The gross motor function measure is valid for Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is the second most common muscular dystrophy in Japan. FCMD is an autosomal recessive disorder caused by mutations in the fukutin gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities, and mental retardation associated with cortical migration defects, and most patients are never able to walk. To date, the development of a quantitative motor scale for FMCD has been difficult due to the moderate-to-severe intellectual impairment that accompanies FCMD. Gross motor function measure (GMFM), originally developed as a quantitative motor scale for cerebral palsy, can precisely and quantitatively assess motor function without complicated instructions, and was recently reported to be useful in the assessment of Down syndrome and spinal muscular atrophy. To confirm the validity of GMFM for the assessment of FCMD, 41 FCMD patients (age range: 0.6–24.4 years) were recruited for this study. The GMFM scores correlated significantly with those of two previously used motor scales, and the time-dependent change in GMFM scores was consistent with the natural course of FCMD. The inter-rater reliability, based on determinations made by four physiotherapists blinded to each other's assessment results, was excellent. We concluded GMFM to be a useful and valid measure of motor function in FCMD patients.     

A genetic study of the Fukuyama type congenital muscular dystrophy

A genetic study was carried out on 153 families with 186 Fukuyama type congenital progressive muscular dystrophy (FCMD) patients. Consanguineous marriage of parents was found in 41 families (26.80%). Inbreeding coefficients in the patients was 10 times as high as that of the general population. Both sexes were almost equally affected (M:F = 1.1:1.0). No single parent of the patients was affected. Recurrence among siblings was frequent (9 out of 41 siblings in offspring of related parents and 18 out of 110 siblings in offspring of unrelated parents were affected. The segregation ratio was 23.91-27.08% in offspring of related parents, 20.00-22.94% in offspring of unrelated parents, these values being not significantly different from the 25% expected from the assumption of autosomal recessive mode of inheritance. In the sample two twin pairs were included, of which one male isosexual pair was concordant. Sporadic cases were not significantly more numerous than expected. All these data indicate that the disorder is caused by homozygosity of an autosomal recessive gene. Frequency of the gene was estimated to be 5.2-9.7 X 10(-3) and frequency of the patients 6.9-11.9 X 10(-5). Mutation rate was estimated to be 6.9-11.9 X 10(-5).     

Epilepsy in patients with advanced Fukuyama congenital muscular dystrophy

BackgroundRecent advances in respiratory management have improved survival for patients with Fukuyama congenital muscular dystrophy (FCMD), characterized by congenital muscular dystrophy and brain malformation. Previous studies reported that more than half of patients exhibit seizures in childhood. However, little is known about epilepsy after childhood.MethodsTo elucidate the long-term clinical course of epilepsy, we retrospectively reviewed all medical records in nine patients (6 males, mean age 20.7 years) with FCMD diagnosed between 1981 and 2019.ResultsThe follow-up periods ranged from 6 to 30 years (mean 18.4 years). A total of 75 EEG recordings were available from nine patients. In some patients, EEGs were normal during early childhood but tended to show paroxysmal discharges with age. Overall, epileptic seizures were observed in six patients. Except for one presenting with afebrile seizure at one year of age, the remaining five patients developed epilepsy between 13 and 22 years of age. The most common seizure type was focal impaired awareness seizure. After adolescence, four patients exhibited status epilepticus. Their convulsive movements of the seizures became less prominent with progression of the disease. At the last evaluation, most patients (5/6) had uncontrolled seizures.ConclusionsDespite presence of distinct brain malformation, epileptic seizures may develop after childhood in FCMD patients. Our experience suggests that clinicians should be careful not to overlook epileptic seizures, especially in advanced-stage patients who had profound muscle weakness.     

Altered glycosylation of alpha-dystroglycan in neurons of Fukuyama congenital muscular dystrophy brains

To test the hypothesis that the disruption of fukutin protein produces the brain pathology through hypoglycosylation of alpha-dystroglycan (alpha-DG), we immunostained Fukuyama congenital muscular dystrophy (FCMD) brains with an antibody that recognizes the polysaccharide epitope of alpha-DG. Immunoreactivity of the glia-limitans along the cortical surface, as well as that of the glial endfeet around vessel walls, was preserved in the FCMD cerebrum. However, fragmentation of the immunostained glia-limitans was noted in association with parenchymal protrusion and gyral fusion. In the FCMD cerebellum, this fragmentation of alpha-DG labeling was limited to the area of micropolygyria, and immunostaining at the glia-limitans and vessel walls was comparable to that of the control brains, in structurally normal areas. In the hippocampus, neurons of the dentate gyrus and corpus ammonis were immunopositive for alpha-DG in control subjects, but this staining was markedly decreased in FCMD brains. In contrast, immunolabeling of blood vessels and the glia-limitans was preserved in this region. Fukutin antisera clearly labeled hippocampal neurons in control brains, while this labeling was decreased in FCMD brains. Thus, hypoglycosylation of alpha-DG was evident in neurons, but not in the glial cell population of FCMD brains. This suggests that the mechanism of alpha-DG glycosylation may differ between neurons and glial cells, and that a fukutin gene defect may result in functional disruption through hypoglycosylation of both neuronal and glial alpha-DG.     

Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy

Background

One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited.

Fukuyama type congenital muscular dystrophy as a natural model of childhood epilepsy.

Fukuyama type Congenital Muscular Dystrophy, inherited autosomal-recessively, is characterized by muscular dystrophy associated with severe mental retardation and epileptic convulsions. By examining 56 cases, followed for more than three years, 75 EEG records from 40 patients and visual evoked potentials from 11 patients with reference to autopsied materials, the authors aimed at clarifying the causative relationship between congenital central nervous system (CNS) lesions and childhood epilepsy. In 36 out of 56 cases diffuse epileptic seizures were observed with onset at 1.64 +/- 1.01 years average. In 32/36 cases seizures developed before 3 years of age. In 51/75 EEGs focal paroxysmal discharges (FPD), fronto-contro-parietal in younger and centro-occipital in older cases, were observed. Abnormal basic activities (ABA), diffuse-alpha-activity and/or abundant or extreme spindles, were observed more often in older than younger cases. The incidence of FPD was similar between convulsive and non-convulsive cases, but ABA predominated in the former, VEP revealed abnormal findings in 64% of 11 cases examined. Of the CNS pathology, consisting of cerebral and cerebellar gyral abnormalities and a hypoplastic corticospinal tract, the gyral lesions (verrucous polymicrogyria with adhesions of adjacent gyri and cellular disarrangement) were thought to be lesions causing epilepsy. Cortical nonprogressive gyral lesions occurring around the second trimester could cause FPD and clinical diffuse epileptic seizures develop with other factors concerned with ABA.     

Renal dysfunction is rare in Fukuyama congenital muscular dystrophy

Background

The leading cause of death in patients with Fukuyama congenital muscular dystrophy (FCMD) is congestive heart failure or respiratory dysfunction, which is same as that in Duchenne muscular dystrophy (DMD). Recent studies reported that renal dysfunction is a common complication and an increasing cause of death in advanced DMD. It can be attributable to circulatory instability or inappropriate use of drugs for treating cardiac dysfunction.

Fukuyama congenital muscular dystrophy: Cortical dysplasia of the cerebrum in a 20 week fetus

This report describes cerebral cortical dysplasia in a 20 week fetus, aborted as a result of the prenatal genetic analysis which provided evidence of Fukuyama congenital muscular dystrophy (FCMD). The histological appearance of the brain of this fetus was similar to that of previously described cases. However, cortical dysplasia was less severe in this 20 week fetus, and the interesting finding was the existence of a leptomeningeal lesion probably preceding dysplasia. In this case, abnormal findings were found mainly in the cerebral surface, and maturation of the brain seemed appropriate for the gestational age. Furthermore, periodic acid-methenamine-silver-positive linear structure of the cerebral surface was disrupted irregularly. These findings suggest that defects in the pial-glial barrier of the cerebral surface may play a cardinal role for the genesis of cortical dysplasia. It is suggested that the extracortical abnormal tissue would be detectable morphologically at least in the 12-13th week because cells considered as subpial granular cells were contained in the lesion. This report on the brain of a fetus with FCMD provides information on relatively early central nervous system alterations in this disease, and may be of importance in clarifying their pathogenesis.     

Infection-associated decrease of serum creatine kinase levels in Fukuyama congenital muscular dystrophy

BackgroundMarked decreases in serum creatine kinase levels have been noted in Duchenne and Becker muscular dystrophies as rare complications of autoimmune or autoinflammatory diseases.Subjects and methodsThe influence of systemic inflammation on serum creatine kinase levels was reviewed from the charts of three subjects with Fukuyama congenital muscular dystrophy.ResultsA total of 30 infectious events were identified. Elevated serum C-reactive protein levels coincided with decreased creatine kinase levels on 19 occasions. In one subject, administration of 2 mg/kg/d prednisolone for bronchial asthma resulted in a decrease in creatine kinase level on six other occasions.ConclusionApart from an increase in endogenous cortisol secretion, certain inflammation-related molecules could play a role in mitigating muscle cell damage in Fukuyama congenital muscular dystrophy during febrile infectious episodes. Corticosteroids may be a promising agent for the treatment of muscular symptoms in this disorder.     

