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Autosomal dominant Charcot-Marie-Tooth disease type 2W(CMT2W)

MedGen UID:
1798909
•Concept ID:
C5567486
•
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2W; Charcot-Marie-Tooth disease, axonal, type 2w; CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2W
SNOMED CT: Autosomal dominant Charcot-Marie-Tooth disease type 2W (1172634009); Autosomal dominant Charcot-Marie-Tooth disease type 2 due to HARS mutation (1172634009); Autosomal dominant Charcot-Marie-Tooth disease type 2 due to HARS (histidyl-tRNA synthetase 1) mutation (1172634009)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Gene (location): HARS1 (5q31.3)
 
Monarch Initiative: MONDO:0014711
OMIM®: 616625
Orphanet: ORPHA488333

Definition

Charcot-Marie-Tooth disease type 2W is an autosomal dominant neurologic disorder characterized by a peripheral neuropathy mainly affecting the lower limbs and resulting in gait difficulties and distal sensory impairment, although most patients also have upper limb involvement. The age at onset is highly variable, ranging from childhood to late adulthood (summary by Safka Brozkova et al., 2015). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210). [from OMIM]

Clinical features

From HPO
Absent Achilles reflex
MedGen UID:
108240
•Concept ID:
C0558845
•
Finding
Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.
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Pes cavus
MedGen UID:
675590
•Concept ID:
C0728829
•
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
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Hammertoe
MedGen UID:
209712
•Concept ID:
C1136179
•
Anatomical Abnormality
Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.
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Peripheral neuropathy
MedGen UID:
18386
•Concept ID:
C0031117
•
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
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Hyperactive patellar reflex
MedGen UID:
66003
•Concept ID:
C0240116
•
Finding
See: Feature record | Search on this feature
Steppage gait
MedGen UID:
98105
•Concept ID:
C0427149
•
Finding
An abnormal gait pattern that arises from weakness of the pretibial and peroneal muscles due to a lower motor neuron lesion. Affected patients have footdrop and are unable to dorsiflex and evert the foot. The leg is lifted high on walking so that the toes clear the ground, and there may be a slapping noise when the foot strikes the ground again.
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Gait disturbance
MedGen UID:
107895
•Concept ID:
C0575081
•
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
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Distal sensory impairment
MedGen UID:
335722
•Concept ID:
C1847584
•
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
See: Feature record | Search on this feature
Distal muscle weakness
MedGen UID:
140883
•Concept ID:
C0427065
•
Finding
Reduced strength of the musculature of the distal extremities.
See: Feature record | Search on this feature
Distal amyotrophy
MedGen UID:
338530
•Concept ID:
C1848736
•
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAutosomal dominant Charcot-Marie-Tooth disease type 2W

Recent clinical studies

Etiology

The Antiepileptic Valproic Acid Ameliorates Charcot-Marie-Tooth 2W (CMT2W) Disease-Associated HARS1 Mutation-Induced Inhibition of Neuronal Cell Morphological Differentiation Through c-Jun N-terminal Kinase.
Memezawa S, Sato T, Ochiai A, Fukawa M, Sawaguchi S, Sango K, Miyamoto Y, Yamauchi J
Neurochem Res 2022 Sep;47(9):2684-2702. Epub 2022 Apr 5 doi: 10.1007/s11064-022-03587-z. PMID: 35380399

Therapy

The Antiepileptic Valproic Acid Ameliorates Charcot-Marie-Tooth 2W (CMT2W) Disease-Associated HARS1 Mutation-Induced Inhibition of Neuronal Cell Morphological Differentiation Through c-Jun N-terminal Kinase.
Memezawa S, Sato T, Ochiai A, Fukawa M, Sawaguchi S, Sango K, Miyamoto Y, Yamauchi J
Neurochem Res 2022 Sep;47(9):2684-2702. Epub 2022 Apr 5 doi: 10.1007/s11064-022-03587-z. PMID: 35380399

Prognosis

Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome.
Galatolo D, Kuo ME, Mullen P, Meyer-Schuman R, Doccini S, Battini R, Lieto M, Tessa A, Filla A, Francklyn C, Antonellis A, Santorelli FM
Hum Mutat 2020 Jul;41(7):1232-1237. Epub 2020 Apr 29 doi: 10.1002/humu.24024. PMID: 32333447Free PMC Article

Clinical prediction guides

The Antiepileptic Valproic Acid Ameliorates Charcot-Marie-Tooth 2W (CMT2W) Disease-Associated HARS1 Mutation-Induced Inhibition of Neuronal Cell Morphological Differentiation Through c-Jun N-terminal Kinase.
Memezawa S, Sato T, Ochiai A, Fukawa M, Sawaguchi S, Sango K, Miyamoto Y, Yamauchi J
Neurochem Res 2022 Sep;47(9):2684-2702. Epub 2022 Apr 5 doi: 10.1007/s11064-022-03587-z. PMID: 35380399
Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome.
Galatolo D, Kuo ME, Mullen P, Meyer-Schuman R, Doccini S, Battini R, Lieto M, Tessa A, Filla A, Francklyn C, Antonellis A, Santorelli FM
Hum Mutat 2020 Jul;41(7):1232-1237. Epub 2020 Apr 29 doi: 10.1002/humu.24024. PMID: 32333447Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Reviews

    Related information

    • ClinVar
      Related medical variations
    • Gene
      Related information in NCBI Gene
    • GTR
      Related information in GTR
    • GTR(Clinical)
      Clinical tests in GTR
    • OMIM
      Related records in OMIM
    • OMIM(Genes)
      OMIM records containing genes associated with phenotypes registered in MedGen
    • PMC Articles
      Related information in PubMed Central Links
    • PubMed
      Related literature resources in PubMed
    • PubMed (OMIM)
      Related literature resources in PubMed

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