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Fukuyama Congenital Muscular Dystrophy

Synonym: FCMD

, MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: May 8, 2025.

Estimated reading time: 42 minutes

Summary

Clinical characteristics.

Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and brain malformations including, classically, cobblestone lissencephaly with cerebral and cerebellar dysplasia. There is a spectrum of severity and mild, typical, and severe phenotypes are recognized. Disease onset typically occurs in early infancy with poor suck/swallow, weak cry, and floppiness. Serum creatine kinase (CK) levels are usually in the thousands (10-60 times higher than normal). Motor development peaks at around age five to six years and thereafter regresses as muscle atrophy progresses. In the typical case, sitting without support or sliding along the floor on the buttocks may be the peak motor function. Deep tendon reflexes are diminished or absent after early infancy. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later-onset features include a myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after 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 in a proband with biallelic pathogenic variants in FKTN identified by molecular genetic testing.

Management.

Treatment of manifestations: Physical therapy and stretching exercises, treatment of orthopedic complications; mobility assistance devices such as long leg braces and wheelchairs; use of noninvasive respiratory aids or tracheostomy; prompt treatment of respiratory tract infections; anti-seizure medications; medical and/or surgical treatment for gastroesophageal reflux; gastrostomy tube placement when indicated to assure adequate caloric intake; cardiomyopathy treatment per cardiologist.

Surveillance: Monitor gastrointestinal function and for signs/symptoms of gastroesophageal reflux; for orthopedic complications including foot deformities and scoliosis; for myocardial involvement by chest radiography, EKG, and echocardiography in individuals older than age ten years; and respiratory function in individuals with advanced disease.

Genetic counseling.

FCMD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FKTN pathogenic variant, each sib of an affected individual has at conception 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 the FKTN pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for Fukuyama congenital muscular dystrophy (FCMD) have been published.

Suggestive Findings

FCMD should be suspected in individuals with the following clinical, imaging, laboratory, and histopathology findings and family history.

Clinical findings

  • Early-infantile-onset hypotonia and weakness with contractures of the hips, knees, and interphalangeal joints. Muscle weakness is typically progressive with age of onset younger than nine months.
  • Severe motor and speech delays and intellectual disability with relative preservation of social skills
  • A static course until early childhood, followed by diffuse and extensive muscle wasting (most prominent proximally) and progressive joint contractures
  • Myopathic facial appearance
  • Pseudohypertrophy of the calves and forearms in late infancy
  • Seizures (febrile and/or nonfebrile)
  • Ophthalmologic abnormalities, including visual impairment and retinal abnormalities. Retinal abnormalities, when present, are usually mild and focal. Retinal dysplasia, a pathologic diagnosis, is based on the finding of rosettes of immature photoreceptors.
  • Dysphagia and other swallowing issues
  • Respiratory issues
  • Cardiomyopathy

Neuroimaging findings. Early brain MRI reveals several abnormalities:

  • Cortical malformations including, classically, cobblestone lissencephaly with an 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 abnormalities with hyperintensity on T2-weighted images and hypointensity on T1-weighted images indicative of delayed myelination rather than dysmyelination
  • Cerebellar polymicrogyria and cerebellar cysts
  • Mild brain stem hypoplasia in some individuals

Additional findings include:

  • The opercula are poorly developed, leaving an open Sylvian fissure.
  • The cortex is typically no more than approximately 1 cm in thickness.

Laboratory findings. Elevated serum creatine kinase (CK) concentration:

  • Age <6 years: 10-60 times above normal
  • Age ≥7 years: 5-20 times above normal
  • Bedridden individuals: normal

Histopathology. Muscle biopsy may show several abnormalities:

  • Findings characteristic of muscular dystrophy. Primary feature is interstitial fibrosis without muscle degeneration and regeneration, which distinguishes FCMD from Duchenne muscular dystrophy.
  • Immunohistochemical staining using alpha-dystroglycan antibody reveals selective deficiency of alpha-dystroglycan on the surface membrane of skeletal muscle.

Note: With the advent of molecular genetic testing, a muscle biopsy is no longer necessary to establish the diagnosis of FCMD (see Establishing the Diagnosis).

Electromyography (EMG) findings are characteristic of muscular dystrophy, i.e., motor unit action potential shows low amplitude, short duration, and polyphasic myogenic changes.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of FCMD is established in a proband with biallelic pathogenic (or likely pathogenic) variants in FKTN identified by molecular genetic testing (see Table 1 and Figure 1).

Figure 1.

Figure 1.

