Ocular findings in muscle-eye-brain (MEB) disease: a follow-up study

doi:10.1016/0387-7604(94)00101-3

Brain and Development

Volume 17, Issue 1, January–February 1995, Pages 57-61

https://doi.org/10.1016/0387-7604(94)00101-3 Get rights and content

Abstract

We present ocular findings of 20 patients with the recessively inherited muscle-eye-brain (MEB) disease, characterised by severe visual failure, mental retardation, a pachygyria-polymicrogyria type neuronal migration disorder and congenital muscular dystrophy. The ocular findings consisted of myopia ranging from −6 to −27 D, retinal degeneration and optic atrophy. Five infants had congenital glaucoma, and juvenile cataracts developed in 9 children. The visual evoked potentials were abnormally high (> 50 μV) and delayed in 70% of patients. The electroretinogram was abolished in 12 patients. The changes were progressive during the follow-up time, which was up to 20 years.

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α-Dystroglycanopathies are a clinically and genetically heterogeneous group of muscular dystrophies associated with the defective glycosylation of α-dystroglycan (α-DG). Eighteen genes associated with α-dystroglycanopathies have been identified, and the relative prevalence of genetic subtypes varies with ethnicity. Here, we investigated the clinical and genetic characteristics of α-DG-related muscular dystrophy in the Korean pediatric population. We analyzed the clinical characteristics and variant profiles of 42 patients with α-DG-related muscular dystrophies diagnosed by either reduced glycosylation of α-DG and/or genetic confirmation. Genotype-phenotype correlations were explored by a retrospective medical record review. The muscle-eye-brain disease/Fukuyama congenital muscular dystrophy was the most common phenotype (28/42, 66.7%). Homozygous or compound heterozygous variants were detected in 37 patients belonging to 34 unrelated families (37/42; 88.1%). Pathogenic variants were identified in FKTN (n = 24), POMGNT1 (n = 4), GMPPB (n = 4), FKRP (n = 2), POMT1 (n = 2), and ISPD (n = 1). Compound heterozygous retrotransposal insertions and deep-intronic variants in FKTN were the most common genotypes and were associated with severe phenotypes. This study suggests that α-DG-related muscular dystrophy has a wide range of genotypes and phenotypes according to ethnicity. A stratified genetic test according to ethnicity should be considered to diagnose α-DG-related muscular dystrophy.
Congenital muscular dystrophy-dystroglycanopathy, type A, featuring bilateral retinal dysplasia and vertical angle kappa
2018, Journal of AAPOS
Citation Excerpt :
No ophthalmological findings were previously noted for the c.1895 + 1 G > T variant.1,2 Pihko and colleagues6 found exceptionally high visual evoked potentials of >50 μV with delay in 12 of 18 patients tested. Hoang8 described a 12-day-old MEB patient who presented with an avascular retina and full-thickness holes of the left eye.
Muscular dystrophy-dystroglycanopathy type A (MDDGA3), one of a group of diseases collectively known as congenital muscular dystrophies, is an alpha-dystroglycanopathy with characteristic brain and ocular abnormalities. We report the case of a 9-month-old boy with developmental delay whose family sought evaluation for esotropia. Subsequent examination, imaging, and testing revealed significant motor and cognitive delay, marked weakness with appendicular spasticity, and a diffuse brain malformation. In addition, the patient had poor visual acuity, nystagmus, optic nerve hypoplasia, bilateral retinal dysplasia and retinal dragging with a large vertical angle kappa, and an avascular peripheral retina. Genetic testing revealed two known heterozygous mutations in the POMGnT1 gene confirming MDDGA3. He was treated with botulinum toxin injections for his strabismus and continues to be followed, with planned laser ablation of the peripheral avascular retina.
Hypotonia and Weakness: Level of the Muscle
2018, Volpe's Neurology of the Newborn
Disorders of muscle account for a substantial proportion of infants affected with hypotonia and weakness. Although a relatively large number of myopathic disorders may cause manifestations in the neonatal period, only a few disorders account for most of the cases observed. Myotonic dystrophy is the most frequent. Myopathic disorders with nondiagnostic histology include congenital muscular dystrophy, facioscapulohumeral dystrophy, polymyositis, and minimal change myopathy; those with a diagnostic histology include core myopathies, nemaline myopathy, myotubular myopathy, congenital fiber type disproportion, mitochondrial myopathies, and metabolic myopathies. Several disorders of the neuromuscular apparatus are restricted to a small portion of the motor system; restricted disorders that are not established as caused principally by trauma are considered in this chapter. Detection of any of these disorders is valuable for purposes of genetic counseling, determination of prognosis, and institution of therapy.
Clinical, radiological, and genetic survey of patients with muscle-eye-brain disease caused by mutations in POMGNT1
2014, Pediatric Neurology
Citation Excerpt :
The weakened inner limiting membrane results in the disruption of the membrane and subsequent reduction in retinal integrity.28 Ocular abnormalities of muscle-eye-brain disease include a predisposition to glaucoma, progressive myopia, juvenile cataracts, nystagmus, uncontrollable eye movements, retinal atrophy with reduced retinal function, hypoplasia/dysplasia or atrophy of optic nerve, coloboma, and microphthalmus.29 The most common ophthalmologic abnormality in our study was cataracts followed by retinal detachment and optic nerve hypoplasia.
To evaluate clinical, genetic, and radiologic features of our patients with muscle-eye-brain disease.
