G.P.37: Clinical overlap between centronuclear myopathy and axonal neuropathy (CMT2) due to mutation in DNM2 gene

Abstract

Mutations in the DNM2 (dynamin 2) gene can cause centronuclear myopathy (CNM) or Charcot Marie Tooth (CMT) type 2 hereditary neuropathy. This is the first case report to our knowledge of a single patient affected by both CMT and CNM equally. We present a 20 year old lady with normal pre and perinatal history and no family history of muscle disease. She had reduced muscle tone from birth but motor and mental development was normal. She developed abnormal gait at 5 years old, with frequent trips and falls. Objectively there was a high arched palate, mild generalized muscle weakness (4/5 MRC) together with pes cavus foot deformities. At 12 years old incomplete opthalmoparesis and mild facial weakness was noticed. At that time, surgical correction of foot abnormalities was performed. The muscle weakness was slowly progressive. At 19 years old she had atrophy of distal muscles in upper and lower limbs with reduced fine motor skills – she was not able to open a bottle or unlock the door; and had waddling and tripping gait. CK level was normal. FVC was reduced (54%), with no need of nocturnal ventilation support. Cardiac examination was normal. Her EMG and NCV studies repeatedly showed typical pattern of pure motor primary axonal neuropathy. Consequently she was classified as having hereditary motor neuropathy plus and muscle biopsy was never performed. SMN1, HSP22, SH3TC2, HSP27, MFN2, BSCL2, GDAP1 genes were Sanger sequenced with no causal mutation identified. Finally whole exome sequencing was performed. After the detailed research, a heterozygous variant p.E368K (c.1102G>A) in DNM2 gene was identified and confirmed by Sanger sequencing. This mutation was already reported to be pathogenic in CNM patients. The mutation arose de-novo. Our case report shows clear clinical overlap between axonal CMT and CNM and shows the variability of the phenotype, as this mutation is usually not associated with CMT. Mutations in the DNM2 (dynamin 2) gene can cause centronuclear myopathy (CNM) or Charcot Marie Tooth (CMT) type 2 hereditary neuropathy. This is the first case report to our knowledge of a single patient affected by both CMT and CNM equally. We present a 20 year old lady with normal pre and perinatal history and no family history of muscle disease. She had reduced muscle tone from birth but motor and mental development was normal. She developed abnormal gait at 5 years old, with frequent trips and falls. Objectively there was a high arched palate, mild generalized muscle weakness (4/5 MRC) together with pes cavus foot deformities. At 12 years old incomplete opthalmoparesis and mild facial weakness was noticed. At that time, surgical correction of foot abnormalities was performed. The muscle weakness was slowly progressive. At 19 years old she had atrophy of distal muscles in upper and lower limbs with reduced fine motor skills – she was not able to open a bottle or unlock the door; and had waddling and tripping gait. CK level was normal. FVC was reduced (54%), with no need of nocturnal ventilation support. Cardiac examination was normal. Her EMG and NCV studies repeatedly showed typical pattern of pure motor primary axonal neuropathy. Consequently she was classified as having hereditary motor neuropathy plus and muscle biopsy was never performed. SMN1, HSP22, SH3TC2, HSP27, MFN2, BSCL2, GDAP1 genes were Sanger sequenced with no causal mutation identified. Finally whole exome sequencing was performed. After the detailed research, a heterozygous variant p.E368K (c.1102G>A) in DNM2 gene was identified and confirmed by Sanger sequencing. This mutation was already reported to be pathogenic in CNM patients. The mutation arose de-novo. Our case report shows clear clinical overlap between axonal CMT and CNM and shows the variability of the phenotype, as this mutation is usually not associated with CMT.