Diagnostic algorithm for FCMD

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic FKTN variants of uncertain significance (or of one known FKTN pathogenic variant and one FKTN variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FCMD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with muscular dystrophy are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of FCMD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. In individuals who are not of Japanese, Korean, and Chinese ancestry, sequence analysis of FKTN is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
    Note: (1) In individuals of Japanese, Korean, and/or Chinese ancestry, targeted analysis for the Japanese founder variant, a 3062-bp insertion (nt.5889) within the 3' UTR (also known as NM_001079802.1:c.*4392_4393ins3062), is recommended first. If only one or no pathogenic variant is identified, sequence analysis of the entire gene is recommended [Kobayashi et al 1998]. (2) In individuals of Korean descent, if only one or no pathogenic variant is identified, consider sequence analysis to detect the Korean founder variant c.648-1243G>T [Lim et al 2010]. In individuals of Chinese descent, c.139C>T may be a founder variant, so targeted analysis of this variant is recommended; however, the number of reported cases to date is small (2/3) [Yang et al 2015].
  • A muscular dystrophy or brain malformation multigene panel that includes FKTN and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by muscular dystrophy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Note: While most reported pathogenic FKTN variants are within the coding region (e.g., missense, nonsense), several reported pathogenic variants (including a founder variant) are deep intronic variants and likely to be identified by whole-genome sequencing [Kobayashi et al 2017].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Fukuyama Congenital Muscular Dystrophy

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method by Ethnicity
JapaneseNon-Japanese AsianNon-Asian
FKTN Targeted analysis3062-bp insertion (nt.5889) within 3' UTR 398% 3, 477%-92% 5, 60%
c.648-1243G>T8% 3, 438%-58% 5
(Korean)
0%
c.139C>T (p.Arg47Ter)6%-7% 760% 7
(Chinese)
Rare
c.1167dupA (p.Phe390IlefsTer14)Rare
(w/microphthalmos)
0%See footnote 8.
Sequence analysis 3~9%~20%100%
Gene-targeted deletion/duplication analysis 9RareRareRare
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Generally, targeted analysis with allele-specific PCR [Watanabe et al 2005, Kobayashi et al 2017, Ko et al 2023] and Sanger sequence has been performed to identify deep intronic variants (c.648-1243G>T) and other variants. Long-read sequencing using the Oxford Nanopore Technology identified the 3062-bp insertion Japanese founder variant [Shin et al 2023]. Exome and whole-genome sequencing have allowed the detection of the deep intronic variants (c.648-1243G>T) and other variants [Suzuki et al 2022].

4.

In an analysis of 62 Japanese individuals with FCMD, 54 (87%) had the 3062 bp-insertion founder variant; 42(78%) were homozygous for the 3062-bp insertion founder variant and 12 (22%) were compound heterozygous, including three (6%) who were compound heterozygous with the c.139C>T variant [Matsumoto et al 2005]. In an analysis of 107 Japanese individuals with FCMD, 80 (75%) were homozygous for the 3062-bp insertion founder variant and 25 (23%) were compound heterozygous for the 3062-bp insertion founder variant, including nine (8%) who were compound heterozygous with c.648-1243G>T and seven (7%) with c.139C>T [Kobayashi et al 2017].

5.

In an analysis of 13 Korean individuals with FCMD, three (23%) were homozygous for the 3062-bp insertion founder variant and seven (54%) were compound heterozygous for the 3062-bp insertion founder variant, including five (38%) who were compound heterozygous with c.648-1243G>T [Lim et al 2010]. In an analysis of 24 Korean individuals with FCMD, five (21%) were homozygous for the 3062-bp insertion founder variant and 17 (71%) were compound heterozygous for the 3062-bp insertion founder variant, including 14 (58%) who were compound heterozygous with c.648-1243G>T [Ko et al 2023].

6.

Three reported affected individuals were from China [Yang et al 2015].

7.

In individuals of Japanese ancestry, 6% (3/54) [Matsumoto et al 2005] and 7% (7/107) [Kobayashi et al 2017] had the c.139C>T variant, and there have been individual reported cases with this variant [Kitamura et al 2016, Suzuki et al 2022]. In individuals of Chinese ancestry, two of three cases [Yang et al 2015] had this pathogenic variant, and it has also been reported in additional individual reports [Xiong et al 2009, Song et al 2021].

8.

Chang et al [2009] identified a homozygous c.1167dupA FKTN pathogenic variant in four individuals of Ashkenazi Jewish ancestry with features of Walker-Warburg syndrome and suggested that this may be an Ashkenazi Jewish founder variant.

