© Springer International Publishing Switzerland 2015
Raymond A. Huml (ed.)Muscular Dystrophy10.1007/978-3-319-17362-7_33. FSHD: The Most Common Type of Muscular Dystrophy?
(1)
Biosimilars Center of Excellence, Quintiles Inc., 4820 Emperor Boulevard, Durham, NC 27703, USA
(2)
FSH Society, Inc., 450 Bedford Street, Lexington, MA 02420, USA
Keywords
Facioscapulohumeral MDHormone supplementationProtein supplements (creatinine monohydrate)PrednisoneLumbar lordosisScoliosisBeevor’s signDUX4 geneFSHD1FSHD2Infantile FSHDCreatine kinaseElectromyographMuscle biopsyOrthoticsMobility devicesCounselingIntroduction
Facioscapulohumeral muscular dystrophy, a complex, inheritable muscle disease, was historically known as Landouzy–Déjérine disease—named after the French neurologists Dr. Joseph Jules Déjérine (1849–1917) and Dr. Louis Théophile Joseph Landouzy (1845–1917). It is more commonly known today as FSHD or FSH. Landouzy and Déjérine first named the disease FSHD in 1885 in order to distinguish the disease from the only other form of muscular dystrophy (MD) known at the time, DMD [1, 2].
Although frequently reported as the third most common type of MD in older reports and articles, many newer sources [3–5], including a May 2014 report by Orphanet, ranks FSHD as the most prevalent type of MD [6]. According to Orphanet, FSHD is the most prevalent MD with 7 cases/1,000 persons reported as compared with DMD/BMD (5 cases/1,000 persons) and Steinert myotonic dystrophy (4.5 cases/1,000 persons). Other prominent Websites, such as FSH Canada, also list FSHD as “the most prevalent of the nine primary types of MD affecting adults and children” [7]. Informal discussions with those afflicted with FSHD, as well as researchers and proponents of FSHD treatments, indicate that the incidence of FSHD is probably underreported. This may reflect the fact that some patients with FSHD—such as those with mild symptoms, or those with an onset late in life—may not ever be formally diagnosed and thus may not be reported or included in patient registries.
The identification of FSHD as the most common type of MD has important ramifications, for example, when allocating future Federal (U.S.) funding for research. Daniel P. Perez, CEO and Founder of the FSH Society, has testified nearly 50 times before Congress. Due to his leadership efforts and testimony, funding for FSHD has grown from $1.5m/year in 2003 (out of $39.1m for all types of MD) to $5–6m in 2009–2013, a significant increase, but not yet aligned, based on prevalence alone. According to the most recent testimony by Mr. Perez to the U.S. Senate Appropriations Committee on May 16, 2014, FSHD is one of the most common adult MDs with a prevalence of 1:15,000–1:20,000 [6, 7].
Another important factor related to prevalence of disease is the potential market size for future FSHD treatments. Quite simply, a larger prevalence means a larger potential market and this may have an influence on the interest levels of third party capital providers investing in FSHD clinical trials and treatments. This is a win–win situation for both those afflicted with MD and those wishing to invest in the healthcare marketplace.
Despite being the most common form of MD, FSHD has only recently attracted attention from big pharma (e.g., GSK), largely due to major advances in the understanding of the gene/mechanism of disease [8]. For example, recent advances in the understanding of the cause of FSHD point to over-expression of a protein called DUX4, which is normally suppressed in adult muscles, but is activated in FSHD. A more detailed explanation is provided below in the section titled, “The Proposed Cause of FSHD.”
Overview of Symptoms of FSHD
The major symptom of FSHD is progressive weakening and loss of skeletal muscles. The usual location of these weaknesses at onset is the origin of the name: face (facio), shoulder girdle (scapulo), and upper arms (humeral). Early weaknesses of the muscles of the eye (open and close) and mouth (smile, pucker, whistle) are distinctive. These symptoms, in combination with weaknesses in the muscles that stabilize the scapulae (shoulder blades), are often the basis of the physician’s clinical diagnosis of FSHD.
The progression of FSHD is quite variable, even among afflicted siblings [9]. For most patients, the progression of the disease is usually relatively slow; however, it usually worsens during adolescent years as the muscular framework fails to keep pace with the expanding and lengthening skeletal structure.
Other skeletal muscles invariably weaken. Involvement of muscles of the foot, hip girdle, and abdomen is common. With FSHD, most affected people develop unbalanced (side-to-side) weaknesses. The reason for this asymmetry is unknown [10].
In most cases, FSHD muscle involvement starts in the face and slowly progresses to the shoulder and upper-arm muscles and then down to the abdominal and foot-extensor muscles. Foot drop and foot weakness can be early manifestations and are generally accepted as part of the natural course of the disease [11, 12].
Initial signs of FSHD also include difficulty reaching above the shoulder level, scapular winging, and facial weakness. Weakness in the abdominal muscles can cause a protuberant abdomen and lumbar lordosis and scoliosis (curvatures of the lower spine). The inability to run and balance and loss of power may manifest in patients with FSHD and may be more noticeable in FSHD patients who play sports, take dance classes, or even school gymnastics classes, as FSHD patients compete with peers.
