Facts and Statistics about FSHD
- Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular dystrophy. FSHD is also broadly characterized as a neuromuscular disease (NMD), as muscular dystrophy is a subset of NMD.
- FSHD is not a rare muscular dystrophy. FSHD is one of the most common diseases of muscle (also known as a myopathy).
- FSHD is a most prevalent hereditary muscular dystrophy affecting adults and children. FSHD is one of the most prevalent of the nine types of muscular dystrophy. A conservative estimate of incidence for the most common type of FSHD is 1 in 14,000 births throughout the world; however, due to increased experience with FSHD, population-based research and improved genetic testing, this estimate may be low; actual incidence may be 1 in 7,500.
- FSHD generally presents outward signs in 95% of affected individuals by the second decade of life for men and the third decade of life for women. The disease is said to have a penetrance of 95% in men by the second decade and in women by the third decade.
- FSHD causes progressive loss, wasting and atrophy of all skeletal muscles.
- In FSHD muscle atrophy and functional loss occur asymmetrically, with one side being more affected than the other.
- “Generally, FSHD displays a characteristic gradual spread of muscle involvement, starting in the face and slowly progressing to the shoulder and upper-arm musculature and to the abdominal and foot-extensor muscles." 1 “Foot dorsiflexion weakness leading to footdrop is an early manifestation of FSHD and one amenable to the use of molded ankle-foot orthoses (AFO)" 2.
- “The most common initial symptom is difficulty reaching above shoulder level. Less common presentations include foot drop (such patients, however, almost invariably have compensated), asymptomatic scapular fixator, and facial weakness on examination. Truncal weakness is an early and frequent manifestation that is easily overlooked during examination of these patients. Weak abdominal muscles result in a protuberant abdomen and contribute to the lumbar lordosis. Lower abdominal muscles are weaker than the upper abdominal muscles, causing a strikingly positive Beevor’s sign, a physical finding fairly specific for FSHD" 2.
- FSHD has been classified into two types: FSHD1A and FSHD1B.
- FSHD type 1A is the more common form. A conservative estimate of incidence is 1 in 14,000 births throughout the world; however, due to increased experience with FSHD, population-based research and improved genetic testing, this estimate may be low; actual incidence may be 1 in 7,500.
- FSHD type 1A is associated by genetic testing with the deletion of 3.3-kb repeats from a chromosomal tandem repeat called D4Z4 located near the end of chromosome 4 at the 4q35-qter location. The D4Z4 region is a polymorphic variable number tandem repeat (VNTR) array consisting of 3.3 kb units. Unaffected individuals have a chromosome 4 D4Z4 array that has a span of 11 to 150 contiguous units. In individuals with FSHD, the chromosome 4 D4Z4 repeat array is contracted to a range between 1 to 10 contiguous units.
- FSHD type 1B is a rarer type, occurring in several dozen well-documented families. The incidence of FSHD1B is not known at this time but is unlikely to exceed 2% of all cases of FSHD. In FSHD1B the disease is NOT associated with the deletion of 3.3-kb repeats from a chromosomal tandem repeat called D4Z4 located near the end of chromosome 4 at the 4q35-qter location. FSHD1B may be caused by different genes, located on the same or different chromosomes. FSHD1B may also be caused by proximal and distal deletions that extend into D4Z4 that cause the standard genetic test to be “negative” even though the patient has the requisite number of deletions to cause FSHD.
- FSHD type 1B (FSHD2 or FSHD1B or FSHMD1B) is a much rarer type of FSHD, occurring in several dozen well documented families. FSHD1B is clinically identical to FSHD1A but genetically distinct. FSHD1B is sometimes referred to as FSHD type 2 (FSHD2). The incidence of FSHD1B is not known at this time, but is unlikely to exceed 5% of all cases of FSHD. In FSHD1B the disease is NOT associated with the deletion of 3.3-kb repeats from a chromosomal tandem repeat called D4Z4 located near the end of chromosome 4 at the 4q35-qter location. FSHD1B may be caused by different genes, located on the same or different chromosomes.
- The notable difference between FSHD1A and FSHD1B patients is that FSHD1B patients do not have contractions in the 4q35 D4Z4. However, in a similar manner to FSHD1A, in FSHD1B the chromatin structure of the D4Z4 repeats is more open, and at least one 4q35 allele is an A variant. Molecular genetic testing for such patients is available.