9.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

Clinical Characteristics

Clinical Description

Fukuyama congenital muscular dystrophy (FCMD) is characterized by dystrophic changes in the skeletal muscle and by central nervous system migration abnormalities resulting in cerebral and cerebellar cortical dysplasia. Clinical manifestations include hypotonia, weakness, and neurodevelopmental delays. Mild, typical, and severe phenotypes are recognized. The phenotypic spectrum ranges from a Walker-Warburg syndrome-like phenotype at the severe end [Manzini et al 2008, Chang et al 2009, Yis et al 2011] to a limb-girdle muscular dystrophy-like phenotype at the mild end [Puckett et al 2009, Yis et al 2011, Fiorillo et al 2013].

To date, at least 500 individuals have been identified with biallelic pathogenic variants in FKTN [Kondo-Iida et al 1999, Saito & Kobayashi 2001, Matsumoto et al 2005, Yoshioka et al 2008, Kitamura et al 2016, Kobayashi et al 2017, Ishigaki et al 2018, Suzuki et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Fukuyama Congenital Muscular Dystrophy: Frequency of Select Features

Feature% of Persons w/FeatureComment
Hypotonia & muscle weakness 100%Early-infantile-onset hypotonia & weakness w/contractures of hips, knees & interphalangeal joints
Developmental delays 100% (50% typical, 38% severe, 12% mild) 1Intellectual & motor developmental delays & intellectual disability w/relative preservation of social skills
Myopathic facial appearance 100%Progressive w/age 2
Pseudohypertrophy of calves & forearms in late infancy 50%Pseudohypertrophy becomes evident when person begins to use respective muscles 2
Seizures 33%-80% 3Febrile & nonfebrile seizures reported
Ophthalmologic abnormalities 4
  • Myopia: 7/11, 10/33 (30%), 18/207 (8.6%)
  • Optic nerve atrophy: 5/11, 12/33 (36%), 2/207 (1%)
  • Retinal detachment: 1/33 (3%), 2/207 (1%)
Myopia & hypermetropia are relatively common; retinal detachment & cataracts have been noted in persons w/severe involvement.
Gastrointestinal issues: dysphagia & GERD 46/207 (22%) 5Swallowing difficulties increase w/age, but in persons w/severe involvement, they are seen in 6/93 (6.5%) even in those younger than age 5 yrs 5
Cardiac involvement >80%Manifestations are typically evident in 2nd decade; echocardiograph shows normal left ventricular fractional shortening in persons age <10 yrs & ↓ in 10/12 (83%) persons age >15 yrs. 6

GERD = gastroesophageal reflux;

1.

Ishigaki et al [2018]. Typical involvement is defined as individuals who are able to sit unassisted or slide on the buttocks; severe involvement is defined as individuals who can sit only with support or with no head control; mild involvement is defined as individuals who can stand or walk with or without support [Saito & Kobayashi 2001].

2.
3.
4.

Myopia is a relatively common ophthalmologic finding in FCMD; in severe phenotypes, the prevalence of retinal abnormalities is high [Yoshioka et al 1990, Ishigaki et al 2018].

5.
6.

Neurologic features. Disease onset typically occurs in early infancy. Initial clinical manifestations include poor suck, mildly weak cry, floppiness, and motor developmental delays. 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. Up to age three years, the cheeks are round, enlarged, and hard to the touch, and the skin above the cheeks appears shiny, but afterward they become atrophic. 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 difficulties develop after age six years. The disease course may be static until early childhood, followed by diffuse and extensive muscle wasting (most prominent proximally) and later progressive joint contractures.

Developmental and speech delays occur in all individuals. IQ range is usually 30 to 60. In individuals with mild FCMD, the IQ is greater than 35; in individuals with severe FCMD, the IQ is typically lower than 30. The maximum development in an individual with typical FCMD often consists of dozens of spoken words, sitting without help, and 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 rarely observed.

Seizures occur in more than 60% of affected individuals [Yoshioka et al 2008]. Average ages of onset of febrile and nonfebrile seizures were 5.4 and 4.6 years, respectively, in individuals homozygous for the Japanese founder variant (the 3062-bp insertion [nt.5889] within the 3' UTR). The average ages of onset of febrile and nonfebrile seizures were 3.6 and 3.7 years, respectively, in individuals who were compound heterozygous for the Japanese founder variant and an additional pathogenic FKTN variant [Yoshioka et al 2008]. In addition, seizures may develop after childhood in advanced stages of FCMD [Kuwayama et al 2021].

