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Charcot-Marie-Tooth disease, type 4H(CMT4H)

MedGen UID:
324487
Concept ID:
C1836336
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL RECESSIVE, TYPE 4H; CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4H; Charcot-Marie-Tooth Neuropathy Type 4H; Charcot-Marie-Tooth Neuropathy Type 4H (CMT4H); CMT4H
SNOMED CT: Charcot-Marie-Tooth disease type 4H (715802008)
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
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): FGD4 (12p11.21)
 
Monarch Initiative: MONDO:0012250
OMIM®: 609311
Orphanet: ORPHA99954

Definition

Charcot-Marie-Tooth disease, type 4H (CMT4H) is a demyelinating CMT peripheral sensorimotor polyneuropathy. It has been described in 10 individuals from two large consanguineous families from Lebanon and Algeria. Onset occurs within the first two years of life with slowly progressive muscle weakness in the distal extremities. Other common features include delayed walking, an abnormal gait, scoliosis and pes equines with toe retraction. CMT4H is caused by mutations in the FGD4 gene (12p11.1). Transmitted in an autosomal recessive manner. [from SNOMEDCT_US]

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.
Peripheral demyelination
MedGen UID:
451074
Concept ID:
C0878575
Pathologic Function
A loss of myelin from the internode regions along myelinated nerve fibers of the peripheral nervous system.
Upper limb muscle weakness
MedGen UID:
305607
Concept ID:
C1698196
Finding
A reduction in the strength of the upper limb muscles.
Distal lower limb muscle weakness
MedGen UID:
324514
Concept ID:
C1836450
Finding
Reduced strength of the distal musculature of the legs.
Distal lower limb amyotrophy
MedGen UID:
324515
Concept ID:
C1836451
Disease or Syndrome
Muscular atrophy of distal leg muscles.
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 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).
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.

Term Hierarchy

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

Recent clinical studies

Etiology

Boubaker C, Hsairi-Guidara I, Castro C, Ayadi I, Boyer A, Kerkeni E, Courageot J, Abid I, Bernard R, Bonello-Palot N, Kamoun F, Cheikh HB, Lévy N, Triki C, Delague V
Ann Hum Genet 2013 Jul;77(4):336-43. Epub 2013 Apr 2 doi: 10.1111/ahg.12017. PMID: 23550889

Diagnosis

Kondo D, Shinoda K, Yamashita KI, Yamasaki R, Hashiguchi A, Takashima H, Kira JI
Neuromuscul Disord 2017 Oct;27(10):959-961. Epub 2017 Jul 26 doi: 10.1016/j.nmd.2017.07.011. PMID: 28847448
Hyun YS, Lee J, Kim HJ, Hong YB, Koo H, Smith AS, Kim DH, Choi BO, Chung KW
Ann Hum Genet 2015 Nov;79(6):460-9. Epub 2015 Sep 24 doi: 10.1111/ahg.12134. PMID: 26400421
Boubaker C, Hsairi-Guidara I, Castro C, Ayadi I, Boyer A, Kerkeni E, Courageot J, Abid I, Bernard R, Bonello-Palot N, Kamoun F, Cheikh HB, Lévy N, Triki C, Delague V
Ann Hum Genet 2013 Jul;77(4):336-43. Epub 2013 Apr 2 doi: 10.1111/ahg.12017. PMID: 23550889

Prognosis

Argente-Escrig H, Sánchez-Monteagudo A, Frasquet M, Millet-Sancho E, Martínez-Rubio MD, Pitarch I, Tomás M, Espinós C, Lupo V, Sevilla T
J Neurol Sci 2019 Jul 15;402:156-161. Epub 2019 May 15 doi: 10.1016/j.jns.2019.05.015. PMID: 31152969
Hyun YS, Lee J, Kim HJ, Hong YB, Koo H, Smith AS, Kim DH, Choi BO, Chung KW
Ann Hum Genet 2015 Nov;79(6):460-9. Epub 2015 Sep 24 doi: 10.1111/ahg.12134. PMID: 26400421
Arai H, Hayashi M, Hayasaka K, Kanda T, Tanabe Y
Neuromuscul Disord 2013 Aug;23(8):652-5. Epub 2013 Jun 14 doi: 10.1016/j.nmd.2013.04.010. PMID: 23770104

Clinical prediction guides

Argente-Escrig H, Sánchez-Monteagudo A, Frasquet M, Millet-Sancho E, Martínez-Rubio MD, Pitarch I, Tomás M, Espinós C, Lupo V, Sevilla T
J Neurol Sci 2019 Jul 15;402:156-161. Epub 2019 May 15 doi: 10.1016/j.jns.2019.05.015. PMID: 31152969
Hyun YS, Lee J, Kim HJ, Hong YB, Koo H, Smith AS, Kim DH, Choi BO, Chung KW
Ann Hum Genet 2015 Nov;79(6):460-9. Epub 2015 Sep 24 doi: 10.1111/ahg.12134. PMID: 26400421
Boubaker C, Hsairi-Guidara I, Castro C, Ayadi I, Boyer A, Kerkeni E, Courageot J, Abid I, Bernard R, Bonello-Palot N, Kamoun F, Cheikh HB, Lévy N, Triki C, Delague V
Ann Hum Genet 2013 Jul;77(4):336-43. Epub 2013 Apr 2 doi: 10.1111/ahg.12017. PMID: 23550889

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