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Charcot-Marie-Tooth disease type 4J(CMT4J)

MedGen UID:
370808
Concept ID:
C1970011
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL RECESSIVE, TYPE 4J; Charcot-Marie-Tooth Neuropathy Type 4J; Charcot-Marie-Tooth Neuropathy Type 4J (CMT4J)
SNOMED CT: Charcot-Marie-Tooth disease type 4J (720638000)
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).
 
Gene (location): FIG4 (6q21)
 
Monarch Initiative: MONDO:0012640
OMIM®: 611228
Orphanet: ORPHA139515

Definition

Charcot-Marie-Tooth disease type 4J is an autosomal recessive progressive neurologic disorder with a highly variable phenotype and onset ranging from early childhood to adulthood. Most patients have both proximal and distal asymmetric muscle weakness of the upper and lower limbs. There is significant motor dysfunction, followed by variably progressive sensory loss, which may be mild. Nerve conduction studies and nerve biopsies indicate demyelination as well as axonal loss (summary by Nicholson et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400). [from OMIM]

Clinical features

From HPO
Ankle flexion contracture
MedGen UID:
332440
Concept ID:
C1837407
Anatomical Abnormality
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
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.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Axonal loss
MedGen UID:
316962
Concept ID:
C1832338
Finding
A reduction in the number of axons in the peripheral nervous system.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
Peripheral hypomyelination
MedGen UID:
870480
Concept ID:
C4024927
Finding
Reduced amount of myelin in the nervous system resulting from defective myelinogenesis in the peripheral nervous system.
Distal arthrogryposis
MedGen UID:
120512
Concept ID:
C0265213
Disease or Syndrome
An inherited primary limb malformation disorder characterized by congenital contractures of two or more different body areas and without primary neurologic and/or muscle disease that affects limb function.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Frequent falls
MedGen UID:
163408
Concept ID:
C0850703
Finding

Term Hierarchy

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

Recent clinical studies

Etiology

Osmanovic A, Rangnau I, Kosfeld A, Abdulla S, Janssen C, Auber B, Raab P, Preller M, Petri S, Weber RG
Eur J Hum Genet 2017 Feb;25(3):324-331. Epub 2017 Jan 4 doi: 10.1038/ejhg.2016.186. PMID: 28051077Free PMC Article
Nicholson G, Lenk GM, Reddel SW, Grant AE, Towne CF, Ferguson CJ, Simpson E, Scheuerle A, Yasick M, Hoffman S, Blouin R, Brandt C, Coppola G, Biesecker LG, Batish SD, Meisler MH
Brain 2011 Jul;134(Pt 7):1959-71. doi: 10.1093/brain/awr148. PMID: 21705420Free PMC Article

Diagnosis

Wright GC, Brown R, Grayton H, Livingston JH, Park SM, Parker APJ, Patel A, Simonic I, Thomas AG, Vadlamani G, Horvath R, Harijan PD
Clin Genet 2020 Aug;98(2):147-154. Epub 2020 Jun 10 doi: 10.1111/cge.13771. PMID: 32385905
Lenk GM, Berry IR, Stutterd CA, Blyth M, Green L, Vadlamani G, Warren D, Craven I, Fanjul-Fernandez M, Rodriguez-Casero V, Lockhart PJ, Vanderver A, Simons C, Gibb S, Sadedin S; Broad Center for Mendelian Genomics, White SM, Christodoulou J, Skibina O, Ruddle J, Tan TY, Leventer RJ, Livingston JH, Meisler MH
Hum Mutat 2019 May;40(5):619-630. Epub 2019 Feb 28 doi: 10.1002/humu.23720. PMID: 30740813Free PMC Article
Osmanovic A, Rangnau I, Kosfeld A, Abdulla S, Janssen C, Auber B, Raab P, Preller M, Petri S, Weber RG
Eur J Hum Genet 2017 Feb;25(3):324-331. Epub 2017 Jan 4 doi: 10.1038/ejhg.2016.186. PMID: 28051077Free PMC Article
Vaccari I, Carbone A, Previtali SC, Mironova YA, Alberizzi V, Noseda R, Rivellini C, Bianchi F, Del Carro U, D'Antonio M, Lenk GM, Wrabetz L, Giger RJ, Meisler MH, Bolino A
Hum Mol Genet 2015 Jan 15;24(2):383-96. Epub 2014 Sep 3 doi: 10.1093/hmg/ddu451. PMID: 25187576Free PMC Article
Cottenie E, Menezes MP, Rossor AM, Morrow JM, Yousry TA, Dick DJ, Anderson JR, Jaunmuktane Z, Brandner S, Blake JC, Houlden H, Reilly MM
Neuromuscul Disord 2013 May;23(5):399-403. Epub 2013 Mar 13 doi: 10.1016/j.nmd.2013.01.010. PMID: 23489662

