Facioscapulohumeral Muscular Dystropy

Original Editor - Kehinde Fatola
Top Contributors - Kehinde Fatola and Vidya Acharya

Introduction[edit | edit source]

Facioscapulohumeral muscular dystrophy (FSHMD) also called Landouzy-Dejerine muscular dystropy, is an autosomal dominant inherited form of muscular dystrophy (MD) that initially affects the skeletal musculature of the face (facio), scapula (scapulo) and upper arms (humeral). [1] The facial aspect of the disease was described in 1884 and the scapulo-humeral involvement in 1886 by Landouzy and Dejerine.

Epidemiology[edit | edit source]

Though the exact prevalence of FSHMD is not known, it is reportedly the third commonest genetic disease of skeletal muscle. A January 2022 Orphanet Report Series put the prevalence at 4.5 in 100,000. [2]

Clinical Presentation[edit | edit source]

Due of the extreme variability of the disease, there is no authoritative or scientifically confirmed symptomatology for the disease yet. However, symptoms may appear in early childhood and are usually noticed in the teenage years with 95% of patients manifesting disease by 20 years of age. [3] A progressive skeletal muscle weakness usually develops in other areas of the body as well which is often asymmetrical. Life expectancy can be threatened by respiratory insufficiency and up to 20% of affected individuals become severely disabled requiring use of a wheel chair or mobility scooter. [3] Some of the symptoms include;

  • Facial muscle weakness
  • Shoulder weakness
  • Hearing loss
  • Abnormal heart rhythm
  • Unequal weakening of the biceps, triceps, deltoids, and lower arm muscles
  • Loss of strength in abdominal muscles and progression to the legs
  • Foot drop

Types[edit | edit source]

Type 1 (4q35 deletion); This is also called FSHMD1A . More than 95% of cases of FSHD are associated with the deletion of integral copies of a tandemly repeated 3.2kb unit (D4Z4 repeat) at the subtelomeric region 4q35 on Chromosome 4 of the human genome, of which a normal chromosome includes between 11-150 repetitions of D4Z4. There are both heterochromatin and euchromatin structures within D4Z4 and one putative gene called DUX4. [4] Inheritance is autosomal dominant, though up to one-third of the cases appear to be from novel mutations. The heterochromatin is particularly lost in the deletions of FSHD while the euchromatin structures remain. If the entire region is removed, there are birth defects, but no specific defects on skeletal muscle. Individuals appear to require the existence of 11 or fewer repeat units to be at risk for FSHD.

In addition, a few cases of FSHD are the result of rearrangements between subtelomeric chromosome 4q and a subtelomeric region of 10q. This location contains a tandem repeat structure highly homologous to 4q35.[12] Disease occurs when the translocation results in a critical loss of tandem repeats to the 4q site.

Type 2; It was reported that a phenotypically indistinguishable family from FSHMD in which no pathological changes at the 4q site or translocation of 4q-10q are found.[13][14] and it was largely attributed to limitations in available tests. [5]

A majority of FSHD2 cases were reported linked to mutations in the SMCHD1 gene on chromosome 18. This leads to substantially reduced levels of SMCHD1 protein, and subsequently, hypomethylation of the 4q D4Z4 region. The FSHD2 phenotype arises in individuals who inherited both the SMCHD1 mutations plus a normal sized D4Z4 region on a permissive 4qA allele. This establishes a genetic/mechanistic intersection of FSHD1 and FSHD2.[6]

Diagnostic Procedures[edit | edit source]

Creatine kinase (CK) level: This test measures the Creatine kinase enzyme in the blood. Increased levels of CK are related to muscle atrophy.

Electromyogram (EMG): This test measures the electrical activity in the muscle fibers.

Nerve conduction velocity (NCV): This test measures the how fast signals travel from one part of a nerve to another. The nerve signals are measured with surface electrodes (similar to those used for an electrocardiogram), and the test is only slightly uncomfortable.

Muscle biopsy: In this procedure, a small piece of muscle is removed (usually from the arm or leg) and evaluated with a variety of biochemical tests. Researchers are attempting to match results of muscle biopsies with DNA tests to better understand how variations in the genome present themselves in tissue anomalies

Management / Interventions[edit | edit source]

There is presently no known cure or treatment for FSHMD, and management is generally symptomatic. However, four approaches to therapeutic interventions have been proposed; [7]

  • enhance the epigenetic repression of the D4Z4
  • target the DUX4 mRNA, including altering splicing or polyadenylation;
  • block the activity of the DUX4 protein
  • inhibit the DUX4-induced process, or processes, that leads to pathology

Physiotherapy intervention to improve functional capacity may include;

  • Passive and active stretching promote flexibility and avoid contractures
  • Strength exercises in order to maintain and improve muscle strength
  • Respiratory Techniques like assisted coughing, diaphragmatic breathing exercises
  • Encouragement of activity: Assistive devices such as canes, braces, and wheelchairs may be needed to maintain mobility

There is limited evidence on upper limb rehabilitation for people with FSHD. Exercise prescription for rehabilitation in people with FSHD is complex due to the lack of appropriate guidelines, varying symptoms, disease progression, and existing comorbidities of pain and fatigue, which affect functional capacity. [8]According to the results of the study, only 44.4% of patients with FSHD engaged in upper limb exercises despite more than 80% of patients reported shoulder instability that affected daily life. The study indicated patients with FSHD are willing and can engage in upper limb exercises and further research focusing specifically on upper limb exercises is needed to develop appropriate, evidence-based exercise interventions and guidance for exercise prescription for upper limb rehabilitation in FSHD.[8]

Differential Diagnosis
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References[edit | edit source]

  1. Rickard, Amanda; Petek, Lisa; Miller, Daniel (August 5, 2015). "Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways". Hum. Mol. Genet. doi:10.1093/hmg/ddv315
  2. Orphanet Report Series - Prevalence of rare diseases: Bibliographic data – January 2022
  3. 3.0 3.1 Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW (2004). "Ventilatory support in facioscapulohumeral muscular dystrophy". Neurology 63 (1): 176–8. doi:10.1212/01.wnl.0000133126.86377.e8. PMID 15249635
  4. Impossible Things: Through the looking glass with FSH Dystrophy Researchers, Margaret Wahl, MDA, Quest magazine, Vol 14, No 2, March–April 2007
  5. Deak KL, Lemmers RJ, Stajich JM, et al. (February 2007). "Genotype-phenotype study in an FSHD family with a proximal deletion encompassing p13E-11 and D4Z4". Neurology 68 (8): 578–82. doi:10.1212/01.wnl.0000254991.21818.f3. PMID 17229919.
  6. Lemmers, RJ; Tawil, R; Petek, LM; et al. (Dec 2012). "Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2". Nature Genetics 44 (12): 1370–1374. doi:10.1038/ng.2454.
  7. Tawil, Rabi; van der Maarel, SM; Tapscott, SJ (10 June 2014). "Facioscapulohumeral dystrophy: the path to consensus on pathophysiology". Skeletal Muscle 4 (1): 12. doi:10.1186/2044-5040-4-12
  8. 8.0 8.1 Faux-Nightingale A, Kulshrestha R, Emery N, Pandyan A, Willis T, Philp F. Upper Limb Rehabilitation in Facioscapulohumeral Muscular Dystrophy: A Patients’ Perspective. Archives of rehabilitation research and clinical translation. 2021 Dec 1;3(4):100157.