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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. Autosomal dominant inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	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.

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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.

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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).

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Hammertoe

MedGen UID:: 209712
•Concept ID:: C1136179
•: Anatomical Abnormality

Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.

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Distal lower limb muscle weakness

MedGen UID:: 324514
•Concept ID:: C1836450
•: Finding

Reduced strength of the distal musculature of the legs.

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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.

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Hand tremor

MedGen UID:: 68689
•Concept ID:: C0239842
•: Finding

An unintentional, oscillating to-and-fro muscle movement affecting the hand.

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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.

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Gait disturbance

MedGen UID:: 107895
•Concept ID:: C0575081
•: Finding

The term gait disturbance can refer to any disruption of the ability to walk.

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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.

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Impaired pain sensation

MedGen UID:: 373348
•Concept ID:: C1837522
•: Finding

Reduced ability to perceive painful stimuli.

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Distal sensory impairment

MedGen UID:: 335722
•Concept ID:: C1847584
•: Finding

An abnormal reduction in sensation in the distal portions of the extremities.

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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.

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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.

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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.

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Distal muscle weakness

MedGen UID:: 140883
•Concept ID:: C0427065
•: Finding

Reduced strength of the musculature of the distal extremities.

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Frequent falls

MedGen UID:: 163408
•Concept ID:: C0850703
•: Finding

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Distal amyotrophy

MedGen UID:: 338530
•Concept ID:: C1848736
•: Disease or Syndrome

Muscular atrophy affecting muscles in the distal portions of the extremities.

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Fatty replacement of skeletal muscle

MedGen UID:: 866735
•Concept ID:: C4021082
•: Finding

Muscle fibers degeneration resulting in fatty replacement of skeletal muscle fibers

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Abnormality of limbs
Abnormality of the musculoskeletal system
Abnormality of the nervous system

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVCharcot-Marie-Tooth disease, demyelinating, type 1G

Autosomal dominant hereditary demyelinating motor and sensory neuropathy
- Charcot-Marie-Tooth disease, demyelinating, type 1G

Recent clinical studies

Etiology

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

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: 22781092 Free PMC Article

Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.

Micallef J, Attarian S, Dubourg O, Gonnaud PM, Hogrel JY, Stojkovic T, Bernard R, Jouve E, Pitel S, Vacherot F, Remec JF, Jomir L, Azabou E, Al-Moussawi M, Lefebvre MN, Attolini L, Yaici S, Tanesse D, Fontes M, Pouget J, Blin O
Lancet Neurol 2009 Dec;8(12):1103-10. Epub 2009 Oct 7 doi: 10.1016/S1474-4422(09)70260-1. PMID: 19818690

See all (2)

Diagnosis

Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot-Marie-Tooth disease type 4D.

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

Charcot-Marie-Tooth Disease Type 4H Resulting from Compound Heterozygous Mutations in FGD4 from Nonconsanguineous Korean Families.

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

Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.

See all (3)

Therapy

Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.

See all (1)

Prognosis

Charcot-Marie-Tooth Disease Type 4H Resulting from Compound Heterozygous Mutations in FGD4 from Nonconsanguineous Korean Families.

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

The first Japanese case of Charcot-Marie-Tooth disease type 4H with a novel FGD4 c.837-1G>A mutation.

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

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

See all (3)

Clinical prediction guides

Charcot-Marie-Tooth Disease Type 4H Resulting from Compound Heterozygous Mutations in FGD4 from Nonconsanguineous Korean Families.

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

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.

Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy.

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

See all (4)

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

Definition

Clinical features

Term Hierarchy

Recent clinical studies

Etiology

Diagnosis

Therapy

Prognosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Molecular resources

Consumer resources

Reviews

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