- FSHD1B is caused the inheritance of two independent genetic variations e.g. by digenic inheritance. In 80% of the FSHD1B patients the disease is caused by heterozygous loss-of-function mutations in the encoding Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) gene, a chromatin modifier, brought about by two concurrently occurring genetic variations. The first being the mutation of the SMCHD1 gene on chromosome 18p which in turn causes D4Z4 chromatin relaxation; and, the second variation being an FSHD-permissive haplotype on chromosome 4 such as 4qA161 allele needed for DUX4 expression. SMCHD1 mutations are not connected to the FSHD-permissive DUX4 alleles and they segregate independently.
- FSHD also has an infantile form called Infantile FSHD (IFSHD). IFSHD is a more severe course of` FSHD1A or FSHD1B. What makes the disease more severe has not yet been determined. Hearing loss (high frequency bilateral sensorineural), vision problems (Coats’ Disease and retinal telangiectasias), and seizures have been documented in IFSHD. "Hearing loss is often more severe in infantile FSHD, and if not detected and treated early can interfere with learning and cognitive development. Audiograms should be performed on patients diagnosed with infantile FSHD." 2 There is no generally accepted estimate of the incidence of IFSHD, but it is rare.
- Diagnostic and prenatal genetic testing are available for FSHD. Pre-implantation Genetic Diagnosis is available for couples using In Vitro Fertilization (PGD IVF). There are known uncertainties associated with the pre-implantation genetic diagnosis test, as it does not directly test for the FSHD D4Z4 deletion.
- All forms of FSHD are autosomal dominant genetic disorders that can be inherited from a parent who has FSHD or may be the result of a new or "spontaneous mutation" caused by a de novo rearrangement, a somatic mosaicism or a germline mosaicism (only the parent’s sperm or egg cells are affected). Since FSHD is autosomal dominant, the chromosome 4 D4Z4 repeat array is contracted in patients with FSHD type 1A to a range between 1 to 10 contiguous units on only one of the pair of chromosome 4 strands, called an allele.
- FSHD affects men, women and children. FSHD is worldwide in distribution, is equally prevalent in both sexes and has no particular racial, geographic or ethnic distribution. Therefore, FSHD can appear in any family and happen at any time.
- “Males are typically more severely affected than females, and there is a wide clinical inter- and intra-familial variability of the disease, with approximately 20% of patients eventually becoming wheelchair-bound and with an equal frequency of non-penetrant gene carriers."1
- “There is a rough and inverse relationship between clinical severity and the residual repeat size, with the smallest repeats causing the most severe phenotypes."1
- At a minimum, 70% of FSHD patients inherit the disease from a parent, and at a maximum, in 30% of FSHD patients the disease is caused by a spontaneous genetic deletion that had not previously existed in the family.
- Offspring of an FSHD patient have a 50% chance of inheriting the disease. Each child of an affected parent has a 50% chance of inheriting the gene and developing FSHD. The type of FSHD inherited by the child is always the same as that of the affected parent, although the severity of the symptoms may differ from person to person within a family.
- “Associated non-skeletal muscle manifestations include high-frequency hearing loss as well as retinal telangiectasias, both of which are rarely symptomatic."2 “Approximately half of the patients present with subclinical high-tone hearing loss and retinovasculopathy."1
- Respiratory involvement in FSHD is not typical but can seen, especially in patients with severe FSHD. Symptoms and signs of respiratory insufficiency should be sought during routine clinic visits in patients with severe FSHD, and regular monitoring of respiratory function instituted. "Symptomatic respiratory insufficiency can be initially managed with nighttime noninvasive pressure support (BiPAP) but may in severe cases require the use of a ventilator. 2”
1 van der Maarel SM, Frants RR. “The D4Z4 repeat-mediated pathogenesis of facioscapulohumeral muscular dystrophy.” Am J Hum Genet. 2005 Mar; 76(3):375-86. Review. PMID: 15674778
2 Tawil R, van der Maarel SM. “Facioscapulohumeral muscular dystrophy.” Muscle Nerve. 2006 Jul; 34(1):1-15. Review. PMID: 16508966