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81 Cards in this Set
- Front
- Back
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What drug is used to reduce VLCFA in X-linked adrenoleukodystrophy?
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Lovastatin (efficacy not proven)
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What treatment may help with X-linked adrenoleukodystrophy when MRI changes are present but before neurologic symptoms?
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bone marrow transplant
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Gene defective in X-linked adrenoleukodystrophy
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ABCD1
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What compound controls the amout of cholesterol to be made=rate-limiting step in synthesis?
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HMGCoA reductase
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Cholesterol is a precursor for what vitamin?
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Vitamin D
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Gene for Smith-Lemli-Opitz, and its location
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DHCR7, 11q12
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Major findings of Smith-Lemli-Opitz
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2-3 toe syndactyly, postaxial polydactyly, hypogenitalism in males, heart defects, renal agenesis, MR,brain malformations
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Main features of HEM/Greenberg skeletal dysplasia
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hydrops fetalis, short limbs, moth-eaten appearance of bones, intrauterine death
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Name the inborn errors of cholesterol synthesis disorders
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HEM/Greenberh, CHILD, Antley-Bixler, SLO, lathosterolosis, CDPX2
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Features of X-linked chondrodysplasia punctata
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rhizomelic shortening, stippled epiphyses, cataracts, flaky skin, coarse ahir, postaxial polydactyly
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Skeletal findings common to cholesterol defects
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2-3 toe syndactyly, stippled epiphyses, postaxial polydactyly, short limbs, bowed femurs
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Joint findings common to cholesterol defects
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contractures
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Eye findings of peroxisome biogenesis disorders (Zellweger spectrum)
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cataracts, glaucoma, corneal clouding, pigmentary retinopathy
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Bone findings in peroxisome biogenesis disorders
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stippled epiphyses
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Brain findings in peroxisome biogenesis disorders
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heterotopias, pachygyria, polymicrogyria
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Sensory defects in older paietns with peroxisome biogenesis disorders
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sensorineural deafness, RP/blindness
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What is used to treat peroxisomal disorders with some effectiveness, especially in brain and retina?
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DHA
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What % of males with X-linked ALD have only adrenal symptoms with no neurologic findings?
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10-20%
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Location of X-linked ALD gene (ABCD1)
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Xq28
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Percent of carrier females who develop signs of X-linked ALD
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50%, no adrenal insufficiency
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Protein in X-linked ALD
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ALDP (ALD protein)
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Sensory changes in X-linked ALD
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blindness and deafness
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Symptoms of adrenal insuficiency
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weakness, diarrhea
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Gene that causes Gaucher
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GBA
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Gene and location for Barth syndrome
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TAZ1
Xq28 |
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Name the functions of mitochondria
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1. metabolism
2. generate reactive oxygen species 3. regulate cell death 4. affect gene regulation |
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How many electron chain transport peptides are encoded in the mitochondrial genome? How many tRNAs?
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13 polypeptides
22 tRNAs 12s and 16s rRNAs |
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Name 5 things that predispose mitochodrial DNA to mutations
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1, 10X higher mutation rate than nuclear DNA
2. exposed to reactive oxygen species 3. lack of histones 4. no DNA repair machinery 5. minimal noncoding DNA |
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CNS problems assoc. with mitochondrial disease
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encephalopathy
seizure microcephaly central apnea DD ataxia migraine stroke-like episodes gray or white matter disease |
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GI problems assoc. with mitochondrial disease
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liver failure
dysmotility recurrent vomiting villous atrophy/diarrhea |
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Endocrine problems assoc. with mitochondrial disease
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diabetes
hypoparathyroidism |
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Blood problems assoc. with mitochondrial disease
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marrow failure
sideroblastic anemia |
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In diagnosing a mitochondiral disease, what might you learn from a muscle biopsy?
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histology
ultrastructure histochemical staining electron transport chain activity |
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Features of MERRF
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late childhood to adult onset
progressive myoclonic epilepsy myopathy ragged red fibers on muscle biopsy brain MRI abnormalities |
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Features of MELAS
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mean age 10 years
episodic migraine-like attacks seizures dementia or MR stroke-like events lactic acidosis |
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Features of Kearns-Sayre
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progressive external ophthalmoplegia
pigmentary retinal degneration myopathy At least one of: complete heart block, cerebellar ataxia, high CSF protein onset before 20 |
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Molecular causes of Kearns-Sayre
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usually a mtDNA deletion/duplication
ATP6 T8993C can be nuclear genes that generate mtDNA rearrangements (AD/AR) |
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Features of MNGIE
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childhood or adolescence onset
myopathy with GI involvement progressive leukodystrophy, ophthalmoplegia, dementia peripheral neuropahty lactic acidosis |
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Inheritance of Pearson
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mitochondrial
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What mitochondrial disease is caused by an autosomal recessive mutation in nuclear DNA, which leads to multiple mtDNA deletions or depletion?
