Biochemistry Flashcards
What is the most common type of muscular dystrophy?
Duchenne Muscular Dystrophy (DMD)
What is the second most common type of muscular dystrophy?
Myotonic Dystrophy
What is the third most common type of muscular dystrophy?
Facioscapulohumeral Dystrophy
DMD- inheritance
X-linked recessive
DMD- mutation
Dystrophin gene
What is significant about the size of the dystrophin gene on the X chromosome?
It is the largest known human gene (2.4 million base pairs)
In DMD, how much of the dystrophin is missing?
99%
What types of mutations occur in 60% of DMD pts?
deletions
What other mutations can DMD pt’s have in the dystrophin gene?
duplications (~6% of pt’s), and other subtle mutations
What is the role of dystrophin in the skeletal muscle cell?
joins the intracellular cytoskeleton to the extracellular matrix. It interacts with actin and β-dystroglycan
DMD- pathogenesis
relatively normal at birth but show impared muscle fxn by the time they begin to walk, patients are in a wheelchair by age 10 and survive until their late teens or early twenties
What is significant about the calf muscles in DMD pts?
calf muscles gain fat and connective tissue instead of muscle
What % of DMD pt’s have a low IQ?
~25%
What serum protein is high in DMD pts?
Creatinine Kinase (CK)
DMD- Dx
DNA analysis (PCR) for carrier deletion
Becker’s Muscular Dystrophy (BMD)- inheritance
X-linked recessive
Is BMD more or less severe than DMD?
about 10x less severe
BMD- mutation
Dystrophin is reduced or altered in size. From non-frameshift mutations in gene.
BMD- pathogenesis
Occurs later in life (~11 y/o) with a slower progression than DMD, a small minority never lose the ability to walk.
Myotonic Muscular Dystrophy (MMD)- inheritance
Autosomal dominant
MMD1- mutation
trinucleotide repeat of CTG in the DMPK gene
MMD2- mutation
CCTG repeat on CNBP gene.
What is the role of the DMPK enzyme in MMD1 mutations?
This regulates signal transduction and Ca-ion flux in the skeletal muscle, heart and brain
What is the role of the CNBR enzyme in MMD2 mutations?
encodes a zinc finger protein, whose role is unclear
In MMD2 mutations, is there a correclation between size of expansion and age of onset or severity?
Nope
MMD1- pathogenesis
Most common form of muscular dystrophy in adults (1/8000), signs do not appear until after adolescence and progression is slow. Generation-to-generation it appears earlier and more severe (anticipation).
MMD1- clinical presentation
Muscle wasting (mask-like face), myotonia, cataracts, diabetes, testicular atrophy and sometimes mental retardation.
MMD- Dx
Dx by PCR or Southern blot of repeat sequence.
Facioscapulohumeral Dystrophy (FD)- inheritance
Autosomal dominant
FD- mutation
Gene is on long arm of chromosome 4 but protein product is yet to be isolated and characterized
FD- pathogenesis
Affects the upper body (lol look at the name) unlike DMD or BMD. Sx are variable in age on onset, extent and severity. Ususally cocurs between 10-25 y/o. Sx progress slowly and life expectancy is normal, although ~20% are wheelchair bound
FD- clinical features
Facial and upper arm muscle weakness, may progress to legs
Limb-girdle Muscular Dystrophies (LGMD)- inheritance
Both autosomal dominant and recessive
Dominant LGMD- onset
adulthood
Recessive LGMD- onset
childhood/teen years
Dominant LGMD- mutation
affect various muscle proteins.
recessive LGMD- mutation
genes encoding the 4 sarcoglycans (α, β, γ and δ)
LGMD- clinical features
Group of disorders characterized by muscle weakness affecting both arms and legs. Progression is varied.
Bethlem Myopathy (BM)- inheritance
Autosomal Dominant. Rare.
BM- mutation
Mutations in chromosome 21 genes encoding Type VI Collagen.
BM- onset
before 5 y/o
BM- clinical features
Proximal muscle weakness affecting both legs and arms, joint contractures in ankles and elbows.
Oculopharyngeal Muscular Dystrophy (OPMD)- inheritance
Autosomal Dominant.
OPMD- mutation
Expansion of a GCN repeat within the PABPN1 (Poly-A binding protein) gene.
What happens to the PABN1 protein when the GCN repeat is expanded in OPMD?
Extra AA’s cause the protein to clump in the nuclei
OPMD- onset
later in life (40-50)
OPMD- clinical features
Drooping eyelids and weakness in facial pharyngeal muscles, but can extend to limbs.
What types of populations is OPMD frequent in?
Most common in French-Canadian families (1/1000)
Bukharan Jews in Israel (1/600).
Malignant Hyperthermia (MH)- cause
A severe reaction to certain anesthetics and depolarizing skeletal muscle relaxants. There is a pathological elevation in Ca ions in the sarcoplasm.
MH- mechanism of injury
Opening of defective Ca release channel is prolonged –> Ca ions flood sarcoplasm –> myosin ATPase activated –> Ca-ATPase pumps work maximally and try to pump Ca back into SR –> ATP in consumed rapidly –> ATP, CO2 and heat are made by glycogen metabolism –> muscle rigidity, heat production and acidosis.
MH- Sx
Muscle rigidity, hyperthermia, acidosis and tachycardia.
How can MH be treated?
They used to be fatal but dantrolene (which inhibits Ca++ release from the SR) combats it. This reduces it to ~10%.
What is anticipation?
if a heritable repeat expansion disorder occurs earlier and more severe as lineages progress, the next individual can “anticipate” the disease having a larger severity and onset at an earlier age
