clinical presentations Flashcards
what can be used to help diagnose benign joint hypermobility?
Beighton’s Criteria
what is included in Beighton’s criteria?
a point for each:
-passive opposition of thumb to forearm
-passive extension of pinky finger (V-MCP)
-active hyperextension of elbow
-active hyperextension of knee
-ability to flex spine placing palms to floor w/o bending knees
5/9 –> hypermobile joints
key features of ehlers-danlos syndrome:
-fragility of soft CT
-easily damaged/stretched/bruised skin
-pain
-increased flexibility
-early arthritis
what is vascular type ehlers danos?
-severe form
-skin isn’t stretchy, rather THIN and TRANSLUCENT
-excessive bruising/visible veins
-high rate of arterial rupture, aortic root dilation
what mutation causes ehler-danlos?
COL5A1, COL5A2 (encode for production of alpha chain of type V collagen)
characteristics of Marfan syndrome?
thin and distensible skin
joint laxity
long, narrow extremities
tall
ectopia lentis
aortic root dilation, acute dissection, aneurysms
what mutation causes Marfan?
FBN1 gene (encodes for fibrillin-1)
what criteria is used to Dx Marfan?
Ghent criteria
what two signs are positive for those with Marfan?
Steinburg sign - thumb inside clenched fist extends past hand
Walker Murdoch - thumb to finger around wrist overlap
Duchenne syndrome inheritance pattern:
young males
X linked recessive
what criteria/classification is used for suspected ehlers-danlos syndrome patients?
Villefranche classification
Duchenne syndrome onset:
severe, earlier onset
2-3 years old
key features of Duchennes:
-muscle weakness
-calf pseudo hypertrophy
-scoliosis/lumbar lordosis
-club foot
-joint contractures
what mutation causes Duchennes?
X linked recessive (hemizygous, males)
nonsense/frameshift mutation of Xp21.2 dystrophin gene
dystrophin protein ABSENT
what is the function of dystrophin protein?
-links intracellular actin with the “dystrophin-associated glycoprotein complex” (DGC)
-DGC - links cytoskeletal actin and extraceullular matrix while stabilizing the sarcolemma
without dystrophin, sarcolemma wilts and becomes unstable
what clinical findings indicate Duchennes?
Gower’s sign
Trendelenburg sign
elevated creatine phosphatase kinase (CPK)
muscle biopsied showing absent dystrophin
EMG
treatment for Duchennes:
steroids
rehab
eteplirsen - antisense oligonucleotide?
what is Trendelenburg sign?
waddling gait due to muscle weakness
Beckers muscular dystrophy inheritance pattern:
mostly young males (hemizygous - 1 copy)
X linked recessive
Beckers onset:
a milder MD
onset around age 10-20
longer life expectancy than Duchennes
key features of Beckers:
-calf pseudohypertrophy
-dilated cardiomyopathy
what clinical findings indicate Beckers?
-Gowers sign
-elevated CPK levels
-muscle biopsy showing DECREASED dystrophin
-EMG
-ICG for cardiomyopathy
treatment for Beckers:
steroids and rehab
main differences between Duchennes and Beckers:
Duchennes:
more severe, earlier onset, shorter life expectancy, absent dystrophin
Beckers:
milder form, later onset, longer life expectancy, decreased dystrophin, more prone to dilated cardiomyopathy
what is syndactyly?
congenital bone disorder - failure of digits to separate during development due to a combination of genetic and environmental factors
inheritance pattern of syndactyly?
-autosomal dominant, autosomal recessive, or X linked recessive
more common in other genetic syndromes (i.e. trisomy 21)
most common syndactyly presentation?
3rd and 4th finger fusion
bilateral involvement (50% of people)
associated findings of Marfan syndrome?
-pectus excavatum, pectus carinatum
-scoliosis
-spondylolithesis
-protrusion acetabuli
-arachnodactyly
-pes planus (flat feet)
types of syndactyly:
simplex (soft tissue) vs complex (soft tissue + bone)
complete (to fingertips) vs incomplete (not to fingertips)
what is osteogenesis imperfecta?
weak bones that fracture easily
“brittle bone disease”
what mutations cause osteogenesis imperfecta?
autosomal dominant mutations in COL1A1 or COL1A2 –> affect type 1 collagen synthesis
how does osteogenesis imperfecta affect the eyes?
sclera is made of type I collagen
sclera becomes so thin that it looks blue as the blue choroidal vessels are visible underneath
how does osteogenesis imperfecta affect the ears?
fractures and dislocations of the ossicles
leading to hearing loss
how does osteogenesis imperfecta affect teeth?
type 1 collagen –> dentin
therefore, teeth wear easily
what characteristic sets ehlers-danlos apart from Marfan?
it has stretchy skin, Marfan does not
what is osteopetrosis?
thick and heavy bones that fracture easily
“stone bone”
what mutation causes osteopetrosis?
-autosomal dominant or recessive
-mutation in carbonic anhydrase II
-this enzyme typically allows osteoclasts to secrete protons to maintain an acidic environment for bone resorption
-osteoblasts still build as normal (hence, stone bone)
clinical findings of osteopetrosis?