Ocular abnormalities including refractive error (myopia and hypermetropia) are seen 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, Saito & Kobayashi 2001]; however, retinal dysplasia is mild and focal. Pathologic findings in individuals with FCMD, including fetuses, have been demonstrated even in the absence of ophthalmologic findings; retinal dysplasia may occur during the fetal period [Hino et al 2001].

In a few individuals with severe FCMD confirmed with molecular genetic testing, severe ocular anomalies include microphthalmia, retinal detachment, retinal hypoplasia, cataracts, and glaucoma [Mishima et al 1985, Hino et al 2001, Saito & Kobayashi 2001, Manzini et al 2008, Chang et al 2009, Ishigaki et al 2018]. Note: The characteristic ocular findings of muscle-eye-brain disease (MEBD) or Walker-Warburg syndrome (WWS) (e.g., anterior chamber abnormalities, glaucoma) are not present in FCMD (see Differential Diagnosis).

Slowly progressive cardiac involvement is characteristic of FCMD. The clinical progression of cardiac dysfunction is significantly milder than Duchenne muscular dystrophy (DMD) [Yamamoto et al 2017]. Individuals who live more than ten years tend to develop fibrosis of the myocardium, as evidenced by postmortem findings [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 older than age 15 years showed decreased LV systolic function [Nakanishi et al 2006]. The brain natriuretic peptide concentration showed no correlation with age or LV ejection fraction [Yamamoto et al 2017].

Swallowing dysfunction is observed in individuals with infantile FCMD (especially in those with severe FCMD) [Ishigaki et al 2018] and in individuals older than age ten years with advanced disease. 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. On the other hand, it has been reported that CK levels decrease in association with an increase in C-reactive protein (CRP) during febrile infectious episodes, and this may be related to an increase in endogenous cortisol secretion [Takeshita et al 2021].

Neuropathologic findings. Examination of the brain in FCMD shows changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia caused by a defect in neuronal migration [Saito et al 2000b]. These changes are similar to but typically less severe than the abnormalities described in MEBD and WWS (see Differential Diagnosis).

Infants can have extensive areas of pachygyria involving both cerebral hemispheres, a feature that is more prominent over the frontal and temporal lobes than the parietal and occipital lobes.

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, 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 has been observed [Saito & Kobayashi 2001].

In fetal cases, neurons and glia migrate through focal defects in the glia limitans, forming verrucous nodules, the initial manifestation of cortical dysplasia. Thus, the overmigration of central nervous system parenchyma into subarachnoid spaces is a pathologic process that is considered essential to the development of cortical dysplasia [Nakano et al 1996, Yamamoto et al 1997, Saito et al 1998].

Muscle biopsy findings. On muscle biopsy, muscle pathology shows circular, small-diameter fibers and connective tissue proliferation in addition to muscular dystrophy findings. Immunohistochemical staining shows reduced staining with antibodies against the glycan of alpha-dystroglycan.

Genotype-Phenotype Correlations

FCMD is classified into three clinical types based on the individual's maximum motor abilities. (1) The typical type is assigned to individuals who are able to sit unassisted or slide on the buttocks (never stand independently); (2) the mild type is assigned to individuals who can stand or walk with or without support; and (3) the severe type is defined as individuals who can sit only with support or with no head control (they never sit independently) [Kondo-Iida et al 1999, Saito et al 2000a, Saito & Kobayashi 2001]. Typically, brain and ocular findings also show the same severity as motor function [Saito et al 2000a].

Kondo-Iida et al [1999] and Kobayashi et al [2017] analyzed FKTN in 107 unrelated affected individuals. Individuals homozygous for the 3062-bp insertion within the 3' UTR typically have a milder phenotype than individuals who are compound heterozygous for the 3062-bp insertion in combination with a pathogenic missense or nonsense variant on the other allele. The severe phenotype, including Walker-Warburg syndrome (WWS)-like manifestations such as hydrocephalus and microphthalmia, was significantly more common in probands who were compound heterozygous for a single-nucleotide variant and the 3062-bp insertion than in homozygotes for the 3062-bp insertion [Saito et al 2000a, Yoshioka 2009, Kobayashi et al 2017].

Chang et al [2009] identified a homozygous c.1167dupA FKTN pathogenic variant in four individuals of Ashkenazi Jewish ancestry with features of WWS and suggested that this may be an Ashkenazi Jewish founder variant.

Godfrey et al [2006], Godfrey et al [2007], Puckett et al [2009], Yis et al [2011], and Fiorillo et al [2013] reported a milder limb-girdle muscular dystrophy (LGMD)-like phenotype in individuals who are compound heterozygous for a pathogenic missense variant and a frameshift variant or homozygous for pathogenic missense variants (see Genetically Related Disorders).

