MDDGA4 is a severe autosomal recessive muscular dystrophy-dystroglycanopathy with characteristic brain and eye malformations, seizures, and mental retardation. Cardiac involvement in FCMD/MEB occurs in the second decade of life in those who survive. FKTN-related Walker-Warburg syndrome is a ... MDDGA4 is a severe autosomal recessive muscular dystrophy-dystroglycanopathy with characteristic brain and eye malformations, seizures, and mental retardation. Cardiac involvement in FCMD/MEB occurs in the second decade of life in those who survive. FKTN-related Walker-Warburg syndrome is a more severe manifestation of the disorder, with death usually in the first year of life. These entities are part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007; Muntoni and Voit, 2004; Muntoni et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
This disorder has been described as FCMD/muscle-eye-brain disease (MEB) and the more severe Walker-Warburg syndrome; these designations have been retained here when used in the literature.
Fukuyama ... This disorder has been described as FCMD/muscle-eye-brain disease (MEB) and the more severe Walker-Warburg syndrome; these designations have been retained here when used in the literature. - Fukuyama Congenital Muscular Dystrophy/FKTN-Related Muscle-Eye-Brain Disease Fukuyama et al. (1960) described a novel form of congenital muscular dystrophy. Parental consanguinity was present in 6 families; in 2 sibships, multiple cases were observed. Fukuyama et al. (1981) stated that more than 200 cases had been recognized clinically in Japan. Patients manifest generalized muscle weakness and hypotonia from early infancy and most are unable to walk without support. All are mentally retarded and some have seizures, abnormal electroencephalograms, and abnormal CT scans. The brain malformations in FCMD include cerebral and cerebellar micropolygyria, fibroglial proliferation of the leptomeninges, hydrocephalus, focal interhemispheric fusion, and hypoplasia of the corticospinal tracts. Histologic changes in skeletal muscle were similar to those of Duchenne muscular dystrophy (DMD; 310200) (Nonaka et al., 1982). Caucasian patients were studied by Dambska et al. (1982). Miura and Shirasawa (1987) described severe myocardial fibrosis in the autopsy of a 17-year-old Japanese male. Aida et al. (1994) demonstrated cerebellar polymicrogyria and the presence of cerebellar cysts related to the polymicrogyria in 23 of 25 patients with congenital muscular dystrophy. These 2 changes on MRI are distinctive enough to suggest the radiologic diagnosis of this disorder. Yoshioka and Kuroki (1994) performed clinical and genetic studies in 41 families with FCMD in Japan in an attempt to distinguish it from the Walker-Warburg syndrome and muscle-eye-brain disease, both of which, like FCMD, show an association of type II lissencephaly and ocular anomalies. Two or more children were affected in 9 families. Parental consanguinity was documented in 5 of the 32 sporadic cases and in none of the familial cases. In evaluations of 7 sib pairs, a difference between sibs in motor ability was apparent in 4. Mental status also showed wide variation. The EEG findings differed in 2 of 7 sib pairs. The familial FCMD patients showed relatively more severe motor disability than that in the sporadic FCMD patients, whereas the status in regard to mental function and convulsions showed no significant difference in the 2 groups. In 1 family, hydrocephalus was found in only 1 of the sibs; in addition, this patient showed encephalocele and retinal detachment at birth. Yoshioka and Kuroki (1994) emphasized the broad clinical spectrum of FCMD and the phenotypic overlap with mild WWS and MEB disease. Toda et al. (1995) used polymorphic microsatellites flanking the FCMD locus on 9q31-q33 (see MAPPING) to study a family in which 3 sibs were affected with either FCMD or WWS. One sib was labeled as FCMD because he showed severe hypotonia with dystrophic findings on a muscle biopsy, in addition to pachygyria on computed tomographic scan. At the age of 3 years, retinal detachment developed in both eyes. The second pregnancy resulted in a male infant with anencephaly who survived for 5 minutes. At birth, the third sib exhibited pachygyria, cephalocele, hydrocephalus, bilateral retinal detachment, elevated serum creatine kinase, and arthrogryposis multiplex congenita, all features consistent with Walker-Warburg syndrome. Haplotype analysis demonstrated identity of each allele in the 2 surviving sibs. The parents were nonconsanguineous, and the disease-related haplotypes were different on the 2 alleles of the patients. Toda et al. (1995) presented this as evidence that the 2 disorders may be allelic. Godfrey et al. (2007) identified 1 patient with FKTN-related FCMD/MEB among a larger study of 92 probands with muscular dystrophy and evidence of a dystroglycanopathy. Although clinical details were limited, the patient had infantile onset, only achieved sitting, muscle hypertrophy, increased serum creatine kinase, and low IQ. There were no eye abnormalities, but brain MRI showed cerebellar cysts, white matter abnormalities, and hydrocephalus. As part of the larger study, Godfrey et al. (2007) defined FCMD/MEB as congenital onset of muscular dystrophy with fronto-parietal pachygyria, cerebellar dysplasia, and frequent flattening of the pons and brainstem. Eye abnormalities are often seen, and rare patients may acquire the ability to walk or learn a few words. Vuillaumier-Barrot et al. (2009) reported 2 Portuguese sisters with mental retardation and muscular dystrophy associated with compound heterozygous mutations in the FKTN gene (A170E, 607440.0016; Y371C, 607440.0017). Both had congenital hip dislocation, congenital hypotonia, and delayed motor