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- Klinefelter’s (47,XXY) - infertile
- Sanfilippo A
Down’s Syndrome (Trisomy 21) endocardial cushion defects, prominent PDAs / leukemia (AML), lymphoma, myelodysplasia / Fanconi’s / early onset Alzheimer’s (40s) / hypo/hyperthyroid Physical Findings: flat-face, epicanthal folds, Mongolian slant (eye), Brushfield spot, low-set ears, narrow eustachian canal, large tongue, high arch palate, duodenal atresia (double-bubble sign), bilateral Simian crease (50%) (palm, no), brachiodactyly, clindactyly (little finger in), sandal toe Turner’s (46 X,O) - infertile coarctation (and other AV malformations) X,O - shield chest, wide neck, wide nipples, infertility, short stature lymphedema of hands/feet as neonates Klinefelter’s (47,XXY) - infertilevery common / tall stature, delayed puberty (but often with significant initial virilization), gynecomastia from excessive testicular estrogen production, small testes from defective spermatogenesis (in spite of normal testosterone levels) / low testosterone, elevated gonadotropins Trisomy 18 (Edward’s) - 95% die at birth multiple malformations / low set ears? micrognathia? clenching middle finger, rocker-bottom feet / Cardiac: central fibrous body - A/M/T valve all anchored to it / AV node travels through it Trisomy 13 (Patau) Marfan’s syndrome AD / skeletal (long bone deformities) / cardiac (5th yr of life, dissecting aortic aneurysm, floppy mitral valve), eye (subluxation of lens), arachnodactyly (long fingers) / Testicular feminization XLR / end-organ insensitivity to androgens / undescended testes Reifensten syndrome androgen receptor dysfunction (infertile males) – wide range of virilization (male to female phenotype) Prader-Willi Hypotonia, hypogonadism, mental retardation, undescended testes in males, micropenis / feeding problems early, then obesity later Apert’s syndrome syndactyly, craniosynostosis (premature fusion) Bloom’s [dermis] facial erythema, telangiectasia, dwarfism / increased incidence of ALL Congenital Deafness Waardenberg’s (AD) uni/bilateral deafness / white forelock, heterochromic iris Pendred’s (AR) hearing loss and goiter (< 10 yrs) / Treatment: thyroid replacement Usher’s (AR) retinitis pigmentosa (progressive loss of night vision, tunnel vision), deafness Leopard (ADVP) multiple lentigines, ocular hypertelorism, pulmonary stenosis, abnormal genetalia, growth retardation, profound deafness Jervell-Lange-Nielsen hereditary deafness and prolonged QT interval / syncope, sudden death Alport’s syndrome (see renal) More syndromes Beckwith-Wiedermann Syndrome extra part of chromosome 11 / LGA, large tongue – hypoglycemia, polycythemia, which resolves – at risk for Wilm’s tumor, hepatoblastoma? William’s Syndrome Mild MR – aortic stenosis, eye anomalies / diagnosis: FISH probe Fragile X Syndrome XLD (reduced penetrance) / mostly males / most common inherited cause of mental retardation / big ears, elongated face (prognathia), macrorchidia, behavior problems (hyperactivity, aggressivity, autism), seizures Note: ⅓ of affected females have mental retardation
pulmonary hypoplasia – not enough amniotic fluid Holoprosencephaly failure of forebrain to divide and other midline defects – sonic hedgehog gene and other causes Cerebral Palsy ¾ spastic type / 25-30% risk of epilepsy Congenital Nephrogenic Diabetes Insipidus (see renal) XLR, very rare Familial Dysautonomia AR / Ashkenazi Jews FTT, irritability, insensitivity to pain, hypoactive DTR’s, chronic respiratory distress (repeated aspirations?) / crying without tears, absence of fungiform papillae
rare / AR / methylenetetrahydrofolate reductase gene (C677T) (CC variant may be the worst) homocysteine methionine or homocysteine cystathionine Labs: fasting homocysteine level (> 15 is bad), elevated thrombin Hypercoagulability: increased arterial/venous thromboembolism (2-3 x relative risk) inhibition of thrombomodulin (a cofactor for protein C activation and ATIII function) Endothelial damage: increased factor VII release, increased conversion and deposition of LDL may cause some ½ of aortic aneurysms Other: associated with dystonia (primary idiopathic torsion dystonia) Treatment: B12 100 mg qd / B6 3 mg qd / Folate 400 mg qd (goal > 15 nmol/L) Trends: 6/06 HOPE 2 and NORVIT failed to show decreased risk of cardiovascular events with homocysteine supplementation. Homocystinuria 10-25% prevalence / relatively asymptomatic disease / defect in cystathionine synthase (used to metabolize methionine to succinyl CoA) deficiency / Treatment: increase cys, decrease met decreased affinity for pyridoxal, accumulation of cystathione / benign proprionyl-CoA carboxylase deficiency / odd-numbered fatty