	Pooled prevalence: 2.14/100,000; diagnostic yield for pure HMN phenotype: ~32.5%	Broad HMN estimate, not restricted to autosomal dominant dHMN; ~30 causative genes noted (zambon2023earlyonsethereditary pages 1-2)
Frasquet et al. (2021)	Two Spanish tertiary centers; clinic-based dHMN cohort	163 patients, 108 families	Minimum prevalence: 2.3/100,000; genetic diagnosis: 34.2% of families (37/108), 47.8% of patients (78/163); most probands sporadic: 62.3%; gene frequencies among patients: HSPB1 10.4%, GARS1 9.8%, BICD2 8.0%, DNAJB2 6.7%, SORD 3.1%	Historical genetic characterization in prior series cited as 15%–32.5%; VUS in 34.2% (37/108), with 54.0% (20/37) reclassified likely benign after segregation (frasquet2021distalhereditarymotor pages 1-2, frasquet2021distalhereditarymotor pages 7-8)
Rossor (2021)	Editorial summarizing Spanish dHMN cohort, including Valencia defined catchment	Not stated in snippet	Population prevalence: 1 in 50,000; diagnostic yield: 67.4% in familial index cases vs 12.3% in sporadic cases; among genetically confirmed Valencia cases, 60% autosomal dominant and 40% recessive	Barcelona genetically confirmed cases described as ~50/50 AD/AR; SORD accounted for 3% of cases despite common carrier frequency (rossor2021broadeningthegenetic pages 1-3)
Bansagi (2017)	North-East England referral/catchment population; inherited neuropathy clinic cohort	64 dHMN patients from 40 families; 105 HMN patients from 73 families; 461 inherited neuropathy referrals	dHMN prevalence: 2.14/100,000 (95% CI 1.62–2.66); dHMN among included HMN cohort: 60.9% (64/105); dHMN among inherited neuropathy referrals: 13.8% (64/461); dominant dHMN families: 16/40; dHMN cumulative detection rate: 42.5%, confirmed pathogenic rate: 32.5%; testing yields: targeted testing 4.7% (5/105), IPN panel 26% (12/46), WES 45% (18/40)	Mean age at onset in dHMN ~16 years in snippet; inheritance data emphasize autosomal dominant families plus many isolated cases (bansagi2017clinicalandgenetic pages 62-73, bansagi2017clinicalandgenetica pages 62-73, bansagi2017clinicalandgenetica pages 76-82, bansagi2017clinicalandgenetic pages 76-82)
Xie et al. (2020)	Mainland China dHMN family cohort	24 families	Inheritance distribution: 6 AD (25.0%), 5 AR (20.8%), 13 sporadic (51.2%); definite genetic diagnosis: 29.2% (7/24)	Diagnosed genes included GARS, WARS, SORD, SIGMAR1, HSPB1; authors note ARS genes may be frequent causes of AD-dHMN (xie2020geneticandclinical pages 1-2)

Table: This table compiles explicit epidemiology and diagnostic-yield statistics for distal hereditary motor neuropathy across key cohort and review sources, highlighting autosomal dominant proportions where reported. It is useful for comparing prevalence estimates, inheritance mix, and genetic testing performance across settings.

10. Diagnostics

Core diagnostic approach (real-world)

Clinical pattern recognition: distal motor-predominant weakness/atrophy, often with foot deformities and preserved sensation (bansagi2017clinicalandgenetic pages 58-62, frasquet2021distalhereditarymotor pages 1-2).
Electrophysiology: NCS/EMG to demonstrate predominantly motor involvement and chronic denervation, and to exclude demyelinating neuropathy (zambon2023earlyonsethereditary pages 1-2, bansagi2017clinicalandgenetica pages 62-73).
Exclude acquired mimics via laboratory/metabolic and other testing (in at least one regional cohort, extensive investigations including imaging/biopsy were used to exclude acquired neuropathies) (bansagi2017clinicalandgenetic pages 58-62).
Genetic testing: massively parallel sequencing using targeted gene panels and/or WES/WGS; diagnostic yield varies by family history and testing approach (rossor2021broadeningthegenetic pages 1-3, bansagi2017clinicalandgenetica pages 76-82, theuriet2024apreviouslyunreported pages 1-3).