development. Muscle weakness was diffuse and progressive with axial and proximal limb predominance and moderate facial involvement; both had significantly increased serum creatine kinase. One sister lost the ability to walk in the first decade of life and developed multiple contractures and severe respiratory insufficiency. She was mentally retarded and had epileptic seizures from age 13 years. The other sister had knee contractures from the first year of life, spinal rigidity, and scoliosis. She developed severe and progressive restrictive respiratory insufficiency and nondilated left ventricular dysfunction in her teens. At age 19 years, she had diffuse amyotrophy, severe multiple joint contractures, and a stiff hyperextended neck. Both were mentally retarded, but 1 had significantly better verbal abilities. Brain MRI showed brainstem atrophy, marked cerebellar vermis hypoplasia and cysts, and cortical brain atrophy. One patient had cerebellar polymicrogyria. Vuillaumier-Barrot et al. (2009) commented that few patients outside of Japan had been reported with this disorder. Tunc et al. (2009) reported a female infant with FCMD, born of consanguineous Turkish parents, who had severe hypotonia and abnormal limb movements. Just after birth, she showed rhythmic and jerky movements of all 4 limbs both spontaneously and in response to stimulus, but associated with a normal EEG. The findings were consistent with hyperekplexia. Brain imaging showed absent corpus callosum, lissencephaly, pachygyria, ventricular dilatation, subcortical white matter abnormalities, and brainstem and cerebellar hypoplasia. She died at day 15. Xiong et al. (2009) reported a Chinese boy with FCMD. He showed hypotonia from birth, achieved head control at age 2 years, and sat unsupported at age 4 years, but was unable to slide on his buttocks. He developed progressive knee and ankle contractures since age 1 year. He had facial muscle and generalized muscle weakness with severe muscle atrophy, but hypertrophy of the calf muscle. Brain MRI showed patchy periventricular hyperintensities, frontal lobe polymicrogyria, cerebellar cysts, and cerebellar and brainstem hypoplasia. IQ was 52, and he spoke only a few words. Muscle biopsy showed prominent dystrophic features and decreased alpha-dystroglycan staining. Genetic analysis identified compound heterozygosity for 2 mutations in the fukutin gene: the common Japanese founder allele (607440.0001) and R47X (607440.0002). Although the boy's parents were born in Henan and Shanxi Provinces and had no known Japanese ancestry, haplotype analysis showed that both mutant alleles were on Japanese-derived haplotypes. - FKTN-Related Walker-Warburg Syndrome Silan et al. (2003) reported a Turkish patient with a severe congenital muscular dystrophy phenotype most closely resembling Walker-Warburg syndrome. The patient presented at birth with hypotonia, hydrocephalus, respiratory difficulties, ocular abnormalities, and elevated muscle enzymes, and died on the tenth day of life. Postmortem examination revealed severe malformations of the central nervous system, including agyria and cortical disorganization, and congenital muscular dystrophy. Beltran-Valero de Bernabe et al. (2003) reported a Turkish patient with Walker-Warburg syndrome. Born to second-degree consanguineous parents, the patient had macrocephaly, anterior chamber abnormalities, severe hypotonia, and severe brain malformations, including hydrocephalus, agyria/pachygyria, absent corpus callosum and cerebellar vermis, and white matter hyperlucencies. The patient died at 4.5 months of age. Godfrey et al. (2007) identified 1 patient with FKTN-related WWS among a larger study of 92 probands with muscular dystrophy and evidence of a dystroglycanopathy. Although clinical details were limited, the patient had neonatal onset, contractures, muscle hypertrophy, and increased serum creatine kinase. Eye abnormalities included retinal detachment and microphthalmia. Brain MRI showed cerebellar hypoplasia, white matter abnormalities, hydrocephalus, and brainstem involvement. As part of the larger study, Godfrey et al. (2007) defined WWS as prenatal onset or onset at birth of no motor development and severe structural brain abnormalities, including complete agyria or severe lissencephaly, marked hydrocephalus, severe cerebellar involvement and complete or partial absence of the corpus callosum. Common eye abnormalities included congenital cataracts, microphthalmia, and buphthalmos. Death usually occurred before 1 year of age. Genetic analysis identified a homozygous truncating mutation in the FKTN gene (R307X; 607440.0018). Cotarelo et al. (2008) described a Spanish female infant, born of nonconsanguineous parents, who was diagnosed with Walker-Warburg syndrome and died on day 5 of life after suffering respiratory apnea and bradycardia. She had a dysmorphic face with low-set malformed ears, left preauricular tag, thoracic hemivertebrae, and cardiac defects. Brain CT scan showed overriding cranial bones, severe left microphthalmia, monolobar holoprosencephaly, and internal and external hydrocephalus. Cortex and white matter could not be differentiated, and no details could be observed in the posterior fossa. At autopsy, the medial aspect of the brain showed an interhemispheric cyst, incomplete cleavage of the thalamus and corpora quadrigemina, an absent corpus callosum, and rhombencephalic hypoplasia. Punctate hemorrhages were seen in the parenchyma, and ventriculitis was identified. An atrial septal defect (foramen ovale), double subaortic ventricular defect, hypoplastic left ventricle outlet, stenotic pulmonary valve, and infundibular transposition of the great vessels with no innominate vein were also found. The eyes were malformed and exhibited retinal dysplasia.
