Disease relevance of FCMD

• Muscle eye brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations [1].
• These phenomena are quite similar to those found in Duchenne muscular dystrophy (DMD) at the preclinical stage and suggest an as yet undetermined process in blood vessels in FCMD as well as DMD [2].
• Four boys, all from the sixth generation of the same family, were afflicted with severe neuromuscular diseases beginning in early life, three of them presenting the typical phenotype of FCMD and one, that of DMD [3].
• The association of congenital muscular dystrophy with brain changes and ocular anomalies were found in FCMD, muscle, eye and brain disease (MEB) and Walker-Warburg syndrome (WWS) [4].
• Our survey of 33 cases with FCMD revealed that high myopia and optic atrophy are common in FCMD [4].

Psychiatry related information on FCMD

• Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci [5].

High impact information on FCMD

• Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain [6].
• Multipoint analysis placed FCMD between D9S58 and D9S59, with a maximum lod score of 16.93 [6].
• Twenty-one FCMD families, 13 of them with consanguineous marriages, were analysed by genetic linkage analyses with polymorphic microsatellite markers to map the FCMD gene [6].
• Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33 [6].
• Two independent point mutations confirm that mutation of this gene is responsible for FCMD [7].

Chemical compound and disease context of FCMD

• The behavior of the tubular system in muscles from six patients with Fukuyama type congenital muscular dystrophy (FCMD) was examined by electron microscopy using a lanthanum nitrate stain for a comparison with that in Duchenne muscular dystrophy (DMD) [8].
• Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy [9].
• 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 [10].

Biological context of FCMD

• Recently FCMD was localized to chromosome 9q31-33 by linkage [11].
• Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation [12].
• Thus, the present study yielded molecular genetic evidence of a broad clinical spectrum in FCMD [12].
• Y371C, a missense mutation found in FCMD, retains fukutin in the ER and also redirects POMGnT1 to the ER [13].
• The biopsied six muscles with FCMD, six histochemically normal muscles and eight disease control muscles were analyzed by means of immunoblots, immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR) [14].

Anatomical context of FCMD

• Selective deletion of dystroglycan in the central nervous system (CNS) produces brain abnormalities with striking similarities to WWS, MEB, FCMD and the myd mouse [15].
• Decrease of glycosylated alpha-dystroglycan has been reported in the skeletal muscle of FCMD, MEB, and WWS [16].
• In situ hybridization reveals that fukutin, POMGnT1, and POMT1 are expressed especially in astrocytes [16].
• Disruption of the basal lamina in FCMD muscle was also seen [17].
• Pathological study of brain tissue from FCMD fetuses revealed frequent breaks in the glia limitans and basement membrane complex [17].

Associations of FCMD with chemical compounds

• The FCMD gene encodes a protein of unknown function, fukutin, though sequence analysis predicts it to be a phosphoryl-ligand transferase [18].
• The function of fukutin is not known yet, but is suggested to be an enzyme that modifies the cell-surface glycoprotein or glycolipids [19].
• Immunoreactivities for vimentin, glutamate transporter-1, glutamine synthase and ornithine aminotransferase, expressed in the Müller cells, were undetectable in the fetal FCMD retinas, and reduced in the postnatal FCMD retinas compared with the control retinas [20].
• Freeze-fracture analysis of cholesterol in muscle plasma membrane of Fukuyama-type congenital muscular dystrophy [21].
• 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 [22].

Other interactions of FCMD

• Here we identify the gene for a new member of the fukutin protein family (fukutin related protein [FKRP]), mapping to human chromosome 19q13 [18].
• The quantitative RT-PCR demonstrated that the AQP4 mRNA level of the FCMD muscles was markedly reduced [14].
• On the other hand, there were no FCMD homozygotes but four heterozygous carriers among 335 patients with DMD mutations [23].
• Fukutin, POMGnT1, and POMT1 are expressed in immature neurons, suggesting they are also involved in neuronal migration itself [16].
• A number of the perivascular glial cells containing S-100 protein and glial fibrillary acidic protein were increased in the postnatal FCMD cases [20].

Analytical, diagnostic and therapeutic context of FCMD

• The immunohistochemistry revealed that most of the FCMD myofibers showed negative immunostaining with anti-AQP4 antibody, although the partially positive immunostaining of sporadic FCMD myofibers was noted [14].
• Differential diagnosis of FCMD from Duchenne and Becker muscular dystrophies (DMD/BMD) or other types of congenital muscular dystrophy is occasionally difficult, because of their phenotypic similarity [23].
• In FCMD muscle, we found a significant reduction of laminin M (merosin; a striated muscle specific basal lamina-associated protein) with approximately 26% of levels seen in controls by quantitative immunofluorescence [24].
• Direct interaction between fukutin and POMGnT1 was confirmed by co-immunoprecipitation and two-hybrid analyses [13].
• Recent identification of the FCMD gene locus at 9q31-q33 provided the basis for prenatal diagnosis and carrier detection [25].

References