Broader clinical spectrum of Fukuyama-type congenital muscular dystrophy manifested by haplotype analysis

Fukuyama-type congenital muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease are clinically similar autosomal-recessive diseases, characterized by congenital muscular dystrophy, cobblestone lissencephaly, and eye anomalies. The classification of these disorders remains controversial. We analyzed five patients with congenital muscular dystrophy from four families who had severe eye and brain anomalies, such as retinal dysplasia and hydrocephalus, using polymorphic microsatellite markers flanking the Fukuyama-type congenital muscular dystrophy locus on chromosome 9q31. All patients were heterozygous for the Fukuyama muscular dystrophy founder haplotype with 3-kb insertion. In three cases, the other chromosome without the 3-kb insertion exhibited the same haplotype with a nonsense mutation on exon 3 of the Fukuyama gene. Thus, these three patients were compound heterozygotes for the condition. Severe eye anomalies such as retinal dysplasia or detachment and hydrocephalus could be included in the clinical spectrum of Fukuyama muscular dystrophy. The clinical spectrum of this disease is much broader than previously presumed.     

A new form of alpha-dystroglycanopathy associated with severe drug-resistant epilepsy and unusual EEG features

We describe two unrelated girls with congenital muscular dystrophy associated with alpha-dystroglycan deficit with no identified genetic defect, both presenting severe drug-resistant epilepsy with predominant myoclonic seizures and an unusual similar EEG pattern. Severe epilepsy has been unusually described in patients with congenital muscular dystrophies, mainly associated with Walker-Warburg, Fukuyama and muscle-eye-brain diseases. [Published with video sequences].     

Congenital muscular dystrophy with cerebral and ocular malformations (cerebro-oculo-muscular syndrome)

Two children with the features of the "Muscle, Eye and Brain (MEB) Disease" (SANTAVUORI 1977), i.e. congenital muscular dystrophy (CMD), cerebral malformations and ocular abnormalities are reported and correlations with other inherited autosomal recessive syndromes of CMD, Fukuyama type of CMD and the Walker-Warburg syndrome discussed. The association of CMD and cerebral lesions indicate an unfavourable clinical prognosis.     

Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging

Children with merosin-deficient congenital muscular dystrophy (CMD) have striking white matter changes on T-2 weighted brain magnetic resonance imaging (MRI). There have been occasional cases with structural abnormalities, mainly involving the occipital cortex. We report our brain imaging findings in 14 children with merosin-deficient CMD. Ten cases had a severe reduction or absence of merosin on immunocytochemistry and four cases had partial reduction. All 14 cases had white matter changes, which appeared after the first 6 months of life and persisted with time. The changes were diffuse and the oldest child scanned (14 years) also showed involvement of the U fibres. Five children with total absence of merosin also had structural abnormalities. One child had moderate mental retardation and epilepsy, mainly characterised by complex partial seizures, with atypical absences, which had been difficult to treat. Brain MRI showed marked occipital agyria and pontocerebellar hypoplasia. The gyral pattern of the rest of the brain looked normal. The four other cases, all with normal intelligence, also had cerebellar hypoplasia with variable involvement of the pons. They did not, however, have neuronal migration defects. It is recognised that several forms of congenital muscular dystrophy, namely Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, have structural brain abnormalities and associated severe mental retardation. Our cases demonstrate that a range of structural malformations can also be found in a significant number of children with merosin-deficient CMD.     

Congenital muscular dystrophy with adducted thumbs,ptosis, external ophthalmoplegia,mental retardation and cerebellar hypoplasia: a novel form of CMD

