MTM Exam 4 Diseases Latest Update with Verified Solutions

MTM Exam 4 Diseases Latest Update with Verified Solutions DMD -loss of function, recessive, haplosufficiency -symptoms present < 5 yoa -progressive symmetrical muscular weakness -wheelchair dependent by 12-13 yoa -life expectancy = teens - 30s -do not reproduce -calf pseudohypertrophy -elevated serum creatine kinase -unable to perform neck flexion -complete absence of dystrophin -mutations: deletions, frameshift, nonsense -exon length is NOT a multiple of 3 -frameshifts -> null mutations -> no protein BMD -loss of function, recessive, haplosufficiency -milder presentations, slower progression, high variability -progressive symmetrical muscular weakness -ambulatory until age 15-16 -life expectancy = 40-50s -may reproduce and have carrier daughters -calf pseudohypertrophy -elevated serum creatine kinase -neck flexion maintained -partially functional dystrophin -mutations: in-frame deletions -exon length IS a multiple of 3 -no frameshift -> protein w/ reduced function Phenylketonuria (PKU) -loss of function, recessive, haplosufficiency -elevated pheylalanine -deficiency of phenylalanine hydroxylase (PAH) -intellectual disability, developmental delays, microcephaly, musty odor, hypopigmentation -screened in newborns -Tx: dietary restrictions of Phe -classical = most severe - absence of PAH -variant = intermediate - residual PAH -non-PKU - mildest - greater residual activity of PAH Tetrahydrobiopterin (BH4) Deficiency -loss of function, recessive, haplosufficiency -BH4 is required for PAH, as well as for tyrosine hydroxylase and tryptophan hydroxylase -BH4 defective = hyper-phenylalaninemia, deficiency of catecholamines and serotonin -intellectual activity will occur even with a Phe-restricted diet due to def. of NTs Oculocutaneous Albinism (OCA) -loss of function, recessive, haplosufficiency -multiple AR forms (locus heterogeneity) -ORCA1 = deficiency of tyrosinase (TYR) -inability to convert tyrosine -> melanin -ORCA1A = severe form with no functional tyrosinase, lack pigmentation, visual acuity defects, photophobia, easily sunburned -ORCA1B = residual activity with mild presentation Maple Syrup Urine Disease (MSUD) -loss of function, recessive, haplosufficiency (AR) -Pennsylvanian Mennonites (founder effect) -def. of branched-chain alpha ketoacid dehydrogenase complex (BCKDC) -defective metabolism of branched-chain AA: Val, Leu, Ile -neuro damage: intellectual disability and seizures -sweet smell urine -fatal if untreated Nail Patella Syndrome (NPS) -loss of function, dominant, haploinsufficiency -complete penetrance & variable expressivity -mutations in LMX1B -> normally controls dorso-ventral patterning of limbs -nail dysplasia, absent/hypoplastic patella, elbow dysplasia, extoses of the ilia, contractures and hyperextensibility of interphalangeal joints, kidney disease, glaucoma Cleidocranial dysplasia -loss of function, dominant, haploinsufficiency -mutations in RUNX2 -> bone and cartilage development & maintenance -complete or partial absence of clavicles, hypermobile joints, failure of fontanelles to close, supernumerary teeth, micrognathia, hypertelorism -guy from "stranger things" Acute Hepatic Porphyrias -acute attacks of vomiting and pain -neurological/psychiatric problems -cardiovascular symptoms Acute Intermittent Porphyria (AIP) -loss of function, dominant, haploinsufficiency -10% penetrance -def. of porphobilinogen deaminase -accum. of porphobilinogen and aminolevulinic acid -major acute hepatic porphyria, onset 20-30s, abdominal pain, weakness, hallucinations, wine red urine, no photosensitivity, exacerbated by hormones and drugs Variegate Porphyria (VP) -loss of function, dominant, haploinsufficiency -reduced penetrance due to latency -higher in europe, south africa, and chile (founder effect) -def. of protoporphyrinogen oxidase -less common, abdominal pain, weakness, hallucinations, photosensitivity, exacerbated by hormones and drugs Thanatophoric Dysplasia (TD) -very strong gain of function of FGFR3 (AD) -sporadic mutations, genetically lethal -perinatal lethal, micromelic limb shortening, severe frontal bossing, very small chest (death due to resp failure) -TD1 = curved femurs, possible cloverleaf skull -TD2 = straight femurs, cloverleaf skull Achondroplasia -intermediate gain of function of FGFR3 (AD) -80% sporadic mutations, all missense mutations -p.G380R mutation -disproportionate dwarfism, shortening of long bones, large head, low nasal bridge, lumber lordosis, normal life expectancy and intelligence Homozygous Achondroplasia -more likely to mate with other achondroplasias (non random mating) -severe phenotype -perinatal lethal -comparable to TD1 Spider Lamb Syndrome -FGFR3 loss of function -missense -> p.V700Q -affects tyrosine kinase domain -long and bent limbs, long neck, twisted spine CATSHLS -FGFR3 loss of function -p.T546K mutation -tall stature, severe lateral tibial deviation, scoliosis, camptodactyly Osteogensis Imperfecta (OI) -AD -type I collagen mutation -type I OI = null mutations, haploinsufficiency (milder) -type II-IV OI = missense, dominant negative (more severe) -locus heterogeneity -> COL1A1 (pro-alpha-1) and COL1A2 (pro-alpha-2) -weak bones, short stature, blue sclera, "brittle bone disease" -C terminus OI more severe Type II OI -dominant negative -glycine substitutions -perinatal lethal -multiple in utero fractures AR OI -abnormal collagen modification with NO COL1A1 OR COL1A2 mutations -deficient for enzymes involved in post-translational modifications -perinatal lethal to mild Alpha-1 Antitrypsin Deficiency -AD codominance -most common in caucasians of european descent -mutation in SNERPINA1 -F (fast) = relatively rare, normal levels of alpha1-AT, impaired elastase inhibitory activity -M (medium) = wild type allele -S (slow) = relatively mild disease -COPD, emphysema, bronchitis, asthma, greatly exacerbated by smoke -MM = normal -SZ = greater risk of lung disease -ZZ = lung disease and possible liver disease Polydactyl -common birth defect -can occur either in isolation or as part of a symptom -significant locus heterogeneity AD Polydactyl -no mutations in SHH coding sequence -insertion in an intron of LMBR1 (upstream of SHH) -polydactyl, no holoprosencephaly Sonic Hedge Hog (SHH) -morphogen -complete loss of function causes alobar-holoprosencephaly (severe) -normally controls limb patterning and brain development, forebrain fails to develop into 2 hemispheres, prenatal lethal Lobar Holoprosencephaly -milder form -different enhancers can direct expression of the game gene in diff. tissues -point mutation in an enhancer activating SHH expression in a part of the brain -NOT polydactyl -NO severe alobar holoprosencephaly Campomelic Dysplasia -AD -"bent limb" -mutation in Sox9 -skeletal abnormalities, bowing of long bones, underdeveloped shoulder blades, dislocated hips, 11 pairs of ribs, ambiguous or female genitalia, lethal within first year Lactose Intolerance -lactase not expressed -inability to catabolize lactose -diarrhea, abdominal pain, flatulence, nausea Lactose Persistence -C -> T substitution 13910bp upstream of lactase gene -increased binding of Oct1 TF Williams Syndrome (WBS) -7q11.23 mutation -includes elastin -abnormal pairing resulting in crossing over with deletion and duplication products -mild growth deficiency, Elfin-like facies, medial eyebrow flare, supravalvular stenosis, pulmonary stenosis, septal defects, IQ range 40-80, language > cognitive ability -WSBCR duplication = language delay Fragile X Syndrome (FRAXA) -XD -maternal expansion bias -CGG expansion in 5'UTR of FMR1 -Dx: southern blotting -inherited intellectual disability -reduced penetrance in females -males = autism spectrum, tantrums, abnormal craniofacies, prominent forehead and jaw, shyness & gaze aversion, joint hyperextensibility, pes planus, mitral valve prolapse Fragile X-associated tremor/ataxia syndrome (FXTAS) -gain of function at RNA level -presumed FMR1 & mRNA toxicity with premutation repeat lengths -males = late onset neurodegeneration, reduced