Prevalence

FCMD is pan ethnic but is most common in individuals of Japanese ancestry. FCMD is second in prevalence to DMD among all subtypes of childhood progressive muscular dystrophy in Japan, with an incidence of 0.7-1.2 in 10,000 births. Chromosomes bearing the FKTN Japanese founder variant (the 3062-bp insertion within the 3' UTR) are derived from a single ancestral founder who lived 2,000-2,500 years ago. It was found in only one of 176 chromosomes in unrelated healthy individuals [Kobayashi et al 1998].

The average occurrence of heterozygous carriers identified in various regions of Japan is estimated to be one in 188. However, in Korean populations, one carrier was detected in 935 individuals, and researchers were unable to detect any heterozygous pathogenic variants in 203 individuals of Mongolian ancestry and 766 individuals from mainland China [Watanabe et al 2005].

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:

The three major phenotypes of the alpha-dystroglycanopathies are [Taniguchi et al 2003, Voglmeir et al 2011, Carss et al 2013]:

  • FCMD;
  • Walker-Warburg syndrome (WWS);
  • Muscle-eye-brain disease (MEBD).

The alpha-dystroglycanopathies are characterized by CMD associated with characteristic brain malformations (cobblestone lissencephaly and cerebellar malformations), eye malformations (typically involving the retina), profound intellectual disability, and early death. These entities have been consolidated under the single designation "congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (MDDGA)" in OMIM. FCMD is milder than WWS and MEBD, particularly with respect to brain and ophthalmologic involvement [Bouchet-Séraphin et al 2016, Taniguchi-Ikeda et al 2016]. The alpha-dystroglycanopathies are inherited in an autosomal recessive manner.

Table 4a.

Distinguishing Features Between the Major Phenotypes of the Alpha-Dystroglycanopathies: FCMD, MEBD, and WWS

PhenotypeSeverity of FindingsBrain MRI
MDEyeIDBrain stemCerebellumCerebellar cystsHydrocephalus
FCMDModerate to severeMildModerateUsually normal; in rare cases, hypoplasticUsually normal; occasionally smallObservedRare
MEBDMildSevere 1SevereAlmost always smallAlways smallObservedCommon
WWSMildSevere 2SevereVery small & kinked at junction of midbrain & ponsVery smallObservedAlmost universal

FCMD = Fukuyama congenital muscular dystrophy; ID = intellectual disability; MD = muscle dystrophy; MEBD = muscle-eye-brain disease; WWS = Walker-Warburg syndrome

1.

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

2.

Microphthalmia, retinal detachment, retinal hypoplasia, anterior chamber malformation, cataracts

Table 4b.

FCMD, MEBD, and WWS: Associated Genes

GeneAlpha-Dystroglycanopathy
Phenotypes 1
FCMDMEBDWWS
FKTN ++
B3GALNT2 2+
B4GAT1 +
CRPPA (ISPD)+
DAG1 ++
FKRP +
GMPPB ++
LARGE1 ++
POMGNT1 ++
POMGNT2 ++
POMK ++
POMT1 3+
POMT2 3+
RXYLT1 (TMEM5)+

FCMD = Fukuyama congenital muscular dystrophy; MEBD = muscle-eye-brain disease; WWS = Walker-Warburg syndrome

1.
2.
3.

Management

No clinical practice guidelines for Fukuyama congenital muscular dystrophy (FCMD) have been published. Consensus statements on standard of care and medical management for congenital muscular dystrophies (CMD) broadly have been published [Wang et al 2010, Kang et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FCMD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Fukuyama Congenital Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Neurologic Neurologic eval
  • At initial diagnosis & at least once every 3 mos 1 thereafter, esp for mgmt of seizures that should include an epilepsy specialist
  • Prolonged video EEGs may be required to fully characterize seizure burden &/or spells of unclear clinical etiology.
  • To incl early brain imaging to characterize & assess brain malformation; when hypomyelination is present, eval after 1 year is recommended to check for white matter maturation; when ventricular enlargement is significant, repeat brain imaging to monitor progression of hydrocephalus & indications for surgery is recommended.
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language evals
  • Eval for early intervention / special education
Ophthalmologic/
Vision
OphthalmologistAssess visual acuity, retina for retinal abnormalities, ocular movement, & refractive errors &/or strabismus
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team eval
  • To incl eval of aspiration risk, caloric intake, & nutritional status
  • GERD and gastrointestinal dysmotility, i.e., delayed gastric emptying & constipation, are common.
  • A videofluoroscopic exam, upper GI exam, & esophageal pH monitoring are performed to evaluate swallowing function & GERD. Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (> 30 minutes/meal), &/or aspiration risk.
Cardiac Cardiac evalAt time of diagnosis, cardiac screening incl EKG & echocardiogram is recommended. If no abnormalities are found, echocardiogram is performed 1x/yr from age 10 yrs. After age 15 yrs, LV fraction shortening on echocardiography may ↓.
Orthopedics/
Rehabilitation
Orthopedic evalDeformities incl joint & neck contractures, scoliosis, foot deformities, & hip dislocation or subluxation. Early rehab intervention improves future quality of life.
Respiratory Pulmonary evalRegular evals for persons age >10 yrs; in severe cases, mechanical ventilation by nocturnal NPPV may be necessary. 2
Genetic counseling By genetics professionals 3To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of FCMD to facilitate medical & personal decision making
Family support
& resources
By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

