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Charcot-Marie-Tooth disease type 2A1(CMT2A1)

MedGen UID:
350076
•Concept ID:
C1861678
•
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2A1; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A1; CHARCOT-MARIE-TOOTH DISEASE, NEURONAL, TYPE 2A1; CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2A1; HEREDITARY MOTOR AND SENSORY NEUROPATHY IIA1
SNOMED CT: Autosomal dominant Charcot-Marie-Tooth disease type 2A1 (717016001)
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): KIF1B (1p36.22)
 
Monarch Initiative: MONDO:0007308
OMIM®: 118210
Orphanet: ORPHA99946

Disease characteristics

Excerpted from the GeneReview: MFN2 Hereditary Motor and Sensory Neuropathy
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Genetically Related (Allelic) Disorders  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Stephan Züchner   view full author information

Additional description

From OMIM
Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a slow motor median nerve conduction velocity (NCV) (less than 38 m/s), and type 2, the axonal form, with a normal or slightly reduced NCV. Distal hereditary motor neuropathy (dHMN), also known as spinal CMT, is a third type of CMT characterized by normal motor and sensory NCV and degeneration of spinal cord anterior horn cells. See CMT1B (118200) and CMT1A (118220) for descriptions of autosomal dominant slow nerve conduction types of Charcot-Marie-Tooth disease. See CMT4A (214400) and CMTX1 (302800) for autosomal recessive and X-linked forms of Charcot-Marie-Tooth disease, respectively. Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 2 Several forms of axonal CMT neuropathies caused by mutations in different genes or at different loci have been described, including CMT2B (600882), CMT2B1 (605588), CMT2B2 (605589), CMT2C (606071), CMT2D (601472), CMT2E (607684), CMT2F (606595), CMT2H (607731), CMT2I (607677), CMT2J (607736), CMT2K (607831), CMT2L (608673), CMT2M (see 606482), CMT2N (613287), CMT2O (614228), CMT2P (614436), CMT2Q (615025), CMT2R (615490), CMT2S (616155), CMT2T (617017), CMT2U (616280), CMT2V (616491), CMT2W (616625), CMT2X (616668), CMT2Y (616687), CMT2Z (616688), CMT2CC (616924), CMT2DD (618036), CMT2EE (618400), CMT2FF (619519), CMT2GG (606483), CMT2HH (619574), and CMT2II (620068). A form of axonal CMT that was previously designated CMT2G was found to be the same as CMT2P (614436).  http://www.omim.org/entry/118210

Clinical features

From HPO
Limb muscle weakness
MedGen UID:
107956
•Concept ID:
C0587246
•
Finding
Reduced strength and weakness of the muscles of the arms and legs.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Foot dorsiflexor weakness
MedGen UID:
356163
•Concept ID:
C1866141
•
Finding
Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.
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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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Areflexia
MedGen UID:
115943
•Concept ID:
C0234146
•
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
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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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Hyporeflexia
MedGen UID:
195967
•Concept ID:
C0700078
•
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
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Peripheral axonal neuropathy
MedGen UID:
266071
•Concept ID:
C1263857
•
Disease or Syndrome
An abnormality characterized by disruption of the normal functioning of peripheral axons.
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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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Onion bulb formation
MedGen UID:
376237
•Concept ID:
C1847906
•
Finding
Repeated episodes of segmental demyelination and remyelination lead to the accumulation of supernumerary Schwann cells around axons, which is referred to as onion bulb formation. This finding affects peripheral nerves.
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Decreased number of peripheral myelinated nerve fibers
MedGen UID:
346872
•Concept ID:
C1858285
•
Finding
A loss of myelinated nerve fibers in the peripheral nervous system (in general, this finding can be observed on nerve biopsy).
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Decreased motor nerve conduction velocity
MedGen UID:
388130
•Concept ID:
C1858729
•
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
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Axonal degeneration/regeneration
MedGen UID:
368889
•Concept ID:
C1968790
•
Finding
A pattern of simultaneous degeneration and regeneration of axons (see comment).
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Peripheral axonal atrophy
MedGen UID:
871146
•Concept ID:
C4025619
•
Disease or Syndrome
Atrophic changes of axons of the peripheral nervous system.
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Facial palsy
MedGen UID:
87660
•Concept ID:
C0376175
•
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
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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.
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Charcot-Marie-Tooth disease type 2A1 in Orphanet.

Professional guidelines

Curated

Clinical utility gene card for: HMSN/HNPP HMSN types 1, 2, 3, 6 (CMT1,2,4, DSN, CHN, GAN, CCFDN, HNA); HNPP.
Aretz S, Rautenstrauss B, Timmerman V
Eur J Hum Genet 2010 Sep;18(9) Epub 2010 May 26 doi: 10.1038/ejhg.2010.75. PMID: 20512157Free PMC Article

Recent clinical studies

Clinical prediction guides

Selective mitochondrial depletion, apoptosis resistance, and increased mitophagy in human Charcot-Marie-Tooth 2A motor neurons.
Rizzo F, Ronchi D, Salani S, Nizzardo M, Fortunato F, Bordoni A, Stuppia G, Del Bo R, Piga D, Fato R, Bresolin N, Comi GP, Corti S
Hum Mol Genet 2016 Oct 1;25(19):4266-4281. Epub 2016 Aug 9 doi: 10.1093/hmg/ddw258. PMID: 27506976

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    Curated

    • EuroGenetest, 2010
      Clinical utility gene card for: HMSN/HNPP HMSN types 1, 2, 3, 6 (CMT1,2,4, DSN, CHN, GAN, CCFDN, HNA); HNPP

    Reviews

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