Early-onset FSHD

O. Brouwer et al. in the Netherlands defined early-onset FSHD (IFSHD) as follows:

1. Signs or symptoms of facial weakness before age five.
2. Signs or symptoms of shoulder girdle weakness before age 10.

They showed the same broad range of clinical signs and symptoms as can be seen normally in FSHD. In 7 patients Southern blotting with p13E-11 was performed which showed an abnormal EcoRI fragment (13-22 kb) in 6 of them. “We conclude that early onset FSHD does not differ from regular FSHD clinically or genetically,” the authors write. “However, the precise mechanisms involved in the extensive clinical variability of the disease are still unknown.”

Jardine et al. in the United Kingdom reported that patients with de novo 4q35 deletions tend to have larger deletions than familial cases, and also to have more severe disease. The mean age at onset of this population was 6.8 years, 30 percent used a wheelchair before 18 years of age, and three had congenital facial diplegia and sensorineural deafness. This age at wheelchair use contrasts sharply with the overall statistics reporting that 20 percent of FSHD patients require a wheelchair by age 50.

Arahata et al. in Japan analyzed the data from 78 independent families with 4q35 FSHD. They found that 16-17 percent of the patients had early-onset disease. Approximately one-half of these had EcoRI fragments of less than 11 kb, the smallest fragments. All of the patients with these smallest fragments had early-onset disease. In Japan, 50 percent of the small fragment group of patients also had epilepsy, and almost 90 percent had mental retardation.

Korf et al. reported six patients with facial diplegia occurring in the first year. All had severe progressive disability prior to adolescence. In Deymeer’s Neuromuscular Diseases from Basic Mechanism to Clinical Management, Lunt writes in his chapter “Facioscapulohumeral Muscular Dystrophy Diagnostic and Molecular Aspects” that “In more severe infantile onset cases, facial weakness is the earliest and most prominent sign. Thus, the infant may show little or no facial expression, appearing unable to smile, and may be initially misdiagnosed as having Mobius syndrome. Pelvic girdle weakness in the most severe cases can be prominent by age 10 years, leading to consideration of Xp2l or limb girdle types of muscular dystrophy, but unlike these conditions, FSHD is still characterized by an even greater degree of shoulder girdle weakness rather than pelvic weakness.

FSHD is inevitably progressive, and an overall 20 percent of patients require a wheelchair by the fifth decade, although this can be required before age 20 years in many of the most severe new mutation cases.” This might suggest that very early-onset FSHD patients are more likely to have de novo mutations and that the clinical manifestations may include congenital facial diplegia, congenital deafness, mental retardation, or seizures. These patients are likely to require wheelchairs in childhood.

Some new ideas, definitions, and criteria being put forth by researchers working on IFSHD are:

• Clinically severe FSHD; patients who report needing a wheelchair greater than 50 percent of the time by age 18 years; and
• Those predicted to have severe FSHD; those patients with EcoRI fragments smaller than 15 kb. This is a conservative value and is expected to identify patients with a milder phenotype in addition to the more severe. This corresponds to roughly three or fewer residual 3.3 kb repeats.