Diseases Flashcards
- autosomal recessive disorder
- mutation in both alleles of PAH gene on chromosome 12 leading to deficiency in phenylalanine hydroxylase (PAH)
- Symptoms: mental retardation, organ damage, unusual posture, microcephaly, seizures, hyperactivity, musky diaper smell
- Milder form: hyperphenylalanemia
- Can also be caused by mutation in genes involved in production or recycling of tetrahydrobiopterin (BH4)
- Accumulation of phenylalanine (normal is
Phenylketonuria (PKU)
- converts phenylalanine to tyrosine by hydroxylating the phenolic ring
- deficiency causes accumulation of phenylalanine leading to PKU
Phenylalanine Hydroxylase (PAH)
- a cofactor of PAH
Tetrahydrobiopterin (BH4)
- autosomal recessive
- Caused by frameshift mutation of TATC insertion in exon 11 of HEXA gene on chromosome 15 leading to deficient Hexosaminidase A enzyme
- accumulation of GM2 ganglioside in the brain
- Common in Ashkenazi Jews
- Symptoms: progressive neurological deterioration until death at 2-4 yrs if affected as infant, cherry-red spot in retina,
- In later onset: vision and intelligence remains normal, spinocerebellar degeneration (lower motor neuron dysfunction and ataxia), psychosis
Tay-Sachs Disease
- cleaves the terminal N-acetyl-B-galactosamine residue from the ganglioside
- composed of alpha subunit (HEXA) and beta subunit (HEXB)
- requires an activator protein
Hexosaminidase A
- autosomal recessive
- mannose-6-phosphate defect
- defect in Golgi-specific N-acetylglucosamine-1-phosphotransferase by mutation in GNPTAB on chromosome 12q23.2 which leads to a defect in protein trafficking
- abnormal lysosomes (inclusion bodies)
- Symptoms: unusual facial features, skeletal changes, severe growth retardation, mental retardation, increased acid hydrolases levels in body fluids
I-Cell Disease
- autosomal recessive
- deficiency in cystathionine B-synthase, methionine synthase, Vit B6 deficiency, Folate, or B12
- Symptoms: dislocation of the lens, mental retardation, osteoporosis, long bones, thromboembolism of the veins and arteries
Homocystinuria
- autosomal recessive
- associated with chronic obstructive lung disease (emphysema) and liver cirrhosis
- inherited conformational disease - changes the shape or size of a protein
- mutation in Z allele (Glu342Lys) leading to formation of long bead-like necklaces of mutant a1AT polymers
- Symptoms: SOB, cough or wheeze, rhonchi, can develop emphysema, cirrhosis
a1-Antitrypsin Deficiency
- a serine protease inhibitor (serpin)
- binds to and inhibits activity of elastase
- methionine 358 oxidized by cigarette smoke and inflammatory cells reducing affinity for elastase
a1-Antitrypsin
- autosomal dominant
- caused by mutation in gene encoding for porphobilinogen (PBG) deaminase (PBGD) on chromosome 11
- occurs in response to events that decrease concentration of heme in liver cell [barbiturates, drugs, steroid hormones, surgery]
- Symptoms: GI and neuropathic episodes, abdominal pain, vomiting, confusion, emotional, hallucinations, psychosis
Acute Intermittent Porphyria
- autosomal dominant
- elevated plasma cholesterol carried by LDL
- mutation in LDL receptor (chr 19), ApoB-100 (chr 2), PCSK9 protease (chr 1), or ARH adaptor protein (chr1)
- symptoms: premature heart disease, xanthomas, arcus corneae
Familial Hypercholesterolemia
- autosomal recessive
- Caucasian children (1/2000; 1/25 carriers)
- Mutation of CFTR gene at deltaF508, C to T, Phe to Ile
- Chromosome 7q31
- Symptoms: recurrent lung infections, positive salt sweat test, large greasy stools light in color with foul odor, congenital bilateral absence of the vas deferens, infertile
- Diagnostic feature: increased concentrations of sweat Na+Cl-
Cystic Fibrosis
- X-linked
- age of onset about 3-5 years
- progressive muscle weakness, awkward gait, pseudohypertrophy of calves, Gower maneuver, lordosis, death by 18 due to cardiorespiratory failure
- elevated serum level of creatine kinase (CK)
- absence of dystrophin
- most often a frameshift mutation deletion of the dystrophin gene (60%)
- considered a “genetic lethal” condition
Duchenne Muscular Dystrophy
- X-linked
- age of onset about 11 years
- progressive muscle weakness, awkward gait, pseudohypertrophy of calves, but ambulant into adult life, decreased life span
- truncated dystrophin
- inframe deletion mutation of dystrophin gene (60%)
Becker Muscular Dystrophy
- joint hypermobility, cutaneous fragility, cigarette paper skin, hyperextensibility
- genetic defect in collagen structure, synthesis, secretion, or degradation
Ehlers-Danlos Syndromes (EDS)
- mutations in loci containing COL5A1 or COL5A2 genes encoding the alpha-chains of Type V collagen
