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G.P.315
916
Abstracts / Neuromuscular Disorders 24 (2014) 791–924
1 The MRC Centre for Neuromuscular Diseases, Newcastle, UK; 2 The Dubowitz Neuromuscular Centre, London, UK; 3 Centre for Mitochondrial Research, Newcastle Upon Tyne, UK; 4 Department of Neurology, Newcastle upon Tyne, UK
We describe two brothers who presented with different phenotypes and progression, sharing compound heterozygous mutations in the GMPPB gene. The index case, 34 years old, was referred to the muscle clinic for increased CK (>2.000), proximal weakness and calf hypertrophy. He is on therapy for myoclonic epilepsy following encephalitis in infancy and has mild cognitive and motor delay. Because of his symptoms, a muscle biopsy was performed: the immune-histochemistry showed a reduction in alpha dystroglycan labelling, with a secondary reduction of laminin alpha2 chain on western blot. Genes known to be associated to alpha-dystroglycanopathy have been excluded by direct sequencing (FKRP,POMT1, POMT2, POMGnT1,LARGE, FKTN). Two heterozygous variants in the GMPPB gene, a previously described mutation[c.860G>A (p.Arg287Gln)] and a novel variant [c.656T>C (p.Ile219Thr)]. The older brother, 36 years old, shares the same mutations having been shown to also have increased CK (2.832). He has global developmental delay presenting with speech and language difficulties, motor delay, impaired fine motor coordination and autistic spectrum disorder. He is not affected by weakness or fatigue, nor has weakness at physical examination. GMPPB catalyses the formation of GDP-mannose, required for O-mannosylation of alpha-dystroglycan. Mutations in this gene have been recently described in association to a spectrum of muscular dystrophy variants (Carss et al. AJHG, 2013), ranging from congenital to limb girdle muscular dystrophy, with additional symptoms as intellectual disability, epilepsy or brain structural anomalies. The family we describe highlights the clinical variability of these patients, with different presentation despite sharing the same mutations. Furthermore, it underlines the importance of testing CK in children presenting with global developmental delay: if the younger brother had not presented with a LGMD phenotype, the diagnosis in the older brother would have continued to be missed. http://dx.doi:10.1016/j.nmd.2014.06.403
G.P.314 Alpha-dystroglycanopathy: Two new patients with GMPPB mutations and a mild limb-girdle phenotype M. Sframeli 1, A. Sarkozy 1, C. Longman 2, L. Feng 1, S. Robb 1, A.Y. Manzur 1, R. Mein 3, M. Yau 3, R. Barresi 4, R. Phadke 1, C. Sewry 1, F. Muntoni 1 1 University College London, Institute of Child Health, London, UK; 2 West of Scotland Regional Genetics Service, Glasgow, UK; 3 Guy’s Hospital, London, UK; 4 NCST Diagnostic & Advisory Service for Rare Neuromuscular Diseases, Newcastle upon Tyne, UK Recessive mutations in the guanosine diphosphate mannose pyrophosphorylase B (GMPPB) gene have recently been reported to cause muscular dystrophies with hypoglycosylation of alpha-dystroglycan. Associated phenotypes range from severe congenital muscular dystrophies with structural brain involvement to limb girdle muscular dystrophy (LGMD). Here we describe two new patients with mild LGMD phenotype and GMPPB gene mutations. The first patient, a girl, was referred to our attention with a clinical history of acute-onset weakness at 10 years of age and increased CK level (4807 UI). A diagnosis of polymyositis was first suggested in view of changes on muscle biopsy suggestive of myositis, but steroid and immunosuppressive treatment showed no benefits and symptoms gradually worsened. Clinical examination at the age of 16 years showed waddling gait with prevalent proximal lower limb muscle wasting and
weakness. She had cataract diagnosed at the age of 11 years. There was no cardiac and respiratory involvement, nor learning difficulties. Review of the muscle biopsy demonstrated decreased alpha-dystroglycan immunostaining and GMPPB gene sequencing identified two pathogenic changes (c.559C>T and c.578T>C). The second patient is a 43 years old woman, referred to our NSCT service for genetic testing. She was born with congenital hip dislocation and she was delayed in walking. Onset was in the third decade with predominant proximal weakness, scapular winging, mild axial and facial weakness. CK level was increased up to 2668 UI. Muscle biopsy immunoanalysis showed reduction in alpha-dystroglycan labelling and secondary reduction of Laminina2 chain labelling on western blot. GMPPB gene analysis showed compound heterozygosity for two mutations (c.79G>C and c.907C>T). In summary these two patients with GMPPB gene mutations further expand the clinical spectrum associated with this type of secondary dystroglycanopathy, in particular with regard to age at onset and prevalent skeletal involvement. http://dx.doi:10.1016/j.nmd.2014.06.404
