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Charcot-Marie-Tooth disease, dominant intermediate G(CMTDIG)

MedGen UID:
1642893
Concept ID:
C4693509
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE G; CMTDIG
 
Gene (location): NEFL (8p21.2)
 
Monarch Initiative: MONDO:0036484
OMIM®: 617882

Definition

CMTDIG is an autosomal dominant neurologic disorder with a highly variable phenotype. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. More severely affected individuals may have pes cavus and claw hands and become wheelchair-bound, whereas other affected individuals have later onset with a milder disease course. Electrophysiologic studies tend to show median motor nerve conduction velocities (NCV) in the 'intermediate' range, between 25 and 45 m/s (summary by Berciano et al., 2017). In a review of intermediate CMT, Berciano et al. (2017) noted that advanced axonal degeneration may induce secondary demyelinating changes resulting in decreased NCV and attenuated compound muscle action potential (CMAP) in median nerve conduction studies. They thus suggested that testing the upper arm, axilla to elbow, may provide more accurate assessment of NCV and CMAP and reveal an intermediate phenotype (review by Berciano et al., 2017). For a discussion of genetic heterogeneity of CMTDI, see 606482. [from OMIM]

Clinical features

From HPO
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.
Split hand
MedGen UID:
397570
Concept ID:
C2699510
Congenital Abnormality
A condition in which middle parts of the hand (fingers and metacarpals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic middle fingers over absent middel fingers as far as oligo- or monodactyl hands.
Sensorineural hearing impairment
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
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.
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.
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.
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.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Professional guidelines

PubMed

Bansagi B, Antoniadi T, Burton-Jones S, Murphy SM, McHugh J, Alexander M, Wells R, Davies J, Hilton-Jones D, Lochmüller H, Chinnery P, Horvath R
J Neurol 2015 Aug;262(8):1899-908. Epub 2015 Jun 2 doi: 10.1007/s00415-015-7778-4. PMID: 26032230Free PMC Article

Recent clinical studies

Etiology

Bansagi B, Antoniadi T, Burton-Jones S, Murphy SM, McHugh J, Alexander M, Wells R, Davies J, Hilton-Jones D, Lochmüller H, Chinnery P, Horvath R
J Neurol 2015 Aug;262(8):1899-908. Epub 2015 Jun 2 doi: 10.1007/s00415-015-7778-4. PMID: 26032230Free PMC Article
Soong BW, Huang YH, Tsai PC, Huang CC, Pan HC, Lu YC, Chien HJ, Liu TT, Chang MH, Lin KP, Tu PH, Kao LS, Lee YC
Am J Hum Genet 2013 Mar 7;92(3):422-30. Epub 2013 Feb 21 doi: 10.1016/j.ajhg.2013.01.014. PMID: 23434117Free PMC Article

Diagnosis

San Luis CV, Schwartzlow C, Nozaki K, Ubogu EE
J Investig Med High Impact Case Rep 2022 Jan-Dec;10:23247096221117801. doi: 10.1177/23247096221117801. PMID: 35993408Free PMC Article
Lee AJ, Nam DE, Choi YJ, Nam SH, Choi BO, Chung KW
Genes Genomics 2020 Jun;42(6):663-672. Epub 2020 Apr 20 doi: 10.1007/s13258-020-00933-9. PMID: 32314272
Bansagi B, Antoniadi T, Burton-Jones S, Murphy SM, McHugh J, Alexander M, Wells R, Davies J, Hilton-Jones D, Lochmüller H, Chinnery P, Horvath R
J Neurol 2015 Aug;262(8):1899-908. Epub 2015 Jun 2 doi: 10.1007/s00415-015-7778-4. PMID: 26032230Free PMC Article

Prognosis

San Luis CV, Schwartzlow C, Nozaki K, Ubogu EE
J Investig Med High Impact Case Rep 2022 Jan-Dec;10:23247096221117801. doi: 10.1177/23247096221117801. PMID: 35993408Free PMC Article
Lee AJ, Nam DE, Choi YJ, Nam SH, Choi BO, Chung KW
Genes Genomics 2020 Jun;42(6):663-672. Epub 2020 Apr 20 doi: 10.1007/s13258-020-00933-9. PMID: 32314272

Clinical prediction guides

San Luis CV, Schwartzlow C, Nozaki K, Ubogu EE
J Investig Med High Impact Case Rep 2022 Jan-Dec;10:23247096221117801. doi: 10.1177/23247096221117801. PMID: 35993408Free PMC Article
Lee AJ, Nam DE, Choi YJ, Nam SH, Choi BO, Chung KW
Genes Genomics 2020 Jun;42(6):663-672. Epub 2020 Apr 20 doi: 10.1007/s13258-020-00933-9. PMID: 32314272

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