FCMD = Fukuyama congenital muscular dystrophy; GERD = gastroesophageal reflux disease; GI = gastrointestinal; LV = left ventricular; MOI = mode of inheritance; NPPV = non-invasive positive pressure ventilation

1.

Children younger than age 12 months with severe or worsening medical issues (e.g., refractory seizures, severe hypotonia, and respiratory and nutritional issues) should be evaluated at least every three to four months; individuals older than age 12 months who are in stable condition can be evaluated every four to six months [Wang et al 2010].

2.
3.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no cure for Fukuyama congenital muscular dystrophy. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

Fukuyama Congenital Muscular Dystrophy: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay /
Intellectual disability
See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Approach should balance seizure control w/side effects w/goal of limiting number of ASMs.
  • Education of parents/caregivers 1
Poor weight gain
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for a clinical feeding eval &/or radiographic swallow study when showing clinical signs of dysphagia (choking, chronic cough, history of aspiration pneumonia) or prolonged feeding times (>30 min/meal)
Gastrointestinal Pharmacologic therapies
  • Stool softeners, prokinetics, osmotic agents, or laxatives as needed. Continuous use of these agents is safe.
  • Medical &/or surgical treatment for GERD when indicated
  • Gastrostomy tube placement when indicated to assure adequate caloric intake
Musculoskeletal
  • PT/OT
  • Referral for orthopedic surveillance & correction
  • Vitamin D supplementation if indicated
  • PT helps maintain & promote mobility & prevent contractures. Orthotics & special adaptive chairs or positioners or other measures may support sitting & mobility.
  • OT may help improve fine motor skills & oral motor control.
  • Orthopedic surgery may be indicated for scoliosis &/or large joint displacements. When scoliosis is present, spinal fusion to preserve breathing function & improve sitting balance.
  • Steroid therapy has been shown to contribute to maintenance & improvement of motor functions in persons w/deteriorating motor function. 2
Cortical visual impairment Evaluate as part of psychoeducational activities & therapiesInclude affected persons in early intervention &/or school district programs, consistent w/federal law reg access to educational services by visually impaired persons.
Neurobehavioral/
Psychiatric
  • Although autistic features are rare, if applicable, therapies to address features of ASD such as ABA can be considered.
  • Pharmacologic therapies for anxiety
Pharmacologic therapies w/sedative side effects should be carefully weighed against overall benefits & effect on abilities to participate in education, therapies, sleep, & general quality of life.
Respiratory Respiratory interventions
  • Use of respiratory aids such as NIPPV when indicated
  • Non-invasive ventilation should be considered, particularly at night, before respiratory distress becomes acute.
  • Prompt treatment of acute respiratory tract infections is particularly important, as these infections are most common cause of hospital admissions & death in persons w/FCMD. Persons who survive beyond age 20 yrs may require tracheostomy or non-invasive respiratory support.
Cardiac Treatment of cardiomyopathy by cardiologistIf worsening ventricular dysfunction is observed, prompt medical treatment using angiotensin-converting enzymes & beta-blockers are the most appropriate cardioprotective drugs.
Orthopedic/
Rehabilitation
  • Appropriate positioning for sleeping, sitting, & standing
  • Correct fit & use of orthoses
As severe spinal deformity is life-threatening due to respiratory insufficiency, careful eval & monitoring are essential. When conservative mgmt fails, surgical mgmt may be necessary.
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.
  • Referral to community or online family support resources such as Parent to Parent patient advocacy groups for further support & resources.