Genetic testing strategy (current and emerging)

Panel/WES/WGS: A regional cohort reported modality-associated yields (targeted testing 4.7%, IPN panel 26%, WES 45%), and emphasized pedigree-level analysis to avoid ascertainment bias (bansagi2017clinicalandgenetic pages 76-82).
Segregation testing is critical: in one cohort, segregation reclassified ~54% of VUS to likely benign, underscoring the need for family studies rather than relying solely on in silico predictions (frasquet2021distalhereditarymotor pages 7-8).
Emerging variant classes: 2024 expert review emphasizes that structural variants and short tandem repeat expansions contribute to inherited peripheral neuropathy “missing heritability” and that long-read/optical mapping and improved informatics may improve diagnosis (parmar2024geneticsofinherited pages 1-2, parmar2024geneticsofinherited pages 5-6).

Differential diagnosis (high-level)

Given overlap, key clinical differentials include axonal CMT2 (motor-predominant forms), SMA-LED, juvenile ALS and other lower motor neuron disorders (zambon2023earlyonsethereditary pages 1-1, zambon2023earlyonsethereditary pages 1-2).

11. Outcome / prognosis

The disease is generally slowly progressive; subtype/genotype influences severity and whether additional signs appear (e.g., pyramidal signs in REEP1-labelled AD-dHMN) (frasquet2021distalhereditarymotor pages 1-2, carroll2019inheritedneuropathies pages 11-12, wu2022geneticspectrumin pages 5-6). Robust survival/mortality statistics are not provided in the retrieved evidence and are likely less relevant than in ALS-spectrum disorders.

12. Treatment

Current standard of care (current evidence in retrieved set)

For inherited neuropathies broadly, management remains largely symptomatic/supportive, with limited disease-modifying options for most genetic neuropathies (hustinx2023noveltherapeuticapproaches pages 1-2). In the AD-dHMN literature retrieved here, specific disease-modifying pharmacotherapies were not established.

Rehabilitation and assistive devices (real-world implementation)

A completed observational study in dHMN evaluated: * bilateral carbon-fibre ankle–foot orthoses (AFOs), and
a 16-week home-based resistance program* with remote supervision and app monitoring, alongside quantitative MRI and gait outcomes (NCT04193228 chunk 1). This demonstrates that structured rehabilitation interventions and orthotic management are being implemented and studied with objective endpoints in dHMN.

Therapeutic research landscape and outcome measurement (2023–2024 perspective)

A 2023 systematic review of emerging therapies in inherited neuropathies identified 28 studies with neuropathy outcomes and concluded that neuropathy symptoms/biomarkers were assessed in only a minority of trials; it recommended objective and consistent methods such as wearables, motor unit indexes, MRI/sonography, blood biomarkers, and standardized NCS endpoints to improve comparability (hustinx2023noveltherapeuticapproaches pages 1-2).

Suggested MAXO terms (ontology suggestions)

Ankle-foot orthosis use (MAXO:0000808; if not available, “orthotic device therapy”), Physical therapy (MAXO:0000011), Resistance training/exercise therapy (MAXO:0000127), Genetic counseling (MAXO:0000071).

13. Prevention

No primary prevention exists for Mendelian AD-dHMN beyond family planning and risk assessment. Secondary prevention includes early recognition and genetic diagnosis to shorten the diagnostic odyssey and optimize supportive interventions (parmar2024geneticsofinherited pages 1-2).

14. Other species / natural disease

No naturally occurring non-human disease analogs were identified in the retrieved evidence set.

15. Model organisms and experimental systems (research direction)

A 2024 review on inherited peripheral neuropathy genetics highlights the need for functional evidence and recommends animal models (e.g., C. elegans and rodents) for variant validation and mechanistic work, while noting barriers to scalability and cost for high-throughput functional assays (parmar2024geneticsofinherited pages 5-6). A 2024 dominant dHMN report used yeast complementation assays as functional validation for an ARS gene variant (NARS1), reflecting increasing use of orthogonal functional systems to support pathogenicity claims (theuriet2024apreviouslyunreported pages 1-3).

Key statistics (selected)

Prevalence estimates for HMN/dHMN around ~2 per 100,000 across multiple cohorts/reviews (bansagi2017clinicalandgenetic pages 62-73, frasquet2021distalhereditarymotor pages 1-2, zambon2023earlyonsethereditary pages 1-2).
Autosomal dominant constitutes a substantial fraction of genetically confirmed cases in at least one catchment cohort (e.g., 60% AD among genetically confirmed cases in Valencia) (rossor2021broadeningthegenetic pages 1-3).
Diagnostic yield is strongly influenced by family history (67.4% familial vs 12.3% sporadic in one cohort summary) (rossor2021broadeningthegenetic pages 1-3).
Genetic diagnostic yield for a “pure HMN phenotype” reported as ~32.5% in a 2023 review (zambon2023earlyonsethereditary pages 1-2).

