Walker-Warburg syndrome diagnosed by findings of typical ocular abnormalities on prenatal ultrasound

Walker-Warburg syndrome (WWS) is a rare, lethal autosomal recessive disorder characterized by congenital muscular dystrophy and brain and eye anomalies. A prenatal finding of hydrocephalus associated with posterior fossa anomalies and/or encephalocele is nonspecific, whereas additional ocular anomalies are typical for WWS. We report a fetus of consanguineous parents found to have encephalocele at US in week 15 of gestation. The parents did not wish to terminate the pregnancy. Follow-up US revealed bilateral abnormal ocular echoic structures suggesting a major form of persistent primary vitreous. WWS was suspected. The POMT2 mutation confirmed this diagnosis. In hydrocephalus associated with posterior fossa anomalies and/or encephalocele, we recommend detailed US examination of the fetal eyes. Ocular anomalies in this context strongly suggest WWS.     

Profound skeletal muscle depletion of alpha-dystroglycan in Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by the combined involvement of the central nervous and skeletal muscle systems. Although the molecular basis of WWS remains unknown, defects in the muscle fibre basal lamina are characteristic of other forms of congenital muscular dystrophy (CMD). In agreement with this, some forms of CMD, due to glycosyltransferase defects, display a reduction in the immunolabelling of alpha-dystroglycan, whilst beta-dystroglycan labelling appears normal. Here we describe an almost complete absence of alpha-dystroglycan using both immunohistochemistry and immunoblotting in two patients with WWS. In addition, there was a mild reduction of laminin-alpha 2. In contrast, immunohistochemical labelling of perlecan and collagen VI was normal. Linkage analysis excluded the recently identified POMT1 locus, responsible for a proportion of WWS cases. These results confirm that WWS is a genetically heterogeneous condition and suggest that disruption of the alpha-dystroglycan/laminin-alpha 2 axis in the basal lamina may play a role in the degeneration of muscle fibres in WWS-also in cases not due to POMT1 defects.     

Fukuyama-type congenital muscular dystrophy (FCMD) and alpha-dystroglycanopathy

ABSTRACT  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, lissencephaly, and eye anomalies. Through positional cloning, we identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein O -linked mannose β1, 2-N-acetylgIucosaminy ltransferase (POMGnT1), respectively. Recent studies have revealed that posttranslational modification of α-dystro-glycan is associated with these congenital muscular dystrophies with brain malformations. In this review Fukuyama-type congenital muscular dystrophy (FCMD), other CMDs with brain malformations, and their relation with α-dystroglycan are discussed.     

Congenital muscular dystrophies: muscle-eye-brain disease

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. We report on two brothers with MEB. The clinical and radiological characteristics are demonstrated.     

The congenital muscular dystrophies: recent advances and molecular insights.

Over the past decade, molecular understanding of the congenital muscular dystrophies (CMDs) has greatly expanded. The diseases can be classified into 3 major groups based on the affected genes and the location of their expressed protein: abnormalities of extracellular matrix proteins (LAMA2, COL6A1, COL6A2, COL6A3), abnormalities of membrane receptors for the extracellular matrix (fukutin, POMGnT1, POMT1, POMT2, FKRP, LARGE, and ITGA7), and abnormal endoplasmic reticulum protein (SEPN1). The diseases begin in the perinatal period or shortly thereafter. A specific diagnosis can be challenging because the muscle pathology is usually not distinctive. Immunostaining of muscle using a battery of antibodies can help define a disorder that will need confirmation by gene testing. In muscle diseases with overlapping pathological features, such as CMD, careful attention to the clinical clues (e.g., family history, central nervous system features) can help guide the battery of immunostains necessary to target an unequivocal diagnosis.     