acids accumulate in liver / developmental problems / biotin cofactor Untreated: thromboembolisis, ectopia lentis (subluxation of lens), mental retardation (mild to severe), renal stones (can lead to ESRD) Acquired: B6, B12, folate deficiency Maple syrup urine blocked degradation of branched amino acids leucine, isoleucine, valine due to absence of alpha-ketoacid dehydrogenase / severe CNS defects, mental retardation, death / Treatment: special synthetic diet Methylmalonic acidurea AR inheritance / 2 types absence of methylmalonyl-CoA mutase (converts methylmalonyl-CoA to succinyl-CoA diagram) impaired glucogenic utilization of val, ile, met, thr [diagram] defect in converting B12 to deoxyadenosylcobalamin cofactor (also cannot convert homocysteine to methionine) Symptoms: lethargy, failure to thrive, RDS, mental retardation Treatment: can give B12 for type 2 PKU (Phenylketonuria) AR deficient phenylalanine hydroxylase leads to high serum phenylketones, diffusion into CNS untreated leads to skin depigmentation (decreased melanin), eczema, musty odor, mental retardation, seizures / (4) PAH mutations or defect in BH4 cofactor (tetrahydrobiopterin) synthesis or recycling / Treatment: decreased phenylalanine, increased tyrosine / diagnosis: newborn screening (> 20 mg/dl)
defect in homogentisic acid oxidase (degradation of tyrosine) / alkapton bodies produce dark urine on standing, dark connective tissue / benign condition Albinism congenital deficiency of tyrosinase / lack of melanin / can result from failure of neural crest cell migration / increased risk of skin cancer Porphyria [diagram] Defects in heme synthesis / erythropoietic or hepatic / AD inheritance (except congenital erythropoietic porphyria is AR) Presentation: acute abdominal pain (severe) and neuropathy, neuropsychiatric / symptoms often triggered by barbiturate induction of P450 Diagnosis: Watson-Schwartz detects excess urinary PBG (qualitative) ?during acute attack visceral/neurological symptoms check urine ALA and PBG (random or 24 hr) cutaneous symptoms check total plasma porphyrins, if (+) check more specific tests Treatment: IV dextrose and IV hematin to decrease ALA synthase, avoid sunlight, take lots of free-radical scavenging vitamins Acute Intermittent Porphyria (Swedish) – uroporphyrinogen I synthetase (AD) / confusion, hallucination, seizures, weakness, paralysis, HTN? / urine darkens on exposure to light, air Congenital Erythropoietic Porphyria – uroporphyrinogen III cosynthetase (AR) Porphyria Cutanea Tarda – uroporphyrinogen decarboxylase (AD) / skin lesions (fragility of the skin on the dorsal surface of his hands) but no GI symptoms [dermis] / can be associated with HCV / ? phlebotomy if iron stores elevated Hereditary coproporphyria – coproporphyrinogen oxidase (AD) Metabolic disorders of carbohydrates high fructose / entry not insulin-dependent (also does not stimulate insulin secretion) / bypass of diet PFK regulation, direct metabolism to DHAP (pyruvate) and glyceraldehyde (TG, pyruvate) / overwhelming of aldolase B / accumulation of ADP (catabolism leads to hyperuricemia) / high glucose/fructose leads to sorbitol accumulation (cataracts) Fructosuria deficiency of fructokinase / mild or asymptomatic Fructose intolerance deficiency of aldolase B / fructose-1-P accumulated / depletes Pi / inhibits glycogenolysis, gluconeogenesis / severe hypoglycemia Treatment: no fructose or sucrose Galactosuria (mild) deficiency of galactokinase / buildup of galactitol / mild or asymptomatic / cataracts (common), benign increase in ICP (rare) Galactosemia (severe) absence of galactose-1-P- uridyltransferase / buildup of galactitol, galactose-1-P Presentation: vomiting, hepatomegaly, jaundice, cataracts, mental retardation, death Treatment: no galactose or lactose, contraindication for breast feeding Other Enzyme Deficiencies Urea cycle defect AR or XLR deficient OTC (ornithine transcarbamylase) leads to buildup of ammonium and “sepsis” picture / may present late in some males and female carriers Treatment: low protein diet, dialysis Pyruvate dehydrogenase deficiency backup of pyruvate and alanine (major amino acid entering cycle) results in lactic acidosis Presentation: neurological Treatment: increase intake of ketogenic (enter at level of acetyl-CoA) amino acids (e.g. lysine, leucine, etc.) Lesch Nyhan XLR deficient HGPRTase (hypoxanthine to inosine monophosphate, guanine to guanine monophosphate) leads to uric acid buildup / defective purine salvage pathway Presentation: spasticity, choreoathetosis, self-mutilation, hyperuricemia (resulting in obstructive neuropathy and nephrolithiasis), growth retardation, mental retardation, aggressivity / mild cases may present with gout / Diagnosis: urate to creatinine ratio > 2 is suspicious Treatment: allopurinol reduces urate levels (does not affect CNS problems) Kelley-Seegmiller syndrome partial HPRT deficiency / hyperuricemia but no neurological decline Bilirubin Disorders Crigler-Najjar, Gilbert’s, Dubin-Johnson, Rotor’s Lysosomal Storage Diseases Note: mostly all result in very early death except Gaucher’s Sphingolipidoses (all autosomal recessive except Fabry’s) Tay-Sach’s (infant death) (example of allelic heterogeneity) 3 proteins for ganglioside metabolism: hexosaminidase A (alpha, beta), B (beta, beta), and activator protein / results in GM2 ganglioside accumulation
