ABSTRACT A term female infant was evaluated for global developmental delay, hypotonia, hyporeflexia, diffuse weakness including facial muscles, and visual impairment with optic nerve hypoplasia. In the absence of family history or perinatal concerns, an extensive investigation was performed, including lab studies, muscle biopsy, brain MRI and focused genetic testing. This revealed elevated serum CK, a structurally abnormal brain, and a dystrophic-appearing muscle biopsy with evidence of a glycosylation defect in the alpha-dystroglycan complex. Of the 6 known related genes, testing of the POMGnT1 gene showed three heterozygous missense mutations. Thus her history, examination, biopsy specimen, imaging, laboratory, and genetic studies are all consistent with the diagnosis of Muscle-Eye-Brain (MEB) disease. MEB is one of an emerging spectrum of congenital disorders that involve both central and peripheral nervous systems, described further in this case report.
Full-textDOI: · Available from: Aaron Bossler, Oct 22, 2014
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ABSTRACT: Congenital muscular dystrophies have a broad spectrum of genotypes and phenotypes and there is a need for a better biochemical understanding of this group of diseases in order to aid diagnosis and treatment. Several mutations resulting in these diseases cause reduced O-mannosyl glycosylation of glycoproteins, including α-dystroglycan. The enzyme POMGnT1 (protein-O-mannose N-acetylglucosaminyltransferase 1; EC 2.4.1.-) catalyses the transfer of N-acetylglucosamine to O-linked mannose of α-dystroglycan. In the present paper we describe the biochemical characterization of 14 clinical mutants of the glycosyltransferase POMGnT1, which have been linked to muscle-eye-brain disease or similar conditions. Truncated mutant variants of the human enzyme (recombinant POMGnT1) were expressed in Escherichia coli and screened for catalytic activity. We find that three mutants show some activity towards mannosylated peptide substrates mimicking α-dystroglycan; the residues affected by these mutants are predicted by homology modelling to be on the periphery of the POMGnT1 surface. Only in part does the location of a previously described mutated residue on the periphery of the protein structure correlate with a less severe disease mutant.Biochemical Journal 03/2011; 436(2):447-55. DOI:10.1042/BJ20101059 · 4.78 Impact Factor
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ABSTRACT: Lipid storage diseases, also known as the lipidoses, are a group of inherited metabolic disorders in which there is lipid accumulation in various cell types, including the central nervous system, because of the deficiency of a variety of enzymes. Over time, excessive storage can cause permanent cellular and tissue damage. The brain is particularly sensitive to lipid storage as the contents of the central nervous system must occupy uniform volume, and any increases in fluids or deposits will lead to pressure changes and interference with normal neurological function. In addition to primary lipid storage diseases, lysosomal storage diseases include the mucolipidoses (in which excessive amounts of lipids and carbohydrates are stored in the cells and tissues) and the mucopolysaccharidoses (in which abnormal glycosylated proteins cannot be broken down because of enzyme deficiency). Neurological dysfunction can be a manifestation of these conditions due to substrate deposition as well. This review will explore the modalities of neuroimaging that may have particular relevance to the study of the lipid storage disorder and their impact on elucidating aspects of brain function. First, the techniques will be reviewed. Next, the neuropathology of a few selected lipid storage disorders will be reviewed and the use of neuroimaging to define disease characteristics discussed in further detail. Examples of studies using these techniques will be discussed in the text. © 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013;17:269-282.Developmental Disabilities Research Reviews 06/2013; 17(3):269-282. DOI:10.1002/ddrr.1120 · 0.29 Impact Factor
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ABSTRACT: PURPOSE: To report an association of congenital optic nerve anomalies with peripheral retina nonperfusion and to describe the clinical manifestations and treatment. DESIGN: Retrospective, observational case series. PARTICIPANTS: Fifteen patients with congenital optic nerve anomalies referred for pediatric retina consultation were studied. Sixteen eyes of 9 patients with optic nerve hypoplasia and 8 eyes of 6 patients with other congenital optic nerve anomalies, including optic nerve coloboma, morning glory disc, and peripapillary staphyloma, were included. METHODS: All patients underwent examinations under anesthesia. Wide-angle retina photographs and fluorescein angiograms were reviewed. The severity of nonperfusion was graded. The presence of fibrovascular proliferation (FP), vitreous hemorrhage (VH), and tractional retinal detachment (TRD) were documented. Anatomic outcome after treatment was recorded. MAIN OUTCOME MEASURES: Severity of nonperfusion, occurrence of secondary complications, and the anatomic outcome of patients who underwent laser treatment. RESULTS: In patients with optic nerve hypoplasia, 12 of 16 eyes (75%) had severe peripheral nonperfusion, 12 of 16 eyes (75%) had FP, 3 of 16 eyes (19%) had VH, and 10 of 16 eyes (63%) had TRD. Six of these eyes with severe nonperfusion received laser photocoagulation to the nonperfused retina; laser-treated retinas remained attached in all 6 eyes. In patients with the other optic nerve anomalies, 7 of 8 eyes (88%) had mild to moderate nonperfusion, 2 of 8 eyes (25%) had FP, 1 of 8 eyes (12%) had VH, and 2 of 8 eyes (25%) had TRD. Six of 9 patients (67%) with optic nerve hypoplasia and 1 of 6 patients (17%) with other anomalies had a coexisting congenital brain disease. CONCLUSIONS: Congenital optic nerve anomalies may be associated with peripheral retina nonperfusion and the secondary complications of FP, VH, and TRD. In this select group of patients, the nonperfusion associated with optic nerve hypoplasia seemed to be more severe and associated more frequently with secondary complications. Peripheral retina examination in eyes with optic nerve anomalies may identify nonperfusion or FP. Laser treatment of the avascular retina may have helped prevent complications from proliferative retinopathy in eyes clinically observed to have progressed or considered at risk for progression to proliferative retinopathy. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.Ophthalmology 11/2012; 120(3). DOI:10.1016/j.ophtha.2012.08.027 · 6.17 Impact Factor