Table 8 Glycosylation defects

Beltran-Valero de Bernabé et al., 2004 [289]

Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome

University Medical Centre Nijmegen, Nijmegen, The Netherlands

2 Patients, 200 Controls

German, Asian

Case series

Dandy walker-like malformation, intellectual disability

Muscular dystrophy, left ventricular hypertrophy, retinal and eye developmental issues

Communicating

TES

Direct sequencing, linkage analysis

-

19q13.32 (FKRP)

Beltrán-Valero de Bernabé et al., 2002

[290]

Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome

University Medical Centre Nijmegen, Nijmegen, The Netherlands

30 Subjects, 105 Controls

Turkish, Italy, Dutch, Australian

Case series

Cobblestone lissencephaly, occipital encephalocele

Eye malformations, congenital muscular dystrophy or elevated creatine kinase

Obstructive

TES

Linkage analysis, SSCP, restriction enzyme analysis

AR

9q34.13 (POMT1)

Biancheri et al., 2006 [291]

POMGnT1 mutations in congenital muscular dystrophy: genotype–phenotype correlation and expanded clinical spectrum

University of Genova, Italy

3 Subjects, 192 Controls

Italian

Case series

Intellectual disability, epilepsy, and lissencephaly

Congenital muscular dystrophy, ocular abnormalities

Communicating

TGS

Direct sequencing

AR

1p34.1 (POMGnT1)

Bouchet et al., 2007 [292]

Molecular heterogeneity in fetal forms of type II lissencephaly

Bichat-Claude Bernard Hospital, Biochimie Métabolique, Paris, France

47 Subjects, 100 Controls

French

Case series

Agyria, thick leptomeninges, disorganized cortical ribbon, cerebellar dysplasia

Communicating

TGS

-

AR

9q34.13 (15 in POMT1); 14q24.3 (five in POMT2); 1p34.1 (POMGNT1)

Cormand et al., 2001 [293]

Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease

University of Helsinki, Finland

29 Subjects

Turkish, Netherlands, German, Pakistani, Swedish, Palestinian, Dutch, and American

Case series

Malformation of neuronal migration compatible with cobblestone complex

Elevated serum creatine kinase level or abnormal muscle biopsy, and ocular abnormalities

-

Genotyping

Linkage analysis

AR

MEB gene locus localized to 1p32-p34

Currier et al., 2005 [294]

Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome

Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

30 Subjects, 110 Controls

Asian, African, and Caucasian

Case series

Cerebellar hypoplasia, brainstem hypoplasia, agenesis of the corpus callosum, agenesis of the septum pellucidum, interhemispheric fusion, and the presence of an encephalocele

Ocular abnormalities, congenital muscular dystrophy

Obstructive

TES

Microsatellite marker assay

AR

9q34.13 (POMT1)

Geis et al., 2019 [295]

Clinical long-time course, novel mutations and genotype–phenotype correlation in a cohort of 27 families with POMT1-related disorders

Klinik St. Hedwig, University Children's Hospital Regensburg (KUNO), Steinmetzstr. 1–3, 93,049, Regensburg, Germany

35 Subjects

German, Turkish, Indonesian, Gipsy, African

Case series

Lissencephaly type II, hypoplasia of the pons and/or brainstem, cerebellar hypoplasia, hypoplasia of the corpus callosum, encephalocele

Muscle weakness, muscular dystrophy, GI malformations

Communicating

TGS

Direct sequencing, sanger sequencing, massive parallel sequencing

AR

9q34.13 (POMT1)

Godfrey et al., 2007 [69]

Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan

Hammersmith Hospital, Imperial College, London, UK

92 Subjects

Australia, Turkey

Case series

Cobblestone lissencephaly

Limb girdle muscular dystrophy, congenital muscular dystrophy, elevated serum ck

Communicating

TGS

Unidirectional sequencing, HA, segregation analysis,

AR, De novo

9q34.13 (POMT1); 14q24.3 (POMT2); 1p34.1 (POMGnT1); 9q31.2 (FKTN); and 22q12.3 (LARGE)

Hehr et al., 2007 [296]

Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease

University of Regensburg, Universitätklinikum D3, Franz-Josef-Strauss-Allee 11, Regensburg, Germany

9 Subjects

German, Turkish, English

Case series

Global developmental delay, seizures, cerebellar cysts, intellectual disability

Congenital muscular dystrophy, se- vere congenital myopia, glaucoma, retinal hypoplasia

Communicating

TGS

Cycle sequencing, linkage analysis, restriction enzyme analysis

AR

1p34.1 (POMGnT1)

Ichiyama et al., 2016 [297]

Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency

Kyushu University, Fukuoka, Japan

1 Subject

Asian

Case study

Isolated hydrocephalus

Slight developmental delay

-

TES

Direct sequencing

-

2q14.3 (PROC c.574_576delAAG)

Kano et al., 2002 [298]

Deficiency of alpha-dystroglycan in muscle-eye-brain disease

Osaka University Graduate School of Medicine, 2–2 B9, Yamadaoka, Suita, Osaka, Japan

3 Subjects, 1 Control

Turkish, French

Case series

Type II lissencephaly, Intellectual disability

Congenital muscular dystrophy, congenital myopia, congenital glaucoma, pallor of the optic discs, retinal hypoplasia, hydrocephalus, myoclonic jerks

