Walker-Warburg Syndrome with POMT1 mutations can be associated with cleft lip and cleft palate

Walker-Warburg Syndrome (WWS) is an alpha-dystroglycan deficient congenital muscular dystrophy that is associated with brain and eye abnormalities. Patients present with hypotonia, weakness, developmental delay, mental retardation and occasional seizures. Other abnormalities were also described including cleft lip and palate. Mutations in POMT1, POMT2, fukutin, FKRP and LARGE genes are found in 20-30% of children with WWS. We report a novel mutation in POMT1 gene and provide further evidence that WWS with cleft lip and palate is associated with POMT1 mutations. We recommend POMT1 analysis in WWS cases associated with cleft lip and palate when considering which gene to sequence first.     

Neurosurgical management of Walker-Warburg syndrome

The Walker-Warburg syndrome (WWS) is a lethal complex of the central nervous system and the eyes. At present its cause is unknown, but clinical evidence strongly suggests that it is an autosomalrecessively inherited disorder. We report a series of nine children with WWS. The diagnosis was established by the detection of lissencephaly, hydrocephalus, and cerebellar malformation on computed tomography. All children exhibited profound psychomotor retardation and ocular abnormalities (in their anterior or posterior eye chambers). The existence of an occipital encephalocele in eight cases was the main diagnostic clue to WWS. Six patients were investigated for the presence of congenital muscular dystrophy, which was confirmed in only four of them. There were no patients with a cleft lip or palate. We studied the incidence of WWS in Spain and estimated it at 0.21 cases per 10 000 live-born children. In our series, WWS was prevalent in the Spanish gypsy population. Consanguinity was present in five of seven affected families. In a case of preganancy with twins, one of the siblings was unaffected. Eight patients were treated with ventriculoperitoneal shunts and seven underwent encephalocele repair. Histological study of the excised encephaloceles demonstrated two different patterns. Interestingly, one of the infants showed coronal craniosynostosis. Finally, we include in the appendix, for completeness, a report of the case of the sibling of a WWS patient with acrania-exencephaly.     

Basal lamina abnormality in the skeletal muscle of Walker-Warburg syndrome

The basal lamina of skeletal muscle fibers has been reported to be thinned and disrupted in patients with Fukuyama and laminin-alpha-2-deficient congenital muscular dystrophies. The basal lamina is normal in other, later-onset, muscular dystrophies, but the plasma membrane is disrupted. It is unknown whether the dystrophic process in Walker-Warburg syndrome (WWS) is characterized by a basal laminal abnormality, a sarcolemmal abnormality, or both. The present study examined the skeletal muscle of a 3-month-old patient with WWS by immunohistochemistry and electron microscopy and compared the findings with control muscle samples. In control samples the basal lamina of skeletal muscle fibers was a continuous, uniformly dense structure associated with sarcolemma. In WWS the basal lamina appeared deranged, with disruptions in nonnecrotic muscle fibers. Furthermore, in some fibers the basal lamina was thinner, and in others, it was duplicated. Dystrophin, laminin-alpha-2, and adhalin stains revealed normal immunoreactivity. The disruptions in the basal lamina may play a primary role in the degeneration of muscle fibers in WWS. When compared with the dystrophies with a primary sarcolemmal defect, it appears that those with primary basal lamina abnormalities (WWS, laminin-alpha-2-deficient, and Fukuyama congenital muscular dystrophies) present early in life, and the phenotype is more severe.     

A case of Walker-Warburg syndrome

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by type II lissencephaly, cerebellar and retinal anomalies, and congenital muscular dystrophy. We report a female diagnosed with WWS based on clinical criteria. This patient was found to have fetal hydrocephalus on ultrasonography at 29 weeks of gestation, and exhibited severe hypotonia, ocular malformations, and hydrocephalus at birth. MRI revealed type II lissencephaly, hydrocephalus, and other severe brain malformations. Genetic analysis was performed to distinguish WWS from severe Fukuyama-type congenital muscular dystrophy (FCMD), which has numerous findings in common. This revealed no expression of the founder haplotype or single-stranded conformation polymorphism (SSCP) abnormalities. Since the life expectancy of patients with FCMD is longer, differential diagnosis should be performed precisely.     

