Fukuyama Congenital Muscular Dystrophy

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Background    Pathology    Reference

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary    Genetics    Clinical Features    

Summary: Fukuyama congenital muscular dystrophy (FCMD) is a multisystem disorder that involves muscle, eye, and brain. It is transmitted in an autosomal recessive pattern and the FCMD gene has been mapped to chromosome 9q31; the protein that is involved in FCMD is named fukutin. FCMD is the first human disease to be caused by an ancient retrotransposal integration. FCMD is characterized invariable association of infantile hypotonia with severe mental retardation, structural abnormalities of the brain and frequently associated febrile or afebrile convulsion. It is almost confined to Japan but it is the most common neuromuscular causes of infantile hypotonia in Japan. The muscle weakness affects both facial and limb muscles and there is also joint contracture. Muscle biopsy gives a dystrophic picture.

Incidence: Fukuyama congenital muscular dystrophy is extremely uncommon in the western country. However, it is the second most common form of childhood muscular dystrophy and one of the most common autosomal recessive disorders in Japan; the incidence is about one-half to one third that of Duchene muscular distrophy. [Toda T et al., Neuromuscul Disord 2000 10:153-9]

Genetics: Autosomal recessive. The FCMD gene has been mapped to chromosome 9q31. Most chromosomes bearing the FCMD mutation could be derived from a single ancestor. There is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The gene product is the protein fukutin, presumably a secreted protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. FCMD is the first human disease to be caused by an ancient retrotransposal integration. [Kobayashi K et al., Nature 1998 394:388-92; Kondo-Iida E et al., Hum Mol Genet 1999 8:2303-9; Toda T and Kobayashi K, J Mol Med 1999 77:816-23; Toda T et al., Neuromuscul Disord 2000 10:153-9]

Clinical:

·        Manifestation: The generalized hypotonia usually appears before nine months of age; the infant is floppy and has developmental delay. Severe feeding or respiratory difficulties are uncommon during the infantile stage. The patients have severe hypotonia and muscular weakness which may be associated with some spasticity. Facial diplegia, strabismus, progressive joint contractures and kyphoscoliosis are often present.

·        Characteristic facial appearance: There is hypertrophy of the cheeks a tendency for the mouth to remain half open fron infancy. Seizure occurs in half of the cases.

·        Clinical course: The clinical course is usually progressive and few patients are able to walk. Death is usually resulted from respiratory complications during the 1^st decade of life although some patients may survive into adolescence.

·        Severe mental retardation: Severe mental retardation is consistently associated with Fukuyama muscular dystrophy. The IQ is usually between 30-50.

·        CK is consistently elevated.

·        Malformationof the brain: Consistently associated with structural abnormalities of the brain.

·        Myopathic EMG and abnormal EEG.

PATHOLOGY: Muscle Pathology    CNS Pathology

MUSCLE PATHOLOGY Head  

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:

Histology of muscle: Essentially a picture of dystrophic myopathy. Muscle fibers are small and with increased variation in size but no hypertrophy. There is also necrosis, fibrosis, and regeneration. Inflammatory infiltrates may be seen in some cases.

Immunohistochemistry: Decreased staining for dystrophin-associated proteins and for merosin.

DIFFERENTIAL DIAGNOSIS:

CNS PATHOLOGY Head

GROSS PATHOLOGY:

Cerebral hemispheres: Smooth areas are present in the cerebral surface. Primary sulci are formed but the secondary sulci may be shallow. The brain surface may also have a coarse granular surface and with many small protuberances (brain warts). Ventricles are slightly dilated.

 Cerebellum: Variable amount of smaooth area and aberrant bands of myelin course across the surface.

Leptomeninges: Fibroglial proliferation of the leptomeninges similar to those seen in resolved meningitis is present.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:

Three types of cortical dysplasia have been described:

·        Type I: Supercicial and intracortical verrucous dysplasia (brain warts). Normal vascular architecture.

·        Type II: Micropolygyria of the unlayered type with a single thick cellular layer separated by numerous narrow acellular zones. Four-layered micropolygyria is uncommon. Distorted vascular architecture.

·        Type III: This is seen in the smooth cortical surfaces and is characterized by four-layered architecture. The superficial layer has numerous myuelinated fibers, then a thick and extremely disorganized cellular layer, a layer of islands of myelinated fibers, and a deep cellular layer with irregularly arranged neurons. Distorted vascular architecture.

Cerebellum: The smooth areas have polymicrogyria

REFERENCES: Head

Takada K et al., J Neuropathol Exp Neurol 1984 43:395-407

Takada K, Nakamura H, Brain Dev 1990 12:774-8

Takada K et al., Acta Neuropathol (Berl) 1988 76:170-8