Facioscapulo-humeral dystrophy
| Facioscapulo-humeral dystrophy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2]
History
- The first documented case of FSHD in medical records dates back to 1852 in an autopsy report by Jean Cruveilhier.
- In 1868, Duchenne mentioned FSHD in his important work on Duchenne muscular dystrophy.
- FSHD was identified in 1884 by French doctors Louis Landouzy and Joseph Dejerine with their publications in 1874, 1884 and 1885.
- In their 1886 study, Landouzy and Dejerine highlighted that FSHD runs in families, affecting four generations in one family they studied.
- The clinical features of FSHD were officially described in 1952 after studying a large family in Utah.
- Interest in FSHD grew from around 1980, leading to a better understanding of how the disease varies and its genetic and physiological complexities.
- By the late 1990s, researchers began to identify the specific areas of Chromosome 4 linked to FSHD.
- The DUX4 gene was identified in 1999, recognized for its expression and harmful effects in 2007, and in 2010, researchers unveiled the genetic process behind its expression.
- In 2012, scientists pinpointed the gene commonly mutated in FSHD2.
- By 2019, the initial medication aimed at combating DUX4 expression commenced clinical trials.
- FSHD is also called:
- Landouzy-Dejerine Disease
- Landouzy-Dejerine syndrome
- Erb-Landouzy-Dejerine syndrome
- Landouzy-Dejerine dystrophy or atrophy
- FSHD is also called:
Classification
- There are two genetically distinct but clinically similar forms of FSHD- FSHD1 and FSHD2.
- Over 95% of patients have FSHD type 1 (FSHD1), which is characterized by the deletion of large repeated elements on chromosome 4q's long arm (known as the D4Z4 region).
- A minority of patients have FSHD type 2 (FSHD2), which is caused by a mechanism independent of deletion.
- Both FSHD1 and FSHD2 share a common downstream mechanism, involving loss of methylation in the D4Z4 region and the activation of a normally silenced gene, DUX4 (double homeobox 4).
- It is believed that the derepression of DUX4 leads to disease through a toxic gain-of-function mechanism.
- DUX4 is identified as a retrogene responsible for encoding a transcriptional regulator. Its typical expression occurs within germline cells but undergoes repression within somatic tissues.
Pathophysiology
Despite some remaining disagreements, there is growing consensus on a model explaining the pathophysiology of FSHD, which incorporates most of the current experimental findings.
- This model revolves around the ineffective epigenetic repression of the DUX4 retrogene located near the subtelomeric region of chromosome 4.
- Consequently, there is sporadic expression of DUX4 in the nuclei of skeletal muscle cells in individuals with FSHD.
- The genes controlled by the DUX4 transcription factor suggest various potential mechanisms of disease pathophysiology, including apoptosis, inhibition of regeneration, and an initial immune response.
- Genetic Basis
FSHD type 1 (FSHD1) – accounts for ~95% of cases.
Caused by a contraction (shortening) of the D4Z4 macrosatellite repeat array on chromosome 4q35.
Normally, healthy individuals have 11–100 D4Z4 repeats; FSHD1 patients have only 1–10 repeats.
The contraction alone is not sufficient—disease occurs only if the chromosome carries a “permissive” 4qA haplotype containing a functional polyadenylation signal for the DUX4 gene.
FSHD type 2 (FSHD2) – ~5% of cases.
Patients have a normal-sized D4Z4 array but mutations in genes controlling epigenetic silencing (e.g., SMCHD1, DNMT3B, LRIF1).
This leads to loss of DNA methylation and chromatin relaxation at 4q35, allowing aberrant DUX4 expression.
- Epigenetic Derepression
In healthy muscle cells, the D4Z4 region is heavily methylated, maintaining a condensed chromatin state that silences DUX4.
In FSHD, whether due to repeat contraction (FSHD1) or epigenetic mutations (FSHD2), there is hypomethylation and heterochromatin relaxation at 4q35.
This abnormal chromatin state enables inappropriate transcription of DUX4.
- Aberrant DUX4 Expression
DUX4 (double homeobox 4) is normally expressed only in early embryonic development and is silenced in somatic tissues.
In FSHD, toxic expression of DUX4 occurs in skeletal muscle.
DUX4 acts as a transcription factor and:
Activates germline and early embryonic gene programs in muscle.
Induces immune mediators and apoptotic pathways.
Causes oxidative stress, protein aggregation, and mitochondrial dysfunction.
This leads to muscle fiber damage, inflammation, and progressive atrophy.
- Muscle Involvement and Clinical Correlates
Facial, scapular, and humeral muscles are most affected due to selective vulnerability to DUX4-mediated toxicity.
- Histopathology shows:
Muscle fiber necrosis and regeneration.
Inflammatory infiltrates.
Fibrosis and fatty replacement over time.
Synonyms and related keywords: Facio-Scapulo-Humeral Dystrophy, FSH, FMD, FSHD, Muscular Dystrophy, Facioscapulohumeral, Muscular Dystrophy, Landouzy Dejerine
Facioscapulohumeral muscular dystrophy (FSHD), also known as Landouzy-Dejerine muscular dystrophy, is a neuromuscular disorder.
- Facial Muscle Weakness (Early Feature)
Onset usually in adolescence or early adulthood.
Weakness is often asymmetrical.
Patients may have:
Difficulty whistling, blowing out candles, or using a straw.
Inability to fully close the eyes during sleep (lagophthalmos).
Reduced ability to smile, leading to a “mask-like” facial appearance.
- Shoulder and Scapular Weakness
Prominent scapular winging due to weakness of stabilizing muscles (serratus anterior, trapezius, rhomboids).
Difficulty lifting the arms above shoulder level.
Early fatigue with overhead activities (combing hair, reaching shelves).
- Upper Arm and Trunk Weakness
Weakness of biceps and triceps leads to difficulty lifting objects.
Asymmetry is common.
Truncal weakness can cause lumbar lordosis and postural imbalance.
- Lower Limb Weakness
In ~20–30% of patients, pelvic girdle and leg muscles are affected.
Symptoms include:
Foot drop → tripping while walking.
Difficulty climbing stairs or rising from a chair.
- Extramuscular Manifestations
Hearing loss (sensorineural, especially in early-onset FSHD).
Retinal vascular abnormalities (rare, but risk of vision problems).
Respiratory involvement in severe or advanced cases, though uncommon.
- Disease Course
Slowly progressive, with variable severity.
Many patients remain ambulatory throughout life.
Some may require wheelchairs in later stages.
- Facial weakness is the initial manifestation with inability to smile, whistle, etc.
- Shoulder muscles are weak with scapular “winging” during arm abduction.
- Biceps / triceps are involved with sparing of the deltoids.
- 20% progress to involve the pelvic girdle.
- Labile hypertension, ocular involvement (Coat’s disease) and deafness can occur.
Facioscapulohumeral muscular dystrophy is usually inherited as an autosomal dominant trait. However, in up to approximately 30 percent of affected individuals, there is no apparent family history of the disorder.