Evidence-backed gene summary (AD-dHMN focus)

Gene (symbol)	Evidence for AD-dHMN association (study + year)	Example pathogenic/likely pathogenic variant(s) mentioned in evidence	Mechanistic category	Key clinical notes (phenotype highlights)	Notes/limitations
NARS1	Theuriet et al., 2024 reported a previously unreported heterozygous NARS1 variant segregating with dominant dHMN in a French family (theuriet2024apreviouslyunreported pages 1-3)	c.1555G>C, p.(Gly519Arg) (heterozygous); functional yeast complementation supported loss of function (theuriet2024apreviouslyunreported pages 1-3)	Aminoacyl-tRNA synthetase	Distal weakness, osteoarticular deformities, pure motor neuropathy on NCS/EMG, brisk reflexes/possible UMN involvement; patients remained ambulatory, suggesting slowly progressive disease (theuriet2024apreviouslyunreported pages 1-3)	Strong recent AD-dHMN-specific evidence, but based on one family in the available snippet; variant absent from population databases in report (theuriet2024apreviouslyunreported pages 1-3)
GARS1	Xie et al., 2020 identified novel heterozygous GARS variants with typical dHMN-V phenotype and concluded ARS genes may be frequent causes of AD-dHMN; Carroll 2019 lists AD-dHMN-GARS / HMN5A (xie2020geneticandclinical pages 1-2, carroll2019inheritedneuropathies pages 11-12)	c.373G>C p.E125Q; c.1015G>A p.G339R; also GARS listed as AD-dHMN gene in classification table (xie2020geneticandclinical pages 1-2, carroll2019inheritedneuropathies pages 11-12)	Aminoacyl-tRNA synthetase	Typical dHMN-V with upper-limb predominance/hand wasting in classification framework; overlaps with axonal CMT phenotypes (xie2020geneticandclinical pages 1-2, carroll2019inheritedneuropathies pages 11-12)	AD association is well supported in available evidence, but phenotype overlaps with CMT2D and exact variant-specific expressivity varies (xie2020geneticandclinical pages 1-2, carroll2019inheritedneuropathies pages 11-12)
HSPB1	Carroll 2019 lists HMN2B as AD-dHMN-HSPB1; Lupo 2016 reviews HSPB1 as one of the main dHMN chaperone genes with ~30 reported mutations (carroll2019inheritedneuropathies pages 11-12, lupo2016chaperonopathiesspotlighton pages 1-2)	No specific HSPB1 nucleotide/protein variant named in the available snippets used here (lupo2016chaperonopathiesspotlighton pages 1-2, carroll2019inheritedneuropathies pages 11-12)	Chaperone / proteostasis (small heat-shock protein)	Canonical AD-dHMN form in modern classification; hereditary motor neuropathy with distal weakness/atrophy and little sensory involvement (carroll2019inheritedneuropathies pages 11-12, lupo2016chaperonopathiesspotlighton pages 1-2)	Gene-disease association is established, but this evidence subset does not provide a named variant or variant-level phenotype details (lupo2016chaperonopathiesspotlighton pages 1-2, carroll2019inheritedneuropathies pages 11-12)
HSPB8	Carroll 2019 lists HMN2A as AD-dHMN-HSPB8; Lupo 2016 reviews HSPB8 as a dHMN chaperone gene and notes many cases affect residue K141 (carroll2019inheritedneuropathies pages 11-12, lupo2016chaperonopathiesspotlighton pages 1-2)	Mutations affecting K141 residue (specific substitutions not detailed in the snippet) (lupo2016chaperonopathiesspotlighton pages 1-2)	Chaperone / proteostasis (small heat-shock protein)	Classified AD-dHMN form; motor-predominant distal neuropathy with overlap across neuromuscular phenotypes (carroll2019inheritedneuropathies pages 11-12, lupo2016chaperonopathiesspotlighton pages 1-2)	Variant examples are only residue-level in the available evidence; more granular pathogenicity data are not given in retrieved snippets (lupo2016chaperonopathiesspotlighton pages 1-2, carroll2019inheritedneuropathies pages 11-12)
HSPB3	Carroll 2019 lists HMN2C as AD-dHMN-HSPB3; Lupo 2016 notes HSPB3 is a rare dHMN chaperone gene with only one mutation described at that time (carroll2019inheritedneuropathies pages 11-12, lupo2016chaperonopathiesspotlighton pages 1-2)	No specific variant named in the available snippets (lupo2016chaperonopathiesspotlighton pages 1-2, carroll2019inheritedneuropathies pages 11-12)	Chaperone / proteostasis (small heat-shock protein)	Rare AD-dHMN subtype in classification framework (carroll2019inheritedneuropathies pages 11-12)	Association is supported by classification/review evidence, but variant-level and phenotype-detail evidence are sparse in available snippets (lupo2016chaperonopathiesspotlighton pages 1-2, carroll2019inheritedneuropathies pages 11-12)
