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Charcot-Marie-Tooth disease, demyelinating, type 1G(CMT1G)

MedGen UID:
1648290
Concept ID:
C4748940
Disease or Syndrome
Synonym: CMT1G
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.
 
Gene (location): PMP2 (8q21.13)
 
Monarch Initiative: MONDO:0033135
OMIM®: 618279
Orphanet: ORPHA476394

Definition

Charcot-Marie-Tooth disease type 1G is an autosomal dominant progressive peripheral sensorimotor neuropathy characterized by distal muscle weakness and atrophy with onset in the first or second decade. Affected individuals have difficulty walking, distal sensory impairment with decreased or absent reflexes, and often have foot deformities. Median motor nerve conduction velocities (NCV) are decreased (less than 38 m/s) and sural nerve biopsy shows myelin defects and onion bulb formation (summary by Hong et al., 2016 and Motley et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200). [from OMIM]

Clinical features

From HPO
Absent patellar reflexes
MedGen UID:
643630
Concept ID:
C0558844
Finding
Absence of the knee jerk reflex, which can normally be elicited by tapping the patellar tendon with a reflex hammer just below the patella.
Absent Achilles reflex
MedGen UID:
108240
Concept ID:
C0558845
Finding
Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.
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).
Hammertoe
MedGen UID:
209712
Concept ID:
C1136179
Anatomical Abnormality
Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.
Distal lower limb muscle weakness
MedGen UID:
324514
Concept ID:
C1836450
Finding
Reduced strength of the distal musculature of the legs.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Hand tremor
MedGen UID:
68689
Concept ID:
C0239842
Finding
An unintentional, oscillating to-and-fro muscle movement affecting the hand.
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.
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.
Impaired pain sensation
MedGen UID:
373348
Concept ID:
C1837522
Finding
Reduced ability to perceive painful stimuli.
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.
Impaired distal vibration sensation
MedGen UID:
381262
Concept ID:
C1853767
Finding
A decrease in the ability to perceive vibration in the distal portions of the limbs.
Decreased compound muscle action potential amplitude
MedGen UID:
908357
Concept ID:
C4230625
Finding
Reduced level of the compound muscle action potential (CMAP), which is recorded following electrical stimulation of a nerve from surface electrodes overlying a muscle supplied by that nerve.
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).
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
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Fatty replacement of skeletal muscle
MedGen UID:
866735
Concept ID:
C4021082
Finding
Muscle fibers degeneration resulting in fatty replacement of skeletal muscle fibers

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCharcot-Marie-Tooth disease, demyelinating, type 1G

Recent clinical studies

Etiology

Nicolaou P, Cianchetti C, Minaidou A, Marrosu G, Zamba-Papanicolaou E, Middleton L, Christodoulou K
Eur J Hum Genet 2013 Feb;21(2):190-4. Epub 2012 Jul 11 doi: 10.1038/ejhg.2012.146. PMID: 22781092Free PMC Article

Diagnosis

Li LX, Liu GL, Liu ZJ, Lu C, Wu ZY
Hum Mutat 2017 Nov;38(11):1569-1578. Epub 2017 Aug 23 doi: 10.1002/humu.23309. PMID: 28776325
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

Prognosis

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
Nicolaou P, Cianchetti C, Minaidou A, Marrosu G, Zamba-Papanicolaou E, Middleton L, Christodoulou K
Eur J Hum Genet 2013 Feb;21(2):190-4. Epub 2012 Jul 11 doi: 10.1038/ejhg.2012.146. PMID: 22781092Free PMC Article

Clinical prediction guides

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
Nicolaou P, Cianchetti C, Minaidou A, Marrosu G, Zamba-Papanicolaou E, Middleton L, Christodoulou K
Eur J Hum Genet 2013 Feb;21(2):190-4. Epub 2012 Jul 11 doi: 10.1038/ejhg.2012.146. PMID: 22781092Free PMC Article
Senderek J, Bergmann C, Ramaekers VT, Nelis E, Bernert G, Makowski A, Züchner S, De Jonghe P, Rudnik-Schöneborn S, Zerres K, Schröder JM
Brain 2003 Mar;126(Pt 3):642-9. doi: 10.1093/brain/awg068. PMID: 12566285

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