Small size of orthogonal array in muscle plasma membrane of Fukuyama type congenital muscular dystrophy

Summary Freeze fracture analysis was carried out on the density of orthogonal array subunit particles in the plasma membrane of skeletal muscle of six patients with Fukuyama type congenital muscular dystrophy and seven control cases. The group mean density of orthogonal array subunit particles per one orthogonal array was significantly lower in the plasma membrane of Fukuyama patients. The results suggested the possible impairment of orthogonal array function in the plasma membrane of muscle fibers in congenital muscular dystrophy of the Fukuyama type.Supported in part by grant from the National Center for Nervous, Mental and Muscular Disorders of the Ministry of Health and Welfare (No. 85-04-34), Japan     

Severe muscle damage following viral infection in patients with Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD), which is characterized by cortical migration defect and eye abnormalities, is the most common subtype of CMD in Japan. Fukutin (FKTN), the responsible gene for FCMD, encodes a protein involved in the glycosylation of alpha-dystroglycan. We have experienced some patients with FCMD who showed sudden exacerbation of muscle weakness with marked elevation of serum creatine kinase (CK) and urinary myoglobin levels a few days after a febrile episode of viral infection, occasionally leading to death. To describe this peculiar phenomenon, we focused on 12 patients who developed a sudden exacerbation of muscle weakness among 96 genetically defined FCMD patients and hospitalized because of a febrile illness at Tokyo Women's Medical University between 1997 and 2008. All the 12 patients were homozygous for a 3-kb insertion mutation of FKTN. The patients developed exacerbation of muscle weakness ranging from paralysis to loss of head control. The onset was concentrated in summer, and coxsackieviruses and enteroviruses were most often detected, especially in infantile patients. Eight of the 12 patients were treated with corticosteroids and recovered within 2 weeks. Four patients were treated without steroid, and needed 18.5 days on mean for improvement. None developed renal failure. The reason for muscle damage induced by viral infection remains unknown; however, physicians should consider its risk, sometimes leading to death, and draw it to parents' attention, especially in the defervescent stage.     

Localization of laminin subunits in the central nervous system in Fukuyama congenital muscular dystrophy: an immunohistochemical investigation

We have undertaken an immunohistochemical study of laminin subunits in the central nervous system (CNS) of fetuses and patients with Fukuyama congenital muscular dystrophy (FCMD) and of controls including five fetuses. Immunoreaction product deposits with antibodies to laminin α1, α2, β1 and γ1, and β-dystroglycan were detected on the surface and vessels of the CNS of controls. No staining with anti-α-sarcoglycan antibody was detected in the CNS. Neurons and glia did not react with any of the antibodies used. In utero expression of laminin subunits and β-dystroglycan seemed to be lower in the cerebrum than in the spinal cord. Moreover, immunostaining for laminin α2 and β1 tended to be weak on the fetal spinal cord surface. Expression of laminin subunits and dystrophin-associated proteins in the CNS may be modulated during development, as in the skeletal muscle. The distribution of immunoreaction product deposits was basically the same in FCMD and controls, although laminin α2 and β-dystroglycan expression appeared to be decreased in the CNS of the FCMD cases. Defects of the pial-glial barrier of the fetal brain surface have been considered the main cause of micropolygyria in FCMD, and these observations suggest that the co-localization and secondary loss of these proteins in association with the unknown product(s) of the FCMD gene might be involved in the CNS lesions of this disorder. Received: 15 July 1996 / Revised, accepted: 13 January 1997     

Novel FKRP mutations in a Japanese MDC1C sibship clinically diagnosed with Fukuyama congenital muscular dystrophy

Introduction

Fukuyama congenital muscular dystrophy (FCMD), caused by fukutin mutations, is the most common form of Japanese CMD. We followed a Japanese CMD sibship without fukutin mutation, and herein identified new FKRP mutations causing MDC1C rarely reported in Oriental countries.

A Portuguese case of Fukuyama congenital muscular dystrophy caused by a multi-exonic duplication in the fukutin gene

Fukuyama congenital muscular dystrophy (FCMD) is one of the most common autosomal recessive diseases among the Japanese population, due to a founder mutation of the fukutin gene (FKTN). Mutations in FKTN are now being described in an increasing number of non-Japanese patients. We report a Portuguese child with FCMD. The diagnosis was supported by clinical, histological, magnetic resonance imaging (MRI) and genetic studies. Genetic analysis of FKTN by Multiplex Ligation Probe Amplification (MLPA) revealed a homozygous duplication from exon 4 to exon 7. This in-frame duplication was confirmed by cDNA analysis. To our knowledge this is the first report of a FCMD case caused by an intragenic gross exonic duplication in the FKTN gene. This report widens the clinical and mutational spectrum in FCMD and corroborates the importance of screening for large deletions and duplications in CMD patients.     

