Muscular dystrophies with defective O-glycosylation of alpha-dystroglycan

The longstanding interest of the Hehr laboratory in congenital brain malformations also includes autosomal recessive inherited cobblestone lissencephalies resulting from defective O-glycosylation of alpha-dystroglycan. These are commonly associated with congenital or limb girdle muscular dystrophy,  Most affected patients have highly elevated Serum CK values and in addition may present with a variety of congenital eye malformations such as cataract or hypoplastic nervi optici. Today the most severe form of the early lethal Walker-Warburg syndrome is usually recognized prenatally due to the severe hydrocephalus in combination with agenesis/ hypoplasia of the corpus callosum and hypoplasia of the cerebellum, brainstem and pons resulting in a characteristic hook-like appearance. Disturbed termination of radial neuronal migration is assumed to result in the histologically distinct cortical phenotype of cobblestone lissencephaly, which may radiologically appear like polymicrogyria and can sometimes be difficult to recognize at all due to the severe hydrocephalus. Less severe phenotypes may be recognized in early infancy as proximally pronounced congenital muscular dystrophy with early and global developmental delay. In contrast, limb girdle muscular dystrophies manifest after normal psychomotor development in childhood, adolescence or adulthood. Both postnatal forms are associated with a wide spectrum of milder brain and eye malformations, which in a substantial portion of the patients may result in characteristic cognitive deficits.

In our accredited laboratory we offer:

  • pretest evaluation of your patient’s clinical information and cerebral MR imaging in order to develop an individual genetic testing strategy;
  • diagnostic genetic testing by Sanger sequencing as well as MLPA
  • Linkage analysis for suitable families
  • Next Generation Sequencing with our disease specific panel for neuronal migration disorders including all genes currently associated with muscular dystrophies resulting from defective O-glycosylation
  • carrier testing of pre- and postnatal samples
  • rapid prenatal testing of provided fetal samples with sonographically suspected Walker-Warburg syndrome.

All identified sequence alterations, relevant or potentially relevant for the clinical findings of your patient, are

  • confirmed by Sanger sequencing,
  • carefully assessed using our in house evaluation workflow including comparison with the human reference genome hg19, publically available and our own extensive mutation database as well as in silico prediction of functional consequences applying different algorithms,
  • rated and summarized in an individual medical report considering provided clinical and imaging data.

In addition to our NGS panel, covering 107 genes associated with Neuronal Migration DisordersNM, we offer at our center genetic testing by Sanger sequencing for:

Disease Disease
OMIM
Gene Gene
OMIM
Chromosomal
location
limb-girdle muscular dystrophy 609308      
Panel Neuronal migration disorders (107 genes associated with Lissencephaly, Double cortex, Microcephaly, PMG)NM pdf
Limb-girdle muscular dystrophy LGMD2I (MDDGC5) (+MLPA, Linkage) 607155 FKRP NM 606596 19q13.32
Limb-girdle muscular dystrophy LGMD2K (MDDGC1) (+MLPA, Linkage) 609308 POMT1 NM 607423 9q34.13
Limb-girdle muscular dystrophy LGMD2M (MDDGC4) (+MLPA, Linkage) 611588 FKTN HPE, NM 607440 9q31.2
Limb-girdle muscular dystrophy LGMD2N (MDDGC2) (+MLPA, Linkage) 613158 POMT2 NM 607439 14q24.3
Limb-girdle muscular dystrophy LGMD20 (MDDGC3) (+MLPA, Linkage) 613157 POMGNT1 NM 606822 1p34.1
Limb-girdle muscular dystrophy LGMD2P (MDDGC9) 613818 DAG1 NM 128239 3p21.31
Congenital Muscular dystrophy incl. WWS / MEB 236670      
Panel Neuronal migration disorders (107 genes associated with Lissencephaly, Double cortex, Microcephaly, PMG)NM pdf
POMT1-associated (+MLPA, Linkage) 236670
613155
POMT1 NM 607423 9q34.13
POMT2-associated (+MLPA, Linkage) 613150
613156
POMT2 NM 607439 14q24.3
POMGnT1-associated (+MLPA, Linkage) 253280
613151
POMGNT1 NM 606822 1p34.1
FKRP-associated (+MLPA, Linkage) 613153
606612
FKRP NM 606596 19q13.32
FKTN-associated (incl. 3kb-Founderinsertion) (+MLPA, Linkage) 253800
613152
FKTN HPE, NM 607440 9q31.2
LARGE-associated (+MLPA, Linkage) 613154
608840
LARGE NM 603590 22q12.3
IPSD-associated (+Linkage) 614643 ISPD NM 614631 7p21.2
GTDC2-associated (+Linkage) 614830 GTDC2 NM 614828 3p22.2
TMEM5-associated (+Linkage) 615041 TMEM5 NM 605862 12q14.2
B3GNT1-associated (+Linkage) 615287 B3GNT1 NM 605517 11q13.2
COL4A1-associated (+Linkage) COL4A1 NM 120130 13q34
RELN-associated (only Linkage + NM) 257320 RELN NM 600514 7q22.1

Related Publications of our group

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Czeschik JC, Hehr U, Hartmann B, Lüdecke HJ, Rosenbaum T, Schweiger B, Wieczorek D. 160 kb deletion in ISPD unmasking a recessive mutation in a patient with Walker-Warburg syndrome. Eur J Med Genet. 2013 Oct 10. doi:pii: S1769-7212(13)00226-7.

Geis T, Marquard K, Rödl T, Reihle C, Schirmer S, von Kalle T, Bornemann A, Hehr U, Blankenburg M. Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy. Neurogenetics. 2013 Sep 20. [Epub ahead of print]

Lommel M, Cirak S, Willer T, Hermann R, Uyanik G, van Bokhoven H, Körner C, Voit T, Barić I, Hehr U, Strahl S. Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies. Neurology. 2010 Jan 12;74(2):157-64.

Judas M, Sedmak G, Rados M, Sarnavka V, Fumić K, Willer T, Gross C, Hehr U, Strahl S, Cuk M, Barić I. POMT1-associated walker-warburg syndrome: a disorder of dendritic development of neocortical neurons. Neuropediatrics. 2009 Feb;40(1):6-14.

Hehr U, Uyanik G, Gross C, Walter MC, Bohring A, Cohen M, Oehl-Jaschkowitz B, Bird LM, Shamdeen GM, Bogdahn U, Schuierer G, Topaloglu H, Aigner L, Lochmüller H, Winkler J. Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease. Neurogenetics. 2007 Nov;8(4):279-88.

Yis U, Uyanik G, Kurul S, Dirik E, Ozer E, Gross C, Hehr U. A case of Walker-Warburg syndrome resulting from a homozygous POMT1 mutation. Eur J Paediatr Neurol. 2007 Jan;11(1):46-9.

Haliloglu G, Gross C, Senbil N, Talim B, Hehr U, Uyanik G, Winkler J, Topaloglu H. Clinical spectrum of muscle-eye-brain disease: from the typical presentation to severe autistic features. Acta Myol. 2004 Dec;23(3):137-9.

Balci B, Uyanik G, Dincer P, Gross C, Willer T, Talim B, Haliloglu G, Kale G, Hehr U, Winkler J, Topaloğlu H. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscul Disord. 2005 Apr;15(4):271-5.

Meyer S, Struffert T, Uyanik G, Oehl-Jaschkowitz B, Hehr U, Shamdeen MG. [Congenital muscular dystrophies: muscle-eye-brain disease]. Klin Padiatr. 2005 Mar-Apr;217(2):68-9. German.