G.P.315 Cases of normal to mildly elevated creatine kinase in muscle-eye-brain disease patients and delay in diagnosis S. Joseph 1, C. Longman 2, F. Muntoni 3, I. Horrocks 1 1 The Royal Hospital for Sick Children, Yorkhill., Glasgow, UK; 2 Southern General Hospital, Glasgow, UK; 3 Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, UK The dystroglycanopathies are a genetically heterogeneous group of autosomal recessive muscular dystrophies that have in common abnormal glycosylation of alpha-dystroglycan. The spectrum of clinical features is wide and includes muscle-eye-brain disease (MEB), which typically encompass congenital muscular dystrophy, cobblestone lissencephaly and eye abnormalities. Serum creatine kinase (CK) is often elevated greater than fivefold. We describe three cases of MEB in whom the combination of low or normal serum CK and predominant upper motor neurone features led to delayed diagnosis. Case 1: 4-year-old boy presented antenatally with ventriculomegaly. MRI revealed cobblestone lissencephaly and cerebellar polymicrogyria. He was myopic. CK was 173 IU/L at 4 days. He appeared to have an evolving CP with central hypotonia, limb spasticity. His CK was 563 IU/L and compound heterozygous mutations in POMGnT1, c.511C>T and c.1895+1G>T was found at 2 years. Case 2: 4-year-old girl presented at 5 days with hypotonia. CK was 228 IU/L at 2 weeks and 248 IU/L by 3 months. MRI showed lissencephaly and widespread polymicrogyria with cerebellar cysts. She was myopic. She is bottom shuffling with preserved strength but evolving CP-like picture. At 2 years compound heterozygous mutations in POMGnT1, c.385C>T and c.1460delG were found. Case 3: 14 year-old male presented at 3 months with myopia. MRI was consistent with a neuronal migration defect. CK was 386 IU/ L at 11 months. Presentation was that of an evolving motor disorder. He was diagnosed age 8 with a compound heterozygous mutations in LARGE. These cases highlight that patients with dystroglycanopathies with POMGnT1 and LARGE mutations can have normal or only mildly elevated CK levels, even beyond the first 6 months. The presentation suggests CP with preservation of muscle strength. It is important to suspect dystroglycanopathies with typical MRI changes and eye involvement, even in the light of normal CK without weakness. http://dx.doi:10.1016/j.nmd.2014.06.405
Abstracts / Neuromuscular Disorders 24 (2014) 791–924
1 The MRC Centre for Neuromuscular Diseases, Newcastle, UK; 2 The Dubowitz Neuromuscular Centre, London, UK; 3 Centre for Mitochondrial Research, Newcastle Upon Tyne, UK; 4 Department of Neurology, Newcastle upon Tyne, UK
We describe two brothers who presented with different phenotypes and progression, sharing compound heterozygous mutations in the GMPPB gene. The index case, 34 years old, was referred to the muscle clinic for increased CK (>2.000), proximal weakness and calf hypertrophy. He is on therapy for myoclonic epilepsy following encephalitis in infancy and has mild cognitive and motor delay. Because of his symptoms, a muscle biopsy was performed: the immune-histochemistry showed a reduction in alpha dystroglycan labelling, with a secondary reduction of laminin alpha2 chain on western blot. Genes known to be associated to alpha-dystroglycanopathy have been excluded by direct sequencing (FKRP,POMT1, POMT2, POMGnT1,LARGE, FKTN). Two heterozygous variants in the GMPPB gene, a previously described mutation[c.860G>A (p.Arg287Gln)] and a novel variant [c.656T>C (p.Ile219Thr)]. The older brother, 36 years old, shares the same mutations having been shown to also have increased CK (2.832). He has global developmental delay presenting with speech and language difficulties, motor delay, impaired fine motor coordination and autistic spectrum disorder. He is not affected by weakness or fatigue, nor has weakness at physical examination. GMPPB catalyses the formation of GDP-mannose, required for O-mannosylation of alpha-dystroglycan. Mutations in this gene have been recently described in association to a spectrum of muscular dystrophy variants (Carss et al. AJHG, 2013), ranging from congenital to limb girdle muscular dystrophy, with additional symptoms as intellectual disability, epilepsy or brain structural anomalies. The family we describe highlights the clinical variability of these patients, with different presentation despite sharing the same mutations. Furthermore, it underlines the importance of testing CK in children presenting with global developmental delay: if the younger brother had not presented with a LGMD phenotype, the diagnosis in the older brother would have continued to be missed. http://dx.doi:10.1016/j.nmd.2014.06.403
