Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) that include a broad phenotypic spectrum ranging from late-onset limb-girdle muscular dystrophy to severe muscle-eye-brain disease, Walker-Warburg syndrome, and Fukuyama congenital muscular dystrophy. In addition to clinical heterogeneity, CMDs are characterized by genetic heterogeneity. To date, 18 genes have been associated with CMDs. One of them is B3GALNT2, which encodes the β-1,3-N-acetylgalactosaminyltransferase 2 that glycosylates α-dystroglycan. In this study, using exome sequencing, we identify a homozygous frameshift variant in B3GALNT2 due to a mixed uniparental disomy of chromosome 1 in a 7-year-old girl with global developmental delay, severely delayed active language development, and autism spectrum disorder but without any symptoms of muscular dystrophy. In addition to this case, we also provide an overview of all previously reported cases, further expanding the phenotypic spectrum.

The canonical O-mannosylation pathway in humans is essential for the functional glycosylation of α-dystroglycan. Disruption of this post-translational modification pathway leads to congenital muscular dystrophies. The first committed step in the construction of a functional matriglycan structure involves the post-translational modification of α-dystroglycan. This is essential for binding extracellular matrix proteins and arenaviruses, and is catalyzed by β-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2). While another glycosyl transferase, β-1,4-N-acetylglucosaminyltransferase 1 (POMGNT1), has been shown to be promiscuous in extending O-mannosylated sites, POMGNT2 has been shown to display significant primary amino-acid selectivity near the site of O-mannosylation. Moreover, several single point mutations in POMGNT2 have been identified in patients with assorted dystroglycanopathies such as Walker-Warburg syndrome and limb girdle muscular dystrophy. To gain insight into POMGNT2 function in humans, the enzyme was expressed as a soluble, secreted fusion protein by transient infection of HEK293 suspension cultures. Here, crystal structures of POMGNT2 (amino-acid residues 25-580) with and without UDP bound are reported. Consistent with a novel fold and a unique domain organization, no molecular-replacement model was available and phases were obtained through crystallization of a selenomethionine variant of the enzyme in the same space group. Tetragonal (space group P4212; unit-cell parameters a = b = 129.8, c = 81.6 Å, α = γ = β = 90°) crystals with UDP bound diffracted to 1.98 Å resolution and contained a single monomer in the asymmetric unit. Orthorhombic (space group P212121; unit-cell parameters a = 142.3, b = 153.9, c = 187.4 Å, α = γ = β = 90°) crystals were also obtained; they diffracted to 2.57 Å resolution and contained four monomers with differential glycosylation patterns and conformations. These structures provide the first rational basis for an explanation of the loss-of-function mutations and offer significant insights into the mechanics of this important human enzyme.

Objective Herein, we report a case of a deceased newborn with prenatally detected hydrocephalus. Postnatal findings included abnormal brain imaging and electroencephalogram, optic nerve abnormalities, and elevated creatine kinase (CK). No underlying genetic etiology had been previously identified for the proband, despite testing with a congenital muscular dystrophy gene panel. Methods Diagnostic exome sequencing (DES) was performed on the proband-parents trio, and candidate alterations were confirmed using automated fluorescence dideoxy sequencing. Results Exome sequencing of the proband, mother and father identified a previously unreported apparently de novo heterozygous tubulin, beta-3 ( TUBB3) c.523G>C (p.V175L) alteration in the proband. Conclusion Overall, DES established a likely molecular genetic diagnosis for a postmortem case after traditional testing methods were uninformative. The DES results allowed for reproductive options, such as preimplantation genetic diagnosis and/or prenatal diagnosis, to be available to the parents in future pregnancies.