Phenotypic spectrum of Fukutinopathy: most severe phenotype of Fukutinopathy

Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, cobblestone lissencephaly, and eye anomalies. Among them, WWS is the most severe syndrome. Causative genes for FCMD (Fukutin), WWS (POMT1), and MEB (POMGnT1) have been identified. The vast majority of Japanese FCMD patients carry at least one copy of an ancestral founder insertion mutation. Patients homozygous for this insertion show a milder phenotype than do compound heterozygotes, carrying the insertion in combination with a missense or nonsense mutation on the other allele. No Japanese FCMD patients have been identified with nonfounder mutations on both alleles. A Turkish boy with characteristics of WWS was detected to have a homozygous nonsense mutation in exon 5 of Fukutin. This is the first case worldwide in which a Fukutin mutation has been found outside the Japanese population. Later, another Turkish boy with WWS phenotype was found to have a homozygous nonsense mutation in exon 4 of Fukutin. These two Turkish boys represent the most severe end of the phenotypic spectrum of Fukutin mutations. The Japanese FCMD patients carrying at least one copy of a founder mutation in the noncoding region may produce a lower level of mature Fukutin than normal and generate a relatively mild FCMD phenotype. The homozygous nonsense mutations within the coding region identified in Turkish patients are predicted to cause a total loss of fukutin activity and are likely to produce a more severe phenotype which closely resembles WWS.     

Ocular findings in Walker-Warburg syndrome

Ocular symptoms are frequently observed in Walker-Warburg (WWS) and associated syndromes. The majority of patients present with malformations of the anterior segment and severe retinal dysplasia. We report on the findings in a female patient with WWS who died at the age of 9 months. Major ocular findings were: severe iridocorneal malformation, a membran-like structure of the lens and funnel-shaped retinal dysplasia. The retina presented various grades of differentiation with rosettes and atypical sequences of cells, e.g. ganglion cells intermingled between granular layers. The anterior part of the retina presented as a primitive homogeneous layer with a cell-free space that might be interpreted as the primary optic ventricle. This finding suggests that we are dealing with a primary dysplastic non-attachment rather than a real detachment of the retina in WWS. The malformation of the anterior segment was not typical of the Peters' anomaly, as usually described in WWS, but of Rieger's syndrome.Presented at the Symposium on Lissencephaly and Related Disorders, Münster, Germany, 13 July 1992     

Muscle—eye—brain disease: A neuropathological study

A combination of congenital central nervous, ocular and muscular abnormalities is characteristic of muscle—eye—brain disease (MEB), of Fukuyama congenital muscular dystrophy (FCMD), and of Walker-Warburg syndrome (WWS). The nosological relationship of these inherited malformative disorders is still unestablished, although the genetic locus for FCMD has been excluded in MEB. We present the first postmortem neuropathological study of MEB based on 2 male patients. Apart from sharply limited occipital agyric areas, their brain showed coarse gyri with an abnormally nodular surface (?cobblestone cortex”?). Both the cerebral and cerebellar cortices showed a total disorganization without horizontal lamination. The haphazardly oriented cortcal neurons formed irregular custers or islands, separated by gliovascular strands extending from the pia. The ocular abnormalities included a pronounced glial preretinal membrane. Although MEB shares the cobblestone cortex—type malformation with FCMD and WWS, the cerebral and ocular manifestations are less severe than in WWS. Furthermore, a consistently weak staining for laminin α2 chain (merosin) was found in muscle biopsy specimens from 4 MEB patients, while normal immunoreactivity was observed for the laminin α2 chain, reported to be severely deficient in WWS. These finding support nosological independence of MEB.     

