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
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Feature | % of Persons w/Feature | Comment |
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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) 1 | Intellectual & 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% 3 | Febrile & 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%) 5 | Swallowing 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;
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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].
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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.