Distinguishing Cardiac Features of a Novel Form of Congenital Muscular Dystrophy (Salih CMD)

The cardiac features of a novel form of congenital muscular dystrophy (Salih CMD) are described in two adolescent siblings. The patients presented with severe hypotonia at birth, associated with delayed development. They could walk independently and managed to maintain walking after 13 years of age. Their muscle immunohistochemistry differed from that seen in Duchenne and Becher muscular dystrophy (DMD and BMD), severe childhood autosomal recessive muscular dystrophy (SCARMD) due to sarcoglycan deficiency (sarcoglycanopathies), and lamininα2 (merosin)-deficient CMD. However, both patients had associated cardiomyopathy. Electrocardiography (ECG) in Salih CMD was characterized by delayed atrioventricular (AV) conduction, left anterior fascicular block (left axis deviation), and left atrial enlargement without evidence of atrial dysarrhythmia. Echocardiography showed features of severe left ventricular dysfunction with estimated left ventricle ejection fraction (LVEF) of 25% at 16 years-of-age in the older patient. A year later, multigated aquisition MUGA scan showed LVEF of 21% and dilatation of the right ventricle. Echocardiography and MUGA scan were normal in the younger patient at 15 years-of-age. ECG, echocardiography, and MUGA scan are effective techniques for diagnosing and monitoring the cardiomyopathy in Salih CMD. They can also distinguish it from features seen in the other common forms of MD, including DMD, BMD, and sarcoglycanopathies.     

先天性肌营养不良的诊断及层黏连蛋白表达的意义

目的 探讨先天性肌营养不良（CMD）的临床诊断、肌肉免疫组织化学特点及随访情况。方法 对8例CMD患儿的病例资料进行综合分析,并进行肌肉活检,利用抗层黏连蛋白以（laminin α2,又称merosin）、α抗肌萎缩相关糖蛋白（α-dystroglycan,α-DG）和β抗肌萎缩相关糖蛋白（β-dystroglycan,β-DG）抗体行肌肉活检组织免疫组织化学染色。结果 8例均于出生时或生后半年之内出现肌无力、肌张力低下,有的合并关节挛缩、喂养困难或呼吸功能不全。肌肉病理检查均发现肌营养不良改变特点。其中merosin染色阴性者4例,头颅MRI示脑白质髓鞘化不良;4例为merosin染色阳性,呈散发或常染色体隐性遗传,2例合并有智力低下,抗α-DG（1IH6）抗体染色显示α-DG糖基化低下,其中1例伴视神经萎缩,头颅MRI提示脑结构异常。结论 本组CMD中merosin染色既有阴性,也有阳性,merosin缺乏症（先天性肌营养不良1A型）更为常见,伴随脑白质病变。merosin染色阳性者中存在抗肌萎缩相关糖蛋白糖基化低下病例。     

Brain magnetic resonance imaging abnormalities in merosin-positive congenital muscular dystrophy.

We report the brain magnetic resonance imaging (MRI) findings in 23 patients with merosin-positive congenital muscular dystrophy (CMD). Twelve patients had normal scans. Eight other children had essentially normal scans but showed mild non-specific periventricular white matter changes. Three children had structural abnormalities on imaging. The first patient, a 15-month-old boy with hypotonia, muscle weakness and global development delay, had moderate cerebellar atrophy and mild dilatation of the lateral ventricles. The second child, a 3-year-old ambulant girl with subtle learning problems, had mild cerebellar hypoplasia and a large subarachnoid space when scanned at 16 months. The third patient, a 15-year-old ambulant male with normal intelligence and complex partial seizures, had polymicrogyria of both temporoparietal lobes on brain MRI. The clinical features and motor ability of children with merosin-positive CMD are variable, although usually milder than merosin-deficient CMD. Our findings confirm that central nervous system involvement can occur in some merosin-positive cases. We suggest performing brain MRI in children with merosin-positive CMD, as this may help in our understanding of this very heterogeneous disease.     