Kondo-Iida et al. (1999) noted that the frequency of severe phenotypes, including Walker-Warburg syndrome-like manifestations such as hydrocephalus and microphthalmia, was significantly higher among probands who were compound heterozygotes carrying a point mutation on one allele and a ... Kondo-Iida et al. (1999) noted that the frequency of severe phenotypes, including Walker-Warburg syndrome-like manifestations such as hydrocephalus and microphthalmia, was significantly higher among probands who were compound heterozygotes carrying a point mutation on one allele and a founder mutation on the other, than among probands who were homozygous for the 3-kb retrotransposon (607440.0001). Remarkably, they detected no FCMD patients with nonfounder (point) mutations on both alleles of the gene, suggesting that such cases might be embryonic lethal. This could explain why few FCMD cases are reported in non-Japanese populations. Their results provided strong evidence that loss of function of fukutin is the major cause of FCMD, and appeared to shed some light on the mechanism responsible for the broad clinical spectrum seen in this disorder. To establish a genotype-phenotype correlation, Saito et al. (2000) performed haplotype analysis using microsatellite markers closest to the FKTN gene in 56 Japanese FCMD families, including 35 families whose children were diagnosed as FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 probands with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder haplotype, whereas the other 2 were heterozygous for the haplotype. Of the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmologic abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype were heterozygous for the ancestral founder haplotype, and the other 1 homozygous for the haplotype. Saito et al. (2000) confirmed that at least 1 chromosome in each of the 56 FCMD patients had the ancestral founder haplotype. The rate of heterozygosity for this haplotype was significantly higher in severe cases than in typical or mild cases (P less than 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation.
Kobayashi et al. (1998) described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. They reported that there is a ... Kobayashi et al. (1998) described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. They reported that there is a retrotransposal insertion (607440.0001) of tandemly repeated sequences in the FKTN gene in all FCMD chromosomes carrying the founder haplotype (87%). The authors stated that FCMD is the first human disease known to be caused by an ancient retrotransposal integration. Two independent point mutations (607440.0002 and 607440.0003) in patients with FCMD confirmed that mutation in this gene is responsible for FCMD. Kondo-Iida et al. (1999) performed a systematic analysis of the FKTN gene in 107 unrelated patients and identified 4 novel nonfounder mutations in 5 of them: 1 missense, 1 nonsense, 1 L1 insertion (607440.0004), and one 1-bp insertion (607440.0005). Silan et al. (2003) identified a homozygous truncating mutation in the FKTN gene (607440.0006) in a Turkish patient with WWS. The first-cousin parents and an unaffected brother were heterozygous for the mutation. Silan et al. (2003) noted that this was the first reported case of a fukutin mutation found outside the Japanese population and the first reported case of a homozygous nonfounder mutation, which was believed to be embryonic lethal. Although the patient may be considered to have Fukuyama congenital muscular dystrophy (253800) because of the mutation in the FKTN gene, the authors noted that classification of the disease in this patient may be difficult because the phenotype was slightly different and more closely resembled Walker-Warburg syndrome. In a Turkish patient with WWS, Beltran-Valero de Bernabe et al. (2003) identified a homozygous nonsense mutation in the FKTN gene (607440.0007). The authors noted that the phenotype in this patient was more consistent with WWS than with FCMD, and established a genotype/phenotype correlation for fukutin mutations that cause complete loss of protein function. In a Spanish infant with WWS, Cotarelo et al. (2008) identified compound heterozygosity for 2 mutations in the FKTN gene (607440.0012 and 607440.0013). In cell lines from unrelated Ashkenazi Jewish parents and their son, who was diagnosed with WWS, Cotarelo et al. (2008) identified a 1-bp insertion in the FKTN gene (607440.0005) that had previously been identified in compound heterozygosity in patients with FCMD and a less severe form of muscular dystrophy (611588). The son was homozygous for the insertion, and the unaffected parents were heterozygous carriers.
Kobayashi et al. (1998) reported that the retroposon sequence insertion (607440.0001) was found in 125 of 144 (87%) FCMD chromosomes, whereas it was found in only 1 of 176 chromosomes in unrelated normal individuals; the frequency of 1 ... Kobayashi et al. (1998) reported that the retroposon sequence insertion (607440.0001) was found in 125 of 144 (87%) FCMD chromosomes, whereas it was found in only 1 of 176 chromosomes in unrelated normal individuals; the frequency of 1 in 88 individuals corresponded well to that of FCMD carriers in the Japanese population. Watanabe et al. (2005) developed a rapid PCR-based diagnostic method for detecting the FCMD retroposon insertion mutation using 3 primers simultaneously. Fifteen founder chromosomes were detected among 2,814 Japanese individuals. Heterozygous carriers were identified in various regions throughout Japan, with a carrier frequency of approximately 1 in 188. The insertion mutation was found in 1 in 935 Korean individuals but not among 203 Mongolians and 766 mainland Chinese, suggesting that FCMD carriers are rare outside Japan.
The diagnosis of Fukuyama congenital muscular dystrophy (FCMD) is suspected in individuals with the following findings [Fukuyama et al 1960, Fukuyama et al 1981, Osawa et al 1997, Saito & Kobayashi 2001]:...
