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Charcot-Marie-Tooth disease axonal type 2P(CMT2P; CMT2G, FORMERLY)

MedGen UID:: 482427
•Concept ID:: C3280797
•: Disease or Syndrome

Synonyms:	Charcot-Marie-Tooth disease type 2P; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2G; Charcot-Marie-Tooth Neuropathy Type 2G; CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2P; CMT 2G
SNOMED CT:	Charcot-Marie-Tooth disease type 2P (782826009); CMT2P - Charcot-Marie-Tooth disease type 2P (782826009)
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.	LRSAM1 (9q33.3-34.11)

Monarch Initiative:	MONDO:0013753
OMIM®:	614436
Orphanet:	ORPHA99941

Definition

A rare genetic axonal hereditary motor and sensory neuropathy disorder with characteristics of adulthood-onset of slowly progressive, occasionally asymmetrical, distal muscle weakness and atrophy (predominantly in the lower limbs), pan-modal sensory loss, muscle cramping in extremities and/or trunk, pes cavus and absent or reduced deep tendon reflexes. Gait anomalies and variable autonomic disturbances, such as erectile dysfunction and urinary urgency, may be associated. The disease can be caused by homozygous or heterozygous mutation in the LRSAM1 gene on chromosome 9q33. [from SNOMEDCT_US]

Clinical features

From HPO

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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Foot dorsiflexor weakness

MedGen UID:: 356163
•Concept ID:: C1866141
•: Finding

Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.

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Fasciculations

MedGen UID:: 5124
•Concept ID:: C0015644
•: Sign or Symptom

Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units.

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Areflexia

MedGen UID:: 115943
•Concept ID:: C0234146
•: Finding

Absence of neurologic reflexes such as the knee-jerk reaction.

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Tip-toe gait

MedGen UID:: 98104
•Concept ID:: C0427144
•: Finding

An abnormal gait pattern characterized by the failure of the heel to contact the floor at the onset of stance during gait.

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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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Hyporeflexia

MedGen UID:: 195967
•Concept ID:: C0700078
•: Finding

Reduction of neurologic reflexes such as the knee-jerk reaction.

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Axonal degeneration

MedGen UID:: 332464
•Concept ID:: C1837496
•: Finding

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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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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 motor nerve conduction velocity

MedGen UID:: 388130
•Concept ID:: C1858729
•: Finding

A type of decreased nerve conduction velocity that affects the motor neuron.

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Axonal degeneration/regeneration

MedGen UID:: 368889
•Concept ID:: C1968790
•: Finding

A pattern of simultaneous degeneration and regeneration of axons (see comment).

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Peripheral axonal degeneration

MedGen UID:: 871339
•Concept ID:: C4025830
•: Finding

Progressive deterioration of peripheral axons.

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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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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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Abnormality of limbs
Abnormality of the musculoskeletal system
- Distal amyotrophy
- Distal muscle weakness
Abnormality of the nervous system

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVCharcot-Marie-Tooth disease axonal type 2P

Fetal anomaly
- Congenital Systemic Disorder
  - Abnormality of the nervous system
    - Hereditary motor and sensory neuropathy
      - Charcot-Marie-Tooth disease
        Charcot-Marie-Tooth disease type 2
        Charcot-Marie-Tooth disease axonal type 2P

Follow this link to review classifications for Charcot-Marie-Tooth disease axonal type 2P in Orphanet.

Recent clinical studies

Etiology

LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P.

Hakonen JE, Sorrentino V, Avagliano Trezza R, de Wissel MB, van den Berg M, Bleijlevens B, van Ruissen F, Distel B, Baas F, Zelcer N, Weterman MAJ
Hum Mol Genet 2017 Jun 1;26(11):2034-2041. doi: 10.1093/hmg/ddx089. PMID: 28335037

A novel missense mutation of CMT2P alters transcription machinery.

Hu B, Arpag S, Zuchner S, Li J
Ann Neurol 2016 Dec;80(6):834-845. Epub 2016 Sep 27 doi: 10.1002/ana.24776. PMID: 27615052 Free PMC Article

See all (2)

Diagnosis

LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond.

Palaima P, Berciano J, Peeters K, Jordanova A
Orphanet J Rare Dis 2021 Feb 10;16(1):74. doi: 10.1186/s13023-020-01654-8. PMID: 33568173 Free PMC Article

See all (1)

Clinical prediction guides

Ubiquitin ligase LRSAM1 suppresses neurodegenerative diseases linked aberrant proteins induced cell death.

Mishra R, Amanullah A, Upadhyay A, Dhiman R, Dubey AR, Singh S, Prasad A, Mishra A
Int J Biochem Cell Biol 2020 Mar;120:105697. Epub 2020 Jan 23 doi: 10.1016/j.biocel.2020.105697. PMID: 31982566

See all (1)

MedGen

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Links from Gene

Charcot-Marie-Tooth disease axonal type 2P(CMT2P; CMT2G, FORMERLY)

Definition

Clinical features

Term Hierarchy

Recent clinical studies

Etiology

Diagnosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

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Molecular resources

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