A truncating mutation in B3GNT1 causes severe Walker–Warburg syndrome

Walker–Warburg syndrome (WWS) is a genetically heterogeneous form of congenital muscular dystrophy with significant brain and ocular involvement. In a multiplex consanguineous family with severe WWS phenotype, autozygome-guided sequencing of previously reported WWS genes was negative. Exome sequencing followed by autozygome filtration revealed a homozygous two-base pair insertion in B3GNT1 (NM_006876.2:c.821_822insTT), leading to premature truncation of the protein (p.Glu274Aspfs*94). Recently, two missense mutations in this gene have been reported as probably causal in a family with WWS. This report describes the first truncating mutation in B3GNT1 and confirms that this gene, which plays a role in αDG glycosylation, is a bona fide disease gene in WWS.     

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

BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).     

Genetic identity of Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome

Both Fukuyama-type congenital muscular dystrophy (FCMD) and Walker-Warburg syndrome (WWS) are unusual genetic syndromes consisting of congenital muscular dystrophy and complex malformations of the brain and eye. It has been intensively discussed whether FCMD and WWS belong to the same disease entity or not. We analyzed a family in which 3 siblings were affected with either FCMD or WWS by using polymorphic microsatellites flanking the FCMD locus on chromosome 9q31–33. The results suggested that both FCMD and WWS siblings shared the identical combination of mutations on either allele of the FCMD locus. FCMD and WWS could be “genetically” identical.     

Synemin expression in developing normal and pathological human retina and lens

Synemin (Syn) is an intermediate filament (IF) protein. To gain insight into a morphogenetic role of Syn, we have studied its expression patterns in the developing human retina and lens and compared it with those of other IF proteins. In addition, we have tested Syn expression in fetuses (23 and 28 weeks) affected by Walker-Warburg syndrome (WWS), Meckel syndrome, and trisomy 13. In the retina, Syn expression starts in the nerve fiber and ganglion cell layers (NFL and GCL) at 15 weeks, remains there in up to 20 weeks, and spreads to other layers and may be colocalized with vimentin, GFA, or neurofilaments in the subsequent 16 weeks. This expansion of Synemin expression from 20 to 28 weeks is not observed in WWS in which Syn immunoreactivity in NFL is reduced and Vim expression is increased. Changes are seen in Syn or vimentin expressions in the retinae of 23-week-old Meckel syndrome or 28-week-old trisomy 13 fetuses. Syn expression in the lens is, at first (16 weeks), uniformly distributed, becoming stronger in the epithelium of the anterior part at 25 weeks and later. As in the retina, Syn expression in lens is also selectively affected in WWS. The colocalization of Synemin with vimentin, GFA, or NF supports the idea that Syn is a key cross-linking protein that connects different cytoskeletal structures. Moreover, stagnant Syn expression in WWS retina and lens reinforces the notion of a significant role of this protein in morphogenesis.     

POMT1 mutation results in defective glycosylation and loss of laminin-binding activity in alpha-DG

Walker-Warburg syndrome (WWS) is a congenital muscular dystrophy associated with neuronal migration disorder and structural eye abnormalities. The mutations in the O-mannosyltransferase 1 gene (POMT1) were identified recently in 20% of patients with WWS. The authors report on a patient with WWS and a novel POMT1 mutation. Their patient expressed alpha-dystroglycan (alpha-DG) core protein, but fully glycosylated alpha-DG antibody epitopes were absent, associated with the loss of laminin-binding activity.     

Congenital muscular dystrophy,brain and eye abnormalities: one or more clinical entities?