Therapy

Lewis HS, Willis E, Veerapandiyan A
J Clin Neuromuscul Dis 2019 Dec;21(2):117-118. doi: 10.1097/CND.0000000000000258. PMID: 31743256

Prognosis

Gentil BJ, O'Ferrall E, Chalk C, Santana LF, Durham HD, Massie R
J Neuropathol Exp Neurol 2017 Sep 1;76(9):789-799. doi: 10.1093/jnen/nlx062. PMID: 28859335Free PMC Article
Osmanovic A, Rangnau I, Kosfeld A, Abdulla S, Janssen C, Auber B, Raab P, Preller M, Petri S, Weber RG
Eur J Hum Genet 2017 Feb;25(3):324-331. Epub 2017 Jan 4 doi: 10.1038/ejhg.2016.186. PMID: 28051077Free PMC Article
Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J
Brain 2008 Aug;131(Pt 8):1990-2001. Epub 2008 Jun 12 doi: 10.1093/brain/awn114. PMID: 18556664Free PMC Article

Clinical prediction guides

Lafontaine M, Lia AS, Bourthoumieu S, Beauvais-Dzugan H, Derouault P, Arné-Bes MC, Sarret C, Laffargue F, Magot A, Sturtz F, Magy L, Magdelaine C
Ann Clin Transl Neurol 2021 Feb;8(2):471-476. Epub 2021 Jan 6 doi: 10.1002/acn3.51175. PMID: 33405357Free PMC Article
Edgar JR, Ho AK, Laurá M, Horvath R, Reilly MM, Luzio JP, Roberts RC
Acta Neuropathol Commun 2020 Oct 15;8(1):165. doi: 10.1186/s40478-020-01043-z. PMID: 33059769Free PMC Article
Lenk GM, Berry IR, Stutterd CA, Blyth M, Green L, Vadlamani G, Warren D, Craven I, Fanjul-Fernandez M, Rodriguez-Casero V, Lockhart PJ, Vanderver A, Simons C, Gibb S, Sadedin S; Broad Center for Mendelian Genomics, White SM, Christodoulou J, Skibina O, Ruddle J, Tan TY, Leventer RJ, Livingston JH, Meisler MH
Hum Mutat 2019 May;40(5):619-630. Epub 2019 Feb 28 doi: 10.1002/humu.23720. PMID: 30740813Free PMC Article
Mironova YA, Lin JP, Kalinski AL, Huffman LD, Lenk GM, Havton LA, Meisler MH, Giger RJ
Hum Mol Genet 2018 Jul 15;27(14):2443-2453. doi: 10.1093/hmg/ddy145. PMID: 29688489Free PMC Article
Gentil BJ, O'Ferrall E, Chalk C, Santana LF, Durham HD, Massie R
J Neuropathol Exp Neurol 2017 Sep 1;76(9):789-799. doi: 10.1093/jnen/nlx062. PMID: 28859335Free PMC Article

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