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| Loss of ___ protein is responsible for the clinical phenotype in Fragile X syndrome |
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| how many of female carriers of premutation will have premature ovarian failure by age 40 |
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| Risk of mental retardation in grandchildren of normal transmitting ___ (i.e. who have premutation) |
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Autosomal dominant neurodegenerative disorder
50% risk to each offspring
Heterozygous and homozygous patients have similar phenotypes
Homozygotes may have a more rapid progress of the disease
Neuropathological hallmark is degeneration of striatum and cortex |
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Mutation is an abnormal increase in the number of CAG nucleotide repeats in the coding region
normal repeats : 9-35
Premutation : 29-35
Borderline repeats : 36-39 associated in some individuals with HD at advanced age
Full mutation : 40 and more than 40 |
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| 70-121 repeats in this dieasese leads to |
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| Soluble mutant huntingtin |
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what is responsible for pathogenesis
in huntington's disease |
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the following are all clinical features of what disease? Age of onset is highly correlated to number of repeats age dependent penetration
Mean age is 40
Early minor motor abnormalities
Clumsiness, hyperreflexia, eye movement disturbances
Gradually evolving involuntary movements, progressive dementia and psychological disturbances
Involuntary movements chorea most prominent; also parkinsonism, dystonia, & involuntary motor impairment
Psychiatric disturbances mood disorder and personality changes |
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| Juvenile form of HD (70-121 repeats) almost always inherited from an affected _____ |
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Autosomal recessive inheritance
Most common inherited spinocerebellar ataxia
Prevalence is 2-4 /100,000 in Europeans, and people from middle east and India
Expansion of GAA repeats in the first intron of the gene FRDA
Triplet length
Normal 5 - 34 repeats
Pathologic > 100 - 1200 repeats
Loss of function from both alleles is required to produce the disease |
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FRDA gene on chromosome __
Codes for a protein ______
Mitochondrial iron binding protein
Regulates iron homeostasis in mitochondria |
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this disease causes increased levels of mitochondrial iron, impaired heme synthesis (not in RBC), reduced activity of Fe-S containing protein like complexes I to III
Onset before adolescence
incordination of limb movements,
difficulty with speech,
diminished or absent tendon reflexes, impairment of position and vibration sense
Cardiomyopathy
Scoliosis and foot deformities
Type 2 diabetes |
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Autosomal dominant myopathy
Most frequent muscular dystrophy of adult life
Progressive muscle weakness and wasting with |
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what is the Mutated gene in myotonic dystrophy?
the Gene is located on Chromosome? |
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The following are associated with what disease; Expansion of CTG at 3’ UT region impairs mRNA stability
Normal 5-30 repeats
Premutations : 38-54
Pathologic > 50 (sometimes 1000-2000 copies)
Severity and age of onset correlated with number of repeats |
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Lack of Penetrance and Variable Expressivity is common with this disease; the following are the clinical features; Progressive neuromuscular weakness
Cardiac conduction defect (A-V block) and cardiomyopathy
Myotonia ( tonic muscle spasm, prolonged relaxation time)
Disturbed GI peristalsis
Lack of facial expression
Frontal balding
Testicular atrophy |
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Myotonic dystropy is Associated with
Anticipation corresponds to enlargement of molecular defects
parental transmission bias almost all congenital cases are _____ inherited |
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is a genocopy of DM1 but has no congenital form
Due to expansion of CCTG |
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| this expansion in DM1 and DM2 is considered to be pathologic; the repeats bind to RNA binding proteins explains pleiotropy of DM |
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Most common adult onset neurodegenerative disorder
Affects 1.4% of persons in developed countries
Presents in 6th -9th decades
Clinical features include progressive deterioration of memory and higher cognitive functions and behavioral changes
Due to degeneration of neurons in specific regions of cerebral cortex and hippocampus |
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| this allele of APOE modestly increases susceptibility to nonfamilial AD and influences age at onset for some of the monogenic forms |
