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FSHD Type 1A (Chromosome-4-Linked)

FSHD Type 1B (Non-Chromo-4-Linked)

Infantile FSHD

 Facts and Statistics about FSHD
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  • 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 the most prevalent hereditary muscular dystrophy affecting men, women and children. FSHD is more prevalent than any of the other types of muscular dystrophy. A conservative estimate of incidence for the most common type of FSHD is 1 in 14,286 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 20,000 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 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

Reprinted with permission from FSH Society, Inc.
Source: http://www.fshsociety.org/pages/abtFacts.html

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The Diagnosis of FSHD Type 1A Chromosome-4-Linked

Facioscapulohumeral Muscular Dystrophy 1A; FSHMD1A

Facioscapulohumeral muscular dystrophy type 1A (FSHD1A or FSHMD1A) is the more common form of FSHD. A conservative estimate of incidence is 1 in 14,286 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. In FSHD1A the disease 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. Over time and through evolution the D4Z4 repeat array propagated to other parts of the human genome. D4Z4 is also present on the sub-telomere of chromosome 10. However, a shortened D4Z4 repeat on 10q26 does not cause FSHD.

Additionally, it is currently thought that a short array caused by the deletion of the D4Z4 region on chromosome 4q35 alone does not cause FSHD. Going towards the end of the chromosome beyond (distal to) the D4Z4 region, a specific genetic sequence has been identified as being needed to cause FSHD. Genetic variations of this type are called allelic subtypes or specificities; this particular variation is called allele type 4qA and 4qB. The two alleles are equally distributed in the entire population. Interestingly, patients with FSHD carry the 4qA variant in parallel to the shortened D4Z4 repeat region. Individuals who have a shortened D4Z4 array and a 4qB allele are unaffected for FSHD. The defining genetic feature that distinguishes the two allelic variants is the presence of a 6.2 kilobase beta-satellite repeat on the 4qA allele.

The online database Online Mendelian Inheritance in Man (OMIM) is an excellent source for further information on the science and medicine of FSHD 1A. OMIM was designed for use by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. OMIM is developed and maintained by the National Center for Biotechnology Information (NCBI). This database is a catalog of human genes and genetic disorders and has hyperlinks to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere.

To see the Online Mendelian Inheritance in Man pages on facioscapulohumeral muscular dystrophy 1A; FSHMD1A please click HERE.

Reprinted with permission from FSH Society, Inc.
Source: http://www.fshsociety.org/pages/abt1A.html

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The Diagnosis of FSHD Type 1B Non-Chromosome-4-Linked

Facioscapulohumeral Muscular Dystrophy 1B; FSHMD1B

Facioscapulohumeral muscular dystrophy type 1B (FSHD1B or FSHMD1B) is a much 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. FSHD1B is also referred to as non-chromosome 4 linked FSHD. A common misconception is that FSHD1B is linked to the D4Z4 that is also present on the sub-telomere of chromosome 10. In fact, however, a shortened D4Z4 repeat on 10q26 does not cause FSHD or have anything to do with FSHD1B.

The online database Online Mendelian Inheritance in Man (OMIM) is an excellent source for further information on the science and medicine of FSHD 1B. OMIM was designed for use by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. OMIM is developed and maintained by the National Center for Biotechnology Information (NCBI). This database is a catalog of human genes and genetic disorders and has hyperlinks to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere.

To see the Online Mendelian Inheritance in Man pages on facioscapulohumeral muscular dystrophy 1B; FSHMD1B please click HERE.

Reprinted with permission from FSH Society, Inc.
Source: http://www.fshsociety.org/pages/abt1B.html

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The Diagnosis of Infantile FSHD (IFSHD)

Early Onset or Infantile FSHD

FSHD also has a 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. There is no generally accepted estimate of its incidence, but it is rare.

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

1. Signs or symptoms of facial weakness before age five; and

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

He identified only six patients who met those criteria, and their phenotypes did not differ significantly from patients with later onset. Only four of the six had documented 4q35 deletions. Brouwer's population strongly favored familial cases (only 9 of 96 patients studied had sporadic disease).

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% 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% 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% of the patients had early onset disease. Approximately one-half of these had EcoRI fragments of less than 11kb, the smallest fragments. All of the patients with these smallest fragments had early onset disease. In Japan 50% of the small fragment group of patients also had epilepsy and almost 90% 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, Dr. 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% 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 and emerging definitions and criteria being put forth by researchers working on IFSHD are:

  • clinically severe FSHD; patients who report needing a wheelchair greater than 50% of the time by age 18 years; and
  • those predicted to have severe FSHD; those patients with EcoRI fragments smaller than 15kb. 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 3.3kb repeats.

The online database Online Mendelian Inheritance in Man (OMIM) is an excellent source for further information on the science and medicine of infantile facioscapulohumeral muscular dystrophy. OMIM was designed for use by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. OMIM is developed and maintained by the National Center for Biotechnology Information (NCBI). This database is a catalog of human genes and genetic disorders and has hyperlinks to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere.

To see the Online Mendelian Inheritance in Man pages on infantile facioscapulohumeral muscular dystrophy, Infantile FSHMD please click HERE.

Reprinted with permission from FSH Society, Inc.
Source: http://www.fshsociety.org/pages/abtInfantile.html

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