DiagnosisClinical DiagnosisThe diagnosis of Fukuyama congenital muscular dystrophy (FCMD) is suspected in individuals with the following findings [Fukuyama et al 1960, Fukuyama et al 1981, Osawa et al 1997, Saito & Kobayashi 2001]:Early-infantile onset of hypotonia and weakness with contractures of the hips, knees, and interphalangeal joints (100%)Severe developmental delay with motor and speech retardation and intellectual disability in spite of relative preservation of socialization (100%)Static course until early childhood, followed by diffuse and extensive muscle wasting (most prominent proximally) and later progression of joint contractures (100%)Myopathic facial appearance (100%)Pseudohypertrophy of the calves and forearms in late infancy (50%)Seizures (febrile or afebrile) (50%)Ophthalmologic abnormalities, including visual impairment in 53% (15/28) and retinal abnormalities in 32% (9/28) [Saito & Kobayashi 2001]. Retinal abnormality when present is mild and focal. Retinal dysplasia, a pathologic diagnosis, is based on the finding of rosettes of immature photoreceptors.Family history consistent with autosomal recessive inheritanceNeuroimaging. MRI reveals the findings of cobblestone lissencephaly comprising five major abnormalities including: Irregular or pebbled brain surface, broad gyri with a thick cortex (pachygyria) in the frontal, parietal, and temporal regions, and sometimes areas of small and irregular gyri that resemble polymicrogyriaDilated lateral ventriclesWhite matter abnormality with hyperintensity on T2-weighted images and hypointensity on T1-weighted images [Kato et al 2000] indicative of delayed myelination [Kato et al 2006, Kato et al 2010] rather than dysmyelinationMild brain stem hypoplasia in someCerebellar polymicrogyria and cerebellar cysts (observed on MRI in 23 of 25 individuals with FCMD [Aida et al 1994]In addition:The cortex is typically no more than approximately 1 cm in thickness.The opercula are poorly developed, leaving an open Sylvian fissure.EMG findings are characteristic of muscular dystrophy.TestingSerum creatine kinase (CK) concentrationAge <6 years: 10-60 times higher than normalAge ≥7 years: 5-20 times higher than normalBed-ridden individuals: NormalMuscle biopsyFindings are characteristic of muscular dystrophy.Immunohistochemical staining using α-dystroglycan antibody reveals selective deficiency of α-dystroglycan on the surface membrane of skeletal muscle [Hayashi et al 2001].Note: (1) Fukutin antibody for immunohistochemical staining was not available until recently. (2) With the development of molecular genetic testing, muscle biopsy is no longer necessary to establish the diagnosis of FCMD.Molecular Genetic TestingGene. FKTN (known formerly as FCMD) is the only gene in which mutations are known to cause FCMD.Table 1. Summary of Molecular Genetic Testing Used in Fukuyama Congenital Muscular DystrophyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityJapaneseNon-JapaneseFKTN Targeted mutation analysisc.*4287_*4288ins3062 2See footnote 3See footnote 4ClinicalSequence analysis of coding and flanking intronic regionsSequence variants 5See footnotes 6, 7Sequence analysis of cDNA or targeted intronic sequencing 8mRNA variants, particularly intronic variants with splicing effects (e.g., pseudoexon mutation 9)UnknownSee footnote 41. The ability of the test method used to detect a mutation that is present in the indicated gene2. A. c.*4287_*4288ins3062, a 3 kb retrotransposonal insertion of tandemly repeated sequences into the 3' untranslated region of FKTN, is a Japanese founder mutation [Kato et al 2004].3. In an analysis of 117 Japanese individuals with FCMD: 94 (80%) were homozygous for the founder mutation; 17 (15%) were compound heterozygous for the founder mutation and an identifiable point mutation on the second allele (of the 17, 14 had the nonsense mutation p.Arg47*, two had the missense mutation p.Cys250Gly, and one had the missense mutation p.His172Arg in exon 5); and six (5%) were compound heterozygotes for the founder mutation and an unidentified mutation on the second allele [Saito, in preparation].4. Molecular genetic testing confirmed the clinical diagnosis of FCMD in 13 individuals of Korean heritage: two were homozygous for the Japanese founder retrotransposal insertion mutation; of the seven who were compound heterozygous for the retrotransposal insertion mutation, five had the novel intronic mutation (c.647+2084G>T) that is specific to the Korean population [Lim et al 2010].5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.6. Silan et al [2003] and de Bernabe et al [2003] independently reported two Turkish individuals with FCMD with an extremely severe phenotype that resembled Walker-Warburg syndrome (WWS) with homozygous FKTN nonsense mutations on both alleles. 7. Chang et al [2009] reported c.1167_1168insA as a founder mutation in Ashkenazi Jews with FCMD.8. From muscle or lymphocytes9. Lim et al [2010] reported a novel mutation (c.647+2084G>T; p.Arg216Serfs*10) that is specific to the Korean population. In this mutation a single base-pair change activates a pseudoexon between exon 5 and 6. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. For individuals who meet clinical criteria, have a high serum creatine kinase concentration, and have characteristic findings on neuroimaging, perform FKTN molecular genetic testing (See Figure 1. Diagnostic algorithm):FigureFigure 1. Diagnostic algorithm for FCMD 1.Perform targeted mutation analysis for the 3-kb founder insertion mutation in individuals of Japanese, Korean, and Chinese ancestries first.2.If only one or no mutation is identified, perform sequence analysis of the entire gene. Note: In persons of Korean descent, if only one or no mutation is identified, consider sequence analysis of cDNA or targeted intronic sequencing to detect the Korean founder mutation. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersDilated cardiomyopathy (DCM).FKTN mutations have been associated with DCM. Affected individuals had high serum CK concentration, mild or no muscle weakness, and normal intellect [Murakami et al 2006, Arimura et al 2008].Limb-girdle muscular dystrophy (LGMD). Godfrey et al [2006] and Godfrey et al [2007] reported individuals not of Japanese ancestry who had LGMD2M caused by compound heterozygous FKTN mutations; central nervous system involvement was not observed. Puckett et al [2009] described two brothers of northern European and Japanese ancestry who had LGMD caused by compound heterozygous FKTN mutations; intellect was normal.Walker-Warburg syndrome (WWS). Homozygosity for the FKTN Ashkenazi Jewish founder mutation c.1167insA was reported in four non-consanguineous Ashkenazi Jewish families with WWS [Chang et al 2009]. (See Congenital Muscular Dystrophy Overview.)
