G.P.92 Study of an autosomal recessive spinocerebellar ataxia with peripheral neuropathy

Abstracts / Neuromuscular Disorders 22 (2012) 804–908 Mutations in the mitofusin 2 gene (MFN2), encoding an outer mitochondrial membrane protein of the dynamin family GTPase, cause mainly Charcot–Marie–Tooth 2A (CMT2A), hereditary motor and sensory neuropathy type VI (HMSN VI) and axonal neuropathy with spastic paraparesis. Hereby, we report eight genetically confirmed patients with MFN2 defects. The mean current age of the patients is 14.5 years, (range 4–28), three are male and five female. A dominant familial inheritance was confirmed in two cases while six are sporadic. All patients were submitted to neurological, electrophysiological, ophthalmological and cranial MRI evaluation.. Symptoms started in all patients within the two first years of life with falls, and difficulties to walk consisting in: flat foot (4), equinovarus foot position (3), stepage (7) and spastic paraparesis (1). Distal upper limb involvement was observed in all patients, being severe in four. Two patients developed diaphragmatic paresis and one vocal cord paresis. Learning difficulties were observed in four and one manifested disartic episodes that lasted several days. Two patients were chair bound at 12 years old requiring nocturnal non invasive ventilatory support (BIPAP). The remaining of the patients were able to walk with orthesis (DAFOS). Axonal neuropathy was identified in all the patients. We also discuss cranial MRI, visual evocated potentials (VEP), genetic and ophthalmological findings. Early onset mitofusin deficiency constitutes a severe and disabling condition. Because several organs may be involved, systemic evaluation and follow up is required, especially when respiratory function is compromised.

http://dx.doi:10.1016/j.nmd.2012.06.219

G.P.90 Dislocating patellae in children with CMT1a M. Main 1, A. Hiscock 2, F. Muntoni 3 1 Great Ormond Street Hospital for Children, Dubowitz Neuromuscular Service, London, United Kingdom; 2 UCL, Dubowitz Neuromuscular Service, London, United Kingdom; 3 ICH and Great Ormond Street Hospital for Children, Dubowitz Neuromuscular Service, London, United Kingdom The incidence of children with dislocating patella in the normal population in the UK has never been defined, although there is reportedly a higher occurrence in children with benign laxity. The incidence of patellar instability in adults (as opposed to dislocation due to injury) is reported as 4 per 100,000 of the population. In the Dubowitz neuromuscular service at Great Ormond Street Hospital we follow a total of 70 children affected by Charcot–Marie–Tooth disease (CMT), the largest group having CMT1A. Out of a current cohort of 50 children with CMT1A, seven have reported unilateral or bilateral dislocation of the patellae, an incidence of 14%. Affected parents of three children have reported previous dislocating patellae. Treatment, frequently led by orthopaedic surgeons, varies from prescription of exercises for strengthening medial thigh musculature, to knee braces, POP cylinders and surgery. The literature on management of dislocating patellae shows no consensus on best practise, more so in children than adults, with no agreement on whether surgical or conservative management is most effective in the long term. We suggest that it is important to be able to identify the children who may be at risk; therefore allowing us to use strengthening techniques to try and prevent dislocation. We are currently assessing all children with CMT1A if there is a correlation between the Q angle, (a measurement of patellar alignment) quadriceps length measured in prone and quadriceps power measured by myometry to see if there are indicators of greater risk. Generalised joint laxity, gait asymmetry and foot posture are also routinely assessed. http://dx.doi:10.1016/j.nmd.2012.06.220

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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 E.H. Niks 1, T.P. Potjer 2, R. Al Momani 2, Y. Sun 2, R.W. Koot 3, J.G. van Dijk 4, D.A.J. Haring 5, E. Aten 2, M. Kriek 2, G.W.E. Santen 2, S.A.M. Lesnik Oberstein 2 1 Leiden University Medical Center, Neurology, Leiden, Netherlands; 2 Leiden University Medical Center, Center for Human and Clinical Genetics, Leiden, Netherlands; 3 Leiden University Medical Center, Neurosurgery, Leiden, Netherlands; 4 Leiden University Medical Center, Neurology and Clinical Neurophysiology, Leiden, Netherlands; 5 Diaconessenhuis, Pediatrics, Leiden, Netherlands 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 aminoacyltRNA 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 H2O). 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. http://dx.doi:10.1016/j.nmd.2012.06.221

