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Fukuyama Congenital Muscular Dystrophy

Synonyms: Fukuyama Type Congenital Muscular Dystrophy, FCMD
, MD, PhD
Professor, Institute of Medical Genetics
Tokyo Women's Medical University School of Medicine
Tokyo, Japan

Initial Posting: ; Last Update: May 10, 2012.

Summary

Disease characteristics. Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and CNS migration disturbances that result in changes consistent with cobblestone (previously type II) lissencephaly with cerebral and cerebellar cortical dysplasia. Mild, typical, and severe phenotypes are recognized. Onset typically occurs in early infancy, with a poor suck, weak cry, and floppiness. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech retardation, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement in individuals older than age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death.

Diagnosis/testing. The diagnosis of FCMD is established by clinical findings; elevation of serum creatine kinase concentration; characteristic findings on neuroimaging, electromyography, muscle biopsy; and molecular genetic testing of FKTN, the only gene in which mutations are known to cause FCMD.

Management. Treatment of manifestations: Physical therapy and stretching exercises, treatment of orthopedic complications, assistance devices such as long leg braces and wheelchairs, use of noninvasive respiratory aids or tracheostomy, antiepileptic drugs, medical or surgical treatment for gastroesophageal reflux, and gastrostomy when indicated.

Surveillance: Monitoring for respiratory function in individuals with advanced disease and monitoring of myocardial involvement by chest x-ray, ECG, and echocardiography in individuals older than age ten years.

Genetic counseling. FCMD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

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]:

  • 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 inheritance

Neuroimaging. 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 polymicrogyria
  • Dilated lateral ventricles
  • White 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 dysmyelination
  • Mild brain stem hypoplasia in some
  • Cerebellar 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.

Testing

Serum creatine kinase (CK) concentration

  • Age <6 years: 10-60 times higher than normal
  • Age ≥7 years: 5-20 times higher than normal
  • Bed-ridden individuals: Normal

Muscle biopsy

  • Findings 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 Testing

Gene. 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 Dystrophy

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
JapaneseNon-Japanese
FKTN Targeted mutation analysisc.*4287_*4288ins3062 2See footnote 3See footnote 4
Sequence analysis of coding and flanking intronic regionsSequence variants 5See footnotes 6, 7
Sequence analysis of cDNA or targeted intronic sequencing 8mRNA variants, particularly intronic variants with splicing effects (e.g., pseudoexon mutation 9)UnknownSee footnote 4

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 lymphocytes

9. 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 Strategy

To 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):

Figure 1

Figure

Figure 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.

Clinical Description

Natural History

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].

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.

Genotype-Phenotype Correlations

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:

  • 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.

Prevalence

FCMD is second in prevalence only to Duchenne muscular dystrophy (DMD) among all subtypes of childhood progressive muscular dystrophy in Japan. FCMD is seldom reported outside of Japan. In the cohort of 337 cases of progressive muscular dystrophy followed in a pediatric neuromuscular clinic over 23 years (1971-1994), DMD accounted for 50.2% of cases and FCMD for 35.3% of cases [Fukuyama 1997]. Based on data obtained from a nationwide multi-institutional study, the annual incidence of FCMD in Japan is in the range of 1.92 to 3.68 in 100,000 live births [Osawa et al 1997].

Molecular genetic testing confirmed the clinical diagnosis of FCMD in 13 individuals of Korean heritage [Lim et al 2010].

The average occurrence of heterozygous carriers identified in various regions of Japan is one in 188 [Watanabe et al 2005].

In individuals of Korean heritage, one carrier in 935 individuals had the ancestral mutation c.*4287_*4288ins3062 in the 3' UTR.

Differential Diagnosis

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).

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 WWS
  • Cerebellum. Usually normal (occasionally small) in FCMD; always small in MEBD; very small in WWS
  • Cerebellar cysts. Observed in all three disorders
  • Hydrocephalus. Rare in FCMD; common in MEBD; almost universal in WWS

Table 2. CMD with CNS Abnormalities: α-Dystroglycanopathy

PhenotypeSeverity of Findings
Muscle DystrophyEyeIntellectual Disability
Fukuyama CMD (FCMD)Moderate-severeMildModerate
Muscle-eye-brain disease (MEBD)MildSevere 1 Severe
Overlap between MEBD and WWS 2Severe 1, 3
Walker-Warburg syndrome (WWS)Severe 3

1. Severe congenital myopia, congenital glaucoma, pallor of the optic discs, and retinal hypoplasia

2. 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, cataracts

MEBD. 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 MRI
  • Developmental assessment including assessment of motor skills, cognition, and speech
  • Physical therapy evaluation of joint range of motion
  • Ophthalmologic evaluation
  • Feeding and swallowing assessment in individuals with lack of head control or lack of the ability to sit without support
  • Assessment of caloric intake and nutritional status
  • Medical genetics consultation

Treatment of Manifestations

There 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 contractures
  • Monitoring 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 mobility
  • Use 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 indicated
  • Surgical treatment for gastroesophageal reflux when indicated
  • Gastrostomy when indicated to assure adequate caloric intake
  • Routine therapy of cardiomyopathy

Surveillance

Surveillance 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 reflux
  • Monitoring for foot deformities and scoliosis

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Taniguchi-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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Fukuyama congenital muscular dystrophy (FCMD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband. Individuals with FCMD do not reproduce.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation [Kondo et al 1996, Saito et al 1998, Saito 2006]. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cure CMD
    PO Box 701
    Olathe KS 66051
    Phone: 866-400-3626
    Email: info@curecmd.com
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Netherlands
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • Congenital Muscle Disease International Registry (CMDIR)
    The CMD International Registry is a patient self-report registry with the goal to register the global congenital muscle disease population which includes congenital myopathy and congenital muscular dystrophy.
    1712 Pelican Avenue
    San Pedro CA 90732
    Phone: 800-363-2630
    Fax: 310-872-5374
    Email: counselor@cmdir.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FKTN9q31​.2FukutinFKTN homepage - Leiden Muscular Dystrophy pagesFKTN

Data 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)

253800MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 4; MDDGA4
607440FUKUTIN; FKTN

Molecular Genetic Pathogenesis

The 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 Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.139C>Tp.Arg47*NM_001079802​.1
NP_001073270​.1
c.[345G>C;346C>T]p.Gln116*
c.454dupTp.Ser152Phefs*6
c.626A>Gp.His172Arg
c.748T>Gp.Cys250Gly
c.*4287_*4288ins3062 2
(5889_5890ins3062)
--
c.1167_1168insA 3p.Phe390Ilefs*14
c.647+2084G>Tp.Arg216Serfs*10

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. 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].

References

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Chapter Notes

Revision History

  • 10 May 2012 (me) Comprehensive update posted live
  • 26 January 2006 (me) Review posted to live Web site
  • 8 October 2004 (ks) Original submission
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