The data of patients who were diagnosed with muscle-eye-brain disease from a cohort of patients with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylül University School of Medicine and Gaziantep Children's Hospital between 2005 and 2013 were analyzed retrospectively.
From a cohort of 34 patients with congenital muscular dystrophy, 12 patients from 10 families were diagnosed with muscle-eye-brain disease. The mean age of the patients was 9 ± 5.5 years (2-19 years). Mean serum creatine kinase value was 2485.80 ± 1308.54 IU/L (700-4267 IU/L). All patients presented with muscular hypotonia at birth followed by varying degrees of spasticity and exaggerated deep tendon reflexes in later stages of life. Three patients were able to walk. The most common ophthalmologic and radiologic abnormalities were cataracts, retinal detachment, periventricular white matter abnormalities, ventriculomegaly, pontocerebellar hypoplasia, and multiple cerebellar cysts. All of the patients had mutations in the POMGNT1 gene. The most common mutation detected in 66% of patients was c.1814 G > A (p.R605H). Two novel mutations were identified.
We suggest that muscle-eye-brain disease is a relatively common muscular dystrophy in Turkey. It should be suspected in patients with muscular hypotonia, increased creatine kinase, and structural eye and brain abnormalities. The c.1814 G > A mutation in exon 21 of the POMGNT1 gene is apparently a common mutation in the Turkish population. Individuals with this mutation show classical features of muscle-eye-brain disease, but others may exhibit a milder phenotype and retain the ability to walk independently. Congenital muscular dystrophy patients from Turkey carrying the clinical and radiologic features of muscle-eye-brain disease should be evaluated for mutations in POMGNT1 gene.
Reactive gliosis of astrocytes and Müller glial cells in retina of POMGnT1-deficient mice
2011, Molecular and Cellular Neuroscience
Citation Excerpt :
The alpha-DG in the OPL is localized around the site of expression of ribbon synapses of rod and cone photoreceptor terminals (Ueda et al., 1995; Montanaro et al., 1995). Abnormal electroretinograms (ERGs) have been recorded from patients with MEB disease (Pihko et al., 1995; Fahnehjelm et al., 2001), and have frequently been recorded from individuals with Duchenne and Becker muscular dystrophies (Pillers et al., 1999). The findings in several mouse models with disruption of dystrophin, Largevls and fukutin indicated that DGC is associated with the normal physiology of the retina (Pillers et al., 1995; Kameya et al., 1997; Lee et al., 2005; Takeda et al., 2003).
Protein O-linked mannose beta1, 2-N-acetylglucosaminyltransferase 1 (POMGnT1) is an enzyme that catalyzes the transfer of N-acetylglucosamine to O-mannose of glycoproteins. Alpha-dystroglycan, a substrate of POMGnT1, is concentrated around the blood vessels, in the outer plexiform layer (OPL), and in the inner limiting membrane (ILM) of the retina. Mutations of the POMGnT1 gene in humans cause muscle-eye-brain (MEB) disease. Several ocular abnormalities including retinal dysplasia, ERG abnormalities, and retinal detachments have been reported in patients with MEB. We have analyzed the eyes of POMGnT1-deficient mice, generated by standard gene targeting technique, to study the retinal abnormalities. Clinical examination of adult mutant mice revealed a high incidence (81% by 12-months-of-age) of retinal detachments. Sheathing of the retinal vessels and the presence of ectopic fibrous tissues around the optic nerve head were also found. Histological examinations showed focal retinal detachment associated with GFAP immunopositivity. The ILM of the mutant mice was disrupted with ectopic cells near the disruptions. The expression of Dp71, a shorter isoform of dystrophin, was severely reduced in the ILM and around retinal blood vessels of POMGnT1-deficient mice. The expression of Dp427, Dp260, Dp140 were also reduced in the OPL of the mutant mice. Electroretinographic (ERG) analyses showed reduced a- and b-wave amplitudes. Examinations of flat mounts revealed abnormal vascular network associated with highly irregular astrocytic processes. In addition, ER-TR7-positive fibrous tissue was found closely associated with reactive astrocytes especially around the optic nerve head. Our results suggest that altered glycosylation of alpha-DG may be responsible for the reactive gliosis and reticular fibrosis in the retina, and the subsequent developments of retinal dysplasia, abnormal ERGs, and retinal detachment in the mutant mice.
Congenital muscular dystrophies
2011, Handbook of Clinical Neurology
Congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders characterized by muscle weakness from birth, or shortly after, and variable clinical manifestations of the eye and central nervous system. Some of these disorders are fatal in the first years of life, whereas others have a milder course, with survival into adulthood. The CMDs were initially classified by clinical features and country of origin; however, with new molecular techniques it is now possible to classify these patients better. More than 10 genes have been identified to date that cause forms of CMD. However, even with current molecular diagnostic techniques, only approximately 25–50% of patients with CMD have an identifiable genetic mutation. In addition, some phenotypic classifications have been attempted. There is significant overlap between the phenotypic and molecular classifications, making diagnosis within this heterogeneous group of disorders difficult.

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Ocular findings in muscle-eye-brain (MEB) disease: a follow-up study

Abstract

Brain Dev (Tokyo)

Brain Dev (Tokyo)

Brain Dev (Tokyo)

Brain Dev (Tokyo)

MRI of the brain in the muscle-eye-brain (MEB) disease

Neuroradiology

Cerebro-ocular dysgenesis (Walker-Warburg syndrome): neuropathologic and etiologic analysis

Neurology

Diagnostic criteria for Walker-Warburg syndrome

Am J Med Genet