P 43 A novel deletion in two exons of the SH3TC2 gene with mutation in the DPYD gene in Charcot-Marie-Tooth disease type 4C

摘要

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating neuropathy associated with SH3TC2 mutations. More than 60 variants including nonsense, frameshift, and splice site variants have been reported in families of different ethnic origins as well as in sporadic patients. CMT4C is clinically characterised by early onset neuropathy, cranial nerve involvement and spine deformities. We present a family from Kuwait with a novel deletion of exons 13 and 14 in the SH3TC2 gene combined with a novel homozygous mutation in the DPYD gene. The 40 year-old male patient had foot deformities in infancy and delayed walking after the age of two. He first required walking aids when ten years old and became wheelchair-bound since the age of 18. He had progressive hearing loss over five years. Walking difficulties and wheelchair-dependency were reported in his father as well as a cousin of his mother while there were no symptoms reported in his own siblings and child. Clinical examination showed hypoacusis requiring the use of hearing aids, marked widespread symmetric muscular atrophies with weakness, and areflexia. He could walk a few steps with bilateral support. He had sensory neuropathy with skin atrophy and loss of hair on the lower legs. Spinal examination and X-ray showed slight hyperkyphosis of the thoracic spine but no signs of kyphoscoliosis. Electrophysiological studies showed severe motor and sensory neuropathy with very low amplitudes, markedly prolonged distal motor latencies and very slow motor nerve conduction velocities in the ulnar nerve. Needle electromyography detected fibrillations, positive sharp waves and complex repetitive discharges. High resolution sonography of the median nerve at the wrist showed a few enlarged fascicles with only moderately raised cross sectional area. Creatin kinase levels were constantly and significantly raised. Genetic testing revealed a homozygous large deletion in the SH3TC2 gene comprising exons 13 and 14 that had not been described before. Furthermore a second homozygous novel mutation (c.680+1GT;p.?) was found in the DPYD gene. The same combination in heterozygous form was detected in the asymptomatic eight year old daughter. This newly described family with CMT4C broadens the spectrum of genetic causes and underlines the clinical variability of phenotypes as the absence of scoliosis does not exclude mutations in the SH3TC2 gene even in patients with severe disabling . ]]>