ABA = applied behavior analysis; ASD = autism spectrum disorder; ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; NIPPV = nasal intermittent positive pressure ventilator; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

2.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Fukuyama Congenital Muscular Dystrophy: Recommended Surveillance

System/ConcernEvaluationFrequency
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features.
At least every 3 mos; EEG every 6 mos
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
Gastrointestinal Monitor for constipation, feeding issues, weight gain, & overall nutritional status; videofluoroscopic swallow assessments, upper GI tract imaging, & pH monitor for GERD may be needed routinely.Every 6-12 mos
Development Monitor developmental progress & educational needs.At each visit
Neurobehavioral/
Psychiatric
Autistic features are rarely observed; although affected persons have the ability to understand, they may feel stressed because they lack verbal expression.As needed
Musculoskeletal Physical medicine & OT/PT assessment of mobility, foot deformities, scoliosis, & self-help skillsAt each visit
Ophthalmologic involvement
  • Low vision services
  • Retinal observation by fundoscopy
Per treating ophthalmologist(s)
Respiratory Monitor for evidence of aspiration & respiratory insufficiency.At each visit (esp in those w/severe FCMD or those age >10 yrs)
Cardiac Monitor myocardial involvement by chest radiograph, EKG, & echocardiography.Per treating cardiologist; generally recommended every 6 mos in those age >10 yrs
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit
Transition to Adult Care Develop realistic plans for adult life (see Transitions from Pediatric Epilepsy to Adult Epilepsy Care).Starting by age ~10 yrs

GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Antisense oligonucleotide therapy. Taniguchi-Ikeda et al [2011] reported that introduction of targeted antisense oligonucleotides in cell cultures from individuals with FCMD and in mouse models rescued normal ribitol-5-phosphate transferase FKTN (FKTN; also called fukutin) mRNA expression and protein production, demonstrating the promise of splicing modulation therapy as a precision therapy for FCMD. Enkhjargal et al [2023] reported that an antisense oligonucleotide targeting the exonic splice enhancer region significantly induced pseudoexon skipping and restored normal FKTN production and functional O-mannosyl glycosylation of alpha-dystroglycan in FCMD patient-derived cells carrying compound heterozygous pathogenic variants (the deep intronic variant c.648-1243G>T and the 3062-bp insertion founder variant). This study demonstrates the feasibility of treating FCMD caused by compound heterozygous pathogenic variants.

Supplementation therapy. Kanagawa et al [2016] reported that ribitol-5-phosphate is a functional glycan unit in mammals and that defects in its post-translational modification pathway are a cause of ISPD-, FKRP-, and FKTN-related alpha-dystroglycanopathies. Since ISPD deficiency leads to a loss of or severe reduction in cellular CDP-ribitol, the supplementation of CDP-ribitol may be effective in treating FCMD. Gerin et al [2016] showed that ribitol supplementation to fibroblasts from individuals with ISPD pathogenic variants leads to a partial rescue of alpha-dystroglycan glycosylation.

Gene therapy. The effectiveness of recombinant adeno-associated virus serotype 9-mediated FKTN and FKRP gene delivery has been demonstrated using FCMD and limb-girdle muscular dystrophy (LGMD) model mice, respectively [Kanagawa et al 2013, Xu et al 2013]. Earlier intervention would be highly preferred [Vannoy et al 2017].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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 presumed to be heterozygous for an FKTN pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FKTN pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an FKTN pathogenic variant, each sib of an affected individual has at conception 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with FCMD are not known to reproduce.

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

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the FKTN pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk 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.
  • Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestral background. Founder variants have been identified in Japanese, Korean, and Chinese populations (see Table 8).

Prenatal Testing and Preimplantation Genetic Testing

Once the FKTN pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Note: In families segregating the 3062-bp insertion (nt.5889) Japanese founder variant, prenatal testing using haplotype analysis is considered the most accurate method for prenatal testing [K Saito, personal observation]. In Japanese individuals, as detection of the ancestral haplotype facilitates the most accurate prenatal diagnosis of FCMD, prenatal diagnosis is performed by haplotype analysis by markers closest to the gene using fetal DNA from chorionic villus sampling (CVS) at 10-12 weeks' gestation [Saito et al 1998, Saito 2006].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

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
  • European Neuromuscular Centre (ENMC)
    Phone: 31 35 5480481
    Email: enmc@enmc.org
  • Japan Muscular Dystrophy Association
    Japan
    Phone: 03-6907-3521
  • Muscular Dystrophy Association (MDA) - USA
    Phone: 833-275-6321
    Email: ResourceCenter@mdausa.org
  • Muscular Dystrophy UK
    United Kingdom
    Phone: 0800 652 6352
  • Congenital Muscle Disease International Registry (CMDIR)
    The CMDIR is a global partnership of patient advocacy organizations, researchers, and clinicians, all working toward the same goal: to find treatments for congenital muscle disease.
    CMDIR/Cure CMD