先天性肌营养不良1A型患儿临床特征及LAMA2变异分析：病例报告1例及文献复习

LAMA2双等位基因致病性变异导致先天性肌营养不良1A型（CMD1A）。该研究患儿为19月龄男孩，临床表现为运动发育落后，伴血清肌酸激酶、转氨酶及乳酸脱氢酶升高。遗传学分析发现患儿LAMA2基因存在复合杂合变异，其中母源性c.7147C > T （p.Ala2383Ter）为已报道的无义变异，而父源性c.8551_8552insAA （p.Ile2852ArgfsTer2）为未报道的移码变异，且根据ACMG指南确定为致病性变异。该患儿最终确诊为CMD1A。国内外文献复习发现：该病患儿多在生后6个月内起病，以严重的运动发育落后为特点，伴有血清肌酸激酶升高，可有脑白质受累的影像学改变；LAMA2基因变异具有明显的异质性，且绝大部分属于零效变异；目前CMD1A患儿无特异性治疗，远期预后不良。     

Clinical and Histopathological Study of Merosin-deficient and Merosin-positive Congenital Muscular Dystrophy

The clinical features of merosin-positive congenital muscular dystrophy (CMD) and merosin-deficient CMD are well known, with those of merosin-deficient CMD being more severe. Whether the severity of histopathological findings correlates with these clinical features remains unanswered. In this study, the clinical and histopathological findings of 39 merosin-deficient and 37 merosin-positive CMD patients were compared. Merosin-deficient CMD patients were found to be younger, with earlier onset of symptoms, age of diagnosis, and a more severe clinical state (reflecting maximum motor capacity and contractures). On histopathological evaluation, endomysial fibrosis, perimysial fibrosis, and histopathological state (reflecting fibrosis, adiposis, necrosis, and variation in fiber size) were more severe in merosin-deficient CMD. There was a correlation between clinical and histopathological states only in merosin-deficient CMD. Received January 15, 1999; accepted April 7, 1999.     

An unusual case of congenital muscular dystrophy with normal serum CK level, external ophtalmoplegia, and white matter changes on brain MRI

We report a sporadic case of congenital muscular dystrophy (CMD) in a 13-year-old girl with early manifestation of muscle weakness and hypotonia, severe contractures, bulbar syndrome, progressive external ophtalmoplegia, and white matter changes on magnetic resonance imaging (MRI) of the brain, but no mental defect. Serum creatine kinase (CK) level was normal. Muscle biopsy revealed a dystrophic picture with a prominent inflammatory infiltrate mimicking inflammatory myopathy-typical histological findings in CMD. Immunostaining showed normal expression of merosin, alpha and beta-dystroglycans. Mutation analyses of calpain3, dysferlin, and SEPN1 genes were negative. An electron microscopy revealed the accumulation of abnormally enlarged mitochondria located under the sarcolemma. Measurement of respiratory chain enzyme activities did not reveal any biochemical defect and mitochondrial genetic studies, including sequencing of the entire mitochondrial genome, were unremarkable. Phenotypic presentation of our patient is very unusual and differs considerably from other CMD variants.     

Congenital muscular dystrophy,brain malformation and ocular problems (muscle,eye and brain disease) in two german families

We report on two brothers and an unrelated girl with congenital muscular dystrophy (CMD), brain malformation and ocular changes (strabismus, myopia, glaucoma, cataracts, retinal dystrophy). Correlations with the inherited autosomal recessive syndromes of CMD, including the Fukuyama-type CMD with CNS malformation, and the Muscle, Eye and Brain Disease published by Santavuori are discussed.     

A fourth case of POMT2-related limb girdle muscle dystrophy with mild reduction of α-dystroglycan glycosylation

BackgroundPOMT2 mutations have been identified in Walker–Warburg syndrome or muscle–eye–brain-like, but rarely in limb girdle muscular dystrophy (LGMD).ResultsTwo POMT2 mutations, one null and one missense, were found in a patient with LGMD and mild mental impairment, no brain or ocular involvement, minor histopathological features, and slight reduction of α-dystroglycan (α-DG) glycosylation and α-DG laminin binding.ConclusionsOur case, the fourth LGMD POMT2-mutated reported to date, provides further evidence of correlation between level of α-DG glycosylation and phenotype severity.     