The lower abdominal muscles are usually weaker than the upper abdominal muscles. This distribution of weakness causes a positive Beevor’s sign—a characteristic weakness of the lower abdominal muscles, involving the movement of the navel towards the head on flexing the neck—and, according to the FSH Society’s Website and other sources [13], prognostic for FSHD.
Other symptoms in FSHD patients include chronic pain in the majority of patients (50–80%) with severe pain in up to 23% [14–16], vision abnormalities (due to vascular abnormalities of blood vessels in the back of the eye, which cause visual problems in only about 1% of the cases) [13], progressive hearing loss (correlated with the severity of genetic abnormalities and especially in severe infantile cases), cardiac arrhythmias (generally asymptomatic), and cognitive impairment, sometimes with epilepsy. The latter conditions are rare, but may be seen in severe, early-onset cases.
Autosomal Dominance
Most individuals with FSHD inherit the mutation from a parent with the disease. DNA is the means of transmission of inheritable traits from parent to child and occurs via chromosome transfer from one generation to the next. Each chromosome contains a strand of DNA. Human cells usually contain 46 chromosomes, 23 from each parent. Children inherit one member of each of the 23 pairs of chromosomes from each parent. Forty-four of the chromosomes, also called autosomes, are homologous pairs (numbered 1 through 22), with each strand of the pair having the same size, order, and arrangement with genes for the same traits in the same position on the chromosome. The remaining chromosome pair consists of the nonhomologous sex chromosomes X and Y. A mother donates an X chromosome, and a father donates either an X or Y chromosome. Therefore, males have one X chromosome and one Y chromosome, while females have two X chromosomes [17].
FSHD is the result of a DNA mutation on one member of the chromosome 4 pair. FSHD is highly penetrant. This means that when a person inherits a chromosome 4 with the FSHD mutation, there is a high probability that discernible muscle weaknesses will develop. Since weakness still occurs in the presence of the normal member of the chromosome 4 pair, the disease is considered dominant. FSHD is, therefore, a dominant inherited disease, meaning only one parent has to have the disease gene or deletion for his or her child to inherit FSHD. Since each parent donates only one member of each chromosome pair to a child, the probability of passing the disease to an offspring is 50%.
If one has a blood parent, sibling, or other relative who has the FSHD mutation, there may be a risk of carrying that mutation. Often, when a person is diagnosed with FSHD, the disease is discovered to be throughout the extended family tree and over many generations. It is important to be aware that there may be other family members who are affected but unaware that they may have FSHD or may be at risk for FSHD. Professionals with knowledge of genetics and inheritance of FSHD can advise them regarding that risk.
The Proposed Cause of FSHD
A DNA mutation causes FSHD. The gene that is linked to FSHD is unknown, but its approximate location is toward the end of the DNA of the long arm of chromosome 4. The specific genetic location of the FSHD deletion is 4q35 in the D4Z4 DNA region. Although the precise details are not yet known, the most probable cause of FSHD is inappropriate expression of protein called DUX4 by a “double homeobox protein 4 gene” [18, 19]. According to the FSH Society’s Website, approximately 2% of FSHD cases are not linked to the 4q35 deletion on chromosome 4.
Researchers are investigating the molecular connection between deletion and FSHD. The size of the deletion has a relationship to the severity of the disease—patients with the fewest repeats (the largest deletion) typically have the most severe symptoms.
The DUX4 gene is normally expressed in germ line tissue (cells associated with reproduction, such as sperm and ovaries) and repressed in somatic cells (non-germ cells associated with forming other parts of the human body), but becomes over-expressed in FSHD patients and is toxic to muscle cells.
Two forms of the disease are recognized and reported in the literature: FSHD1 and FSHD2. About 95% of patients with FSHD have the FSHD1 form, where one allele (called D4Z4) is contracted and the other D4Z4 allele is normal [20, 21]. De novo, or sporadic contraction of D4Z4, account for 10–30% of FSHD1 cases [22, 23].
Less than 5% of FSHD patients have no contracted D4Z4 repeat arrays, but may still have abnormal DNA and are termed FSHD2 cases [24]. Patients with FSHD2 sometimes have another mutated gene, called SMCHD1, which appears to upregulate D4Z4 and be the cause of some, if not most, cases of FSHD2 [25]. There is no generally accepted estimate of its incidence, but this is unlikely to exceed 2% of all cases of FSHD.
Infantile FSHD (IFSHD) is characterized by onset in early childhood. There is no generally accepted estimate of its incidence, but it is rare. FSHD occurs in all racial groups and with equal frequency in both sexes.
One cannot clinically distinguish one type of FSHD from the other.
De Novo Cases of FSHD [19]
Studies report from 10% to as high as 33% of all FSHD cases result from a de novo (or sporadic) mutation. Approximately 20% of reported de novo cases are those inherited from a seemingly unaffected parent who is a “germline mosaic,” meaning that only the mother’s or father’s germ cells (the egg or sperm) are affected. When a germline mosaic is involved, the parent appears unaffected but the children are at risk.
In the remaining 80% of de novo cases, neither parent’s genes are affected; a new spontaneous mutation results in a chromosome 4 deletion that causes FSHD. When the 4q35 deletion fragment appears in a sporadic FSHD case, it is transmitted in an autosomal dominant (only one parent needs to be affected) manner to succeeding generations. The probability, then, of passing the disease to an offspring is 50%.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