G.P.92 Study of an autosomal recessive spinocerebellar ataxia with peripheral neuropathy K.S. Yau 1, P.J. Lamont 2, K.J. Nowak 3, N. Kresoje 4, E.L. McNamara 3, R.J. Allcock 4, M.R. Davis 5, N.G. Laing 3 1 Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Perth, Australia; 2 Neurogenetics Unit, Royal Perth Hospital, Department of Neurology, Perth, Australia; 3 Western Australian Institute for Medical Research, Molecular Neurogenetics, Perth, Australia; 4 Lotterywest State Biomedical Facility Genomics, Perth, Australia; 5 Royal Perth Hospital, Department of Anatomical Pathology, Perth, Australia The autosomal recessive spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders associated with 10 disease genes and seven other loci. Because of the genetic and phenotypic heterogeneity of this disease, a large percentage of cases go without a genetic diagnosis. In the family under investigation, two out of eight sib-

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Abstracts / Neuromuscular Disorders 22 (2012) 804–908

lings are affected, and the parents are second cousins, suggesting a recessive disease. The two affected brothers presented at 55 and 54 years respectively with weakness about the ankles, poor balance and chronic cough. There were cerebellar signs with saccadic interruption of eye movements and a wide-based gait, and later on dysarthria. Creatine kinase was elevated, to between 580 and 1020 (N < 195). Nerve conduction studies showed a severe sensorimotor peripheral neuropathy and muscle biopsy showed numerous atrophic fibres and group atrophy, in keeping with a neurogenic cause. Electron microscopy additionally showed subsarcolemmal accumulation of pleomorphic mitochondria with large electron dense inclusions. MRI of the head showed progressive atrophy of the cerebellum, principally of the vermis, and thinning of the brainstem. No cause for the cough has been found. This combination of pathologies has not previously not been described in the literature, thus suggesting that this is a novel phenotype of recessive spinocerebellar ataxia. We have combined SNP-based linkage analysis with whole exome capture and next generation sequencing to attempt to identify the causative mutation in this family. Linkage exclusion analysis combined with whole exome sequencing has eliminated all known autosomal recessive spinocerebellar ataxia disease genes, indicating that a novel disease gene may be the cause of disease in this family. http://dx.doi:10.1016/j.nmd.2012.06.222

G.P.93 Study of a novel autosomal dominant spinocerebellar ataxia P.J. Lamont 1, K.S. Yau 2, R.M. Duff 2, W. Carroll 3, M.R. Davis 4, N.G. Laing 2 1 Royal Perth Hospital, Neurogenetics, Perth, Australia; 2 Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Perth, Australia; 3 Sir Charles Gairdner Hospital, Neurology, Perth, Australia; 4 Royal Perth Hospital, Anatomical Pathology, Perth, Australia The spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders. There are currently 18 known disease genes and nine other loci that have been associated with autosomal dominant spinocerebellar ataxia. Because of this genetic heterogeneity, a large number of cases still go without a genetic diagnosis. The family under investigation is a four-generation family of Anglo-Saxon lineage, with eight known affected members. The phenotype is of an autosomal dominant spinocerebellar ataxia, with evidence of anticipation. The initial symptom is gait ataxia, followed within 5 years by slurring dysarthria, saccadic interruption of eye movements, intention tremor, and clumsy hand movements. There is evidence of long tract involvement with increased deep tendon reflexes in the legs and urinary urgency. There is progression of all the symptoms, with the second generation requiring a wheelchair by 70 years, and the third generation by 50 years. Progressive atrophy of the cerebellum, brain stem and cerebellar peduncles develops on MRI. All other investigations were within normal limits. Molecular testing for trinucleotide repeat expansions for SCA 1, 2, 3, 6, 7, 8 and 17 was negative. We then used SNP-based linkage analysis to attempt to identify the causative locus in the family. SNP linkage analysis excluded all known autosomal dominant spinocerebellar ataxia disease genes except for SCA8 (already excluded) and (SCA10). SCA10 has not as yet been excluded. However, mutations in this gene have only been reported in families of South American or Mexican descent, and the phenotype is usually complicated with seizures and mood disorders, unlike our family. The SCA 19/22, 21 and 29 loci were not excluded. Thus, the disease in our family is either caused by a novel disease gene, or it is the first SCA10 family outside of South America and Mexico to be described. http://dx.doi:10.1016/j.nmd.2012.06.223

