The expanding phenotype of<i>POMT1</i>mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation

Reeuwijk, Jeroen van; Maugenre, Svetlana; Elzen, Christa van den; Verrips, Aad; Bertini, Enrico; Muntoni, Francesco; Merlini, Luciano; Scheffer, Hans; Brunner, Han G.; Guicheney, Pascale; Bokhoven, Hans van

doi:10.1002/humu.20313

Cited by 108 publications

(90 citation statements)

References 23 publications

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“…12 It is the main CNS feature of CMDs with O-glycosylation defects of ␣-dystroglycan, even though it is difficult to differentiate the genetic causes on the basis of brain MRI because of overlapping phenotypes. [19][20][21][22][23] Cerebral, cerebellar, and brainstem abnormalities have been well documented in the major phenotypes: FCMD, WWS, and MEB. WWS displays severe cerebral cortical dysplasia, hypomyelination, dysplastic tectum, pontomedullary kink, severe hypoplasia of the vermis, and dysplastic cerebellar hemispheres.…”

Section: Resultsmentioning

confidence: 99%

Midbrain–hindbrain involvement in lissencephalies

Jissendi-Tchofo¹,

Kara²,

Barkovich³

2009

Neurology

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Objectives:To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities.Methods: MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal-Wallis and 2 McNemar tests. Results:There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p ϭ 0.0029). Conclusion: GLOSSARYA ϭ autosomal; ACC ϭ agenesis of corpus callosum; AD ϭ autosomal dominant; AP ϭ anteroposterior; AR ϭ autosomal recessive; CBL ϭ cerebellar; CBSC ϭ cobblestone complex; cLIS ϭ classic lissencephaly; CMD ϭ congenital muscular dystrophy; CSZ ϭ cell-sparse zone; DV ϭ dorsal-ventral; FCMD ϭ Fukuyama congenital muscular dystrophy; IVH ϭ inferior vermis hypoplasia; LV ϭ lateral ventricle; m ϭ medulla; M ϭ midbrain; MDS ϭ Miller-Dieker syndrome; MEB ϭ muscle-eyebrain; MHB ϭ midbrain and hindbrain; MR ϭ magnetic resonance; ND ϭ not determined; P ϭ pons; RC ϭ rostrocaudal; SCBH ϭ subcortical band heterotopia; SELH ϭ subependymal linear heterotopia; V ϭ vermis; vLIS ϭ variant lissencephaly; WI ϭ weighted image; WWS ϭ Walker-Warburg syndrome; XLD ϭ X-linked dominant; XLR ϭ X-linked recessive.The term lissencephaly (smooth outer brain surface) refers to a paucity of gyral and sulcal development. 1 It encompasses a spectrum of gyral malformations ranging from complete agyria to regional pachygyria and includes subcortical band heterotopia. Lissencephaly has been traditionally classified in two distinct groups: classic (cLIS, formerly called lissencephaly type 1) and cobblestone complex (CBSC, formerly called lissencephaly type 2) based on both brain imaging and pathology. To date, five genes have been identified as causing or contributing to human cLIS: LIS1, 14-3-3 in Miller-Dieker syndrome (MDS), DCX, RELN, and ARX. [1][2][3][4][5][6] A new classification has recently been proposed defining four groups of cLIS differing from each other by genetics and neuropathologic features of the cerebral cortex, cerebellum, and brainstem. 3 1)

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Section: Resultsmentioning

confidence: 99%

Midbrain–hindbrain involvement in lissencephalies

Jissendi-Tchofo¹,

Kara²,

Barkovich³

2009

Neurology

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“…however, out of these classical phenotypes, different types and degrees of cortical and posterior fossa malformations have been described 156,[169][170][171][172][173][174] , with or without eye involvement; mental retardation, and calf as well as thigh enlargement has also been related 170,171 . yanagisawa et col 172 hypothesized that patients with PoMT1 and PoMT2 mutations could share the same phenotype because, according to Manya et al 21 , both glycosyltransferases form a heterodimeric complex that is responsible for the catalysis of the first step in O-mannosyl glycan synthesis.…”

Section: Disorders Of Glycosylation Of Alphadg (Alpha-dystroglycanopamentioning

confidence: 99%

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

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“…3 a-DG has a structural role in muscle fiber integrity, connecting the dystrophin-glycoprotein complex to the extracellular matrix. 4 POMT1 mutations result in a reduction in a-DG glycosylation in skeletal muscles [5][6][7] and the clinical spectrum of the phenotype ranges from severe Walker-Warburg syndrome (WWS, OMIM 236670) 5 to milder forms of congenital muscular dystrophy (CMD) with microcephaly and mental retardation without eye abnormalities (CMD-MR, OMIM 613155), 6 and to limb-girdle muscular dystrophy (LGMD) with normal brain structure and mental retardation (LGMD2K, OMIM 609308). 7,8 Five other genes -POMT2, protein o-mannose b-1, 2-N-acetylglucosaminyltransferase (POMGnT1, OMIM *606822), fukutin (FKTN, OMIM *607440), FKTN-related protein (FKRP, OMIM *606596) and like-glycosyltransferase (LARGE, OMIM *608840) -are involved in a-DG glycosylation and their mutations lead to heterogeneous phenotypes characterized by combinations of muscular, cerebral and ophthalmic involvement.…”

Section: Introductionmentioning

confidence: 99%

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

et al. 2012

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Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in a-dystroglycan (a-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent a-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.

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The expanding phenotype ofPOMT1mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation

Cited by 108 publications

References 23 publications

Midbrain–hindbrain involvement in lissencephalies

Midbrain–hindbrain involvement in lissencephalies

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

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