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G.P.311
Abstracts / Neuromuscular Disorders 24 (2014) 791–924 G.P.310 The cognitive profile of ALS: update of a meta-analysis E. Beeldman 1, J. Raaphorst 2, R.J. De Haan 1, M. De Visser 1, B.A. Schmand 1 1 Academic Medical Centre Amsterdam, Amsterdam, Netherlands; 2 Academic Medical Centre Amsterdam and Radboud University Medical Center Nijmegen, Amsterdam, Netherlands There is a clinical, genetic and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In 2008, our meta-analysis on the cognitive profile of ALS showed that fluency deficits, executive dysfunction and impairment of language and memory can be present in non-demented ALS patients. To further elucidate the cognitive profile of ALS we aimed to update the meta-analysis. We searched Embase, Medline and PsycInfo. Articles were selected if healthy volunteers and non-demented ALS patients, fulfilling El Escorial criteria, underwent at least one validated cognitive test. All tests were categorized in cognitive domains and effect sizes were calculated per domain. Demographic and clinical data were also extracted. We included 29 new articles, resulting in a total of 45 articles (n = 1292 patients and 1144 controls). The median number of neuropsychological (sub) tests administered to patients and controls was 8 (1–34). Patients (63% men, 33% bulbar onset) had a mean age of 59.1 years, a mean educational level of 11.8 years and a mean disease duration of 24 months. Most patients had mild to moderate disability (mean ALSFRS-R 33.1). The domains with the largest, significant effect sizes (Hedges’ g > 0.50) were visuoconstructive functions (0.63), global cognition (0.59), fluency (0.58), language (0.56), social cognition (0.55) and delayed verbal memory (0.52). Executive function had a significant effect size of 0.44. The update of the meta-analysis revealed a new cognitive domain with a large effect size, i.e. social cognition, which encompasses insight into social situations and recognition of emotional states of others. This highlights the clinical overlap between ALS and FTD. The update further reinforces that the cognitive profile extends beyond executive dysfunction and includes language and memory impairment and deficits in social cognition. In the visuoconstructive domain bias due to motor impairment could not be ruled out. http://dx.doi:10.1016/j.nmd.2014.06.400
CMD ALPHA-DYSTROGLYCAN G.P.311 A new homozygous ISPD mutation is associated with either early limb-girdle or congenital muscular dystrophy within the same family depending on different levels of alpha-dystroglycan glycosylation G. Baranello 1, L. Morandi 1, S. Sansanelli 1, P. Savadori 1, S. Saredi 1, C. Pantaleoni 1, P. Balestri 2, A. Malandrini 2, M.T. Arnoldi 1, L. Chiapparini 1, M. Mora 1 1 Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy; 2 Universita` degli studi di Siena, Siena, Italy Dystroglycanopathies represent an important subgroup of recessively inherited disorders within the group of muscular dystrophies. Their severity may vary from the mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies with cerebral and ocular involvement. Although mutations in at least 17 genes have been identified so far, about 50% of the cases with dystroglycanopathy still remain unsolved. Recently, mutations in the isoprenoid synthase domain containing (ISPD) gene have been reported as a common cause of congenital muscular dystrophy and LGMD. We report clinical, histopathological, immunochemical, genetic and muscular MRI findings in 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation (Gly123Arg) in
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the ISPD gene. Case 1 is a 8 year-old female with an early limb-girdle phenotype, who lost ambulation at the age of 7.5 years. Case 2 is a 2.5 year-old male and second degree cousin of case 1, showing a congenital muscular dystrophy phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both the patients. Western blot showed greater reduction of alpha-dystroglycan glycosylation in patient 2, and may be responsible for the greater severity of his clinical presentation. To our knowledge, this is the first report on the co-occurrence of both early limb-girdle and congenital muscular dystrophies within the same family carrying a new homozygous ISPD mutation. http://dx.doi:10.1016/j.nmd.2014.06.401
G.P.312 Intrafamilial variability in GMPPB associated alpha-dystroglycanopathy and broadening of the clinical phenotype D.X. Bharucha-Goebel 1, E. Neil 2, S. Donkervoort 3, S. Moore 4, T. Winder 5, J. Dastgir 3, S. Iannaccone 6, C.G. Bo¨nnemann 3 1 National Institutes of Health and Children’s National Medical Center, Bethesda, USA; 2 UT Southwestern Medical Center, Dallas, USA; 3 National Institutes of Health, Bethesda, USA; 4 University of Genetics, Marshfield, Iowa, Iowa City, USA; 5 Prevention USA; 6 Southwestern Medical Center, Dallas, USA Alpha-dystroglycanopathies (aDGs) represent a heterogeneous group of muscular dystrophies. There are currently 18 known genes leading to forms of alphaDG, with mutations of GDP-mannose pyrophosphorylase B (GMPPB) being one of the most recently described in one case series. The spectrum of reported GMPPB patients spans from severe neonatal to a mild later onset limb-girdle muscular dystrophy (LGMD) phenotype with or without intellectual disability. GMPPB is important for synthesis of GDP-mannose, a mannosyl donor in 4 glycosylation pathways. We present a 3 affected siblings with compound heterozygous mutations (previously described p.Asp27His and novel p.Gln264TER) in GMPPB presenting as LGMD with variable degrees of muscle weakness but a broader spectrum of early intellectual impairment, epilepsy (1 of 3 patients), and ocular findings. Onset and degree of weakness was variable. Patient P1 has severe intellectual disability, cataracts, glaucoma, and a history of intractable epilepsy, but minimal weakness; while patient P2 has severe weakness with near full time