Congenital Muscular Dystrophies -Problems of Classification

The classification of congenital muscular dystrophies (CMD), based on perceived clinical and morphological similarities or differences, is controversial. CMD without cerebral involvement has sometimes been divided into a mild and a severe form. This distinction is, however, arbitrary and not uncontested. Whether Ullrich's disease, formerly called atonic-sclerotic dystrophy, is a disease entity and if so, whether it is a primary muscle disorder, is uncertain. CMD without cerebral involvement is inherited in an autosomal recessive fashion in the great majority of cases. CMDs with cerebral involvement are usually classified into at least three forms: the Fukuyama type of CMD, occurring almost exclusively in Japanese patients; CMD with hypomyelination, sometimes also called the occidental type of cerebromuscular dystrophy; and Walker-Warburg syndrome. Muscle-eye-brain disease, described in a number of Finnish patients, may or may not belong in this last category. In CMD with cerebral involvement inheritance is also autosomal recessive. It is possible that single sporadic cases are pheno-copies due to infectious or other exogenous causes. Reports of clinical and morphological findings from an increasing number of patients show a high degree of variability within and, on the other hand, certain similarities between the forms of CMD with cerebral involvement. In addition, neuroradiological changes are also found with increasing frequency in CMD patients without clinical neuropsychological abnormalities. It is not unreasonable to speculate that molecular genetic techniques will reveal in the near future a variable defect in one gene locus or defects in a few gene loci as the cause of the various clinical forms of CMDs.     

LAMA2 stop-codon mutation: Merosin-deficient congenital muscular dystrophy with occipital polymicrogyria,epilepsy and psychomotor regression

Merosin-deficient congenital muscular dystrophy (MD) type 1A (MDC1A) is one of the most frequent forms of CMD in Western countries.The classical form, characterized by a total lack of laminin α2 chain expression, usually shows severe clinical features; cases with complete laminin α2 deficiency and mild phenotype have also been reported, although the mechanisms underlying the lack of genotype–phenotype correlation have not been elucidated. Epilepsy and focal cortical dysplasia—in addition to the classical diffuse white matter abnormalities—have been described in some of these patients associated with cognitive deterioration.We report on a patient with total laminin α2 deficiency due to a homozygous stop-codon mutation in the LAMA2 gene, with mild evolution. When 6.9 years old, she developed focal occipital seizures and absence-like status when awake, with probable relation to an extensive bilateral occipital micropolygyria. Soon afterwards she lost ambulation and developed cognitive deterioration.Our case confirms that the clinical spectrum of MDC1A is more heterogeneous than previously thought.     

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目的探讨金属蛋白酶组织抑制剂-1(TIMP-1)在进行性肌营养不良(PMD)发病中的作用。方法中国医科大学附属第一医院等单位于2002年4月至2003年3月,借助免疫组织化学、双免疫荧光标记和Western印迹分析的方法,检测Duchenne型肌营养不良(DMD)、Becker型肌营养不良(BMD)和先天性肌营养不良(CMD)患儿活检肌肉标本中TIMP-1的表达和细胞定位。结果免疫组织化学和双免疫荧光标记结果显示TIMP-1在正常肌肉的血管内皮细胞处表达;免疫组织化学和Western印迹分析均显示在PMD萎缩的肌肉中TIMP-1的表达明显增强;双免疫荧光标记进一步显示TIMP-1在再生肌肉纤维、巨噬细胞和巨噬细胞浸润的坏死纤维中明显表达,DMD和CMD肌肉中的肌内膜和肌束膜中某些激活的成纤维细胞也强烈表达TIMP-1。结论在PMD病变部位TIMP-1产生增多及其分布类型提示TIMP-1可能参与了PMD的发病。     

Lethal Congenital Muscular Dystrophy with Arthrogryposis Multiplex Congenita: Three New Cases and Review of the Literature

Congenital muscular dystrophy (CMD) comprises a heterogeneous group of muscle disorders. We report on two stillborn sibs with early lethal CMD and a prematurely born boy who died within minutes after birth. The pregnancies were complicated by polyhydramnios. All presented with arthrogryposis multiplex congenita, severe muscle wasting, lung hypoplasia, and hydrops. The muscle biopsies showed fibrosis, variation in fiber size, and extensive fat replacement compatible with muscular dystrophy. Fatal CMD seems to be distinct from CMD with survival after birth and is probably autosomal recessively inherited.     