Fukuyama congenital muscular dystrophy (FCMD) is characterized by dystrophic changes in the skeletal muscle and by CNS migration disturbances resulting in cerebral and cerebellar cortical dysplasia. The clinical features are hypotonia, weakness, and psychomotor retardation. Mild, typical, and severe phenotypes are recognized. The phenotypic spectrum ranges from a Walker-Warburg syndrome (WWS)-like phenotype at the severe end [Chang et al 2009] to a limb-girdle muscular dystrophy-like phenotype at the mild end [Akiyama et al 2006, Godfrey et al 2006, Godfrey et al 2007, Puckett et al 2009]....
Natural HistoryFukuyama congenital muscular dystrophy (FCMD) is characterized by dystrophic changes in the skeletal muscle and by CNS migration disturbances resulting in cerebral and cerebellar cortical dysplasia. The clinical features are hypotonia, weakness, and psychomotor retardation. Mild, typical, and severe phenotypes are recognized. The phenotypic spectrum ranges from a Walker-Warburg syndrome (WWS)-like phenotype at the severe end [Chang et al 2009] to a limb-girdle muscular dystrophy-like phenotype at the mild end [Akiyama et al 2006, Godfrey et al 2006, Godfrey et al 2007, Puckett et al 2009].Disease onset typically occurs in early infancy. Initial symptoms include poor suck, mildly weak cry, floppiness, and motor developmental delay. Symmetric generalized muscle weakness and hypotonia are present. Some infants exhibit poor weight gain.Predominantly proximal hypotonia manifests as hyperextensibility of the shoulders and trunk. Limitation of hip extension, hip abduction, and knee extension is also observed and increases with time. 'Puffy' cheeks and pseudohypertrophy of the calves and forearms are evident in late infancy. Muscles are hard with a fibrous texture. Deep tendon reflexes are diminished or absent after early infancy. Facial muscle involvement (myopathic facies) is obvious from age six to 12 months and increases with age [Osawa et al 1997]. Open mouth, prognathism, and macroglossia become more evident in childhood. Swallowing difficulty develops after age six years.Developmental delay and speech delay occur in all individuals. IQ range is usually 30 to 60. In individuals with mild FCMD, the IQ is more than 35; in individuals with severe FCMD the IQ is less than 30. The maximum development in an individual with typical FCMD often consists of dozens of spoken words, sitting without help, or sliding along the floor on the buttocks. Individuals with mild FCMD may achieve independent walking or standing. Individuals with severe FCMD may lack head control or the ability to sit independently.Social development of individuals with FCMD is not as severely affected as physical and mental abilities [Saito & Kobayashi 2001]. Children with FCMD tend to be the favorites in their nursery, kindergarten, or primary school. Even severely affected individuals with FCMD show eye contact, recognize family members, and make demands through vocalizations. Autistic features are not observed.Seizures occur in more than 50% of affected individuals [Osawa et al 1997]. In nearly 80% of children with seizures, the seizures manifest between age one year [Osawa et al 1997] and age three years [Yoshioka & Higuchi 2005], or after age six years.Ocular abnormalities include refractive error (myopia and hypermetropia) in 40%-53% of individuals. Abnormalities of the retina are seen in 32% of those with more severe FCMD [Chijiiwa et al 1983, Tsutsumi et al 1989, Osawa et al 1997]; however, retinal dysplasia is mild and focal. In a few individuals with severe FCMD confirmed with molecular genetic testing, severe ocular anomalies included microphthalmia, retinal detachment, retinal hypoplasia, and cataracts [Mishima et al 1985, Hino et al 2001, Saito & Kobayashi 2001]. Of note, the characteristic ocular findings of muscle-eye-brain disease (MEBD) or WWS (e.g., anterior chamber abnormalities, glaucoma) are not present in FCMD. (For more information on the eye findings in these disorders, see Congenital Muscular Dystrophy Overview.)Slowly progressive cardiac involvement is characteristic of FCMD. Individuals who live more than ten years tend to develop fibrosis of the myocardium, as evidenced by postmortem findings [Miura & Shirasawa 1987, Finsterer et al 2010]. In an evaluation of left ventricular (LV) function using M-mode and Doppler echocardiography in 34 individuals with FCMD, eight of 11 individuals over age 15 years showed decreased LV systolic function [Nakanishi et al 2006]. Swallowing dysfunction is observed in individuals with infantile FCMD (especially severe FCMD) and also in individuals with advanced disease over age ten years. Inability to swallow leads to recurrent aspiration pneumonia and death [Hill et al 2004].Murakami et al [2012] reported 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.Neuropathology. Examination of the brain in FCMD shows changes consistent with cobblestone (previously type II) lissencephaly with cerebral and cerebellar cortical dysplasia caused by a defect in neuronal migration [Takada et al 1987, Nakano et al 1996, Yamamoto et al 1996, Yamamoto et al 1997a, Yamamoto et al 1997b, Yamamoto et al 1997c, Saito et al 2000b]. These changes are similar to but typically less severe than the abnormalities described in MEBD and WWS.Infantile cases can show extensive areas of pachygyria over the surface of the cerebral hemispheres, a feature that is more prominent over the frontal and especially temporal lobes than the parietal and occipital lobes. A variant of polymicrogyria is frequently noted over the cortical surface of the parieto-occipital lobes (see Polymicrogyria Overview).Cerebellar cysts, lined with the molecular layer and containing leptomeningeal tissue, were observed beneath the malformed cerebellar cortex or areas of polymicrogyria [Aida 1998]. Although distinctive enough to be diagnostic of cobblestone lissencephaly, these changes do not distinguish between FCMD and MEBD or WWS.In juvenile and adult cases, the agyric areas are more focal and restricted to the occipital lobes. Lissencephalic or agyric areas of malformed cortex may alternate with regions of polymicrogyria, based on fusion of gyri and excessive migration of glio-mesenchymal tissue extending into the subarachnoid space.A malformed or flat ventral surface of the medulla caused by secondary hypoplasia associated with a small basis pontis and grooves in the spinal cord was recently observed [Saito & Kobayashi 2001].In fetal cases, neurons and glia migrate through focal defects in the glia limitans, forming verrucous nodules, the initial manifestations of cortical dysplasia. Thus, the overmigration of CNS parenchyma into subarachnoid spaces is considered an essential pathologic process resulting in cortical dysplasia.