G.P.314 Alpha-dystroglycanopathy: Two new patients with GMPPB mutations and a mild limb-girdle phenotype M. Sframeli 1, A. Sarkozy 1, C. Longman 2, L. Feng 1, S. Robb 1, A.Y. Manzur 1, R. Mein 3, M. Yau 3, R. Barresi 4, R. Phadke 1, C. Sewry 1, F. Muntoni 1 1 University College London, Institute of Child Health, London, UK; 2 West of Scotland Regional Genetics Service, Glasgow, UK; 3 Guy’s Hospital, London, UK; 4 NCST Diagnostic & Advisory Service for Rare Neuromuscular Diseases, Newcastle upon Tyne, UK Recessive mutations in the guanosine diphosphate mannose pyrophosphorylase B (GMPPB) gene have recently been reported to cause muscular dystrophies with hypoglycosylation of alpha-dystroglycan. Associated phenotypes range from severe congenital muscular dystrophies with structural brain involvement to limb girdle muscular dystrophy (LGMD). Here we describe two new patients with mild LGMD phenotype and GMPPB gene mutations. The first patient, a girl, was referred to our attention with a clinical history of acute-onset weakness at 10 years of age and increased CK level (4807 UI). A diagnosis of polymyositis was first suggested in view of changes on muscle biopsy suggestive of myositis, but steroid and immunosuppressive treatment showed no benefits and symptoms gradually worsened. Clinical examination at the age of 16 years showed waddling gait with prevalent proximal lower limb muscle wasting and
weakness. She had cataract diagnosed at the age of 11 years. There was no cardiac and respiratory involvement, nor learning difficulties. Review of the muscle biopsy demonstrated decreased alpha-dystroglycan immunostaining and GMPPB gene sequencing identified two pathogenic changes (c.559C>T and c.578T>C). The second patient is a 43 years old woman, referred to our NSCT service for genetic testing. She was born with congenital hip dislocation and she was delayed in walking. Onset was in the third decade with predominant proximal weakness, scapular winging, mild axial and facial weakness. CK level was increased up to 2668 UI. Muscle biopsy immunoanalysis showed reduction in alpha-dystroglycan labelling and secondary reduction of Laminina2 chain labelling on western blot. GMPPB gene analysis showed compound heterozygosity for two mutations (c.79G>C and c.907C>T). In summary these two patients with GMPPB gene mutations further expand the clinical spectrum associated with this type of secondary dystroglycanopathy, in particular with regard to age at onset and prevalent skeletal involvement. http://dx.doi:10.1016/j.nmd.2014.06.404
G.P.315 Cases of normal to mildly elevated creatine kinase in muscle-eye-brain disease patients and delay in diagnosis S. Joseph 1, C. Longman 2, F. Muntoni 3, I. Horrocks 1 1 The Royal Hospital for Sick Children, Yorkhill., Glasgow, UK; 2 Southern General Hospital, Glasgow, UK; 3 Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, UK The dystroglycanopathies are a genetically heterogeneous group of autosomal recessive muscular dystrophies that have in common abnormal glycosylation of alpha-dystroglycan. The spectrum of clinical features is wide and includes muscle-eye-brain disease (MEB), which typically encompass congenital muscular dystrophy, cobblestone lissencephaly and eye abnormalities. Serum creatine kinase (CK) is often elevated greater than fivefold. We describe three cases of MEB in whom the combination of low or normal serum CK and predominant upper motor neurone features led to delayed diagnosis. Case 1: 4-year-old boy presented antenatally with ventriculomegaly. MRI revealed cobblestone lissencephaly and cerebellar polymicrogyria. He was myopic. CK was 173 IU/L at 4 days. He appeared to have an evolving CP with central hypotonia, limb spasticity. His CK was 563 IU/L and compound heterozygous mutations in POMGnT1, c.511C>T and c.1895+1G>T was found at 2 years. Case 2: 4-year-old girl presented at 5 days with hypotonia. CK was 228 IU/L at 2 weeks and 248 IU/L by 3 months. MRI showed lissencephaly and widespread polymicrogyria with cerebellar cysts. She was myopic. She is bottom shuffling with preserved strength but evolving CP-like picture. At 2 years compound heterozygous mutations in POMGnT1, c.385C>T and c.1460delG were found. Case 3: 14 year-old male presented at 3 months with myopia. MRI was consistent with a neuronal migration defect. CK was 386 IU/ L at 11 months. Presentation was that of an evolving motor disorder. He was diagnosed age 8 with a compound heterozygous mutations in LARGE. These cases highlight that patients with dystroglycanopathies with POMGnT1 and LARGE mutations can have normal or only mildly elevated CK levels, even beyond the first 6 months. The presentation suggests CP with preservation of muscle strength. It is important to suspect dystroglycanopathies with typical MRI changes and eye involvement, even in the light of normal CK without weakness. http://dx.doi:10.1016/j.nmd.2014.06.405