Communicating

TGS

-

AR

1p34.1 (POMGnT1)

Karadeniz et al., 2002 [299]

De novo translocation t(5;6)(q35;q21) in an infant with Walker-Warburg syndrome

Burak Woman's Hospital, Department of Medical Genetics, Ankara, Turkey

1 Subject, 2 Parents

-

Case study

Hypoplasia of cerebellar vermis, enlargement of cisterna magna, bilateral dilatation of lateral ventricles, widespread agyria, and irregularity of the white matter-gray matter line

Eye abnormalities with microphthalmia cataract, congenital muscular dystrophy

Communicating

-

G-banding

De novo

translocation t(5;6)(q35;q21)

Preiksaitiene et al., 2020 [300]

Pathogenic homozygous variant in POMK gene is the cause of prenatally detected severe ventriculomegaly in two Lithuanian families

Vilnius University, Vilnius, Lithuania

4 Subjects, 98 Controls

Lithuanian

Case series

Isolated hydrocephalus

Highly variable

Dependent on phenotype of dystroglycanopathy

WES

Sanger sequencing

De novo, AR

8p11.21 (homozygous nonsense variant in the POMK)

Van Reeuwijk et al., 2005 [301]

POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

3 Subjects, Controls used

Moroccan, Pakistani, Bengali

Case series

Lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration

Eye malformations (cataract, microphthalmia, buphthalmos, and peters anomaly)

-

TGS

Homozygosity mapping, direct sequencing

AR

14q24.3 (POMT2)

Van Reeuwijk et al., 2006 [302]

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

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

28 Subjects, 100 Controls

Italy, Netherlands, Pakistan, Lebanon, India, Qatar, Ireland, turkey

Case series

Lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration

Myopia, gait disturbances

Communicating

TGS

Linkage analysis

-

9q34.13 (POMT1)

Van Reeuwijk et al., 2010 [303]

A homozygous FKRP start codon mutation is associated with Walker-Warburg syndrome, the severe end of the clinical spectrum

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

2 Subjects, 2 Parents

Caucasian

Case series

Lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration

Cataracts, muscular dystrophy

Communicating

TGS

SNP

-

19q13.32 (FKRP)

Riemersma et al., 2015 [304]

Absence of α- and β-dystroglycan is associated with Walker-Warburg syndrome

Leiden University Medical Center, the Netherlands, Sydney Children's Hospital, University of New South Wales, Sydney, Australia, Rambam Health Care Campus, Haifa, Weizmann Institute of Science, Rehovot, Israel

5 Subjects, Controls used

Israeli-Arab

Case series

Hypotonia, posterior fossa, a small midline encephalocele, a hypoplastic vermis, intracranial calcifications

Elevated ck, elevated lfts, respiratory failure, bilateral corneal opacities, and glaucoma

Communicating

TES

Homozygosity mapping, CNV, sanger sequencing

-

3p21.31 (homozygous loss-of-function frameshift mutation in the DAG1 gene)

Saredi et al., 2012 [305]

Novel POMGNT1 point mutations and intragenic rearrangements associated with muscle-eye-brain disease

Foundation Neurological Institute C. Besta, Milano, Italy

3 Subjects, 1 Control

Italian

Case series

Microcephaly, spastic tetraparesis

Rounded forehead, thin lips, short neck, micrognathia, motor disability, eye abnormalitie

Communicating

TGS

Cycle sequencing, MLPA

AR

1p34.1 (c.643C > T, c.1863delC

in POMGnT1)

Vervoort et al., 2004 [306]

POMGnT1 gene alterations in a family with neurological abnormalities

J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC, USA

2 Subjects, 2 Parents, 500 Controls

Caucasian

Case series

Hypotonia, bilateral frontal polymicrogyria, abnormal cerebellum, and characteristic flattened dystrophic pons

Congenital muscular dystrophy, congenital glaucoma and severe myopia

-

TGS

Haplotype analysis, SSCP, cycle sequencing

AR

1p34.1 (POMGnT1)

Willer et al., 2012 [307]

ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome

University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA

7 Subjects, Controls used

-

Case series

Cobblestone lissencephaly, severe brainstem hypoplasia with a kink at the isthmus and severe hypoplasia of the cerebellum

Muscular dystrophy, bilateral microphthalmia with cataracts and arrested retinal development

Communicating

TGS, cytogenetics

Linkage analysis, targeted NGS, aCGH, CNV, Sanger sequencing

AR

7p21 (ISPD mutation)

Yis et al., 2007 [308]

A case of Walker-Warburg syndrome resulting from a homozygous POMT1 mutation

University of Dokuz Eylul, 35,340 Izmir, Turkey

1 Subject, 2 Parents

-

Case study

Type II lissencephaly and pontocerebellar hypoplasia

Severe ocular malformations and congenital muscular dystrophy

Communicating

TGS

Linkage analysis, direct sequencing

AR

9q34.13 (mutation (R514X) in the POMT1 gene)

Yoshida et al., 2001 [309]

Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1

Central Laboratories for Key Technology, Kirin Brewery Co., Ltd., Kanazawa-ku, Yokohama, Japan

6 Subjects

Turkish, French

Case series

Lissencephaly

Congenital muscular dystrophy, ocular abnormalities

Communicating

TGS

Direct sequencing

AR

1p34.1 (POMGnT1)