Genet

Genetic Disorders

DiseaseGene/ ChromosomeProduct/Lab/DxPresentationRxClinical Correlation

Hemoglobinopathies

MicrocyticHypochromicAnemiaUneven production of & chainsFe deficiencyLead poisoning

ThalassemiasExcess chains precipitate leading to RBC hemolysis-Thalassemias exemplify reduced gene dosage.-Thalassemias exemplify reduced functional product.

NormocyticNormochromicAnemia

(Sickle cell novel property mutation)HemorrhageBone marrow failure

Dx with electrophoresis of Hb Mst II RFLP normally creates 2 small fragments. HbS mutation destroys one of the Mst sites, which then creates one large fragment.

Sickle cell disease forms fibers in RBC-Hemolytic anemia-crises caused by infection, dehydration, deoxygenation-HbC disease forms crystals in RBC-mild anemia, hemolysisRBCs look like targets (codocytes)Sickle cell HbS chain sub Glu6ValHomozyg = diseaseHeterozyg = trait (normal clinically except in crises)-African Americans 1 in 600 have disease, 8% carriersHbC chain Glu6Lys

Thrombosis, PE, retinal abnormalities

Hb Hammersmith (drops the hammer)Point mutationUnstable globinPhe42Ser (F42S)Heme falls outCyanosis (low O2 affinity)hemolysis

Hb Gun HillSmall deletion b/c of slipped mis-pairingUnstable tetramer hemolysis( chain)

Hb Kempsey (keepsy)(gain of fxn enhanced fxn) Asp99Asn locks Hb into R statealters interface btwn 1 & 2 subunitsHigh O2 affinity polycythemia

Will also see hemolysis

Hb Kansas (kick out O2) Asn102Thr

Locks Hb into T stateAlso in the interfaceLow O2 affinitycyanosis

Hb Tak (takes O2) chain Insertion 2bp, changes reading frame = deletes stop codon, Extends chain

High O2 affinitypolycythemia

Hb E(variant Hb) Glu26Lysstructurally abnormal synthesis is reduced b/c of impaired RNA splicing Thalassemia phenotypeHomozygotes are asymptomatic, but mildly anemic

Lepore Hb(variant Hb) fusion globin-likeDue to uneven crossing overSymptomaticHave neither nor genes

Anti-Lepore(variant Hb)Both fusion and globinas in LeporeNo phenotypic expressionHb Miyada

Hb Barts (-Thalassemia)4Deletion of all 4 genes = no HbF and no HbAUnable to release O2Massive fluid accumulationHydrops fetalislethal

DiseaseGene/ChromosomeProduct/Lab/DxPresentationRxClinicalCorrelation

Hb H(-Thalassemia)4Deletion of 2 genesMost severe form in SE Asia -null (- -/)

Hb Constant Springs(-Thalassemia)Substitution in stop codonAdd 31 aa to -chain(- -/cs)Globin is unstableReduced synthesisExtended polypeptide tailNon Deletional -Thalassemia

Thalassemia Major(-null-Thalassemia)2 alleles affectedNon-deletion type single base pair substitutionSee more 22 (HbA2) & 22 (HbF)-splice site mutationHeinz body due to precipitated chains.No Hb A production= null ThalassemiaIf some HbA is detectable = + Thalassemia

Hypochromic, microcytic severe anemiaTransfusion

Control Fe accumulation

Bone marrow transplantMost pts are genetic compounds not true homozygotes.NOT seen in utero.Splice Jxn mutations most common cause:-cryptic (no globin produced if 0)-intron mutations

Thalassemia Minor(-Thalassemia Trait)

Single thalassemia alleleSee more 22 (HbA2)-intron or exon mutation-capping and tailing of RNA mutations -posttranscriptionalElectrophoresis can Dx HbF and HbA2Hypochromic, microcytic RBCSlight anemia(+ conditions, HbA low)-exon mutations (cryptic donor used 40% of time nonfxnal , + condition, low HbA)-defects in capping & tailing mRNAs-deletions in LCR

HPFH Hereditary Persistence of Fetal Hb

(heterochronic gene expression)Large deletions brings enhancers closer to genesORSubstitutions alter affinity of regulatory proteins reqd for postnatal repression geneFetal Hb left on

Dx of HbS and HbC with electrophoresis

Dx Thalassemias with electrophoresis

DiseaseGene/ChromosomeProduct/Lab/DxPresentationRxClinicalCorrelation

Multifactorial Diseases

Retinitis Pigmentosumdigenic-peripherin locus

HypercoagulabilityIncreased levels of Factor V, X, and prothrombinOral contraceptives in these susceptible pts increase risk of DVT and CVT 30-150 fold.

Hirschsprung Disease (HSCR)9 partially independent genes esp. HSCR 1 (RET, chrom 10q), HSCR 6 (chrom 3p)& HSCR 7 (NNX3, chrom 19q)Intestinal aganglionosis lack intrinsic ganglion cells in myenteric & submucosal complexes.Dx within 24hr of delivery.Loss of peristalsis, S/S of bowel obstr. & massive dilatation of colon proximal to aganlionic segment1 in 5000 newborns.

Disease Gene/ChromosomeProduct/Lab/Dx PresentationRx

ClinicalCorrelation

Diabetes Mellitus Type 120 genes implicated.Largest contributor fr genes of MHC (6p)Autoimmune destruction of pancreatic cellsMost common chronic disease in peds, 2/1000.Undefined relationship with Coxsackie Virus.

Diabetes Mellitus Type 2Heterogeneous disorder (multiple diseases)Primarily environmental influences.Insulin production or insulin resistance Weight loss of 5-7% incidence of DM by 70%Most common form of DM

Alzheimer Disease (AD)Early onset: 3 genes amyloid precursor protein (APP on 21q), presenilin 1 (PSEN1, 14q), presenilin 2 (PSEN2).Postmitotic dinucleotide deletions of microsatellite rgns for APP. Late onset: 100s of genes focus on 4 allele (19q) for ApoEPostmortem demonstration of amyloid deposits, neurofibrillary tangles and neuronal plaques.Most common neurodegenerative disease.3/1000 in US.

Chance of remaining unaffected by AD by 80 y/o for 4/4 homozygote is 80%.

Alzheimer Disease(continued)7-10% monogenic highly penetrant form ADMutations in genes encoding -amyloid precursor protein, presenilin 1 & 2, ApoE gene mutations lead to slight increase in nonfamilial ADDegeneration of neurons due to deposits of -amyloid peptide and tau protein.A peptide (from APP protein) found in amyloid/senile plaques in extracell space of brain.Progressive deterioration of memory & high cognitive fxn (due to the neurofibrillary tangles)1-4% of people in developed countries.4 allele of ApoE gene risk factor for AD

Cardiovascular DiseaseMTHFR gene ala22val (as in neural tube defects).Major environmental influences.Incl: CAD (>50%), cardiomyopathies, conduction abnormalities, HTN, stroke, aneurism, PVD

Neural Tube Defects (NTD)>80 possible genes focus on MTHFR gene (ala677val).Folic acid (vit B9) deficiency.Abnormal closure of neural tube in wk 3-4 of gestation.Folic acid deficiency in mother she develops hyperhomocysteinemia as a result of mutated MTHFR gene (which converts homocysteine to methionine.)

Autism(part of Autism Spectrum Disorder)7q speech/language15q maternally inherited duplications (Angelman)3/1000.Onset 1mM-Impaired brain fxn-Increased pheylpyruvic acid thru alternate paths-Seizure, albinism, musty odour to sweat and urine-Non PKU plasma [Phe]