G.P.91 A new syndrome characterized by demyelinating neuropathy and hydrocephalus caused by a heterozygous mutation in one of the aminoacyl-tRNA synthetase genes

Abstract We report a father and son with hydrocephalus, dysmorphic features and demyelinating neuropathy in whom whole exome sequencing revealed a de novo missense mutation in one of the highly conserved aminoacyl-tRNA synthetase (AARS) genes. Father was born with dysmorphic facial features and hypospadias. At 3 months he developed signs of communicating hydrocephalus treated with lumboperitoneal and ventriculoperitoneal (VP) shunting. Cognitive and motor development was delayed and running never achieved. Tendon reflexes disappeared in puberty when he complained of difficulty walking. Examination showed high arched feet and hammer toes. At 17 years, EMG revealed a demyelinating motor sensory neuropathy with nerve conduction velocities (NCV) of 20 m/s and conduction blocks. Treatment with immunoglobulins and prednisone was unsuccessful. Neurological examination, EMG and genetic studies in both parents were normal. His son was born with similar facial features and hypospadias. Prenatal ultrasound studies had been normal. Normal skull circumference at birth grew to +2.5 SD within 1 month. MRI revealed a communicating hydrocephalus treated with third ventriculostomy and VP shunting. At 17 months he underwent surgery for right coronal suture craniosynostosis. At 2.5 years, he was unable to walk without support. Hydrocephalus was marked by high CSF production (50 cc/h) and low intracranial pressure (7 cm H2 O). Although EMG did not meet criteria of a demyelinating neuropathy, motor NCV of the tibial and peroneal nerve and sensory NCV of the median nerve were below the lower limit (28.1, 35.9 and 36.8 m/s). Relationships between AARS-genes and CMT disease and distal SMA have been shown. Mitochondrial AARS genes have been linked to (leuko-) encephalopathy. This apparently novel syndrome consisting of dysmorphic features, hydrocephalus, hypospadias, demyelinating neuropathy and an autosomal dominant mode of inheritance broadens the spectrum of abnormalities caused by AARS-genes.