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.     

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     

Walker-Warburg syndrome in a Japanese patient

We report the first Japanese female patient with Walker-Warburg syndrome. She had generalized muscle hypotonia with hydrocephalus due to Dandy-Walker malformation and bilateral microphthalmia with opaque corneas. She had severe motor and mental retardation. Muscle histology reflected advanced changes of muscular dystrophy. We discuss the relationship between Fukuyama congenital muscular dystrophy and Walker-Warburg syndrome, both of which fall within a spectrum of developmental abnormalities with a common cause. In Fukuyama congenital muscular dystrophy, ocular abnormalities are less severe.     

Congenital polyneuropathy in Walker-Warburg syndrome.

Polyneuropathy was found in a patient with the Walker-Warburg syndrome. The most dominant features were the presence of extremely and tortuously proliferated myelin sheaths, the most of which having no neurofilaments and neurotubules. The other peculiar findings were the presence of microfilaments in Schwann cell cytoplasms, which were very similar to neurofilaments, and the presence of partial and abrupt disappearance of myelin sheaths. The severity of neuropathy was variable among nerve bundles, and a few nerve bundles looked normal on light microscopy. The above-mentioned lesions did not suggest the degeneration and/or regeneration of normally developed nerve fibers. We could not conclude the pathogenesis of this neuropathy, however, it was logical to consider that they reflected dysplastic myelination due to Schwann cell dysmaturity as well as the cerebral dysplasia.     

Walker-Warburg syndrome: diffusion MR imaging

A 5-month-old boy with Walker-Warburg syndrome is reported. On MR imaging a characteristic pontomesencephalic kink was evident. Collicular fusion, hydrocephalus, callosal dysgenesis, cobblestone lissencephaly, small cerebellar cysts, pontine and cerebellar hypoplasia, and bilateral subretinal hemorrhages were noted. ADC (apparent diffusion coefficient) maps of an echoplanar diffusion MR imaging sequence revealed an elevated diffusion pattern throughout the cerebral white matter, manifested with prominently high ADC values, ranging from 1.82 to 2.45 x 10(-3) mm2/s. This corresponded to prominent hypomyelination. On the other hand, ADC values of the lissencephalic cortex were normal, ranging from 0.95 to 0.97 x 10(-3)mm2/s. In addition, ADC values from the hypoplastic cerebellar hemispheres, and from the hypoplastic pons were normal.     

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.     

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.     

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.     

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).     

Walker-Warburg syndrome is genetically distinct from Fukuyama type congenital muscular dystrophy

A female patient who fulfilled the diagnostic criteria of Walker-Warburg syndrome had muscle biopsy finding of muscular dystrophy. There was normal expression of merosin (laminin alpha2 chain) and dystrophin and only slightly reduced dystrophin-associated glycoprotein expression. On genetic analysis, she had no specific haplotype, the common mutation of 3kb insertion, or point mutations in the Fukuyama-type congenital muscular dystrophy gene, suggesting that the two diseases are not genetically identical.     

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.     

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 case of Wyburn-Mason syndrome

A extremely rare case of unilateral retinocephalic vascular malformation (Wyburn-Mason syndrome) was reported. A 5 year-old girl was seen to a ophthalmologist complaining of exophthalmus of her left eye after trauma on her face for the past 2 months. On ophthalmologic examinations, retinal arteriovenous malformation was recognized in her left eye and she was referred to neurosurgical service for the evaluation on occurrence of traumatic carotid cavernous fistula. Plain CT did not show any abnormality but enhanced CT revealed an abnormally enhanced lesion in the thalamus and basal ganglia and along to the left optic nerve. Left carotid angiography and vertebral angiography revealed a huge arteriovenous malformation in the left thalamus and basal ganglia extending to the left orbita. The arteriovenous malformation was fed from the C3 segment of the carotid artery, anterior, middle and posterior cerebral arteries, and drained to the internal cerebral vein and basal vein. The intraorbital part of the malformation was mainly fed from the external cerebral artery. She was diagnosed as Wyburn-Mason syndrome. We stressed in the paper that enhanced CT was useful for the diagnosis of the Wyburn-Mason syndrome.     

A case of Lambert-Eaton syndrome

A case of the myasthenic syndrome developing in the course of microcellular bronchogenic carcinoma with involvement in the early period of the syndrome of muscles with bulbar innervation is described. Myasthenic symptoms responded well to choline esterase inhibitors.     

A case of Behcet's syndrome

The author reports a case of Behcet's disease in a girl aged 18 years with recurrent lesions of the oral and vulvar mucosa, eyes and nervous system. The disease had a recurrent character with a tendency for progressing deterioration. Treatment was unsuccessful and the patient died.     

A case of poliomyelitis-like syndrome

The authors report the case of a boy aged 4 years who had sudden abdominal pain and inability to walk on the day before admission to hospital and who developed abdominal distention and difficulty urinating. On admission, the abdominal skin reflexes, knee jerks, cremaster and anal reflexes were absent and power in the lower extremities was reduced. Spinal fluid examination showed a cell count of 383/mm³, with 95% neutrophils and 5% lymphocytes; spinal fluid protein of 44 mg/dl; and glucose 75 mg/dl. Serological studies did not reveal any significant antibodies for polio virus type 1, 2, 3, various ECHO viruses, Coxsackie types A4, A7, A9, B1 or B5. However, the titer of Coxsackie virus antibody type A10 was 128 in the acute phase and only 32 in the recovery phase 4 weeks later. Magnetic resonance scans were performed on the second day; the findings were normal in the brain, but interesting lesions were revealed in the thoracic cord with both T1-weighted images and T2-weighted images. Neurological symptoms improved asymmetrically.