Clinical Guidance

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) . Typically, brain and ocular findings also show the same severity as motor function . and analyzed FKTN in 107 unrelated affected individuals.

Source: GeneReviews — "Fukuyama Congenital Muscular Dystrophy"

Diagnostic Criteria

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

Source: GeneReviews — "Fukuyama Congenital Muscular Dystrophy"

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: • Alpha-dystroglycanopathies (see and ); • CMD type 1A (see LAMA2 Muscular Dystrophy); • Congenital myopathy 3 with rigid spine (associated with pathogenic variants in SELENON; OMIM 602771); • LMNA-related CMD (OMIM 613205); • Ullrich CMD (see Collagen VI-Related Dystrophies). The three major phenotypes of the alpha-dystroglycanopathies are : • 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 . 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

Management Guidelines

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 .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FCMD, the evaluations summarized (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/Concern | Evaluation | Comment

Neurologic

| Neurologic eval | • At initial diagnosis at least once every 3 mos1 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

| Ophthalmologist | Assess visual acuity, retina for retinal abnormalities, ocular movement, refractive errors /or strabismus

Source: GeneReviews — "Fukuyama Congenital Muscular Dystrophy"

Therapies Under Investigation

Antisense oligonucleotide therapy. 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. 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.648-1243GT and the 3062-bp insertion founder variant).

Source: GeneReviews — "Fukuyama Congenital Muscular Dystrophy"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 7. Fukuyama Congenital Muscular Dystrophy: Recommended Surveillance

Source: GeneReviews — "Fukuyama Congenital Muscular Dystrophy"