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Charcot-Marie-Tooth disease type 4A(CMT4A)

MedGen UID:
347821
•Concept ID:
C1859198
•
Disease or Syndrome
Synonyms: Charcot-Marie-Tooth disease, demyelinating, autosomal recessive; Charcot-Marie-Tooth disease, demyelinating, autosomal recessive, type 4a; Charcot-Marie-Tooth Neuropathy Type 4A
SNOMED CT: Charcot-Marie-Tooth disease type 4A (715796006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Gene (location): GDAP1 (8q21.11)
 
Monarch Initiative: MONDO:0008961
OMIM®: 214400
Orphanet: ORPHA99948

Definition

GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications. [from GeneReviews]

Additional description

From OMIM
By convention, the designation CMT4 is applied to autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease, which is a peripheral neuropathy characterized by distal motor and sensory impairment resulting in gait difficulties and associated with foot deformities. Motor nerve conduction velocities are decreased, and sural nerve biopsies show loss of myelinated fibers. The age at onset and severity is variable (summary by Patzko and Shy, 2012). Genetic Heterogeneity of Charcot-Marie-Tooth Disease Type 4 Several different subtypes of autosomal recessive demyelinating CMT (CMT4) have been identified, each with particular ethnic, pathologic, or clinical characteristics: CMT4A; CMT4B, which includes CMT4B1 (601382), caused by mutation in the MTMR2 gene (603557), CMT4B2 (604563), caused by mutation in the SBF2 gene (607697), and CMT4B3 (615284), caused by mutation in the SBF1 gene (603560); CMT4C (601596), caused by mutation in the SH3TC2 gene (608206); CMT4D (601455), caused by mutation in the NDRG1 gene (605262); CMT4E (605253), caused by mutation in the EGR2 (129010) or MPZ (159440) genes; CMT4F (614895), caused by mutation in the PRX gene (605725); CMT4G, or Russe-type hereditary motor and sensory neuropathy, (605285), which maps to chromosome 10q23; CMT4H (609311), caused by mutation in the FGD4 gene (611104); CMT4J (611228), caused by mutation in the FIG4 gene (609390); and CMT4K (616684), caused by mutation in the SURF1 gene (185620).  http://www.omim.org/entry/214400

Clinical features

From HPO
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
Ulnar claw
MedGen UID:
871311
•Concept ID:
C4025799
•
Congenital Abnormality
An abnormal hand position characterized by hyperextension of the fourth and fifth fingers at the metacarpophalangeal joints and flexion of the interphalangeal joints of the same fingers such that they are curled towards the palm.
See: Feature record | Search on this feature
Areflexia
MedGen UID:
115943
•Concept ID:
C0234146
•
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
See: Feature record | Search on this feature
Hyporeflexia
MedGen UID:
195967
•Concept ID:
C0700078
•
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
See: Feature record | Search on this feature
Hypertrophic nerve changes
MedGen UID:
322038
•Concept ID:
C1832776
•
Finding
See: Feature record | Search on this feature
Axonal degeneration
MedGen UID:
332464
•Concept ID:
C1837496
•
Finding
See: Feature record | Search on this feature
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
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.
See: Feature record | Search on this feature
Decreased sensory nerve conduction velocity
MedGen UID:
336512
•Concept ID:
C1849148
•
Finding
Reduced speed of conduction of the action potential along a sensory nerve.
See: Feature record | Search on this feature
Motor delay
MedGen UID:
381392
•Concept ID:
C1854301
•
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
See: Feature record | Search on this feature
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).
See: Feature record | Search on this feature
Decreased motor nerve conduction velocity
MedGen UID:
388130
•Concept ID:
C1858729
•
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
See: Feature record | Search on this feature
Inability to walk by childhood/adolescence
MedGen UID:
395200
•Concept ID:
C1859200
•
Finding
See: Feature record | Search on this feature
Basal lamina onion bulb formation
MedGen UID:
401045
•Concept ID:
C1866637
•
Finding
A type of onion bulb formation prominently affecting the area of the basal lamina.
See: Feature record | Search on this feature
Segmental peripheral demyelination
MedGen UID:
870491
•Concept ID:
C4024938
•
Finding
A loss of myelin from the internode regions along myelinated nerve fibers from segments of the peripheral nervous system.
See: Feature record | Search on this feature
CNS hypomyelination
MedGen UID:
892446
•Concept ID:
C4025616
•
Finding
Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis.
See: Feature record | Search on this feature
Peripheral axonal degeneration
MedGen UID:
871339
•Concept ID:
C4025830
•
Finding
Progressive deterioration of peripheral axons.
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
Kyphoscoliosis
MedGen UID:
154361
•Concept ID:
C0575158
•
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
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 4A in Orphanet.

Professional guidelines

PubMed

A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K.
Cassereau J, Chevrollier A, Bonneau D, Verny C, Procaccio V, Reynier P, Ferré M
Orphanet J Rare Dis 2011 Dec 26;6:87. doi: 10.1186/1750-1172-6-87. PMID: 22200116Free PMC Article

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

Diagnosis

Novel compound heterozygous missense mutations in GDAP1 cause Charcot-Marie-Tooth type 4A.
Xue H, Maksemous N, Sidhom D, Ma L, Chen S, Wu J, Feng Y, M Haupt L, R Griffiths L
J Genet 2021;100 PMID: 34470922
Case report: exome sequencing achieved a definite diagnosis in a Chinese family with muscle atrophy.
Jiang H, Guo C, Xie J, Pan J, Huang Y, Li M, Guo Y
BMC Neurol 2021 Mar 2;21(1):96. doi: 10.1186/s12883-021-02093-z. PMID: 33653295Free PMC Article
Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a Colombian family.
Martin AM, Maradei SJ, Velasco HM
Colomb Med (Cali) 2015 Dec 30;46(4):194-8. PMID: 26848201Free PMC Article
Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease.
Ammar N, Nelis E, Merlini L, Barisić N, Amouri R, Ceuterick C, Martin JJ, Timmerman V, Hentati F, De Jonghe P
Neuromuscul Disord 2003 Nov;13(9):720-8. doi: 10.1016/s0960-8966(03)00093-2. PMID: 14561495

Prognosis

A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation.
Kabzińska D, Kotruchow K, Cegielska J, Hausmanowa-Petrusewicz I, Kochański A
Acta Biochim Pol 2014;61(4):739-44. Epub 2014 Oct 22 PMID: 25337607
Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes.
Marco A, Cuesta A, Pedrola L, Palau F, Marín I
Mol Biol Evol 2004 Jan;21(1):176-87. Epub 2003 Oct 31 doi: 10.1093/molbev/msh013. PMID: 14595091

Clinical prediction guides

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease.
Echaniz-Laguna A, Ghezzi D, Chassagne M, Mayençon M, Padet S, Melchionda L, Rouvet I, Lannes B, Bozon D, Latour P, Zeviani M, Mousson de Camaret B
Neurology 2013 Oct 22;81(17):1523-30. Epub 2013 Sep 11 doi: 10.1212/WNL.0b013e3182a4a518. PMID: 24027061Free PMC Article
GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria.
Pedrola L, Espert A, Wu X, Claramunt R, Shy ME, Palau F
Hum Mol Genet 2005 Apr 15;14(8):1087-94. Epub 2005 Mar 16 doi: 10.1093/hmg/ddi121. PMID: 15772096
Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes.
Marco A, Cuesta A, Pedrola L, Palau F, Marín I
Mol Biol Evol 2004 Jan;21(1):176-87. Epub 2003 Oct 31 doi: 10.1093/molbev/msh013. PMID: 14595091

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    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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