Haplotype analysis. Saito et al [2000a] used microsatellite markers closest to FKTN for haplotype analysis of 56 Japanese families, including 35 families with a typical phenotype, 12 families with a mild phenotype, and nine families with a severe phenotype. In total, 38 of 56 families were homozygous for the ancestral haplotype, including 27 of the 35 families with a typical phenotype:...
Genotype-Phenotype CorrelationsHaplotype analysis. Saito et al [2000a] used microsatellite markers closest to FKTN for haplotype analysis of 56 Japanese families, including 35 families with a typical phenotype, 12 families with a mild phenotype, and nine families with a severe phenotype. In total, 38 of 56 families were homozygous for the ancestral haplotype, including 27 of the 35 families with a typical phenotype:The probands with the typical phenotype were able to sit unassisted or to slide on the buttocks. Haplotype analysis revealed that 27 (77%) of 35 individuals with the typical phenotype are homozygous for the ancestral founder haplotype, seven (20%) have the founder haplotype on one chromosome, and one (3%) is a homozygote for another haplotype.Of the 12 probands with the mild phenotype, eight could walk and the other four could stand with support. Ten were homozygous for the ancestral founder haplotype and two were heterozygous for the ancestral founder haplotype.The nine with the severe phenotype lacked head control or the ability to sit without support; three had progressive hydrocephalus, two required a shunt operation, and seven showed ophthalmologic abnormalities. Eight of the nine were heterozygous for the ancestral founder haplotype and one was homozygous for the ancestral founder haplotype.The rate of heterozygosity for the ancestral founder haplotype was significantly higher in those with the severe phenotype than in those with the typical or mild phenotype (p<0.005). Individuals with severe FCMD appeared to be compound heterozygous for the founder mutation and another mutation.Genotype. Kondo-Iida et al [1999] analyzed FKTN in 107 unrelated affected individuals:The vast majority of affected individuals have at least one copy of the same mild FKTN mutation, c.*4287_*4288ins3062. Individuals homozygous for this insertion show a milder phenotype than do compound heterozygotes who have the insertion in combination with a missense or nonsense mutation on the other allele. This hypothesis is supported by the fact that fukutin-deficient chimeric mice show a severe phenotype that closely resembles WWS [Takeda et al 2003].The severe phenotype, including WWS-like manifestations such as hydrocephalus and microphthalmia, was significantly more common in probands who were compound heterozygotes for a point mutation and the founder mutation, c.*4287_*4288ins3062, than in probands who were homozygous for the founder mutation.Silan et al [2003] and de Bernabe et al [2003] reported two Turkish infants homozygous for nonsense mutations with a severe FCMD phenotype resembling WWS who died at age ten days and age four months, respectively. One had the nucleotide change c.454dupT in FKTN, causing a frameshift and a premature termination at codon 158 [Silan et al 2003]; the other was homozygous for a novel dinucleotide substitution at base 345 c.[345G>C;346C>T]+[345G>C;346C>T] that creates a p.Gln116* mutation in exon 4 [de Bernabe et al 2003]. Godfrey et al [2006], Godfrey et al [2007], and Puckett et al [2009] reported a milder LGMD phenotype in individuals heterozygous for a missense mutation / frameshift mutation and homozygous missense mutations, respectively (see Genetically Related Disorders).Chang et al [2009] reported five individuals from five families with a severe phenotype similar to WWS. All five individuals were homozygous for c.1167_1168insA (p.Phe390Ilefs*14), a founder mutation in the Ashkenazi Jewish.
Fukuyama congenital muscular dystrophy (FCMD) is one of the congenital muscular dystrophies, a clinically and genetically heterogeneous group of inherited muscle disorders, characterized by muscle weakness evident at birth or in early infancy. The main congenital muscular dystrophy (CMD) subtypes are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutations in POMT1, POMT2, FKTN, FKRP, LARGE, and POMGNT1), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). (See Congenital Muscular Dystrophy Overview). ...