- autosomal dominant
- skin and joint hypermobility, atrophic scars, easy bruising
Classical EDS (Type I and II)
- Autosomal Dominant
- joint hypermobility, pain, dislocations
EDS Type III
- decreased amount of Type III collagen (reticulin)
- mutation in COL3A1
- Thin skin, arterial or uterine rupture, bruising, small joint hyperextensibility
- autosomal dominant
EDS Type IV
- autosomal recessive
- deficiency in lysyl hydroxylase
- hypotonia, joint laxity, congenital scoliosis, ocular fragility
EDS Type VI
- severe skin fragility, cutis laxa, bruising
- procollagen N-peptidase
EDS Type VIIc
- autosomal dominant
- severe joint hypermobility, mild skin changes, scoliosis, bruising
- defect in COL1A1, COL1A2
EDS Type VIIa,b
- autosomal recessive
- extreme sensitivity to UV radiation and multiple skin cancers
- marked freckling of face, xerosis, poikiloderma, corneal opacification
- result from lack of nucleotide-excision repair
Xeroderma Pigmentosa
- drug that inhibits the calcium pump in the rough ER
- used to prevent calcium-dependent chaperone that traps mutant CFTR protein and impairs its binding in ER for degradation
Curcumin
drug that allows the ribosome to bypass a premature stop codon at relatively low frequency and enables increased expression of full length protein
Gentamycin
- autosomal dominant
- mutation in gene for APC, tumor suppressor gene on chromosome 5q21-q22
- thousands of polyps on the colon which have potential to form a malignant tumor
Familial Adenomatous Polyposis (FAP)
- protein misfolding of Amyloid Precursor Protein (APP) creating neurotoxic peptide (AB-42)
- B-amyloid neuritic plaques
- neurofibrillary tangles
- abnormal cleavage of amyloid precursor protein by alpha, beta, gamma secretases
- Tau protein normally organizes microtubules but abnormal post-translation hyperphosphorylation causes tangles
- Mutation in PSEN1&2 (cofactor of gamma secretase)
- e4 of APOE mutation also causes build of up APOE plaques
- progressive deterioration of memory and higher cognitive functions, agitation, social withdrawal, hallucinations, seizures, rigidity, mutism, eventually bed ridden and will die from malnutrition, infection or heart disease
Alzheimer’s Disease
- mitochondrial disorder
- mutation in tRNA for Lysine
- A->G transition @8344
- myopathy, sensineural deafness, dementia, epilepsy, ataxia
- dx made from: myoclonus, generalized epilepsy, ataxia, ragged red fibers
- Structurally and biochemically abnormal mitochondria appear red in muscle tissue
MERFF (myoclonic epilepsy with ragged red fibers)
- mitochondrial disorder
- point mutation in tRNA for leucine, translation of codons for leucine
- A->G transition @3242
- affects many of the body’s systems (brain, nervous system, muscles)
- muscle weakness, vomiting, seizures, diabetes, vision loss, dementia, deafness, lactic acidosis, stroke like episodes at age 40
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke)
- mutation of Abelson (ABL) proto-oncogene by translocation 9 (ABEL) and 22 (BCR)
- symptoms: enlarged spleen, joint/hip pain, low-grade fever, anemia, thrombocytopenis
CML (chronic myologenous leukemia)
drug that that prevents fusion protein BCR-ABL from binding ATP so it can’t phosphorylate it’s substrates that are involved in enhanced growth of leukemia cells
Gleevec (imantinib)
- autosomal dominant
- results from mutations in genes coding for proteins involved in mismatch repair
- most common mutations are in MLH1 and MSH2 genes for MutL and MutS
- Microsatellite instability
HNPCC
- caused by mutation in tumor suppressor gene
- Rb1 gene, Rb protein - chrom 13
- early symptom is white reflex in cornea of eye while shining a light
Retinoblastoma
- Symptoms include mental retardation and macroorchidism and deep plantar creases
- X-linked dominant
- Caused by abnormal CGG repeat >200 leading to hyper-methylation of 5’ UT and decreased FMR1 expression
- gain of function
Fragile X Syndrome
- B cell tumor of the jaw
- translocation between chromosomes 8 and 14
- c-myc proto-oncogene on 8q24 translocated distal to the immunoglobin heavy chain(IGH) locus at 14q32
- IGH enhancer upregulates c-myc and converts it to oncogene
- common in children in equatorial Africa
- other possible translocations: IGL 22 lambda, 2 kappa
Burkitt Lymphoma
- use to treat sickle cell
- cytosine analog incorporated into gamma globin gene promoter
- causes hypomethylation of HbF, increasing adult HbF
Decitabine
- autosomal recessive
- deficient in ADA
- leads to accumulation of deoxyadenosine
- T and B cell lymphotoxicity leads to SCID
Adenosine Deaminase Deficiency
What does PAH do?
