
Charcot-Marie-Tooth (CMT) disease type 2A is known to be associated with mutations of
The proband, a 44-year-old man, was born from non-consanguineous parents. He visited the department of neurology presenting with slowly progressive weakness of the limbs. At the age of 10, he noticed the dropping of feet while walking on a flat surface. At the age of 20, Achilles tendon lengthening was undergone to minimize ankle contracture. At the age of 37, he noticed atrophy on the distal part of bilateral limbs. At the age of 43, he experienced difficulties writing, using chopsticks, and zipping up the jacket. He denied family history.
A neurologic examination at 45 years of age revealed a weakness in the distal part of bilateral arms and legs. Individually, the patient was not able to move the ankle joint, including dorsi/plantar flexion at all. The motor power of flexion/extension in fingers and wrists and knee extension were four as the Medical Research Council (MRC) grade. The MRC grade of knee flexion was three. The power of the shoulder and hip joints remained normal. Strikingly, the atrophy was severe on the lower legs, in which the circumference was 23 cm at the point of 15 cm below the patella (Fig. 1A). Overall deep tendon reflexes were decreased. Vibration sense was disturbed below both ankles. The hammertoes on both feet were revealed, but pes cavus was not evident. The nerve conduction studies (NCS) demonstrated severely decreased amplitude of compound muscle action potential (CMAP) ranging from 0.2 to 4.5 mV in upper extremities and sensory nerve action potentials ranging from 2.0 to 3.6 mV in lower extremities. The CMAPs were not elucidated in the lower extremities. In contrast, the conduction velocity remained more than 30.4 m/s (Table 1). According to the findings of history, examination, and laboratory, this patient was graded as 14 by the CMT neuropathy score (CMTNS). Based on the results of NCS, we proceeded directly to whole-exome sequencing. To identify the pathogenic variant, we uploaded the variant call format file to the MutationDistiller website (https://www.mutationdistiller.org). Once uploaded, we queried “Charcot-Marie-Tooth” in the phenotype inquiry. The MutationDistiller system identified heterozygous variant c.2228G>T (p.Ser743Ile, NM_014874.3, Fig. 1B) of
We recognized axonal CMT based on the electrophysiological findings, and the diagnosis was confirmed by detecting a novel mutation in
WES is currently considered to be a powerful tool for genetic analysis. However, the more we perform WES, the more we get tons of variants to be sifted. To determine the pathogenic mutation from the results of WES, we have filtered allele frequency and the score of in-silico analysis such as SIFT, Proven, and Polyphen2 manually. MutationDistiller is a recently introduced online tool for the analysis of WES [4]. It combines MutationTaster’s pathogenic predictions with a phenotype database of the Human Phenotype Ontology and provides a list of potential disease mutations [4]. Therefore, this tool can reduce the burden of identifying possible pathogenic variants.
Human
In terms of phenotype-genotype correlation in CMT2A, the type or location of mutation was not associated with severe or mild phenotype [5,6]. The previous study could not reveal any relationship between the site or type of mutation and the age at onset, clinical severity, or additional features [6,7]. However, early-onset patients seem to present with severe phenotype with higher score of CMTNS [5,7].
In conclusion, this study demonstrated the CMT2A patient with a novel mutation c.2228G>T in
The authors declare that they do not have any conflicts of interest.
Nerve conduction studies of the patient
Nerves | Stimulation site | Recording site | Nerve conduction study | ||
---|---|---|---|---|---|
Motor | Latency (msec) | CMAP (mV) | NCV (m/sec) | ||
Median | Wrist | Abductor pollicis brevis | 4.69 ↑ (<3.6) | 0.4 ↓ (>5.0) | |
Elbow | 0.2 ↓ (>5.0) | 44.6 ↓ (>50) | |||
Axilla | 0.2 ↓ (>5.0) | 34.3 ↓ (>55) | |||
Ulnar | Wrist | Abductor digiti minimi | 3.91 ↑ (<3.0) | 2.6 ↓ (>5.0) | |
Below elbow | 1.4 ↓ (>5.0) | 52.6 | |||
Above elbow | 1.3 ↓ (>5.0) | 45.2 | |||
Axilla | 0.7 ↓ (>5.0) | 30.4 ↓ (>52) | |||
Peroneal | Ankle | Extensor digitorum brevis | NR | ||
Knee | NR | ||||
Tibial | Ankle | Abductor hallucis | NR | ||
Knee | NR | ||||
Sensory | SNAP (μV) | NCV (m/sec) | |||
Median | Finger | Wrist | 2.0 ↓ (>10) | 33.5 ↓ (>41) | |
Ulnar | Finger | Wrist | 3.1 ↓ (>10) | 33.1 ↓ (>39) | |
Sural | Midcalf | Lateral malleolus | 3.6 ↓ (>6) | 45.6 |
CMAP, compound muscle action potential; NCV, nerve conduction velocity; NR, no response; SNAP, sensory nerve action potential, normal ranges are described between parentheses.
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