G.P.94 Incidence and severity of peripheral neuropathy in children on vincristine – Do vitamin E levels change during treatment? M.P. Kava 1, P. Walsh 1, A. Berroya 1, Y. Halstead 1, R.M. Srinivasjois 2, B. Lewis 3, C. Cole 4, D. Baker 4, L. Nagarajan 1 1 Princess Margaret Hospital, Neurology, Perth, Australia; 2 Joondalup Health Campus, Paediatrics, Perth, Australia; 3 Princess Margaret Hospital, Biochemistry, Perth, Australia; 4 Princess Margaret Hospital, Oncology, Perth, Australia Chemotherapy induced peripheral neuropathy (PN) is a common dose limiting side effect associated with vincristine treatment. The painful sensori motor neuropathy seen in vincristine is similar to that in vitamin E deficiency. To determine the incidence, severity and type of PN associated with vincristine chemotherapy in children and to determine the levels of Vitamin E in the blood before and after starting vincristine. All children in the oncology unit of a tertiary paediatric hospital on vincristine were included. A detailed history,specifically tailored neurological examination and nerve conduction studies were performed and blood vitamin E levels were measured at baseline and at 3, 6 and 12 months from the time of chemotherapy. Thirty patients were enrolled over a period of 12 months. The mean age of the children was 6.2 years. 14/28(50%) children had pre B acute lymphoblastic leukemia. Peripheral neuropathy was evident in more than 90% patients. The most common subjective features of PN were weakness seen in 39% and pain in 30% at 3 months. The most common objective finding was loss of ankle reflex seen in 57% at 3 months and reduced ankle reflex in a further 21%. The subjective weakness disappeared and the pain reduced at 12 months while the objective signs persisted. The most common autonomic feature was constipation seen in 43% at 3 months. The most common nerve affected was the deep peroneal nerve with axonal involvement in 82% of the subjects tested. The vitamin E levels dropped significantly at 3, 6 and 12 months from baseline although they still remained within normal limits. More than 90% children on vincristine had evidence of neuropathy. It was mild sensorimotor axonal neuropathy that appeared within 3 months of treatment in most. The levels of vitamin E remained in the normal range though there was a significant drop at 3 months, followed by values lower than baseline at 6 and 12 months. http://dx.doi:10.1016/j.nmd.2012.06.224

G.P.95 Two sibs with early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD) due to homozygous exon 7 deletion in MEGF10 K.G. Meilleur 1, T.M. Pierson 1, M. Jain 2, S. Donkervoort 1, T. Markello 3, L. Wolfe 3, J. Accardi 3, D. Adams 3, M. Sincan 3, K. Fuentes-Fajardo 3, P.F. Cherukuri 3, P. Cruz 4, I. Bajraktari 1, T. Lehky 1, J.K. Teer 3, J.C. Mullikin 4, W.A. Gahl 3, C.F. Boerkoel 3, C.J. Tifft 3, C.G. Bonnemann 1 1 National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, United States; 2 National Institutes of Health, Rehabilitation, Bethesda, United States; 3 National Institutes of Health, National Human Genome Research Institute, Bethesda, United States; 4 National Institutes of Health, NIH Intramural Sequencing Center, Rockville, United States MEGF10 was recently implicated as the gene causing EMARDD. We present two consanguineous sibs with EMARDD, a 12-yr-old girl of Egyptian descent and her (deceased) older sister. The proband had decreased fetal movements and, at birth, diffuse hypotonia and finger contractures. At 8 months, she underwent a Nissen fundoplication with gastrostomy tube placement and after required ventilatory support resulting in a tracheostomy. She ambulated with a walker at 2 years of