Differential DiagnosisFukuyama congenital muscular dystrophy (FCMD) is one of the congenital muscular dystrophies, a clinically and genetically heterogeneous group of inherited muscle disorders, characterized by muscle weakness evident at birth or in early infancy. The main congenital muscular dystrophy (CMD) subtypes are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutations in POMT1, POMT2, FKTN, FKRP, LARGE, and POMGNT1), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). (See Congenital Muscular Dystrophy Overview). The three major phenotypes of the dystroglycanopathies are FCMD, Walker-Warburg syndrome (WWS) [Dobyns et al 1985, Dobyns et al 1989], and muscle-eye-brain disease (MEBD) [Santavuori & Leisti 1977, Raitta et al 1978]. The dystroglycanopathies have congenital muscular dystrophy associated with characteristic brain malformations (cobblestone [type II] lissencephaly and cerebellar malformations), eye malformations (typically involving the retina), profound intellectual disability, and early death. FCMD is milder than WWS and MEBD, particularly with respect to brain and ophthalmologic involvement [Dobyns et al 1985, Fukuyama 1997] (see Table 2).Brain MRI is useful in distinguishing between FCMD, MEBD, and WWS [Barkovich 1998]. Comparison of the neuropathologic abnormalities in FCMD, MEBD, and WWS reveals:Brain stem. Usually normal (rarely hypoplastic) in FCMD; almost always small in MEBD; very small and kinked at the junction of the midbrain and pons in WWSCerebellum. Usually normal (occasionally small) in FCMD; always small in MEBD; very small in WWSCerebellar cysts. Observed in all three disordersHydrocephalus. Rare in FCMD; common in MEBD; almost universal in WWSTable 2. CMD with CNS Abnormalities: α-DystroglycanopathyView in own windowPhenotypeSeverity of FindingsMuscle DystrophyEyeIntellectual DisabilityFukuyama CMD (FCMD)Moderate-severeMildModerateMuscle-eye-brain disease (MEBD)MildSevere 1 SevereOverlap between MEBD and WWS 2Severe 1, 3Walker-Warburg syndrome (WWS)Severe 31. Severe congenital myopia, congenital glaucoma, pallor of the optic discs, and retinal hypoplasia2. Mutations in FKRP, LARGE, and POMT2 give rise to phenotypes that overlap between MEBD and WWS.3. Microphthalmia, retinal detachment, retinal hypoplasia, anterior chamber malformation, cataractsMEBD. Taniguchi et al [2003] identified seven disease-causing POMGNT1 mutations among six northern European (non-Finnish), Japanese, and Korean individuals suspected of having MEBD, severe FCMD, or WWS. Mutations were dispersed throughout the entire gene. Beltran-Valero de Bernabe et al [2004] reported a German individual with FKRP-related MEB. WWS. WWS is genetically heterogeneous and can be caused by biallelic mutation in any of the six genes involved in DAG1 glycosylation, caused by mutation in POMT2, POMGNT1, FKTN, FKRP, and LARGE [Mercuri et al 2009]. Sequencing of POMT1 revealed mutations in 7%-20% of unrelated individuals with WWS [Beltran-Valero de Bernabe et al 2002, Currier et al 2005].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Fukuyama congenital muscular dystrophy (FCMD), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Fukuyama congenital muscular dystrophy (FCMD), the following evaluations are recommended:Neurologic evaluation, including EEG and brain MRIDevelopmental assessment including assessment of motor skills, cognition, and speechPhysical therapy evaluation of joint range of motionOphthalmologic evaluationFeeding and swallowing assessment in individuals with lack of head control or lack of the ability to sit without supportAssessment of caloric intake and nutritional statusMedical genetics consultationTreatment of ManifestationsThere is no definite treatment for FCMD. Multidisciplinary and appropriate management can prolong survival and improve the quality of life for individuals with FCMD. Treatment includes the following:Physical therapy and stretching exercises to promote mobility and prevent contracturesMonitoring for orthopedic complications such as foot deformity and scoliosis. When scoliosis is present, spinal fusion can preserve breathing function and improve sitting balance [Takaso et al 2010] Use of mechanical assistance such as long leg braces to maintain standing posture and wheelchairs to help mobilityUse of respiratory aids such as nasal intermittent positive pressure ventilator when indicated Note: Noninvasive ventilation is offered, particularly at night, before respiratory distress becomes acute. Prompt treatment of acute respiratory tract infections; particularly important, as these infections are the most common cause of hospital admissions and death in people with FCMD Antiepileptic drugs (AEDs) when indicatedSurgical treatment for gastroesophageal reflux when indicatedGastrostomy when indicated to assure adequate caloric intakeRoutine therapy of cardiomyopathySurveillanceSurveillance includes:Monitoring of respiratory function in individuals with advanced FCMD over age ten years. Those who survive beyond age 20 years may require tracheostomy or noninvasive respiratory support.Monitoring of myocardial involvement by chest x-ray, ECG, and echocardiography in individuals over age ten years.Observation/evaluation of gastrointestinal function by a qualified specialist, using a video-fluoroscopic swallow assessment, upper gastrointestinal tract image and pH monitor for gastroesophageal refluxMonitoring for foot deformities and scoliosisEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationTaniguchi-Ikeda et al [2011] reported that introduction of antisense oligonucleotides (AONs) targeting the splice acceptor, the predicted exonic splicing enhancer, and the intronic splicing enhancer prevented pathogenic exon-trapping by SINE (short interspersed sequence)-VNTR (variable number tandem repeat)-Alu (SVA) retrotransposon in cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. They have discovered in human disease a role for SVA-mediated exon-trapping and demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Fukuyama Congenital Muscular Dystrophy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFKTN9q31.2FukutinFKTN homepage - Leiden Muscular Dystrophy pagesFKTNData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Fukuyama Congenital Muscular