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| extracellular depositions that contain fibrillary protein Aβ and others notably apoE |
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| intrcellular (intraneuronal) consisting of hyperphosphorylated Tau protein |
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promotes assembly and stability of microtubules and hyperphosphorylation impairs this function
Mutations are not associated with AD |
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is a single pass transmembrane protein
Has 3 distinct proteolytic fates
α-secretase and β-secretase cell surface secretases
γ-secretase atypical protease
90% cleavage is by α-secretase prevents formation of Aβ peptide
10% by β-secretase and γ-secretase either nontoxic Aβ40 or neurotoxic Aβ42 |
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| this is increased in serum of individuals with mutations in βAPP |
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required as cofactor for γ-secretase
Mutations increase production of Aβ42 |
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60% identical in sequence to presenilin 1
May have related function |
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| this allele has a protective effect against Alzheimers |
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Very rare peroxisomal biogenesis disorder
AR inheritance
Patients have severe neurologic deficits, progressive hepatic and renal dysfunction and skeletal abnormalities
Rarely survive their first year
Disruption of peroxisomal metabolism due to defects in import of peroxisomal enzymes into matrix |
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Definition
Rare disorder of lipid metabolism
Inherited in recessive mode. ; Phytanic acid 3-methyl fatty acid (branched fatty acid)
Cannot be oxidised directly
Has to undergo α-oxidation pristanic acid β –oxidation
Phytanoyl CoA hydroxylase
Defect in this pathway leads to accumulation of phytanic acid
Treatment plasmapheresis + dietary measures, continued for life
Clinical features include peripheral neuropathy, cerebellar ataxia, retinitis pigmentosa and bone and skin changes.
Characterized by an accumulation of phytanic acid in the plasma and tissues
Our bodies can not synthesize phytanic acid exclusively dietary in origin diary products, meat, fish, phytol |
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Autosomal recessive disorder of copper transport
Hepatolenticular degeneration
Gene (ATP7B) mapped to chromosome 13
Codes for a transmembrane pump called a P-type ATPase
transports copper into hepatocyte secretory pathway incorporation into ceruloplasmin, and excretion into bile
Impaired excretion into bile accumulation of Cu2+ in liver cell death release of Cu2+ into plasma hemolysis and deposition of copper in extrahepatic tissues signs and symptoms |
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| Menkes Syndrome Kinky or Steely Hair Disease |
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Definition
X-linked recessive mode of inheritance.
Mutation in the gene for P-type ATPase that is responsible for the efflux of copper from cells
Copper accumulates in intestine but is deficient in other tissues, especially the CNS
Clinical features caused by loss of function of cuproenzymes
Abnormal hair (reminiscent of steel wool cleaning pads) and pigmentation, laxity of skin, metaphyseal dysplasia, cerebellar degeneration and failure to thrive; Diagnosis decreased serum copper and ceruloplasmin
Treatment copper histidine |
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| Hereditary Hemochromatosis |
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Definition
AR disorder that increases iron absorption via intestine
Affects primarily Caucasians
Symptoms are caused by excess iron being stored predominantly as hemosiderin
Many mutations in the body's iron transport system can cause hemochromatosis
Most cases are caused by mutations in the HFE gene located on chromosome 6; Normal gene product:
Binds to transferrin receptor may act by modulating its affinity for transferrin
Abnormal gene product:
Impaired cell-surface protein
Does not migrate to the cell surface
Does not bind transferrin receptor no internalization of transferrin into small intestine cell compensatory increase in iron absorption |
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| Hereditary Hemochromatosis |
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Definition
| Venesection and Deferoxamine are treatments for what disease |
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Rare Autosomal Dominant congenital disorder characterized by physical and development problems.
Common features include characteristic "elfin-like" facial features, heart and blood vessel problems, irritability during infancy, dental and kidney abnormalities, hyperacusis (sensitive hearing) and musculoskeletal problems.
Although individuals with Williams syndrome may show competence in areas such as language, music and interpersonal relations, their IQs are usually low. Both the gene for elastin and LIM kinase deleted.
Both genes map to the same small area on chromosome 7. |
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