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PKUmost prevalent IEM (1/2900), cumulative prevalence of IEM is 1/300

-defect in phenylalanine hydroxylase gene (inability to convert phenyalanine to tyrosine)

CFAR, defect in CFTR gene (chloride channel), high in European descent

Neurofibromatosis (NF1)AD w/ variable expressivity (1,3500) due to a mutation in neurofibromin

gene (NF-1)

-has compete penetrance, but variable expressivity-benign tumors (neurofibromas on skin), lisch nodules on eye, caf-au-lait spots, mental retard.

Huntingtons DiseaseAD, dementia, uncontrolled movement of limbs around age 40

-1/20000, occurs due to CAG triplet expansion and is a gain of function mutation

Achondroplasiadwarfism caused by AD in Fibroblast growth receptor gene

-balance between new mutations/fitness

-has nucleotide hotspot(CG dinucleotide)

Collagen Disorders

-Ehlers-Danlos SyndromeAD, mutation in collagen structural gene, AR if mutation is in

enzymes required for processing of collagen

-Osteogenesis Imperfecta 1AD, mutation in structural collagen 1 protein (1/10000)

Familial Hypercholesterolemia - mutated LDL receptor (1/500), AD

RET Gene DisordersAD

Loss of function: Hirschsprung diseaseRet gene required for development of neural tube

-gives rise to aganglionic colon during development

Gain of Function: Multiple Endocrine Neoplasia (MEN)proliferation of neuroendocrine cells

Duchenne Muscular Dystrophy (DMD)1/3000 male births, defect in dystrophin gene essential for

attachment of muscle cells to ECM causing muscles to disintegrate

Becker Muscular Dystrophy (BMD)milder version of DMD (less severe mutation on dystrophin)

Lebers Optical Neuropathy1/50000, most prevalent mitochondrial disorder

-mutation in ND1 gene needed for ETC, rapid deterioration of optic nerve leading to blindness

Turner Syndrome45X femaleKlinefelter Syndrome47XXY male

Cri-du-chat syndromedeletion of chromosome 5 (1/25000 newborns)

-microcephaly, hypertelorism, micrognathia, mental retardation, heart defects, cat-like cry

Di-George Syndromemicrodeletion of chromosome 22 (velocardiofacial syndrome)

-1/4000 live births, fairly common, AD

-most common phenotype is congenital heart defect

-cleft palate, mental retardation, hypoparathyroidism, etc.

Chronic Myelogenous leukemiatranslocation between 9 and 22 (Philadelphia chromosome)

-ABL from 9 to BCR on 22

Robertsonian Translocation(1/1300 very common) between 13q and 14q

Rett Syndromemutation in the methylcytosine binding protein MECP2, XD, 1/10000 female births

-perinatally lethal in boys

Beckwith-Wiedemann Syndrome1/13000, uniparental disomy (chromosome 11 from father)

-overabundance of Insulin-like growth factor 2 leading to kidney/adrenal/and liver problems

Prader-Willi Syndrome1/10000-50000 due to deletion on paternal chromosome 15

-obesity, excessive food seeking behavior, hypogonadism, mental retardation

Angelman Syndrome1/15000 deletion in maternal chromosome 15

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-unusual facial features, seizures, movement and gait disorders, mental retardation

Systemic Lupus Erythematosusautoimmune disease where antibodies against nuclear components

are produced

-genome of T-cells are hypomethylated and activity of DNMT1 is reduced leading to

reexpression of endogenous retroviruses

Chronic lymphocytic leukemiatreat with HDAC inhibitors promoting gene re-expressionAcute myeloid leukemiaDNMT inhibitors like 5-azacytidine cause hypomethylation to counteract

malignances caused by hypermethylation

VACTERLabnormalities occurring w/in first 1-4 weeks of development (damage to mesoderm at 20-25

days after conception)

-maternal diabetes is major risk factor

Holoprosencephalycaused by Shh mutation has variable xpressivity (abnormal face/brain develop)

-midline defects

Smith-Lemli-Optiz Syndromeimpairment of Shh signaling secondary to defect in cholesterol

biosynthesis

-AR, (1/20000-1/40000)

Polycystic kidney diseasekidney cysts develop as a result of mutations in polycystin 1 or 2

-cells unable to detect fluid flow and continue to proliferate

Lissencephalysmooth brain due to mutation in LIS1 gene causing disorderly pattern of migration

Cogenital Adrenal Hyperplasiadefect in 21-hydroxylase involved in cortisol biosynthesis

-results in block of cortisol synthesis w/ intermediates shunted into androgen synthesis pathway

Ellis van Creveld Syndromerecessive form of skeletal dysplasia manifesting as shortening of the

forearms and lower legs, heart defects

Pyloric Stenosisnarrowing between stomach and duodenum resulting in vomiting/constipation

-1/200 incidence in males, 1/1000 females (lower threshold for males vs females)

-female proband has a higher # of contributing alleles

Type 1 Diabetesincidence of 1/200, Haplotype associated disorder (DR-DQ increases/decreases risk)Spondyloarthropathy - HLA-B haplotypes

Psoriatic ArthritisHLA-C haplotypes

Malignant HyperthermiaAD, rare, death during anesthesia

-calcium release in muscle leading to uncontrolled muscle contraction (mutation in Ryanodine-

receptor, RYR1 gene)

Warfarin- inhibits vitamin K metabolism (inhibits vitamin K epoxide reductase)

-polymorphism in P450 protein causes slow metabolism of warfarin

-mutation of vitamin K epoxide reductase (VKORC1) leads to higher warfarin tolerance