- converts phenylalanine to tyrosine by hydroxylating the phenolic ring
Individuals with PKU are often what?
compound heterozygoes
- autosomal recessive
- a-L-iduronidase deficiency (chromosome 4)
- corneal clouding, coarse facies, skeletal abnormalities, hepatosplenomegaly, hearing loss, progressive and profound mental retardation, linear growth ceases, death by cardiorespiratory failure
Hurler Syndrome
What are the 6 types of defects that can cause homocystinuria?
- classic homocystinuria due to defective cystathionine synthase
- methylene-h4-folate reductase defects (impairs methionine synthase)
- defects in the intracellular metabolism of cobalmins which affect methionine synthase
- direct affect on methyl-b12 formation
- cobalmin intestinal absorption
- abnormalities in the major extracellular transport protein, transcobalamin II
How are all defects in cobalamin metabolism inherited?
autosomal recessively
anemia that results from inhibition of DNA synthesis in red blood cell production
- due to a deficiency of vitamin B12 and/or folic acid
- characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow
Megaloblastic anemia
What are the 4 proteins associated with familial hypercholesterolemia?
- LDL receptor (chr 19) binding ApoB-100
- mutation in the LDL receptor binding domain of ApoB-100 (chr 2)
- PCSK9 protease (chr 1) activity leading to degradation of the LDL receptor
- mutation in the ARH adaptor protein (chr1) which impairs LDL clearance
- autosomal recessive
- predisposed to easy fracturing of bones
- mutation in the genes COL1A1 and/or COL1A2
Osteogenesis Imperfecta
-phenotype: mild; blue sclerae, brittle bones but no bony deformity, often presenile deafness
-biochemical defect: collagen made is normal, but quantity is reduced by half
-gene defect: null alleles impair the production of pro α1
chains, such as defects that interfere with mRNA synthesis
Type 1 OI
- phenotype: perinatal lethal: severe abnormalities (fractures, deformities), dark sclerae
- biochemical defect: production of abnormal collagen molecules due to substitution of the gly in Gly-X-Y of the triple helical domain, with some bias toward the COOH-terminal half of the protein
- gene defect: Missense skeletal mutations in the glycine codons of the genes for the α1 and α2 chains
Type 2 OI
- phenotype: progressive deforming; fractures, progressive bone deformity, limited growth, blue sclerae, dentinogenesis imperfects, hearing loss
- biochemical defect: Abnormal collagen molecules: gly substitutions of many types in the triple helix; located throughout the protein
- gene defect: Missense mutations in the glycine codons of the genes for the α1 and α2 chains
Type 3 OI
- phenotype: Deforming; normal sclerae, short stature, mild/moderate bony deformity, hearing loss, fractures, dentinogenesis imperfects
- biochemical defect: Abnormal collagen molecules: gly substitutions of many types in the triple helix; located throughout the protein
- gene defect: Missense mutations in the glycine codons of the genes for the α1 and α2 chains
Type 4 OI
What are the 4 genes/proteins associated with Alzheimer’s Disease?
- APP
- PSEN1
- PSEN2
- APOE
Is MELAS heteroplasmic or homoplasmic?
heteroplasmic
Is MERRF heteroplasmic or homoplasmic?
heterolplasmic
Is Leber heriditary optic neuropathy heteroplasmic or homoplasmic?
homoplasmic
- mitochondrial disease
- Rapid, painless bilateral loss of central vision due to optic nerve atrophy in young adults
- high penetrance in males
Leber Hereditary Optic Neuropathy
What is trinucleotide the expansion repeat in Huntington disease?
CAG
What is the trinucleotide expansion repeat in Fragile X Syndorme?
CGG
What is the trinucleotide expansion repeat in Friedreich ataxia?
AAG
What is the trinucleotide expansion repeat in Myotonic Dystrophy?
CTG
What is the expansion repeat in Spinocerebellar atrophy?
