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Charcot-Marie-Tooth disease X-linked recessive 4(CMTX4)

MedGen UID:
162891
Concept ID:
C0795910
Disease or Syndrome
Synonyms: Charcot-Marie-Tooth disease with deafness and mental retardation; CHARCOT-MARIE-TOOTH DISEASE, X-LINKED RECESSIVE, 4, WITH OR WITHOUT CEREBELLAR ATAXIA; Charcot-Marie-Tooth Neuropathy X Type 4; CMTX 4; CMTX4; Cowchock syndrome; Neuropathy, axonal motor-sensory with deafness and mental retardation
SNOMED CT: Cowchock syndrome (763400005); X-linked Charcot-Marie-Tooth disease type 4 (763400005)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): AIFM1 (Xq26.1)
 
Monarch Initiative: MONDO:0010689
OMIM®: 310490
Orphanet: ORPHA101078

Definition

X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4) is a mitochondrial disorder manifest as progressive neurologic dysfunction with highly variable features. The age at onset ranges from infancy to young adulthood, and patients can present with different features, including hearing loss, delayed motor development, or difficulty walking due to peripheral neuropathy and/or cerebellar ataxia. Most patients develop all features, including a progressive sensorimotor axonal neuropathy and deafness due to auditory neuropathy. Additional more variable features can include cognitive impairment, cerebellar atrophy on brain imaging, cerebellar signs, such as dysarthria, abnormal extraocular movements, tremor, and dysmetria, as well as spasticity. There is significant intrafamilial variability: the variable features are consistent with mitochondrial dysfunction. Prolonged treatment with riboflavin may result in some mild improvement in the ataxia (summary by Rinaldi et al., 2012, Heimer et al., 2018, Bogdanova-Mihaylova et al., 2019). [from OMIM]

Clinical features

From HPO
Distal lower limb muscle weakness
MedGen UID:
324514
Concept ID:
C1836450
Finding
Reduced strength of the distal musculature of the legs.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Sensory neuropathy
MedGen UID:
101791
Concept ID:
C0151313
Disease or Syndrome
Peripheral neuropathy affecting the sensory nerves.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Sensory axonal neuropathy
MedGen UID:
334116
Concept ID:
C1842587
Finding
An axonal neuropathy of peripheral sensory nerves.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Motor axonal neuropathy
MedGen UID:
413108
Concept ID:
C2749625
Disease or Syndrome
Progressive impairment of function of motor axons with muscle weakness, atrophy, and cramps. The deficits are length-dependent, meaning that muscles innervated by the longest nerves are affected first, so that for instance the arms are affected at a later age than the onset of deficits involving the lower leg.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Distal lower limb amyotrophy
MedGen UID:
324515
Concept ID:
C1836451
Disease or Syndrome
Muscular atrophy of distal leg muscles.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Charcot-Marie-Tooth disease X-linked recessive 4 in Orphanet.

Recent clinical studies

Diagnosis

Wang C, Lin Z, Yuan Z, Tang T, Fan L, Liu Y, Wu X
Hereditas 2023 May 12;160(1):22. doi: 10.1186/s41065-023-00282-z. PMID: 37173762Free PMC Article
Bogdanova-Mihaylova P, Alexander MD, Murphy RP, Chen H, Healy DG, Walsh RA, Murphy SM
J Peripher Nerv Syst 2019 Dec;24(4):348-353. Epub 2019 Oct 10 doi: 10.1111/jns.12348. PMID: 31523922
Mierzewska H, Rydzanicz M, Biegański T, Kosinska J, Mierzewska-Schmidt M, Ługowska A, Pollak A, Stawiński P, Walczak A, Kędra A, Obersztyn E, Szczepanik E, Płoski R
Clin Genet 2017 Jan;91(1):30-37. Epub 2016 Jun 2 doi: 10.1111/cge.12792. PMID: 27102849
Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH
Am J Hum Genet 2012 Dec 7;91(6):1095-102. doi: 10.1016/j.ajhg.2012.10.008. PMID: 23217327Free PMC Article

Prognosis

Mierzewska H, Rydzanicz M, Biegański T, Kosinska J, Mierzewska-Schmidt M, Ługowska A, Pollak A, Stawiński P, Walczak A, Kędra A, Obersztyn E, Szczepanik E, Płoski R
Clin Genet 2017 Jan;91(1):30-37. Epub 2016 Jun 2 doi: 10.1111/cge.12792. PMID: 27102849
Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH
Am J Hum Genet 2012 Dec 7;91(6):1095-102. doi: 10.1016/j.ajhg.2012.10.008. PMID: 23217327Free PMC Article

Clinical prediction guides

Bogdanova-Mihaylova P, Alexander MD, Murphy RP, Chen H, Healy DG, Walsh RA, Murphy SM
J Peripher Nerv Syst 2019 Dec;24(4):348-353. Epub 2019 Oct 10 doi: 10.1111/jns.12348. PMID: 31523922
Mierzewska H, Rydzanicz M, Biegański T, Kosinska J, Mierzewska-Schmidt M, Ługowska A, Pollak A, Stawiński P, Walczak A, Kędra A, Obersztyn E, Szczepanik E, Płoski R
Clin Genet 2017 Jan;91(1):30-37. Epub 2016 Jun 2 doi: 10.1111/cge.12792. PMID: 27102849
Diodato D, Tasca G, Verrigni D, D'Amico A, Rizza T, Tozzi G, Martinelli D, Verardo M, Invernizzi F, Nasca A, Bellacchio E, Ghezzi D, Piemonte F, Dionisi-Vici C, Carrozzo R, Bertini E
Eur J Hum Genet 2016 Mar;24(3):463-6. Epub 2015 Jul 15 doi: 10.1038/ejhg.2015.141. PMID: 26173962Free PMC Article
Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH
Am J Hum Genet 2012 Dec 7;91(6):1095-102. doi: 10.1016/j.ajhg.2012.10.008. PMID: 23217327Free PMC Article

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