Four children with congenital muscular dystrophy (CMD), eye and brain abnormalities are described. Their clinical and neuroradiological features are compatible with a diagnosis of Walker-Warburg syndrome (WWS), according to the criteria proposed by Dobyns et al. (i.e., presence of type II lissencephaly, typical cerebellar and retinal malformations, CMD), who also conclude that WWS is indistinguishable from the muscleeye-brain disease (MEBD) described by Santavuori. On the basis of our own experience and two recently published series, we emphasize certain features that are different in patients with WWS and patients with MEBD, which make their inclusion in the same syndrome dubious.     

Clinical variation within sibships in Fukuyama-type congenital muscular dystrophy.

A family in which three siblings were affected with severe cerebral malformations in association with ocular anomalies and muscle disease is reported. One sibling was diagnosed as having Fukuyama type congenital muscular dystrophy (FCMD) because he showed severe hypotonia with dystrophic findings on a muscle biopsy in addition to pachygyria on CT. At the age of 3 years, retinal detachment developed in both eyes. Another sibling exhibited at birth such characteristic features as pachygyria, cephalocele, hydrocephalus, retinal detachment in both eyes, elevated serum creatine kinase activity and arthrogryposis multiplex congenita. We consider these findings to be more consistent with Walker-Warburg syndrome (WWS) than with FCMD. Anencephaly found in the third sibling was regarded as WWS with extreme brain abnormality. The appearance of two syndromes (FCMD and WWS) in the three members of the same family suggests that these syndromes could be allelic with variable phenotypes.     

The neurogenetics of lissencephaly

A comprehensive approach to diagnosis of patients with lissencephaly using clinical, CT and MRI scan, and sometimes other laboratory data will allow a specific diagnosis to be made in a large majority of patients. The most common diagnoses in order of decreasing frequency will probably prove to be WWS, MDS, and ILS. The remainder constitute a heterogeneous group. Both diagnosis and counseling have been modified by several recent and important advances. Diagnostic criteria for WWS have been revised. Several molecular probes have been located within the MDS critical region in chromosome band 17p13.3. Prenatal diagnosis should prove to be reliable in both WWS and MDS.     

Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients

BackgroundWalker-Warburg syndrome (WWS), an autosomal recessive disease, is the most severe phenotype of congenital muscular dystrophies. Its diagnosis remains primarily clinical and radiological. Identification of its causative variants will assist genetic counseling. We aim to describe genetic and neuroimaging findings of WWS and investigate the correlation between them.MethodsWe retrospectively reviewed the clinical, genetic and neuroimaging findings of eleven Saudi neonates diagnosed with WWS between April 2012 and December 2018 in a single tertiary care center. Correlation between neuroimaging and genetic findings was investigated.ResultsAll patients had macrocephaly except one who had intrauterine growth restriction. Dysmorphic features were identified in nearly half of the patients. Creatine kinase levels were available in nine patients and were always elevated. Homozygous pathogenic variants were identified in all patients spanning POMT1 (n = 5), TMEM5 (n = 3), ISPD (n = 2) and POMT2 (n = 1) including one patient who had a dual molecular diagnosis of ISPD and PGAP2. On neuroimaging, all patients showed cobblestone cortex, classical infratentorial findings, and hydrocephalus. Other cerebral cortical malformations included subependymal heterotopia, polymicrogyria and open-lip schizencephaly in four, two and one patients, respectively. Buphthalmos and microphthalmia were the most prevalent orbital findings and found in all patients either unilaterally or bilaterally.ConclusionWWS is a genetically heterogeneous disorder among Saudis. The case with an additional PGAP2-related phenotype exemplifies the increased risk of dual autosomal recessive disorders in consanguineous populations. MRI is excellent in demonstrating spectrum of WWS brain and orbital malformations; however, no definite correlation could be found between the MRI findings and the genetic variant.     