wheelchair use since 16 years old. CK level was elevated in all patients (3015–18,685). Muscle biopsy in P2 revealed dystrophic changes with reduced aDG staining. Brain MRI showed mild posterior cortical thinning in P1. Neuropsychological testing revealed variable intellectual disability in all three patients. Muscle imaging revealed variable changes consistent with areas of fatty infiltration. These siblings further contribute to and expand the spectrum of patients with mutations of GMPPB highlighting that motor and cognitive phenotypes associated with GGMPPB related aDGpathy may not directly correlate. Cognitive deficits and epilepsy can precede recognition of muscle symptoms, thus delaying more targeted testing. Simple CK testing may identify a larger cohort of patients with aDGpathy presenting with minimal motor but more severe cognitive or seizure phenotype whose muscle disease had remained undetected. http://dx.doi:10.1016/j.nmd.2014.06.402
G.P.313 Intrafamilial heterogeneity in an alpha-dystroglycanopathy due to GDPMannose Pyrophosphorylase B (GMPPB) mutations M. Bertoli 1, T. Evangelista 1, A. Sarkozy 2, A. Schaefer 3, P. Goldsmith 4, R. Barresi 1, V. Straub 1, F. Muntoni 2, K. Bushby 1, H. Lochmuller 1
CMD ALPHA-DYSTROGLYCAN G.P.311 A new homozygous ISPD mutation is associated with either early limb-girdle or congenital muscular dystrophy within the same family depending on different levels of alpha-dystroglycan glycosylation G. Baranello 1, L. Morandi 1, S. Sansanelli 1, P. Savadori 1, S. Saredi 1, C. Pantaleoni 1, P. Balestri 2, A. Malandrini 2, M.T. Arnoldi 1, L. Chiapparini 1, M. Mora 1 1 Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy; 2 Universita` degli studi di Siena, Siena, Italy Dystroglycanopathies represent an important subgroup of recessively inherited disorders within the group of muscular dystrophies. Their severity may vary from the mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies with cerebral and ocular involvement. Although mutations in at least 17 genes have been identified so far, about 50% of the cases with dystroglycanopathy still remain unsolved. Recently, mutations in the isoprenoid synthase domain containing (ISPD) gene have been reported as a common cause of congenital muscular dystrophy and LGMD. We report clinical, histopathological, immunochemical, genetic and muscular MRI findings in 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation (Gly123Arg) in
915
the ISPD gene. Case 1 is a 8 year-old female with an early limb-girdle phenotype, who lost ambulation at the age of 7.5 years. Case 2 is a 2.5 year-old male and second degree cousin of case 1, showing a congenital muscular dystrophy phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both the patients. Western blot showed greater reduction of alpha-dystroglycan glycosylation in patient 2, and may be responsible for the greater severity of his clinical presentation. To our knowledge, this is the first report on the co-occurrence of both early limb-girdle and congenital muscular dystrophies within the same family carrying a new homozygous ISPD mutation. http://dx.doi:10.1016/j.nmd.2014.06.401
G.P.312 Intrafamilial variability in GMPPB associated alpha-dystroglycanopathy and broadening of the clinical phenotype D.X. Bharucha-Goebel 1, E. Neil 2, S. Donkervoort 3, S. Moore 4, T. Winder 5, J. Dastgir 3, S. Iannaccone 6, C.G. Bo¨nnemann 3 1 National Institutes of Health and Children’s National Medical Center, Bethesda, USA; 2 UT Southwestern Medical Center, Dallas, USA; 3 National Institutes of Health, Bethesda, USA; 4 University of Genetics, Marshfield, Iowa, Iowa City, USA; 5 Prevention USA; 6 Southwestern Medical Center, Dallas, USA Alpha-dystroglycanopathies (aDGs) represent a heterogeneous group of muscular dystrophies. There are currently 18 known genes leading to forms of alphaDG, with mutations of GDP-mannose pyrophosphorylase B (GMPPB) being one of the most recently described in one case series. The spectrum of reported GMPPB patients spans from severe neonatal to a mild later onset limb-girdle muscular dystrophy (LGMD) phenotype with or without intellectual disability. GMPPB is important for synthesis of GDP-mannose, a mannosyl donor in 4 glycosylation pathways. We present a 3 affected siblings with compound heterozygous mutations (previously described p.Asp27His and novel p.Gln264TER) in GMPPB presenting as LGMD with variable degrees of muscle weakness but a broader spectrum of early intellectual impairment, epilepsy (1 of 3 patients), and ocular findings. Onset and degree of weakness was variable. Patient P1 has severe intellectual disability, cataracts, glaucoma, and a history of intractable epilepsy, but minimal weakness; while patient P2 has severe weakness with near full time wheelchair use since 16 years old. CK level was elevated in all patients (3015–18,685). Muscle biopsy in P2 revealed dystrophic changes with reduced aDG staining. Brain MRI showed mild posterior cortical thinning in P1. Neuropsychological testing revealed variable intellectual disability in all three patients. Muscle imaging revealed variable changes consistent with areas of fatty infiltration. These siblings further contribute to and expand the spectrum of patients with mutations of GMPPB highlighting that motor and cognitive phenotypes associated with GGMPPB related aDGpathy may not directly correlate. Cognitive deficits and epilepsy can precede recognition of muscle symptoms, thus delaying more targeted testing. Simple CK testing may identify a larger cohort of patients with aDGpathy presenting with minimal motor but more severe cognitive or seizure phenotype whose muscle disease had remained undetected. http://dx.doi:10.1016/j.nmd.2014.06.402
G.P.313 Intrafamilial heterogeneity in an alpha-dystroglycanopathy due to GDPMannose Pyrophosphorylase B (GMPPB) mutations M. Bertoli 1, T. Evangelista 1, A. Sarkozy 2, A. Schaefer 3, P. Goldsmith 4, R. Barresi 1, V. Straub 1, F. Muntoni 2, K. Bushby 1, H. Lochmuller 1