-frequent fractures
-hearing and vision loss
-hydrocephalus
-cytopenias (osteoblasts replace bone marrow with bone)
treatment for osteopetrosis?
bone marrow transplant
osteoclasts derived from monocytes in the marrow
what is achondroplasia?
skeletal dysplasia that results in dwarfism
lack of cartilage development
inheritance pattern of achondroplasia:
autosomal dominant
mutation that causes achondroplasia:
FGFR3 - fibroblast growth factor 3
regulates how collagen turns into bone
mutation –> decreased bone production and decreased growth
why do those with dwarfism have short limbs but normal sized heads and torsos?
-FGFR3 mutation only inhibits bone formation that comes from a cartilage template (echondral ossification)
-extremities only
-face, skull, and ribs –> inter membranous ossification
what genetic concept is demonstrated through dystrophinopathies?
allelic heterogeneity
Duchennes and Beckers have different mutations on the same locus –> causing similar presentations
how do Beckers and Duchennes affect females?
-depends on the lyonization pattern (one X chromosome is inactivated)
-if more cells express the defected dystrophin gene –> manifesting carriers/show sx
-phenotypic variation
who is susceptible to Lyonization?
those with 2+ X chromosomes
XX (normal female)
47 XXY (aneuploidy)
inheritance pattern of myotonic dystrophies?
autosomal dominant
type 1 myotonic dystrophy mutation:
trinucleotide repeat (CTG) in untranslated 3’ region of DMPK gene (chromosome 19q)
regulates gene expression! translated into myotonic dystrophy protein kinase and inhibits myosin phosphatase (involved in muscle relaxation and contraction)
type 2 myotonic dystrophy mutation:
CNBP (chromosome 3q)
tetranucleotide repeat (CCTG)
repeats found in the first intron of CNBP
translated into cellular nucleic acid binding protein
what causes the nucleotide repeat expansion in myotonic dystrophies?
slipped nucleotide mispairing
DNA polymerase loses its place and keeps adding to the repeats, expanding the number of repeats
what genetic phenomenon is demonstrated by myotonic dystrophies?
anticipation –> each successive generation has more nucleotide repeats and more severe symptoms because DNA polymerase keeps expanding the repeats. a pre-mutation allele can become a full mutation in the next generation.
disease mechanism of DM1?
toxic DMPK pre-mRNA accumulation sequesters and binds muscle bind-like protein (MBNL), preventing it from leaving nucleus. MBNL normally has splicing function.
normal function of MBNL protein
splicing function
downstream effects of cell growth signaling, cardiac development, sarcomere stabilization
what are the 2 types of DM1?
congenital form
adult form
clinical presentation of adult form DM1?
facial muscle weakness, hollow cheeks, drooping eyelids, weakness of distal hand muscles and lower leg, toe and foot drop
clinical presentation of DM2?
-milder muscle weakness, mostly affecting PROXIMAL muscles of the thighs and hip and shoulder and elbows
-difficulty climbing stairs, rising from seated position, holding/lifting objects
commonality between both types of DM?
both cause myotonia - sustained muscle contractions, difficulty relaxing after use. unable to release hand shake.
other common features of DM?
cataracts, insulin resistance, cardiac conduction effects, abnormalities in electrical activity of heart
triangle shaped mouth
how can mitochondrial myopathies be characterized?
neuromuscular disorders, dysfunctional mitochondria with the inability to produce enough ATP
most affected tissues = brain and skeletal (need high ATP)
usually, mutations in mitochondrial DNA (mtDNA) that encode for ETC subunits
inheritance pattern of mitochondrial genes:
exclusively maternal inheritance
only biological FEMALES can pass onto offspring
father’s mitochondria left behind during fertilization
what genetic concept is demonstrated by mitochondrial inheritance?
heteroplasmy - daughter cells receive a mixture of WT and mutant mitochondria
mutant has to exceed threshold level for sx to emerge
what is homoplasmy?
daughter cell inherits pure sample - either all WT or all mutant (by chance)
main clinical features of mitochondrial myopathies:
pleiotropy - a gene can influence the development of multiple phenotypes
-fatigue
-myalgia
-vision loss, ptosis (drooping eye), ocular dysmotility (abnormal eye alignment/movement)
-seizures, hearing loss, impaired coordination, cognitive deficits
MELAS acronym:
Mitochondrial Encephalomyopathy Lactic Acidosis Stroke like sx
mutation that causes MELAS:
mitochondrial gene MT-TL1
encodes for mitochondrial tRNA leucine
MELAS clinical features:
-muscle fatigue, exercise intolerance
-lactic acid buildup
-fatigue, muscle weakness, abd pain, vomiting, difficulty breathing
-stroke like sx - AMS, hemiparesis, hemianopia
-severe HA and seizures
-weight loss
-repeated stroke like sx can lead to blindness, movement problems, and dementia
exam findings for MELAS:
-elevated lactate and CK in blood
-analyze genes coding for ETC enzymes
-muscle biopsy –> RAGGED RED FIBERS in Gomori trichrome staining
what are the ragged red fibers in MELAS?
compensatory proliferation of abnormal mitochondria in affected muscles