A patient of Walker-Warburg syndrome with a haplotype different from that in Fukuyama-type congenital muscular dystrophy]

A 3-month-old female baby was diagnosed as having Walker-Warburg syndrome (WWS), based on the following clinical findings: type II lissencephaly associated with marked ventricular dilatation, cerebellar malformation, retinal malformation, elevated serum creatine kinase level and abnormal muscle CT findings. She was a product of parents with consanguineous marriage. She presented with severe hypotonia and profound psychomotor retardation since birth. She developed infantile spasms at 8 months of age, and vitamin B6 was very effective. A genetic analysis revealed the absence of the founder haplotype commonly seen in Fukuyama-type congenital muscular dystrophy (FCMD), suggesting that the WWS gene is not always identical to the FCMD gene. When she was examined at the age of 4 years, she had no apparent further psychomotor development. Her clinical symptoms were more severe than those of the typical FCMD.     

Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities

A survey was performed of magnetic resonance imaging (MRI) findings in 21 patients with congenital muscular dystrophy (CMD) with cerebral abnormalities to evaluate the contribution of MRI to the classification of CMD patients. In 5 patients with Walker-Warburg syndrome (WWS), MRI showed hydrocephalus due to aqueduct stenosis, generalized cerebral cortical agyric or pachygyric polymicrogyria, diffuse cerebral hemispheric white matter abnormalities, and malformations of posterior fossa structures. In 4 patients with muscle–eye–brain disease, MRI showed cortical dysplasia, but less severe than in WWS. The cerebral white matter either was normal or contained multiple focal abnormalities. Malformations of posterior fossa structures were present. Eight patients, classified as having classic merosin-deficient CMD (MD-CMD), had diffuse cerebral hemispheric white matter abnormalities, no other abnormalities. One patient with MD-CMD had only a few, focal white matter abnormalities. Three CMD patients had occipital agyria, otherwise normal gyration, multifocal or more diffuse cerebral white matter changes, and variable hypoplasia of pons and vermis. Two of the 3 patients had negative muscle merosin staining. The conclusion of the study is that MRI is an important adjunct in the classification of CMD patients. CMD with occipital agyria can be regarded as a newly recognized, separate CMD subtype.     

Immunofluorescence study of a muscle biopsy from a 1-year-old patient with Walker-Warburg syndrome

A previous study of two patients with Walker-Warburg syndrome (WWS) showed a severe deficiency of the extracellular matrix protein laminin β2 chain and α-sarcoglycan (adhalin) in skeletal muscle fibers. More recently, however, other researchers have shown that in their WWS patients the expression of the laminin β2 chain and α-sarcoglycan was normal. Here we describe a 1-year-old boy affected with WWS. We performed immunohistochemical studies on a muscle biopsy from this patient using monoclonal antibodies against dystrophin, dystrophin-associated glycoproteins and several proteins of the extracellular matrix. We confirm previously reports as far as the diminished expression of laminin β2 chain and α-sarcoglycan is concerned. The expression of some other laminins was unusual, whereas the expression of collagen IV and VI was normal. These results suggest that complex syndromes like WWS are quite heterogeneous, although they might represent variant expressions of a single pathological entity. Received: 9 March 1998 / Revised, accepted: 4 June 1998     

A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease that can be induced in a variety of animal species and which is commonly used as an animal model of multiple sclerosis. In rodent EAE models, the clinical disease is typified by ascending paralysis; however, other clinical patterns can also be observed by inducing disease with particular peptides of myelin proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein. Here we describe EAE induced in C3H/HeJ mice by inoculation with residues 190–209 of PLP. This form of EAE is manifested clinically by a movement disorder, with axial rotation of the head and trunk. Histologically, this form of EAE is characterized by predominant cerebellar or brain stem involvement, depending on whether EAE is induced by active immunization with the PLP peptide, or by passive transfer of T cells specific for the peptide. The inflammatory cell infiltrate is composed of polymorphonuclear cells and mononuclear cells. This rotatory form of EAE may be a useful model for studying the neuropathological characteristics of multiple sclerosis affecting the brain stem and cerebellum. Received: 23 June 1999 / Revised, accepted: 25 October 1999