At least six different forms of congenital muscular dystrophy are associated with structural changes of the central nervous system, and three of these have been mapped: merosin-deficient congenital muscular dystrophy on chromosome 6q2, Fukuyama congenital muscular dystrophy on chromosome 9q31, and muscle eye brain disease on chromosome 1p32. Walker-Warburg syndrome, congenital muscular dystrophy with calf hypertrophy, pontocerebellar hypoplasia, and normal eyes, and congenital muscular dystrophy with severe mental retardation and cerebellar cysts are nosologically distinct and have been excluded from the known congenital muscular dystrophy loci with structural changes of the central nervous system. Here, we describe a novel congenital muscular dystrophy syndrome which is phenotypically distinct from the recognized forms of congenital muscular dystrophy with brain involvement. Two siblings, a boy and a girl, were born to consanguineous parents from Sicily. Both children were born with adducted thumbs and toe contractures. They were floppy from birth, walked late, showed profound generalized muscle weakness including facial muscles, elevated creatine kinase levels of 200-700U/l, and histological changes compatible with muscular dystrophy. In addition, both showed ptosis, external ophthalmoplegia, mild mental retardation, and mild cerebellar hypoplasia on MRI. Immunocytochemistry showed normal expression of muscle membrane proteins including laminin alpha 2, laminin beta 2, and alpha-dystroglycan. Linkage analysis excluded the candidate loci on chromosomes 6q2, 9q31, and 1q32. The gene locus for congenital muscular dystrophy 1B, MDC 1B, on chromosome 1q42 was also excluded. Adducted thumbs are a distinct clinical sign that has not been reported in congenital muscular dystrophy before and should facilitate recognition of further patients with this disorder.     

Alpha-dystroglycanopathy (FCMD, MEB, etc): abnormal glycosylation and muscular dystrophy]

Fukuyama congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are similar disorders characterized by congenital muscular dystrophy, brain and eye anomalies. We previously identified the genes for FCMD and MEB, which encode fukutin and POMGnT1. Recent studies have revealed that posttranslational modification of alpha-dystroglycan is associated with congenital muscular dystrophy with brain malformations. Since hypoglycosylation of alpha-dystroglycan is common amongst several other disorders, a new clinical entity called alpha-dystroglycanopathy is proposed. However, only POMGnT1 (MEB) and POMT1 (WWS) are shown to have a definite enzymatic activity, and no enzymatic activity has been detected in fukutin. We show positive interactions between fukutin and POMGnT1. Fukutin may form a protein complex with POMGnT1 and modulate POMGnT1's enzymatic activity. Through cDNA microarray, we also show aberrant neuromuscular junction formation and delayed muscle fiber maturation in alpha-dystroglycanopathies, suggesting a new pathomechanism.     

Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype

Six genes including POMT1, POMT2, POMGNT1, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of α-dystroglycan (α-DG). Abnormal glycosylation of α-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and 1D and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described.     

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.     

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.     

Cerebro-ocular dysplasia — muscular dystrophy (Walker Warburg) syndrome

Summary A 20-week fetus affected with cerebro-ocular dysplasia and muscular dystrophy (Walker-Warburg Syndrome) is reported. The central nervous system (CNS) findings were typical of those previously described in this disorder, and were characterized by lissencephaly, hydrocephalus, and cerebral and cerebellar cortical dysplasia with glial and neuronal displacement into the leptomeninges. In addition, severe hypoplasia of pyramidal tracts were noted in the brain stem and spinal cord, as well as malformation of the inferior olivary and dentate nuclei. Skeletal muscle and eyes appeared normal on light microscopy. The genetic defect in this disorder is expressed in the CNS early during the first trimester and causes a marked disorder of cellular migration. Overt changes in muscle occur during a later period. The changes in the CNS are similar to, but more severe than, those found in Fukuyama congenital muscular dystrophy, and both may represent a failure of constraint of neuronal migration. Whether the syndromes characterized by cerebro-ocular dysplasia and muscular dystrophy are genetically heterogeneous or allelic variations is unknown. Molecular genetic analysis should elucidate this question.     

Immature astrocytes in Fukuyama congenital muscular dystrophy: an immunohistochemical study

Recent studies of Fukuyama congenital muscular dystrophy have focused on abnormalities of the basement membrane in muscle and brain. The cerebral cortex has a unique basement membrane at the glia limitans, which is intimately related to astrocytes in the developing brain, and the basement membrane may be partially produced by the astrocyte. In this study the cerebral astrocytes in six patients with Fukuyama congenital muscular dystrophy, including two fetal patients, were characterized by immunohistochemical study. In fetal Fukuyama congenital muscular dystrophy, astrocytes reacted less to antibodies of glial fibrillary acidic protein, S-100 protein, and alphaB-crystallin than control astrocytes, but in postnatal Fukuyama congenital muscular dystrophy, astrocytes reacted more to these antibodies and displayed beading of processes. Moreover, vimentin was positive in the astrocytes of two postnatal Fukuyama congenital muscular dystrophy patients. This astrocytic appearance may suggest immaturity of astrocytes in Fukuyama congenital muscular dystrophy. Astrocytes exhibiting beaded cytoplasmic processes were prominent at the subpia of the cortex and around vessels. The authors hypothesize that these immature astrocytes are unable to participate in the function of the cortical basement membrane, which is defective in Fukuyama congenital muscular dystrophy. Studies of neurons and meninges were similar to those of control subjects.     