BSCL2	Carroll 2019 lists HMN5C as AD-dHMN-BSCL2 and links it to Silver syndrome/CMT overlap; Zambon 2023 gene table includes BSCL2 among dominant HMN/dHMN-associated genes (carroll2019inheritedneuropathies pages 11-12, zambon2023earlyonsethereditary pages 1-2)	No specific BSCL2 variant named in the cited snippets used for this table (carroll2019inheritedneuropathies pages 11-12, zambon2023earlyonsethereditary pages 1-2)	ER / lipid droplet biology; often grouped with ER-related motor neuropathy mechanisms	AD-dHMN form with overlap syndromes including Silver syndrome and CMT2D-like features (carroll2019inheritedneuropathies pages 11-12)	AD association is clear in classification tables, but no variant-specific details are available in the retrieved evidence subset here (carroll2019inheritedneuropathies pages 11-12, zambon2023earlyonsethereditary pages 1-2)
REEP1	Carroll 2019 lists HMN5B as AD-dHMN-REEP1 and notes pyramidal signs; Wu 2022 reported truncating/splice REEP variants associated with distal motor neuropathy plus pyramidal signs (carroll2019inheritedneuropathies pages 11-12, wu2022geneticspectrumin pages 5-6)	c.337C>T p.R113*; c.417+1G>A (wu2022geneticspectrumin pages 5-6)	ER shaping / membrane modeling	Distal motor neuropathy with pyramidal signs; overlap with hereditary spastic paraplegia spectrum (carroll2019inheritedneuropathies pages 11-12, wu2022geneticspectrumin pages 5-6)	Evidence supports AD-dHMN classification, but available cohort snippet emphasizes broader motor neuropathy/plus phenotypes rather than pure dHMN only (carroll2019inheritedneuropathies pages 11-12, wu2022geneticspectrumin pages 5-6)
DCTN1	Zambon 2023 gene table includes DCTN1 among genes associated with dominant hereditary motor neuronopathy/dHMN spectrum (zambon2023earlyonsethereditary pages 1-2)	No specific DCTN1 variant named in the available snippet used here (zambon2023earlyonsethereditary pages 1-2)	Axonal transport / dynein-dynactin pathway	Included in dominant motor neuronopathy gene table; relevant to distal hereditary motor neuropathy overlap spectrum (zambon2023earlyonsethereditary pages 1-2)	Available evidence confirms table inclusion but lacks variant-level and phenotype-detail data in retrieved snippets (zambon2023earlyonsethereditary pages 1-2)
BICD2	Frasquet 2021 found BICD2 to be a relatively common gene in a dHMN cohort (8.0% of patients), but AD inheritance is not explicitly stated in the cited snippet; included here as requested with caution (frasquet2021distalhereditarymotor pages 1-2)	No specific BICD2 variant named in the cited evidence used here (frasquet2021distalhereditarymotor pages 1-2)	Axonal transport / dynein adaptor	Associated with dHMN spectrum, including non-length-dependent/SMALED overlap in broader literature context of cohort (frasquet2021distalhereditarymotor pages 1-2)	Inheritance is mixed/unspecified in available snippets; AD assignment should be treated cautiously unless confirmed from a dedicated source (frasquet2021distalhereditarymotor pages 1-2)
DNAJB2	Lupo 2016 reviews DNAJB2 as a dHMN chaperone gene, but emphasizes founder c.352+1G>A cases and does not establish AD inheritance in the available snippet; Frasquet 2021 found DNAJB2 variants in 6.7% of patients (lupo2016chaperonopathiesspotlighton pages 1-2, frasquet2021distalhereditarymotor pages 1-2)	Founder c.352+1G>A mentioned in review (lupo2016chaperonopathiesspotlighton pages 1-2)	Chaperone / proteostasis (HSP40 co-chaperone)	dHMN-associated motor neuropathy gene in cohort/review evidence (lupo2016chaperonopathiesspotlighton pages 1-2, frasquet2021distalhereditarymotor pages 1-2)	Important dHMN gene, but AD inheritance is not certain in the available evidence and may vary; included only with this limitation noted (lupo2016chaperonopathiesspotlighton pages 1-2, frasquet2021distalhereditarymotor pages 1-2)

