Neuromuscular Disorders Flashcards
In general, what are Dystrophinopathies?
umbrella term for a spectrum of muscle disease caused by mutations to DMD (Xp21.2) which encodes dystrophin
they are progressive and symmetric
affect the proximal muscles (eg. hips, pelvic region, thighs, and shoulders)
List the severe (classical) dystrophinopathies.
progressive skeletal (later cardiac) muscle disease:
Duchenne/Becker Muscle Dystrophy
progressive cardiac disease: DMD-associated dilated cardiomyopathy (DCM)
What are the characteristics of milder forms of dystrophinopathies?
asymptomatic increase in [CK] and/or with muscle cramps, myoglobinuria, and isolated quad myopathy
What is Duchenne Muscular Dystrophy?
“big hit” to the DMD gene
onset before 5 years of age
few patients survive past 30 years old (average lifespan in men: 24 y/o)
What are the symptoms of Duchenne Muscular Dystrophy?
delayed milestones (late to sit, stand, and walk)
toe-walking and flat footedness
wheelchair dependent before 13 y/o
gait problems
mild learning difficulties (short term verbal memory/executive function often confused with ADHD)
cardiomyopathy (1/3 by 14 y/o and all by 18 y/o)
calf hypertrophy (due to collections of proteins)
What is Becker Muscular Dystrophy?
milder mutations of DMD
later onset of symptoms
mean survival 5th decade
some milder forms don’t manifest until 4th decade and are ambulatory until 7th decade
What are the symptoms of Becker Muscular Dystrophy?
weakness with calf hypertrophy
activity induced cramping
cardiac failure with DCM often appearing in adolescence (most often cause of death)
What are the other forms of Becker Muscular Dystrophy?
BMD with subclinical skeletal muscle involvement
Benign skeletal muscle involvement with subclinical findings
What is DMD-associated Dilated Cardiomyopathy (DCM)?
DMD mutations that confer risk for DCM and heart failure without skeletal myopathy
males present in 2nd or 3rd decade
females present later (up to 20% of heterozygotes)
CK is elevated
some overlap with Becker Muscular Dystrophy
What is the normal serum [CK] for males with DMD and what percentage are affected?
> 10x normal
100% affected
What is the normal serum [CK] for males with BMD and what percentage are affected?
> 5x normal
100% affected
What is the normal serum [CK] for males with DMD associated DCM and how many are affected?
“increased”
most are affected
What is the normal serum [CK] for females carriers of DMD and what percentage are affected?
2-10x normal
~50% affected
What is the normal serum[CK] for female carriers of BMD and what percentage are affected?
2-10x normal
~30% affected
What kinds of mutations cause dystrophinopathies and how frequent are they?
deletions (60-70%) duplications (5-10%) point mutations including small deletions and insertions, single base changes, and splicing mutations (25-30%) nonsense more likely in DMD missence rare in both DMD and BMD
What are the possible dystrophin transcripts that come from the DMD gene and what tissues are they found in?
full length DP427 (brain, muscle, Purkinje)
From exon 30 DP260 (retina)
*Exons 45-50 DP140 (brain and kidney)
Fron exon 56 DP116 (Schwann cell)
From exon 63 DP71 (ubiquitous except for muscle; increased in brain)
Describe the genotype-phenotype correlation for DMD.
occurs when there is little to no dystrophin produced
caused by out of frame deletions (usually large)
nonsense mutations
some missense and splicing mutations (disrupt reading frame)
Describe the genotype-phenotype correlation for BMD.
occurs when some dystrophin is produced or normal amount is produced but is partially functional
many in-frame del/dups
splicing and missense mutations (less disruptive)
most non-truncating single-base changes that confers a protein product with intact N and C termini
Describe the genotype-phenotype correlation for DMD-associated DCM.
mutations affect muscle promoter and 1st exon (leading to no dystrophin transcripts in muscle)
2 alternate promoters active in skeletal muscle –> dystrophin expression sufficient to prevent manifestation of skeletal muscle disease
What signs and symptoms are present in female heterozygotes with DMD?
none (75%) muscle weakness (19%) myalgia/cramps (5%) LV dilation (19%) dilated cardiomyopathy (8%)
What signs and symptoms are present in female heterozygotes with BMD?
none (81%) muscle weakness (14%) myalgia/cramps (5%) LV dilation (16%)
What are the molecular causes of females with “classic” DMD?
deletion of Xp21.2
UPD of chromosome X
45X karyotype
skewed X inactivation
X chromosome rearrangement involving Xp21.2
compound heterozygotes for 2 DMD mutations
