Facioscapulohumeralmuscular dystrophy: The unmet medical need€¦ · Facioscapulohumeralmuscular...
Transcript of Facioscapulohumeralmuscular dystrophy: The unmet medical need€¦ · Facioscapulohumeralmuscular...
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Facioscapulohumeral muscular dystrophy:The unmet medical need
Kathryn R Wagner, MD, PhDDirector, Center for Genetic Muscle Disorders
Kennedy Krieger InstituteProfessor, Neurology and Neuroscience
Johns Hopkins School of Medicine
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Facioscapulohumeral Muscular Dystrophy (FSHD)
• Prevalence of ~1:8,000 -1:20,000
• Autosomal dominant disorder of families
• Extremely disabling• Can be life shortening
for those with respiratory insufficiency
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FSHD Phenotype• Wide variability of severity
• Asymmetric involvement
• Majority present in adolescence/early adulthood
• Almost pure skeletal muscle disease: Usually no extramuscular symptoms
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FSHD Phenotype• Weakness of facial muscles: Transverse smile, eyelid closure
weakness, buccal muscle weakness
Wagner, Continuum 2019
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FSHD Phenotype• Weakness of muscles of scapular fixation: scapular winging.• Weakness and wasting and muscles overlying humerus:
biceps/triceps
Wagner, Continuum 2019
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FSHD Phenotype
• Pelvic girdle, foot dorsiflexor, abdominal muscle weakness may follow
Beevor signWagner, Continuum 2019
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Early or “Infantile Onset” FSHD• Rapid progression with loss of ambulation• Association with retinal vascular abnormalities and high tone hearing loss• More likely to be associated with respiratory insufficiency
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Current Management • No good pharmacological agents to prevent muscle wasting and
weakness• Aquatic and physical therapy
– Olsen et al., Aerobic training improves exercise performance in FSHD, Neurology 2005.
• Bracing– Foot drop: ankle foot orthoses– Abdominal laxity: abdominal binder
• For prevention of corneal abrasions– Lacrilube at night, artificial tears
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Specific Treatments• Vascular telangiectasia
– Retinal exam with ophthalmologist– Fluorescein angiography if abnormal retinal exam or family history of Coat’s syndrome in FSHD– Laser treatments
• Scapular Fixation – Anticipated benefits: reduced pain,
Improved arm abduction/extension, Less “winging”
– Risks: surgical risks, infection, pain, decreased pulmonary function, long rehab
– No randomized trials
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Scapulofixation on the right, winging on the left
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Normal
1-10 repeatsFSHD1
11-100 repeats
DUX4
~3.3 kb
DUX4DUX4
Within each D4Z4 repeat unit is an open reading frame for a gene called DUX4
FSHD1 is linked to a truncated repetitive region in the subtelomeric region of chromosome 4
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D4Z4 repeat truncation AND a permissive haplotype results in stable DUX4 transcript expression
AAAAAAAAAAAAAAA
DUX4 PolyA
DUX4 DUX4
No PolyA
DUX4 mRNA is degraded
4qA 4qB
DUX4 mRNA is stable
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D4Z4 repeat truncation leads to changes in epigenetic regulation of the region
Normal (11-100 repeats): Highly methylated, closed chromatin structure à transcriptional repression of DUX4
FSHD1 (1-10 repeats): Loss of methylation, open chromatin structure à transcriptional activation of DUX4
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FSHD1 vs FSHD2
Lek et al., Trends Mol Med 2016
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Diagnosis of FSHD
• Clinical phenotype, normal to slightly elevated CK• Genetic Testing FSHD1:
– Determination of the number of D4Z4 units on chromosome 4 by Southern blot or genome-wide optical mapping
– 1 to 10 repeats AND chromosome 4 permissive haplotype 4qA– 95% of FSHD patients carries one allele of 1-10 units– Early or “Infantile Onset” associated with 1-3 units– Mild or reduced penetrance associated with 8-10 units.
• Genetic Testing FSHD2:– Chromosome 4 permissive haplotype 4qA– Hypomethylation of D4Z4 repeat array– Heterozygous pathogenic variant in SMCHD1 or DNMT3B
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Targets for FSHD Therapeutics• 4q35 subtelomeric D4Z4 locus
– Overexpression of SMCHD1– Modulation of histone acetylation
• DUX4 – Knock down mRNA expression– Inhibit DUX4 protein/binding partners
• DUX4 target genes• Downstream pathology
– Inflammation• Immunomodulatory drugs
– Atrophy• Anabolic agents
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Conclusions• FSHD is one of the most
common muscular dystrophies
• It is marked by extensive muscle involvement with resulting disabilities
• The genetic cause is complex and the pathophysiology is incompletely understood
• There are insufficient meaningful treatments.