Table: This table summarizes genes with available evidence for autosomal dominant distal hereditary motor neuropathy, highlighting example variants, mechanism classes, and phenotype notes. It is useful for quickly linking genotype, disease mechanism, and the strength or limitations of the available evidence.

Evidence and reporting limitations (important for knowledge base curation)

Identifiers/ontologies: direct MONDO/OMIM/Orphanet/ICD/MeSH identifiers were not retrieved in the current tool context; the knowledge base should model AD-dHMN as a group with gene-labelled subentities (carroll2019inheritedneuropathies pages 11-12, zambon2023earlyonsethereditary pages 1-2).
Per-phenotype frequencies and QoL: sparse in retrieved evidence; most available statistics are at cohort/diagnostic-yield level (frasquet2021distalhereditarymotor pages 1-2, rossor2021broadeningthegenetic pages 1-3).
Direct abstract quotations: while several records include abstracts, the evidence extraction available here did not preserve short verbatim abstract quotes for most key claims; key statements are therefore paraphrased but tightly linked to the cited primary sources.

Key references (publication date; URL)

Zambon AA et al. Brain. 2023 (online/print Nov 2023). https://doi.org/10.1093/brain/awac452 (zambon2023earlyonsethereditary pages 1-2, zambon2023earlyonsethereditary media 8b9ba4e3)
Theuriet J et al. J Peripher Nerv Syst. May 2024. https://doi.org/10.1111/jns.12635 (theuriet2024apreviouslyunreported pages 1-3)
Parmar JM et al. J Neurol Neurosurg Psychiatry. May 2024. https://doi.org/10.1136/jnnp-2024-333436 (parmar2024geneticsofinherited pages 1-2, parmar2024geneticsofinherited pages 5-6)
Hustinx M et al. Pharmaceutics. May 2023. https://doi.org/10.3390/pharmaceutics15061626 (hustinx2023noveltherapeuticapproaches pages 1-2)
Frasquet M et al. Eur J Neurol. Jan 2021. https://doi.org/10.1111/ene.14700 (frasquet2021distalhereditarymotor pages 1-2, frasquet2021distalhereditarymotor pages 7-8)
Rossor AM. Eur J Neurol. Feb 2021. https://doi.org/10.1111/ene.14734 (rossor2021broadeningthegenetic pages 1-3)
ClinicalTrials.gov: NCT04193228 (UCLH). Posted/updated within registry record; protocol includes MRI Dixon fat fraction and 3D gait analysis. https://clinicaltrials.gov/study/NCT04193228 (NCT04193228 chunk 1, NCT04193228 chunk 2)

References

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(hustinx2023noveltherapeuticapproaches pages 1-2): Manon Hustinx, Ann-Marie Shorrocks, and Laurent Servais. Novel therapeutic approaches in inherited neuropathies: a systematic review. Pharmaceutics, 15:1626, May 2023. URL: https://doi.org/10.3390/pharmaceutics15061626, doi:10.3390/pharmaceutics15061626. This article has 6 citations.

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Classifications

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Source YAML

References & Deep Research

References

Deep Research

Distal Hereditary Motor Neuronopathy, Autosomal Dominant (AD-dHMN) — Comprehensive Disease Characteristics Report

Target disease

1. Disease information (current understanding)

What is the disease?

Key concepts/definitions

Common subtype nomenclature

2. Etiology

Primary causes

Risk factors

Protective factors / gene–environment interactions

3. Phenotypes

Core phenotype (human clinical)

Onset and progression

Electrophysiology and pathology

Functional impact / real-world functional measurement

Suggested HPO terms (not exhaustive; ontology suggestions)

Phenotype frequency/QoL limitation

4. Genetic / molecular information

Causal genes (with emphasis on AD-dHMN)

Example recent (2024) dominant variant and functional consequence

Mechanistic categories (molecular pathways; current synthesis)

Suggested GO/CL/UBERON terms (ontology suggestions)

5. Environmental information

6. Mechanism / pathophysiology (causal chain)

Causal chain (generalized)

Upstream vs downstream

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology (recently summarized quantitative metrics)

10. Diagnostics

Core diagnostic approach (real-world)

Genetic testing strategy (current and emerging)

Differential diagnosis (high-level)

11. Outcome / prognosis

12. Treatment

Current standard of care (current evidence in retrieved set)

Rehabilitation and assistive devices (real-world implementation)

Therapeutic research landscape and outcome measurement (2023–2024 perspective)

Suggested MAXO terms (ontology suggestions)

13. Prevention

14. Other species / natural disease

15. Model organisms and experimental systems (research direction)

Key statistics (selected)

Evidence-backed gene summary (AD-dHMN focus)

Evidence and reporting limitations (important for knowledge base curation)

Key references (publication date; URL)

Artifacts