Flashcards in Single gene defects part 1 and 2 Deck (60)
Hereditary Motor & Sensory Neuropathy
duplication of 1.5 Mb of 17p
peripheral myelin protein 22 (PMP-22)
what are some inheritance patterns of single gene disorders ?
x linked dominant
x linked recessive
Pathology of HMSN
overproduction of PMP 22 which prevents schwann cell proliferation
associated with Charcot-Marie-tooth disease
lethargy and hypotonia
progress to seizure and coma
secondary metabolic abnormalities
Hepatic disease is characterized by
bleeding and bruising (coagulopathy)
indicator of Metabolic acidosis
vomiting, poor feeder
failure to thrive
metabolic decompensation with mild illness
apparent intolerance of certain food types
what characterizes a storage disease?
thickened skin/loss of elasticity
nonimmune fetal hydrops
progressive, degenerative course
what are characteristics of neurologic syndrome?
altered muscle tone and reflexes, not focal
seizure disorder, particularly if progressive
altered state of consciousness
what are some tools for diagnosing inborn errors?
basic chemistries, glucose, anion gap
blood ammonia levels
liver function tests
blood lactate and pyruvate levels
plasma and urine amino acids
urine organic acids
DNA mutational analysis
50% of Homocystinuria is responsive to
what are some Drug therapy strategies?
limit accumulation of toxic metabolites
encourage waste nitrogen excretion
supplement poorly transported nutrient
what are some characteristics of metabolic disorders?
imbalance in body's biochemistry
autosomal recessive inheritance
chronic disease or chronic with acute decompensation
variable treatment options
what problems could be the issue with IEM in which the issue is the enzyme?
-accumulation of substance A
-deficiency of substance B
-both accumulation of sub A and deficiency of sub B
What is peripheral myelin protein-22?
encodes PMP 22 which arrests schwann cell division
duplication of the gene results in dosage effect and interruption of myelin stability
results from inappropriate crossing over and more frequently during male gametogenesis
HMSN Type 1
classification is based on motor nerve conduction velocities
reduced nerve conduction and nerve demyelination
HMSN Type 2
normal nerve conduction but axonal degeneration
what are some symptoms of HMSN?
characterized by slowly progressing distal muscle weakness and wasting
associated with Charcot Marie Tooth disease and Peroneal muscular atrophy
weakness and wasting onset 10-30 yrs
spread to upper limbs and tremors evident
foot high arch and toes curl (hammertoe)
due to mutation (deletion, insertion, duplications, point mutations) of neurofibromin (Nf1) gene 17q
50% due to new mutations
down regulates Ras activity through GTPase action (tumor suppressor gene)
clinical manifestations of Neurofibromatosis
Cafe au lait spots - small pigmented skin lesions and small soft fleshy benign tumors
Axillary/truncal freckling, large head and Lisch nodules (raised pigmented spots of iris)
1/3 cases result in non verbal learning disorder
Most are normal while other develop epilepsy, CNS tumor or scoliosis
clinical diagnostic criteria for NF
six or more cafe au lait spots - if pt is older the spots should be larger
two or more neurofibromas of any type or one plexiform neurofibroma
freckling in the axilla or inguinal regions
two or more Lisch nodules
what is difficult about diagnosing Nf1?
each family typically has a unique mutation making testing complex and labor intensive
95% of pts over the age of 8 yrs who carry Nf-1 gene will have detectable Lisch Nodules on slit lamp ophthamologic
what is the genetic basis of Marfan syndrome?
due to mutation (missense with dominant negative effect resulting in decreased fibrillin) of type 1 fibrillin gene (15q21)
Type 1 fibrillin
coating of ECM protein, elastin
can bind inactive transforming growth factor beta and holds in inactive state
mutated fibrillin cannot retain TGF-b thus ECM proteases activate leading to excess active TGF-b and promotion of inflammation
disorder of fibrous connective tissue
affected pts are tall, reduced upper to lower segment body ratio, scoliosis, long limbs, spider like fingers, cardiovascular abnormalities
Aortic aneurysm is life threatening
dilation rate can be reduced by b-adrenergic blockade
what are some of the skeletal major and minor criteria for Marfan syndrome?
Four should be present
arm span to height ratio is greater than 1.05
hypermobility of wrist and thumbs
pectus excavatum requiring surgery
High arched plate with dental crowding
medial displacement of medial malleolus causing pes planus
what are some the major and minor ocular criteria for dx of Marfans?
what are some cardiovascular criteria for dx of Marfan syndrome?
dilatation of ascending aorta
dissection of the ascending aorta
mitral valve prolapse
Patients with Marfanoid habitus should also be screened for?
Homocystinuria - treatable inborn error of homocystine metabolism