Background Congenital hydrocephalus is a common and often disabling disorder. Various syndromic forms of hydrocephalus have been reported in the Palestinian population including Walker-Warburg syndrome (WWS), Carpenter syndrome, and Meckel syndrome. Aim In this report we discuss the antenatal diagnosis of congenital hydrocephalus in three related Palestinian families. Method Single nucleotide polymorphism (SNP) array was performed prenatally for the third affected fetus. Results A diagnosis of WWS was found and molecular testing revealed a known pathogenic mutation in the POMT2 gene. An affected fetus from the other family was diagnosed and tested postnatally in light of this finding. Testing of another affected stillborn offspring was performed and revealed the same mutation. Conclusions Here, we show that the use of prenatal SNP array testing can be helpful in elucidating the etiology of congenital hydrocephalus and in guiding appropriate perinatal care. Also, testing for this specific POMT2 mutation should be considered in cases of prenatally detected hydrocephalus in Palestinian families.

Walker-Warburg syndrome is a rare congenital disorder. Several features, including muscular dystrophy, hydrocephalus, and oropharyngeal abnormalities, have important implications in the perioperative setting. We present a case of general anesthesia in an infant and discuss perioperative considerations to guide clinicians faced with the management of patients with this syndrome.

Walker-Warburg syndrome (WWS) is a rare form of autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in abnormal α-dystroglycan glycosylation have been implicated in the aetiology of WWS, most recently the ISPD gene. Typical WWS brain anomalies, such as cobblestone lissencephaly, hydrocephalus and cerebellar malformations, can be prenatally detected through routine ultrasound examinations. Here, we report two karyotypically normal foetuses with multiple brain anomalies that corresponded to WWS symptoms. Using a SNP-array examination on the amniotic fluid DNA, a homozygous microdeletion was identified at 7p21.2p21.1 within the ISPD gene. Published data and our findings led us to the conclusion that a homozygous segmental intragenic deletion of the ISPD gene causes the most severe phenotype of Walker-Warburg syndrome. Our results also clearly supports the use of chromosomal microarray analysis as a first-line diagnostic test in patients with a foetus with one or more major structural abnormalities identified on ultrasonographic examination.

OBJECTIVE: Walker-Warburg Syndrome is a rare, autosomal recessive congenital muscular dystrophy manifested by central nervous system, eye malformations and possible multisystem involvement. The diagnosis is established by the presence of four criteria: congenital muscular dystrophy, type II lissencephaly, cerebellar malformation, and retinal malformation. Most of the syndromic children die in the first three years of life because of respiratory failure, pneumonia, seizures, hyperthermia and ventricular fibrillation.
METHODS: The anesthetic management of a two-months-old male child listed for elective ventriculo-peritoneal shunt operation was discussed.
CONCLUSIONS: A careful anesthetic management is necessary due to the multisystem involvement. We reported anesthetic management of a two-months-old male child with Walker-Warburg Syndrome who was listed for elective ventriculo-peritoneal shunt operation.

Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles.

Walker-Warburg syndrome (WWS) is a severe muscular dystrophy with eye and brain malformations. On a molecular level, WWS is a disorder of the O-linked glycosylation of α-dystroglycan and therefore referred to as one of the dystroglycanopathies. The disease family of muscular dystrophy-dystroglycanopathy (MDDG) contains a spectrum of severe to mild disorders, designated as MDDG type A to C. WWS, as the most severe manifestation, corresponds to MDDG type A. Defects in the genes POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GTDC2, G3GALNT2, GMPPB, B3GNT1, TMEM5 and COL4A1 and ISPD have been described as causal for several types of MDDG including WWS, but can only be confirmed in about 60-70% of the clinically diagnosed individuals. The proteins encoded by these genes are involved in the posttranslational modification of α-dystroglycan. Mutations in POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GMPPB, TMEM5 and COL4A1 and ISPD lead to a wide spectrum of phenotypes of congenital muscular dystrophies with or without eye and brain abnormalities. Patients with WWS frequently demonstrate a complete lack of psychomotor development, severe eye malformations, cobblestone lissencephaly and a hypoplastic cerebellum and brainstem, seizures, hydrocephalus and poor prognosis. Here, we present a boy with WWS who showed compound heterozygous changes in ISPD and discuss the clinical and radiological phenotype and the molecular genetic findings, including a novel pathogenic mutation in ISPD.