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MNGIE
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Features of Leigh syndrome
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subacute necrotizing encephalomyopathy
dev. regression symptoms appear within 1st year |
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What is a mitochondrial depletion syndrome?
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disease causes decrease in # of mitochindria per cell. Msut be 70% depleted.
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What % of female carriers show signs of Barth syndrome.
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None. Femal carriers NEVER show signs.
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Features of mucopoluysaccharidoses
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heart disease, DD, coarse facies, contractures, skeletal problems, corneal clouding, hepatosplenomegaly
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Features of adult-onset Tay-Sachs
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auditory hallucinations, proximal muscle weakness, brisk reflexes, tremor, occasional cramping, depressed and moody (psychological changes), no cherry-red spot, cognitive sparing
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Features of OTC deficiency
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protein aversion, nausea, headaches, abdominal pain, worse with protein loading or stress
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Important questions to ask in a metabolic history
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diminished exercise tolerance, severe response to infections, unusual odors, onset of symptoms relative to last meal, avoidance of certain foods
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Important questions to ask about metabolic disorders when taking family history
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Reye syndrome, crib death, consanguinity, multiple miscarriages, family members with same or other presentations
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Criteria for newborn screening
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important health problem, presymptomatic stage, well-known natural history, accepted treatment, facilities available for follow-up, few false positives and negs, acceptable to public, cost balanced to expenditures of medical care, case-finding should be ongoing process
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What is restricted from the tyrosinemia diet? (substrates)
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tyrosine and phenylalanine
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What AAs must be avoided in maple syrup urine disease?
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methionine, threonine, valine, isoleucine
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In urea cycle disorders, what can be given to keep glycine from entering the urea cycle?
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sodium benzoate
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In urea cycle disorders, what can be given to keep glutamine from entering the urea cycle?
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sodium phenylacetate
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What can be given to inhibit enzyme action in Tyrosimemia?
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NTBC--blocks suyccinylacetone to prevent liver disease
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What can be given to help Wilson disease?
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zinc salts, penicillamine
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Name some metabolic disorders for which enzyme replacement is available
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Gaucher, Fabry, Pompe, MPS (Hunter, Hurler)
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How do you treat organic acidemias during acute crisis?
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IV fluids with lots of glucose
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Cofactor in isovaleric acidemia
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riboflavin
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What supplements, besides cofactors, may be helpful in organic acidemias?
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Carnitine, glycine
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What mutation accounts for half of mutant alleles in isovaleric acidemia?
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A282V
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What metabolite is high in cases of MSUD? (newborn screen)
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leucine
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Which 3 branched-chain AAs are affected in MSUD?
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leucine, isoleucine, valine
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Which organic acidemia is assoc. with macrocephaly, which may precede other symptoms?
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Glutaric Acidemia Type I
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Cofactor which may help in Glutaric Acidemia Type I
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riboflavin
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Neonatal signs of organic acidopathies
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vomiting, poor feeding, lethargy, coma, seizuers, tachypnea
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4 most common inborn errors of metabolism
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MMA
PA urea cycle disorders MSUD |
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What does biotinidase deficiency smell like?
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tom cat's urine
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What systemic problem occurs with MMA, even with treatment? (chronic)
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renal failure
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What systemic problem occurs with PA, chronically?
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cardiomyopathy
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Chronic features of MMA and PA
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anorexia, MR, metabolic stroke, pancreatitis, pancytopenia, kidney failure in MMA, cardiomyopathy in PA
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Defects of what mitochondrial type can mimic defects in the electron transport chain?
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pyruvate dehydrogenase complex deficiency
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Most commonly reported type of pyruvate dehydrogenase complex deficiency
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E1 alpha deficiency
X-linked |
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The 4 truths of mitochondrial disease
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Mitochondrial disease can be associated with:
any disease manifestation any degree of severity any age of onset any mode of inheritance |
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Tissues with highest energy demands, and therefore more likely to be affected by mitochodiral disease.
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nerves
muscle endocrine tissue renal tubule growth |
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In Kearns-Sayre, what is difference in inheritance for deletion of mtDNA vs,. duplications?
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deletions tend to be sporadic, while duplications tend to be inherited and have a high recurrence risk.
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What is the common MELAS mutation?
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A3243G point mutation in tRNA-Leu
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What is the most common manifestation of the A3243G mtDNA mutation, which is associated with MELAS?
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diabetes +/- deafness
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What causes LHON?
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Homoplasmic mtDNA mutations in complex I genes
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3 most common LHON mutations
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G11778A (most common)
G3460A T14484C (assoc. with visual recovery) |
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Cofactor to give for MSUD
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thiamine (often doesn't help)
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How many times more prevalent is MSUD among Mennonites than in the general population?
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382 times more prevalent
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