Fukuyama-type congenital muscular dystrophy: a case report in the Japanese population living in Brazil

INTRODUCTION: We present herein clinical, histological and magnetic resonance imaging (MRI) findings in a patient with Fukuyama-type congenital muscular dystrophy (FCMD). He is the first case report in the Japanese population living in Brazil. CASE REPORT: The child presented with neonatal hypotonia, delayed motor abilities and speech, seizures, cerebral and cerebellar gyrus abnormalities with signal intensity change in the white matter by MRI, high serum level of creatinephosphokinase (CK), and dystrophic skeletal muscle with normal merosin, alpha-sarcoglycan and dystrophin expression. The fukutin gene study showed one founder 3-kb retrotransposal insertion in the 3'-non-coding region, and in the other allele no mutation was detected after screening all exons and flanking introns by sequencing. DISCUSSION: This case report emphasizes the importance to consider FCMD in Japanese people living in other countries.     

Merosin-deficient congenital muscular dystrophy in Korea

Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of muscle disorders, presenting at birth or early infancy with hypotonia, muscle weakness, joint contractures, and dystrophic changes in the muscles. Merosin-deficient CMD (MDCMD) is rare in Asian populations, but more common in Caucasians, comprising about 50% of CMDs. We report, for the first time in Korea, eight patients with merosin-deficient CMD, confirmed by immunohistochemical staining of muscle or skin samples. We also describe their wide spectrum of clinical features and neuroimaging findings. Among 35 patients diagnosed as CMD, almost 23% of them were proved to have MDCMD with typical phenotypic presentation. We infer that prevalence of MDCMD in Korea may not be as low as expected. One of the patients was diagnosed by skin biopsy, which is good alternative for diagnosis of MDCMD.     

Experimental intrauterine infection of akabane virus. Pathological studies of skeletal muscles and central nervous system of newborn hamsters with relevances to the Fukuyama type congenital muscular dystrophy

A vertical infection system in hamsters produced by inoculating with Akabane virus was established as an experimental model of congenital muscular dystrophy (Fukuyama type) (FCMD) and arthrogryposis multiplex congenita (AMC) in humans. Swollen fetuses, mummified fetuses, arthrogryposis and cranial deformities were produced in 13 of 415 newborn hamsters inoculated transplacentally (3.1%). The incidence was significantly higher than that in the control group (p less than 0.05). Eight cases presenting apparent abnormalities were examined histologically and virologically. Pictures of skeletal muscles showing such immature features as chains of internal nuclei and myotubular muscle fibers were demonstrated in all cases. In addition, perivascular infiltration of small round cells and thickening of vascular walls were seen in 5 cases, while myogenic changes such as broken myofibrils, small muscle fibers and changes in fiber size were observed in 6 cases. In the anterior horn of the spinal cord, swelling and loss of nuclei and cell matrices were noticed in 4 cases. In the cerebral cortex, disarrangement of cell layers, edematous changes and loss of nerve cells were revealed in 5 cases. In 4 cases virus particles were found on electron microscopy in the cerebral cortex. The authors considered that this experimental system of intrauterine viral infection would be useful for the etiological study of FCMD and AMC in humans in which not only skeletal muscles but also the central nervous system is affected congenitally.     

A new congenital muscular dystrophy with mitochondrial structural abnormalities

We report a new form of congenital muscular dystrophy (CMD) in 4 patients from three unrelated families with probable autosomal-recessive inheritance. All patients had the clinical characteristics of merosin-positive congenital muscular dystrophy, but had marked mental retardation. The disease was slowly progressive and 1 patient died from dilated cardiomyopathy at the age of 13 years. In addition to dystrophic changes with necrosis and regeneration in muscle, the most striking finding was mitochondrial depletion in the center of the sarcoplasm. Mitochondria at the periphery of fibers were markedly enlarged (“megaconial” appearance) with complicated cristae, and contained a normal amount of mitochondrial DNA by in situ hybridization. Mitochondrial enlargement may represent functional compensation for mitochondrial depletion in the central sarcoplasm, where myofibrillar degeneration occurred. © 1998 John Wiley & Sons, Inc. Muscle Nerve, 21: 40–47, 1998.