Congenital muscular dystrophies with cognitive impairment

Bruno, Cristina; Moroni, Isabella; Pegoraro, Elena; D'Amico, A.; Biancheri, Roberta; Berardinelli, Angela; Boffi, P.; Cassandrini, Denise; Farina, L; Minetti, Carlo; Moggio, Maurizio; Mongini, Tiziana; Mottarelli, E.; Pane, Marika; Pantaleoni, Chiara; Pichiecchio, Anna; Pini, Antonella; Ricci, Enzo; Saredi, Simona; Sframeli, Maria; Tortorella, Gaetano; Toscano, Antonio; Trevisan, CP; Uggetti, Carla; Vasco, Gessica; Comi, Giacomo P.; Santorelli, Filippo M.; Bertini, Enrico

doi:10.1212/wnl.0b013e3181f11dd5

Cited by 29 publications

(15 citation statements)

References 13 publications

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“…CMDs are frequently associated to intellective delay (ID) and structural brain involvement and Messina et al [14] report a figure of 92 out of 160 CMDs patients with cognitive impairment: patients affected by alpha-dystroglycan deficiency were the majority (73/92, 79 %), mostly harboring mutations in POMGnT1 gene (42/73, 57.5 %).…”

Section: Introductionmentioning

confidence: 99%

Congenital muscular dystrophy: from muscle to brain

et al. 2016

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Congenital muscular dystrophies (CMDs) are a wide group of muscular disorders that manifest with very early onset of muscular weakness, sometime associated to severe brain involvement.The histologic pattern of muscle anomalies is typical of dystrophic lesions but quite variable depending on the different stages and on the severity of the disorder.Recent classification of CMDs have been reported most of which based on the combination of clinical, biochemical, molecular and genetic findings, but genotype/phenotype correlation are in constant progression due to more diffuse utilization of the molecular analysis.In this article, the Authors report on CMDs belonging to the group of dystroglycanopathies and in particular on the most severe forms represented by the Fukuyama CMD, Muscle-Eye-Brain disease and Walker Walburg syndrome.Clinical diagnosis of infantile hypotonia is particularly difficult considering the different etiologic factors causing the lesions, the difficulty in localizing the involved CNS area (central vs. peripheral) and the limited role of the diagnostic procedures at this early age.The diagnostic evaluation is not easy mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians. Suggestions are reported on the way to reach a correct diagnosis with the appropriate use of the diagnostic means.

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Section: Introductionmentioning

confidence: 99%

Congenital muscular dystrophy: from muscle to brain

et al. 2016

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“…The phenotypic spectrum arising from mutations in these dystroglycanopathy genes is extremely wide and includes (i) forms of congenital onset weakness and severe structural brain abnormalities, including Walker–Warburg syndrome (OMIM 236670; Walker, 1942; Warburg, 1971), muscle–eye–brain disease (OMIM 253280; Raitta et al , 1978) and Fukuyama congenital muscular dystrophy (OMIM 253800; Fukuyama, 1960); (ii) forms with congenital onset of weakness ranging from absent to severe brain involvement, including congenital muscular dystrophy type 1C (MDC1C; OMIM 606612) (Brockington et al , 2001a) and type 1D (MDC1D; OMIM 608840) (Longman et al , 2003); and (iii) forms with later-onset limb-girdle weakness associated with mental retardation and microcephaly but without structural brain defects as seen in LGMD type 2K (LGMD2K; OMIM 609308) (Dincer et al , 2003), and the mildest variants with no brain involvement, such as in LGMD type 2I (LGMD2I; OMIM 607155) (Brockington et al , 2001b). Mutations in these genes mentioned above are responsible for 50–60% of the cases classified as dystroglycanopathy (Godfrey et al , 2007; Mercuri et al , 2009; Messina et al , 2010; Devisme et al , 2012). Using traditional positional cloning, the causative genes for the unsolved dystroglycanopathy cases had escaped discovery.…”

Section: Introductionmentioning

confidence: 99%

ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies

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Foley

Herrmann

et al. 2013

Brain

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Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker–Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker–Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker–Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.

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“…In addition to the skeletal muscle defects, the brains of MDC1A patients exhibit white matter abnormalities that appear in many patients after 2 years of age. Epilepsy and focal cortical dysplasia leading to cognitive deterioration have also been seen in patients affected with MDC1A [7], [8], [9]. Patients with LAMA2 mutations exhibit feeding problems and/or respiratory difficulties and often require feeding tube placement or ventilator assistance in severe cases [10].…”

Section: Introductionmentioning

confidence: 99%

A Splice Site Mutation in Laminin-α2 Results in a Severe Muscular Dystrophy and Growth Abnormalities in Zebrafish

et al. 2012

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Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-α2 gene (LAMA2). Laminin-α2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2cl501/cl501, exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8–15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-α2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-α2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD.

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Congenital muscular dystrophies with cognitive impairment

Cited by 29 publications

References 13 publications

Congenital muscular dystrophy: from muscle to brain

Congenital muscular dystrophy: from muscle to brain

ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies

A Splice Site Mutation in Laminin-α2 Results in a Severe Muscular Dystrophy and Growth Abnormalities in Zebrafish

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