ATTCT
- late onset, progressive cerebellar ataxia and intention tremor due to the formation of intranuclear neuronal inclusions
- GOF
- caused by CGG repeats between 60-200
- mental retardation, learning abnormalities
Fragile X-associated tremor/ataxia Syndrome (FXTAS)
- autosomal dominant
- most pleiotropic phenotype of all unstable repeat expansion disorders
- mutated gene: DMPH on chromosome 19
- CTG repeats in the 3’ UTR
- quenhes RNA binding proteins
- clincial features: prolonged contraction, cardiac conduction defects, testicular atrophy, insulin resistance, cataracts
Myotonic Dystrophy 1
-expansion of the tetranucleotide CCTG int he first intron of the zinc finger protein 9 gene
Myotonic Dystrophy 2
- autosomal recessive
- defect in expression of the gene due to expansion of GAA in intron 1 resulting in transcriptional elongation
- loss of activity results in increased levels of mitochondrial iron, impaired heme synthesis, adn reduced activity of Fe-S containing proteins
Freidreich Ataxia
- autosomal dominant neuodegenerative disorder
- polyglutamine expansion CAG repeats
- insoluble aggregates of the mutant protein in nuclear inclusions
Huntington Disease
IND designed to enable the formation of a functioning protein in patients with genetic disorders due to a nonsense mutation such as in DMD and CF
Ataluren
What are 2 forms of treatment for Adenosine Deaminase Deficiency ?
bone marrow transplant and enzyme replacement therapy
- autosomal recessive
- lysosomal storage disease
- deficiency of glucocerebrosidase; chromosome 1
- accumulateion of lipid glucocerebroside in lysosomes
- anemia, thrombocytopenia, crumpled tissue paper appearance
Gaucher Disease
- white matter degenerative disorder due to beta galactocerbrosidase deficiency
- inhibits formation of myelin sheath
- early onset and late onset
Krabbe disease/Globoid Cell Leukodystrophy
- autosomal dominant mutation in TBX5 on chr 12q2
- results in atrial septal defect and a thumb anomaly
Holt-Oram Syndrome
DCC gene (18q) sproadic mutation leads to what?
colorectal cancer
Wt1 gene (11p) sporadic mutation leads to what?
Kidney cancer
Wt1 gene (11p) familial mutation leads to what?
Wilm’s tumor
Rb1 gene (13q) sporadic mutation leads to what?
Eye cancer
Rb1 gene (13q) familial mutation leads to what?
Retinbolastoma
Tp53 gene (17q) sporadic mutation leads to what?
Breast, colorectal, and lung cancer
Tp53 gene (17q) familial mutation leads to what?
Li Fraumeni syndrome
- autosomal dominant mutation produces an activated oncogene
- high incidence of medullary carcinoma of the thyroid sometimes associated with pheochromocytoma
- responsible mutation is in the RET gene encoding a receptor tyrosine kinase
Multiple Endocrine Adenomatosis, Type 2 (MEN2)
autosomal dominant
chrom 17
tp53 gene mutated
Li-Fraumeni Syndrome
BRCA1
breast and ovarian cancers
BRCA2
breast, gallbladder, pancreatic, and male breast cancer
What is the mode of inheritance for Hurler’s Syndrome?
AR
What is the mode of inheritance for Tay Sachs?
AR
What is the mode of inheritance for I-cell
AR
What is the mode of inheritance for Homocystinuria
AR
What is the mode of inheritance for alpha-1-antitrypsin deficiency
AR
What is the mode of inheritance for cystic fibrosis
AR
What is the mode of inheritance for AIP?
AD
What is the mode of inheritance for DMD?
x-linked recessive
What is the mode of inheritance for BMD
x-linked recessive
What is the mode of inheritance for Ehlers-Danlos
AD
What is the mode of inheritance for familial hypercholesterolemia
AD
What is the mode of inheritance for OI?
AD
What is the mode of inheritance for huntington disease
AD
What is the mode of inheritance for fragile x
x-linked dominant
What is the mode of inheritance for freidrich ataxia
AR
What is the mode of inheritance for myotonic dystrophy
AD
What is the mode of inheritance for adenosine deaminase deficiency
AR
What is the mode of inheritance for Gaucher Disease
AR
What is the mode of inheritance for MEN-2?
AD
What is the mode of inheritance for Li-Fraumeni?
AD
What is the mode of inheritance for Familial Adenomatous Polyposis
AD
What is the mode of inheritance for HNPCC
AD
What is the mode of inheritance for XP
AR
What is the mode of inheritance for Bloom sydrome
AR
What is the mode of inheritance for Ataxia Telangiectasia
AR
What is the mode of inheritance for PKU
AR
