Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy

Pennock, J. M.; Goodwin, Fiona; Sewry, Caroline A.; Cowan, Frances; Dubowitz, Lilly; Dubowitz, Victor; Muntoni, Francesco

doi:10.1016/s0960-8966(96)00383-5

Cited by 45 publications

(23 citation statements)

References 7 publications

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“…Mutations of the human gene LAMA2, encoding for the 2 subunit of laminin211, are responsible for MDC1A-associated neuropathies (Shorer et al, 1995;Mercuri et al, 1996). Similarly, mutations in molecules associated with the laminin211 pathway, such as periaxin and frabin/FDG4, are responsible for Charcot-Marie-Tooth neuropathies (Sherman et al, 2001;Delague et al, 2007;Stendel et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Jab1 regulates Schwann cell proliferation and axonal sorting through p27

Porrello¹,

Rivellini²,

Dina³

et al. 2013

J Cell Biol

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Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211-and, possibly, neuregulin 1 (Nrg1)-derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain-binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies.

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Section: Discussionmentioning

confidence: 99%

Jab1 regulates Schwann cell proliferation and axonal sorting through p27

Porrello¹,

Rivellini²,

Dina³

et al. 2013

J Cell Biol

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“…Mutations in the laminin a2 gene are the primary cause of human congenital muscular dystrophy (now designated CMD1A) which is characterized by early onset myofiber degeneration with an associated dysmyelinating peripheral neuropathy and brain abnormalities (Mercuri et al, 1996;Minetti et al, 1996;Shorer et al, 1995). Mouse models of the disease encompass a mild hypomorphic allele of the a2 gene (dy ), in which a 2J splice-donor defect in an early exon causes an in-frame deletion within the polymerizing LN domain and modest loss of protein; severe hypomorphic alleles which express little functional laminin a2 (dy, dy ); and a W complete knockout (dy ) (Guo et al, 2003;Miyagoe 3K et al, 1997;Sunada et al, 1995;Xu et al, 1994).…”

Section: Pre-and Postnatal Lamininsmentioning

confidence: 99%

Basement membrane assembly, stability and activities observed through a developmental lens

2004

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“…White matter abnormalities seen on brain imaging have been described, with periventricular and subcortical white matter being two areas particularly susceptible. These abnormalities typically are asymptomatic, although there does appear to be an association with epilepsy, low IQ, and mental abnormalities [10]. The specific cause is largely unknown but may be due to disorders of neuronal organization and arrest in myelination, as merosin is important for stimulating the migration of oligodendrocytes and influencing the development and cell attachment of neuronal cells [2,4,11].…”

Section: Discussionmentioning

confidence: 99%

“…The specific cause is largely unknown but may be due to disorders of neuronal organization and arrest in myelination, as merosin is important for stimulating the migration of oligodendrocytes and influencing the development and cell attachment of neuronal cells [2,4,11]. Another hypothesis suggests that abnormalities in the blood-brain barrier lead to increased water content within the white matter, which is thought to be secondary to laminins being present in the basement membrane of blood vessels [10,12]. In a minority of cases, structural cerebral abnormalities can also be seen.…”

Section: Discussionmentioning

confidence: 99%

Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

Hissong

Salvatore

Tanji

et al. 2016

Human Pathology: Case Reports

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Peripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.

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Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy

Cited by 45 publications

References 7 publications

Jab1 regulates Schwann cell proliferation and axonal sorting through p27

Jab1 regulates Schwann cell proliferation and axonal sorting through p27

Basement membrane assembly, stability and activities observed through a developmental lens

Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

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