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

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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 Pathogenesis

The dystroglycanopathy genes FKTN, FKRP, and ISPD encode essential enzymes for their respective functions: FKTN and FKRP transfer ribitol-phosphate onto sugar chains of alpha-dystroglycan, and ISPD synthesizes CDP-ribitol, a donor substrate for FKTN and FKRP [Kanagawa et al 2016]. FKTN, FKRP, and ISPD are directly involved in the synthesis of the tandem RboP: FKTN and FKRP are RboP transferases, and ISPD is involved in cellular CDP-ribitol synthesis [Kanagawa et al 2016]. In addition, TMEM5 is a UDP-xylosyl transferase enzyme required for modification of ribitol that is in a phosphodiester linkage to the core M3 glycan on alpha-dystroglycan [Praissman et al 2016]. FCMD is a disease of ribitol-phosphate deficiency.

Dystroglycans bind to laminin in the basement membrane via sugar chains outside the cell and bind to dystrophin inside the cell, thereby linking the basement membrane with the cytoskeleton. Glycosylation is required for the binding of alpha-dystroglycan to laminin, so sugar chain abnormalities can disrupt the coordination between laminin (basement membrane), dystroglycan, dystrophin, and actin (cytoskeleton), making muscle fibers vulnerable. The foundation structure for the elongation of sugar chains with laminin-binding ability is ribitol-phosphate. FKTN is a ribitol-phosphate transferase, and in individuals with FCMD, ribitol-phosphate structures are not formed; thus, sugar chains with laminin-binding ability are not formed, leading to disease [Kanagawa & Toda 2017].

Mechanism of disease causation. Loss of function

Table 8.

FKTN Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_001079802​.2 3062-bp insertion (nt.5889) w/in 3' UTR 1, 2--Founder variant in Japan [Kobayashi et al 1998] (See Genotype-Phenotype Correlations.)
c.648-1243G>T--Founder variant in Korea [Lim et al 2010]; 2nd most common variant in Japan [Kobayashi et al 20171
NM_001079802​.2
NP_001073270​.1
c.1167dupA 3p.Phe390IlefsTer14Founder variant in Ashkenazi Jewish persons [Chang et al 2009], assoc w/WWS [Cotarelo et al 2008, Manzini et al 2008]; LGMD w/o ID [Godfrey et al 2007]; & severe FCMD w/microphthalmos in Japan [Kondo-Iida et al 1999] (See Genotype-Phenotype Correlations.)
c.139C>Tp.Arg47TerFounder variant in China [Yang et al 2015]; 3rd most common variant in Japan [Kobayashi et al 2017]; assoc w/severe FCMD in Japan [Matsumoto et al 2005, Kobayashi et al 2017]; LGMD in France (compound heterozygous w/c.736A>G [p.Arg246Gly] [Vuillaumier-Barrot et al 2009]; & WWS in Croatia [Yis et al 2011]

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

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

1.

A 3-kb retrotransposon insertion of tandemly repeated sequences in the 3' untranslated region [Kato et al 2004]. Asterisk denotes a variant in the 3' UTR; the number indicates the nucleotide position beyond the stop codon. AB185332​.1 is the accession number of the sequence of the inserted retrotransposon.

2.

Also known as NM_001079802​.1:c.*4392_4393ins3062

3.

This variant has also been reported in the literature as c.647+2084G>T. This is a deep intronic variant that is predicted to create a pseudoexon between exons 5 and 6 resulting in a frameshift and a premature stop codon [Kobayashi et al 2017].

Chapter Notes

Author Notes

Diagnostic guidelines have been developed by the Information Center for Specific Pediatric Chronic Diseases, Japan (see Fukuyama type congenital muscular dystrophy).

Acknowledgements

Thanks to Dr Eri Kondo-Iida for her advice, Mr Mamoru Yokomura for genetic testing, and Dr Naoko Sato for her advice on the interpretation of FKTN variants.

Revision History

  • 8 May 2025 (gm) Comprehensive update posted live
  • 3 July 2019 (sw) Comprehensive update posted live
  • 10 May 2012 (me) Comprehensive update posted live
  • 26 January 2006 (me) Review posted live
  • 8 October 2004 (ks) Original submission

References

Published Guidelines / Consensus Statements

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  • Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R, et al. Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol. 2010;25:1559–81.

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