Dystrophy (View All in OMIM) View in own window 253800MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 4; MDDGA4 607440FUKUTIN; FKTNMolecular Genetic PathogenesisThe discovery of FKTN is important in understanding normal brain development and the pathogenesis of congenital muscular dystrophies. (See Congenital Muscular Dystrophy Overview.) A major manifestation of FCMD is a defect in cortical development, especially neuronal migration, resulting in cobblestone lissencephaly. Similar pathologic changes in muscle and brain occur in the presence of biallelic mutations of other genes involved in this metabolic pathway, including FKRP, LARGE, POMGnT1, POMT1, and POMT2.Matsumura et al [1993] reported that dystrophin-associated proteins such as alpha-dystroglycan (DAG1) have abnormally low expression in FKTN. DAG1 is a cell surface protein that plays an important role in the assembly of the extracellular matrix in muscle, brain, and peripheral nerves by linking the basal lamina to cytoskeletal proteins. Using PCR, immunohistochemistry, and immunoblotting to analyze samples from individuals with FCMD, Hayashi et al [2001] confirmed a deficiency of fukutin and found marked deficiency of highly glycosylated DAG1 in skeletal and cardiac muscle and reduced amounts of DAG1 in brain tissue. Beta-dystroglycan was normal in all tissues examined. These findings supported the suggestion that fukutin deficiency affects the modification of glycosylation of DAG1, which then cannot localize or function properly and may be degraded or eluted from the extracellular surface membrane of the muscle fiber. Hayashi et al [2001] concluded that this disruption underlies the developmental, structural, and functional damage to muscles in individuals with FCMD. Michele et al [2002] demonstrated in individuals with either MEBD or FCMD that alpha-dystroglycan is expressed at the muscle membrane, but hypoglycosylation directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin, and agrin.Several other genes including ARX [Kato et al 2004], DCX [Gleeson et al 1998], PAFAH1B1 (known formerly as LIS1) [Caspi et al 2000], RELN [Hong et al 2000], and VLDLR [Boycott et al 2005] are known to disrupt neuronal migration and cause lissencephaly in humans, but the pathogenesis and pathology are very different from the cobblestone lissencephaly group.Normal allelic variants. The cDNA possesses an open reading frame of 1383 bp. The gene spans more than 100 kb of genomic DNA and comprises ten exons [Kobayashi et al 1998].Pathologic allelic variants. Analysis using microsatellite DNA markers flanking FKTN identified a founder haplotype lying in an approximately 200-kb critical region of chromosome 9q31. This founder haplotype accounts for more than 80% of FCMD chromosomes; more than 90% of individuals with FCMD have this ancestral haplotype in at least one of the two chromosomes [Kobayashi et al 1998].A founder mutation c.*4287_*4288ins3062 (3-kb retrotransposal insertion of tandemly repeated sequences into the 3' untranslated region of the gene) was identified on chromosomes with the founder haplotype. The sequence of inserted DNA fragment was 3,062 bp long and was composed of (TCTCCC)41, 27 copies of a 49-bp sequence, a SINE (short interspersed sequence)-type human retroposon sequence, a polyadenylation signal (AATAAA), and poly (A). Furthermore, a target-site duplication, consisting of a direct repeat of AAGAAAAAAAAAATTGT at both ends, indicated retrotransposal insertion of this 3-kb fragment. The 3-kb insertion was in the 3' untranslated region of this gene between bases 5,889 and 5,890. Kobayashi et al [1998] stated that FCMD is the first human disease known to be caused by an ancient retrotransposal integration. Colombo et al [2000] calculated that the age of the insertion mutation causing FCMD in Japanese persons is approximately 102 generations. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes to the time when the Yayoi people started migrating to Japan from the Korean peninsula.Kondo-Iida et al [1999] analyzed FCMD in 107 unrelated, affected individuals and identified four novel mutations in five cases: one missense, one nonsense, one L1 insertion, and one 1-bp insertion.Lim et al [2010] reported that the insertion of a novel pseudoexon mutation by a single base-pair change in intron 5 (c.647+2084G>T; p.Arg216Serfs*10) is specific to the Korean population.Table 3. Selected FKTN Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.139C>Tp.Arg47*NM_001079802.1 NP_001073270.1c.[345G>C;346C>T]p.Gln116*c.454dupTp.Ser152Phefs*6c.626A>Gp.His172Arg c.748T>Gp.Cys250Glyc.*4287_*4288ins3062 2(5889_5890ins3062)--c.1167_1168insA 3p.Phe390Ilefs*14c.647+2084G>Tp.Arg216Serfs*10See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. The asterisk denotes a mutation located in the 3’ UTR and the number indicates the nucleotide position beyond the stop codon. In this instance the insertion of 3062 nucleotides is between nucleotides that are 4287 and 4288 3’ of the stop codon of the gene.3. Chang et al [2009] reported as a founder mutation in the Ashkenazi Jewish FCMD.Normal gene product. Fukutin is predicted to have 461 amino acids. The predicted protein contains an N-terminal signal sequence which, together with results from transfection experiments, suggested that fukutin is a secreted protein. Kobayashi et al [1998] could not demonstrate fukutin in skeletal muscle using polyclonal or monoclonal antibodies. In transfected COS-7 cells, fukutin colocalized with a Golgi marker as well as showing a granular cytoplasmic distribution, suggesting that fukutin passes through the Golgi before being packaged into secretory vesicles. Unlike other muscular dystrophy-associated proteins, no staining for fukutin was seen at the plasma membrane. Kobayashi et al [1998] suggested that fukutin is located in the extracellular matrix, where it interacts with and reinforces a large complex encompassing the outside and inside of muscle membranes. Alternatively, if fukutin is secreted, it may cause muscular dystrophy by an unknown mechanism.Abnormal gene product. As the 3' untranslated region affects the stability of mRNA, the 3-kb insertion in the 3' UTR (c.*4287_*4288ins3062) may alter the secondary structure and render the mRNA unstable [Kobayashi et al 1998].