translation, inclusions in neurons & astrocytes in the brain -females = premature ovarian failure, unknown etiology Friedreich Ataxia (FRDA) -AR -no anticipation -maternal expansion bias -GAA expansion in intron 1 of FXM (loss of function) -Dx: southern blot -neurodegeneration, muscle weakness, spine curvature, diabetes, progressive heart condition, require wheelchair by 20, diagnosis at age 5-15 -excess iron in mitochondria, heme synthesis and formation of Fe-S, reduction function of ETC and aconitase of Krebs, energy deficiency and excess free radicals Myotonic Dystrophy I (DM1) -AD -RNA gain of function -maternal expansion bias -anticipation = expansion in the female germline -CTG expansion in 3'UTR of DMPK -Dx: southern blot -pleiotropy, myotonia, muscle wasting, weakness, cataracts, hypogonadism, frontal balding, insulin resistance, open/triangle shaped mouth (high arched palate), wasting of temporalis, ptosis Huntington (HD) -AD -anticipation & germline mutation -paternal expansion bias -CAG repeat of HTT encoding huntintin -Dx: PCR -pathogenic > 36 repeats -younger = more repeats -progressive loss of motor function, striatum, caudate nucleus, onset in 30-40s, involuntary jerking/twitching, depression, cognitive decline, death about 15 years after diagnosis, difficulty walking/speaking/swallowing Spinocerebellar Ataxias (SCA) -AD -anticipation -protein gain of function -paternal expansion bias -gain of function of CAG expansion within an exon (PolyQ tracts) -late onset, slow degeneration of cerebellum, variable degeneration of brainstem and other parts of CNS, ataxia, poor coordination of gait, wheelchair bound within 20 yrs of first symptoms, by age 70 - 100% penetrance Angelman Syndrome (AS) -lack of MATERNAL contribution of 15q11-13 -UBE3A -severe intellectual disability, seizures and spasticity, coarse facies, short stature, happy demeanor, hyperactivity Prader-Willi Syndrome (PWS) -lack of PATERNAL contribution of 15q11-13 -SNRPN, HB genes -poor feeding and hypotonia in infancy, moderate intellectual disability, obesity and type II DM, behavioral problems, hypopigmentation due to loss of OCA2 Severe Combined Immunodeficiency (SCID) -XR = def. of IL2RG -AR = def. of adenosine deaminase (ADA) -death or dysfunction of B, T, and NK lymphocytes -no functional adaptive immune system Alpha Thalassemia with Mental Retardation (ATRX) -mutations in ATRX encoding a SWI2/SNF protein (chromatin remodeling) -mental retardation, characteristic facies -mutated protein is essential in virtually all cell types Rett Syndrome -XD (mostly females) -mutations in MECP2 -methyl CpG-binding protein 2 -> mediates silencing by DNA methylation -leading cause of intellectual disability in females (austism), onset 6-18mo, characteristic handwringing, 50% seizures, progressive microcephaly Tay Sachs -AR -mutations in HEXA encoding hexosaminidase A (HexA) -1 in 27 Ashkenazi, French Canadians, Cajuns -1 in 50 Irish Americans -4bp insertion resulting in a frameshift (null mutation) -onset at 6-12mo, progressive neural degeneration, loss of motor skills and responsiveness, seizures, loss of movement/hearing/vision, cherry red spot at fovea, death at 2-5 years mutation in HEXA -Tay Sachs (type 1 gangliosidase) -encodes alpha subunit of HexA and HexS mutation in HEXB -Sandhoff (type 2 gangliosidase) -encodes beta subunit of HexA and HexB Gaucher Disease -AR -mutations in GBA encoding beta-glucocerebrosidase -lysosomal storage disease -lipid filled enlarged cells (Gaucher cells) -accum. in liver, spleen, lung and brain -type 1 = non-neuropathic = bone disease hepatosplenomegaly, anemia, thrombocytopenia -type 2 = acute infantile = onset by 3mo, extensive brain damage, death before 2 years -type 3 = chronic = slower progression, neural damage, seizures, decreased cognition -perinatal lethal = severe neural damage, fluid accum. -Tx: enzyme replacement therapy, cerezyme 46,XX SRY+ -gain of function -infertile phenotypic male with testes 46,XY SRY- -loss of function -infertile phenotypic female with ovaries