Facioscapulohumeral Muscular Dystropy: Difference between revisions
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== Introduction == | == Introduction == | ||
Facioscapulohumeral muscular dystrophy (FSHMD) also called Landouzy-Dejerine muscular dystropy, is an autosomal dominant inherited form of muscular dystrophy (MD) | 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). <ref>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</ref> The facial aspect of the disease was described in 1884 and the scapulo-humeral involvement in 1886 by Landouzy and Dejerine.<br> | ||
== Epidemiology == | == Epidemiology == | ||
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[ | 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. <ref>Orphanet Report Series - [http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf Prevalence of rare diseases: Bibliographic data – January 2022]</ref><br> | ||
== Clinical Presentation == | == Clinical Presentation == |
Revision as of 10:39, 22 March 2022
Top Contributors - Kehinde Fatola, Vidya Acharya and Ananya Bunglae Sudindar
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. 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 6. 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.[10] There are both heterochromatin and euchromatin structures within D4Z4 and one putative gene called DUX4.[10][11] 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.[10] 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. 15
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.[16]
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;
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 to improve flexibility and prevent contractures
Strength exercises in order to maintain and improve muscle strength
Respiratory Techniques like assisted coughing, respiratory muscle training
Encouragement of activity: Assistive devices such as canes, braces, and wheelchairs may be needed to maintain mobility
Differential Diagnosis
[edit | edit source]
Durchennes Muscular Dystropy
Becker Muscular Dystropy
Limb-girdle MD
Emery Dreifuss
Rigid spine syndrome
Myopathies
Myasthenia gravis
Spinal muscular atrophy
References[edit | edit source]
- ↑ 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
- ↑ Orphanet Report Series - Prevalence of rare diseases: Bibliographic data – January 2022