Riboflavin transporter deficiency

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Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249

Further studies are ongoing to evaluate whether modulation of mitophagy could represent a relevant therapeutic strategy in this rare glycogenosis. http://dx.doi.org/10.1016/j.nmd.2017.06.404

P.365 Glycemic control during fasting in patients with low skeletal muscle mass A. Andersen, A. Eisum, C. Høi-Hansen, P. Born, J. Vissing, M. Oerngreen Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Patients with low skeletal muscle mass have shown to react differently to fasting than expected. An earlier study of the glucose metabolism in adults with Spinal muscular atrophy (SMA) and congenital myopathies among others found that especially the patients with low skeletal muscle mass became hypoglycemic after a period of fasting and the same has been described in cases with children with low muscle mass admitted after febrile episodes and fasting. This indicates that further research into the glycemic control of persons with low muscle mass is warranted. The aim of the study is to investigate the carbohydrate and fatty acid oxidation in patients with low muscle mass. Furthermore, the study will investigate the metabolic differences in children and adults with the same diagnosis. These systemic metabolic pathways have never been described in these patient groups before. Fat and carbohydrate metabolism will be measured using metabolic tracers (stable isotopes) combined with indirect calorimetry from measures of oxygen consumption (VO2) and carbon dioxide production (VCO2). The study will focus on adult patients diagnosed with SMA types II and III and paediatric patients diagnosed with SMA type II and congenital muscular dystrophies with mutations in the LAMA2 gene. The primary outcome measure will be registering development of hypoglycaemia during fasting. Secondary outcome measures are changes in fat and carbohydrates metabolisms from fed to fasted state and changes in hormones and metabolites during fasting. Data from the children will be compared to data from WHO and literature on healthy children and their overall energy utilization using the Schofield equation. Data from the adult patients will be compared to a group of matched untrained healthy control subjects for comparison of the primary and secondary outcome measures. The research trials will be conducted in late spring and summer and preliminary data will be available for presentation at the WMS meeting. http://dx.doi.org/10.1016/j.nmd.2017.06.405

P.366 Riboflavin transporter deficiency E. Serdarog˘lu, B. Konus¸kan, G. Halilog˘lu, M. Alikas¸ifog˘lu, H. Topalog˘lu Hacettepe Univiersity, 06100 Turkey Riboflavin is the precursor for coenzymes in carbohydrate, lipid and aminoacid metabolism. Riboflavin transporter deficiency syndrome (BrownVialetto-Van Laere syndrome) is caused by mutations in riboflavin transporter genes SLC52A2, SLC52A3, and rarely by SLC52A1. Inheritance is autosomal recessive. Riboflavin transporter deficiencies result in muscle weakness, feeding and respiratory difficulties, and hearing loss. High dose riboflavin therapy may be beneficial. Here we present 4 new patients with variable presentations. Weakness was prominent and cognition was near normal in all. Patient 1 presented at birth with feeding/respiratory difficulties. Patients 2–4 presented with neuropathy ± hearing loss ± respiratory difficulties ± distal and thenar atrophy. Muscle biopsy revealed non-specific features (patients 1&4), and denervation (patient 3). Electromyography showed varying results: myogenic (patient 2), chronic anterior horn/root involvement (patient 3). Genetic analyses revealed homozygous (patients1&2) and compound heterozygous (patients 3&4) mutations in SLC52A2. A diagnostic clue was the response to riboflavin therapy, all had some benefits especially in motor areas. Tracheotomy was no longer required after 6 weeks of riboflavin initiation for

patient 4. Deafness did not seem to improve. The disease has two basic clinical phenotypes. Firstly, with early-onset respiratory and feeding difficulties (patient 1), and secondly with progressive sensorineural hearing loss and motor neuron disease in the form of axonal involvement (patients 2–4). In conclusion, early onset unexplained respiratory/feeding difficulties or hearing loss with sensorimotor axonal neuropathy point to the diagnosis of riboflavin transporter deficiencies. Oral high dose riboflavin therapy should be initiated, although all symptoms may not fully recover. http://dx.doi.org/10.1016/j.nmd.2017.06.406

P.367 A case of childhood onset of treatable sensory neuronopathy caused by mutations in riboflavin transporter RFVT2 presenting as pure sensory ataxia with excellent response to riboflavin – a five year follow up P. Karachunski, J. Dalton, H. Molero-Ramirez, M. Grames University of Minnesota, Minneapolis, USA Childhood onset neuronopathies are a clinically heterogeneous group of disorders. Its original description is known as Brown-Vialetto-Van Laere syndrome and characterized by motor neuronopathy with early onset of bulbar palsy, hearing loss and respiratory failure. Sensorimotor neuronopathy was described later. No treatment was available for this neurodegenerative disorder until recent discovery of riboflavin transporters RFVT3 and RFVT2. We report a case of early childhood onset of RFVT2 related disorder due to compound heterozygous mutation p.S52F and p.L339P in the SLC52A2 gene presenting as a pure sensory ataxia associated with sensorineural hearing loss, respiratory dysfunction, optic atrophy and retinitis pigmentosa. The patient is a 2-year-old girl at the onset of her condition. Initial presentation consisted of isolated sensory ataxia. Lack of clinically evident muscle weakness and electrodiagnostic studies ruled out motor neuronopathy. 3T high resolution MRI of the brain showed abnormal T2 signal in the reticulospinal tracts. There was biochemical evidence for abnormal acylcarnitine profile. A year later patient developed hearing loss, optic nerve atrophy and retinitis pigmentosa. Polysomnogram revealed central apnea with reduced O2 concentration. We followed prospectively clinical, neurophysiological and biochemical parameters starting at baseline and after initiation of therapy with high doses of riboflavin. We report overt response to high-dose of oral riboflavin therapy in our patient. The clinical and biochemical responses in our patient consistent with reports in the literature that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated early in the course and can be lifesaving. In addition, this case further broadened knowledge of this rare disorder including never reported before findings of abnormal MRI, retinitis pigmentosa and detailed characterization of respiratory dysfunction. http://dx.doi.org/10.1016/j.nmd.2017.06.407

P.368 Biallelic mutation in FDXIL leads to a complex phenotype: optic atrophy, reversible leukoencephalopathy, metabolic myopathy and axonal polyneuropathy J. Gurgel-Giannetti 1, D. Lynch 2, A. Paiva 3, G. Yamamoto 3, L. Lucato 3, S. Amorim 3, F. Freua 3, A. Giannetti 1, B. Ripa 3, F. Monti 3, M. Ribeiro 3, M. Van der Knaap 4, A. Oldfors 5, M. Vainzof 3, H. Holden 2, F. Kok 3 1 Federal University of Minas Gerais, Belo Horizonte, Brazil; 2 UCL Institute of Neurology, London, UK; 3 University of São Paulo, São Paulo, Brazil; 4 Medical Center VU University, Amsterdam, Netherlands; 5 Sahlgrenska University, Gothenburg, Sweden FDX1L encodes Fdx2, one of two 2Fe-2S ferredoxins involved in Fe-S cluster biogenesis. It is ubiquitously expressed but, up to now, the only reported phenotype associated with biallellic mutation of this gene was isolated