deficiency of B-glucocerobrosidase / accumulation in brain, liver, spleen, bone marrow / Gaucher cells (enlarged cytoplasm, ‘crinkled paper’) fill Virchow-Robin spaces / most CNS neurons appear shriveled (but don’t contain abnormal storage lipids) / elevated ACE levels / type 1 (more common) is compatible with normal life span Neimann-Pick (infant death) deficiency of sphingomyelinase / build up of sphingomyelin and cholesterol in RES and parenchymal cells and tissues / CNS: shrunken gyri, sulcal widening / hepatosplenomegaly / cherry red spot in Type A (30%) Fabry’s (XLR) [annals] deficiency of alpha-galactosidase A / ceramide trihexoside (globotriaosylceramide) accummulates in vascular epithelium, kidneys, heart, cornea, other tissues angiokeratomata, painful / acroparesthesias, hypohidrosis, renal failure, cardiac and neurological disease (mostly peripheral nerves) / Treatment: recombinant a-galactosidase A (cool) Cardiac Variant [NEJM] can present later on in life / only manifestation is cardiomyopathy / cause of ~10% of LVH and hypertrophic non-obstructive cardiomyopathy in adults / heart function can actually be ameliorated with enzyme replacement (even as adult!!!) / galactose infusion of 1 g/kg over 4 hrs every other day until forever Metachromatic leukodystrophy aryl sulfatase deficiency causes accumulation of cerebroside sulfates / brain (juvenile), liver, kidney, and peripheral nerves (juvenile) / tissue exhibits metachromasia (salfatides change dye color) / metachromasia found in urine Krabbe’s (infant death) deficiency in galactosylceramide B-galactosidase / accumulation of psychosine optic atrophy, spasticity, early death / loss of myelin in white matter and peripheral nerves / multinucleated globoid cells S positive around blood vessels Other congenital neuronal disorders Adrenoleukodystrophy (XLR) defect in fatty acyl-CoA ligase / spastic paraplegia, adrenal insufficiency / onset at 10-20 yrs / linear membranous inclusions, linear clefts on EM Alexander’s disease demyelinization, megalencephaly, numerous Rosenthal fibers (eosinophilic blobs in white/grey matter) Neuronal ceroid lipofuscinosis vacuolization of neurons / seizures, blindness, retinitis pigmentosa Mucopolysaccharidoses (GAG’s) Hurler 6-18 months: corneal clouding, hepatosplenomegaly, stiff joints, nasal discharge < 10 yrs hydrocephalus, course face, umbilical, large head, large tongue, short neck, ribs splaying, kyphosis, HSM, mental retardation Schei 5 yrs onset, normal intelligence and lifespan / corneal cloudiness, stiff joints, valvular heart disease, visual impairment Hurler/Schei Hunter XLR (gene is cloned) / similar to Hurler w/ slower progression, no corneal clouding, unique pebbly skin lesion / idursulfase first approved treatment being tried 2009 Sanfilippo Aaggression / most severe form / neurodegeneration / mild somatic features / underdiagnosed Sanfilippo B less severe form / heterogeneous clinical picture Glycogen Storage Diseases (locus heterogeneity) Hepatic Hypoglycemia Type Ia – Von Gierke’s (severe) glucose-6-phosphatase deficiency / common / die < 2 yrs (ketoacidosis et al) Symptoms: hypoglycemia, HSM, short stature, bleeding diathesis, delayed adolescence, hepatic adenomas, enlarged kidneys
alpha-1-4-glucosidase deficiency / accumulation of glycogen in lysosome (skeletal and cardiac) infant death from cardiac failure (massive cardiomegaly on CXR) IIb – juvenile form (die < 10 yrs)
debrancher enzyme deficiency / common / hepatomegaly may remit by puberty with relapse of mild myopathy in adulthood / symptoms: hypoglycemia, HSM, short stature, delayed adolescence Labs: increased cholesterol, TG, and SGOT
Brancher enzyme deficiency / die < 10 yrs from hepatic cirrhosis Ketotic hypoglycemia impaired gluconeogenesis / males 1.5 to 4-5 yrs / spontaneous remission usually by 8-9 yrs Labs: low serum alanine, normal insulin levels / patients usually thin / attacks may be induced by high-fat, low-cal diets Download 3.95 Mb. Share with your friends:
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