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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): Gene(s) directly associated with this condition or phenotype.	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

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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.

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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.

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Distal muscle weakness

MedGen UID:: 140883
•Concept ID:: C0427065
•: Finding

Reduced strength of the musculature of the distal extremities.

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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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Abnormality of limbs
Abnormality of the musculoskeletal system
- Distal amyotrophy
- Distal muscle weakness
Abnormality of the nervous system

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVAutosomal dominant Charcot-Marie-Tooth disease type 2W

Fetal anomaly
- Congenital Systemic Disorder
  - Abnormality of the nervous system
    - Hereditary motor and sensory neuropathy
      - Charcot-Marie-Tooth disease
        Charcot-Marie-Tooth disease type 2
        Autosomal 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

See all (1)

Therapy

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

See all (1)

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: 32333447 Free PMC Article

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Clinical prediction guides

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.

See all (2)

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

Definition

Clinical features

Term Hierarchy

Recent clinical studies

Etiology

Therapy

Prognosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Molecular resources

Consumer resources

Reviews

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