Congenital muscular dystrophy: A review of the literature

Congenital muscular dystrophy (CMD) is a condition in which there are already at birth, marked hypotonia, generalized muscle weakness and frequently multiple contractures. CMD has recently been classified into four categories: CMD I, the classical or ‘pure’ CMD without severe impairment of intellectual development; CMD II, the Fukuyama type CMD with muscle and structural brain abnormalities; CMD III and IV with muscle, eye and brain abnormalities: the milder Finnish type CMD (CMD III) and the severe Walker-Warburg syndrome (CMD IV). Data of the literature concerning those different CMD types have been reviewed and are presented with emphasis on signs and symptoms, clinical course, laboratory, neurophysiological, radiological, morphological and genetic characteristics.     

Merosin-positive congenital muscular dystrophy with mental retardation, microcephaly and central nervous system abnormalities unlinked to the Fukuyama muscular dystrophy and muscular-eye-brain loci: report of three siblings

Classical merosin (2 laminin)-positive congenital muscular dystrophy is a heterogeneous subgroup of disorders; a few cases characterized by severe mental retardation, brain involvement and no ocular abnormalities were called Fukuyama-like congenital muscular dystrophy. We report a family of healthy non-consanguineous parents, with four affected siblings, of which one died at the age of 7 months due to an intercurrent illness, who presented congenital hypotonia, severe mental retardation, microcephaly, delayed psychomotor development, generalized muscular wasting and weakness with mild facial involvement, calf pseudohypertrophy, joint contractures and areflexia. Muscle biopsy disclosed severe muscular dystrophy. Immunostaining for laminin 2 80 kDa and clone Mer3/22B2 monoclonal antibodies, 1 and 1 chain was preserved. Magnetic resonance imaging findings were consistent with pontocerebellar hypoplasia, bilateral opercular abnormalities and focal cortical dysplasia as well as minute periventricular white matter changes. Clusters of small T2-weighted focal hyperintensities in both cerebellar hemispheres consistent with cysts were observed in two of the three siblings studied with magnetic resonance imaging. Ophthalmologic and cardiologic examination was normal. Haplotype analysis using microsatellite markers excluded the Fukuyama congenital muscular dystrophy, LAMA2 and muscle-eye-brain disease loci. Thus, a wider spectrum of phenotypes, gene defects and protein deficiencies might be involved in congenital muscular dystrophy with brain abnormalities.     

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.     

Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy

OBJECTIVE: Defects in glycosylation of alpha-dystroglycan are associated with several forms of muscular dystrophy, often characterized by congenital onset and severe structural brain involvement, collectively known as dystroglycanopathies. Six causative genes have been identified in these disorders including fukutin. Mutations in fukutin cause Fukuyama congenital muscular dystrophy. This is the second most common form of muscular dystrophy in Japan and is invariably associated with mental retardation and structural brain defects. The aim of this study was to determine the genetic defect in two white families with a dystroglycanopathy. METHODS: The six genes responsible for dystroglycanopathies were studied in three children with a severe reduction of alpha-dystroglycan in skeletal muscle. RESULTS: We identified pathogenic fukutin mutations in these two families. Affected children had normal intelligence and brain structure and shared a limb girdle muscular dystrophy (LGMD) phenotype, had marked elevation of serum creatine kinase, and were all ambulant with remarkable steroid responsiveness. INTERPRETATION: Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L.     

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.     

Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome

We describe four Italian patients (aged 3, 4, 12, and 13 years ) affected by a novel autosomal form of recessive congenital muscular dystrophy. These patients were from three non-consanguineous families and presented an almost identical phenotype. This was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absent speech, inability to walk and almost no interest in their surroundings. In addition, all patients had a striking enlargement of the calf and quadriceps muscles. Ophthalmologic examination revealed no structural ocular abnormalities in any of the children; one patient had severe myopia. In all cases a magnetic resonance imaging of the brain showed an abnormal posterior cranial fossa with enlargement of the cisterna magna and variable hypoplasia of the vermis of the cerebellum. Abnormality of the white matter was also present in all patients, in the form of patchy signal most evident in the periventricular areas. Serum CK was grossly elevated in all. The muscle biopsy from all cases showed dystrophic changes compatible with congenital muscular dystrophy. Immunofluorescence studies showed mild to moderate partial deficiency of laminin 2 chain. Linkage analysis in the only informative family excluded the known loci for congenital muscular dystrophy, including laminin 2 chain on chromosome 6q2, the Fukuyama congenital muscular dystrophy locus on 9q3 and the muscle-eye-brain disease on chromosome 1p3. We propose that this represent a novel severe variant of congenital muscular dystrophy, with associated central nervous system involvement.     

Oxidative stress in the brain of Fukuyama type congenital muscular dystrophy: immunohistochemical study on astrocytes

Astrocytes in the cerebrum and medulla oblongata of cases of Fukuyama type congenital muscular dystrophy were examined by immunohistochemistry of oxidative modification products and free-radical scavenging enzymes because abnormal glia limitans formed by astrocytic end feet is considered to be involved in the genesis of brain lesions of Fukuywama type congenital muscular dystrophy. The study was performed on two fetal cases of Fukuyama type congenital muscular dystrophy of 18 and 20 weeks' gestation and seven patients with Fukuyama type congenital muscular dystrophy ranging in age from 2 to 27 years. Eight age-matched control cases were used. Polymerase chain reaction (PCR) was performed to ascertain the gene phenotype of two child cases, in which prenatal gene analysis was not performed. Astrocytes, especially layer I astrocytes, of postnatal cases of Fukuyama type congenital muscular dystrophy were weakly positivefor Nepsilon-(carboxymethyl)lysine and argpyrimidine, suggesting that they were sensitive to oxidative stress, and the accumulation may be related to the abnormal glia limitans. Secondary increase of manganese (Mn) superoxide dismutase against the increase of free radicals was considered in patients with Fukuyama type congenital muscular dystrophy more than 14 years old considered to be homozygous for founder haplotype: homozygosity was suggested by PCR in two cases. In contrast, expression of Mn superoxide dismutase was decreased in 2- and 6-year-old children with Fukuyama type congenital muscular dystrophy that were heterozygous. Moreover, accumulation of argpyrimidine was exclusively found in astrocytes of the 2-year-old child that exhibited severe brain lesions. Function of astrocytes might be impaired or immature in severe or heterozygous cases. These results may confirm that astrocytes play an important role in the etiology of the brain lesion.     

Progressive myopathy with circulating autoantibody against giantin in the Golgi apparatus

A woman aged 59 years with adult-onset progressive myopathy had anti-Golgi (giantin) autoantibody in the serum. Limb-muscle biopsy revealed chronic myopathy with paucity of cellular reactions and reduced immunostaining for alpha-dystroglycan. The similarity of the current patient with cases of hereditary alpha-dystroglycanopathies (Fukuyama-type congenital muscular dystrophy, Walker-Warburg syndrome, muscle-eye-brain disease, congenital muscular dystrophy type 1C, and limb-girdle muscular dystrophy type 2I) suggests that the Golgi apparatus is the target organelle in a subset of myopathies.     

Congenital muscular dystrophy with glycosylation defects of alpha-dystroglycan in Japan

Glycosylation defects of alpha-dystroglycan (alpha-DG) cause various muscular dystrophies. We performed clinical, pathological and genetic analyses of 62 Japanese patients with congenital muscular dystrophy, whose skeletal muscle showed deficiency of glycosylated form of alpha-DG. We found, the first Japanese patient with congenital muscular dystrophy 1C with a novel compound heterozygous mutation in the fukutin-related protein gene. Fukuyama-type congenital muscular dystrophy was genetically confirmed in 54 of 62 patients. Two patients with muscle-eye-brain disease and one Walker-Warburg syndrome were also genetically confirmed. Four patients had no mutation in any known genes associated with glycosylation of alpha-DG. Interestingly, the molecular mass of alpha-DG in the skeletal muscle was similar and was reduced to approximately 90 kDa among these patients, even though the causative gene and the clinico-pathological severity were different. This result suggests that other factors can modify clinical features of the patients with glycosylation defects of alpha-DG.