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Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease.

Liao YC, Liu YT, Tsai PC, Chang CC, Huang YH, Soong BW, Lee YC - PLoS ONE (2015)

Bottom Line: The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT.These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.

ABSTRACT

Background: Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive.

Methodology and principal findings: Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.

Conclusion: GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

No MeSH data available.


Related in: MedlinePlus

Clinical features of the patient harboring the GARS p.Asp146Tyr mutation.(A) Severe weakness and atrophy of the muscles in the feet and legs, pes planus and (B, C) severe intrinsic hand muscle atrophy with claw hand deformity.
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pone.0133423.g002: Clinical features of the patient harboring the GARS p.Asp146Tyr mutation.(A) Severe weakness and atrophy of the muscles in the feet and legs, pes planus and (B, C) severe intrinsic hand muscle atrophy with claw hand deformity.

Mentions: Each of the two de novo GARS mutations were identified in one single patient, and the paternities between the two index patients and their parents were confirmed by analyzing 14 microsatellite markers. Patient 1 is heterozygous for the GARS p.Asp146Tyr mutation. She was reported to have pneumonia with respiratory failure at 3 months of age. Axonal polyneuropathy was diagnosed at that time, and pneumonia with respiratory failure was cured with treatment. The patient had delayed motor milestones and was not able to sit by herself until 15 months of age. She could never stand, pinch, or move her toes. She learned to control an electrical wheelchair by using a joystick at age 7. Neurological examination at age 9 revealed pes planus, generalized areflexia and severe and symmetrical weakness and atrophy of the muscles in four limbs (Fig 2). The Medical Research Council (MRC) scale scores were grade 4 for muscles of the shoulder and pelvic girdles, grade 3 for flexors and extensors of the elbows and knees, grade 1–2 for the wrist muscles and finger flexors, and grade 0 for the intrinsic hand and feet muscles and muscles in the legs. All modalities of sensation were diminished in the regions distal to the knees and wrists. The NCS demonstrated a severe polyneuropathy with a failure to elicit any motor or sensory response in the limbs. Patient 2 is heterozygous for the GARS p.Met238Arg mutation. She had no delayed onset of ambulation but began to experience gait difficulty with frequent tripping at age 2. She developed feet drop and difficulty pinching at age 8 and became almost wheelchair-bound at age 11. Neurological examination at age 11 revealed pes cavus, generalized areflexia, and severe weakness and atrophy of the intrinsic feet and hand muscles and the muscles in the legs. The MRC scores were grade 4 for flexors and extensors of the knees, grade 3 for the wrist flexor and extensor and finger flexor muscles, and grade 0 for the intrinsic hand and feet muscles and muscles in the legs. The strength of muscles of the pelvic and shoulder girdles and the elbow flexors or extensors was normal. All modalities of sensation were diminished in the regions distal to the ankles. The NCS demonstrated a severe axonal polyneuropathy with right ulnar nerve motor conduction velocity of 43.5 m/s and a compound motor action potential of 0.1 mV. Other motor or sensory responses in the NCS were absent.


Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease.

Liao YC, Liu YT, Tsai PC, Chang CC, Huang YH, Soong BW, Lee YC - PLoS ONE (2015)

Clinical features of the patient harboring the GARS p.Asp146Tyr mutation.(A) Severe weakness and atrophy of the muscles in the feet and legs, pes planus and (B, C) severe intrinsic hand muscle atrophy with claw hand deformity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526224&req=5

pone.0133423.g002: Clinical features of the patient harboring the GARS p.Asp146Tyr mutation.(A) Severe weakness and atrophy of the muscles in the feet and legs, pes planus and (B, C) severe intrinsic hand muscle atrophy with claw hand deformity.
Mentions: Each of the two de novo GARS mutations were identified in one single patient, and the paternities between the two index patients and their parents were confirmed by analyzing 14 microsatellite markers. Patient 1 is heterozygous for the GARS p.Asp146Tyr mutation. She was reported to have pneumonia with respiratory failure at 3 months of age. Axonal polyneuropathy was diagnosed at that time, and pneumonia with respiratory failure was cured with treatment. The patient had delayed motor milestones and was not able to sit by herself until 15 months of age. She could never stand, pinch, or move her toes. She learned to control an electrical wheelchair by using a joystick at age 7. Neurological examination at age 9 revealed pes planus, generalized areflexia and severe and symmetrical weakness and atrophy of the muscles in four limbs (Fig 2). The Medical Research Council (MRC) scale scores were grade 4 for muscles of the shoulder and pelvic girdles, grade 3 for flexors and extensors of the elbows and knees, grade 1–2 for the wrist muscles and finger flexors, and grade 0 for the intrinsic hand and feet muscles and muscles in the legs. All modalities of sensation were diminished in the regions distal to the knees and wrists. The NCS demonstrated a severe polyneuropathy with a failure to elicit any motor or sensory response in the limbs. Patient 2 is heterozygous for the GARS p.Met238Arg mutation. She had no delayed onset of ambulation but began to experience gait difficulty with frequent tripping at age 2. She developed feet drop and difficulty pinching at age 8 and became almost wheelchair-bound at age 11. Neurological examination at age 11 revealed pes cavus, generalized areflexia, and severe weakness and atrophy of the intrinsic feet and hand muscles and the muscles in the legs. The MRC scores were grade 4 for flexors and extensors of the knees, grade 3 for the wrist flexor and extensor and finger flexor muscles, and grade 0 for the intrinsic hand and feet muscles and muscles in the legs. The strength of muscles of the pelvic and shoulder girdles and the elbow flexors or extensors was normal. All modalities of sensation were diminished in the regions distal to the ankles. The NCS demonstrated a severe axonal polyneuropathy with right ulnar nerve motor conduction velocity of 43.5 m/s and a compound motor action potential of 0.1 mV. Other motor or sensory responses in the NCS were absent.

Bottom Line: The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT.These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.

ABSTRACT

Background: Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive.

Methodology and principal findings: Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.

Conclusion: GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

No MeSH data available.


Related in: MedlinePlus