Merosin-deficient congenital muscular dystrophy and cortical dysplasia.

Congenital muscular dystrophy (CMD) encompasses a heterogenous group of muscle disorders with autosomal recessive inheritance, characterized by muscular weakness and hypotonia at birth or within the first few months of life and developmental delay. Merosin-deficient CMD is a clinically distinct form which may be associated with significant abnormalities of the brain detectable by neuroimaging. We report two siblings of consanguineous parents with merosin-deficient CMD in an Irish family who in addition to the characteristic white matter abnormalities on neuroimaging, had occipital dysplasia. Clinical, electrophysiological muscle biopsy findings and neuroimaging were very similar in both cases. Although merosin-deficient CMD with white matter abnormalities on neuroimaging is well documented in the literature, the association with occipital dysplasia has only rarely been reported. The appearance of an identical cortical defect in these siblings suggests an underlying genetic mechanism.     

进行性肌营养不良患者血浆金属蛋白酶组织抑制剂-1和转化生长因子-β1水平检测(英文)

目的：伴随着肌纤维变性 再生的肌内异常结缔组织增生为肌营养不良的一个特征。金属蛋白酶组织抑制剂 (TIMPs)是多功能蛋白,能改变细胞活性和调节基质转变。转化生长因子 β1(TGF β1)也促进组织纤维化。该文探讨TIMP 1和TGF β1在各种肌营养不良发病机制中的作用。 方法：用ELISA法检测几种肌营养不良患者血浆TIMP 1和TGF β1水平。 结果：Duchenne肌营养不良 (DMD)血浆TIMP 1水平为 12 2 .5 2±6 3.87ng/ml,在先天性肌营养不良 (CMD)为 12 4 .87± 6 3.14ng/ml,较对照组 (85 .71± 2 9.13ng/ml)明显升高 (均P <0 .0 5 ) ,但在Becker型肌营养不良 (BMD)为 86 .93± 4 8.93ng/ml,与对照组比较无明显升高 ;血浆TGF β1水平在DMD为 2 6 .2 6± 5 .79ng/ml,CMD为 31.35± 9.77ng/ml,也较对照组 (6 .2 4± 1.12ng/ml)明显升高 ,差异有显著性 ,均P <0 .0 5 ,但在BMD为 3.4 6± 1.38ng/ml,无升高 ;而且TIMP 1和TGF β1浓度有明显的相关性。结论：血浆TIMP 1和TGF β1水平在DMD和CMD中明显升高 ,而BMD中未见明显升高 ,似乎与肌营养不良的临床严重性相关 ,表明TIMP 1和TGF β1在肌营养不良的发病中可能起作用。     

Congenital muscular dystrophy with laminin α2 chain deficiency: Identification of a new intermediate phenotype and correlation of clinical findings to muscle immunohistochemistry

The laminins comprise of a family of heterotrimeric proteins of the extracellular matrix. The cross-shaped proteins consist of a heavy α-chain and two light chains, called β and γ. Each group of chains, classified on their sequence identity and domain organization, include different isoforms. A deficiency of the α2 chain of laminin-2, previously termed merosin or M component, was shown to be responsible for one form of congenital muscular dystrophy (CMD). We investigated muscle biopsies of 20 patients with the clinical diagnosis of CMD and histological evidence of muscular dystrophy for the expression of different laminin chains. Patients with evidence of pachygyria/lissencephaly of the CNS were excluded from this series. The immunohistochemical analysis was correlated to clinical findings and MRI data of the brain. Of 20 patients, 11 (55%) revealed complete or near-complete deficiency of the α2 chain in their skeletal muscle specimens. So far none of these patients became ambulant. Of 20 patients 2 showed partial but clear-cut α2 chain-deficiency. These two patients became ambulant at 18 months and 3 years. All 13 patients with complete or partial α2 chain-deficiency demonstrated cerebral white matter changes on MRI. In contrast, 6/7 CMD patients with normal α2 chain expression became ambulant and none of the 6/7 tested showed evidence of cerebral abnormal T2 sequence signal of the myelin on MRI.