Amino acid metabolism disorders Notes


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Cystinuria (NORD)

Hartnup disease


Maple syrup urine disease

Ornithine transcarbamylase deficiency

Phenylketonuria (NORD)

NOTES NOTES AMINO ACID METABOLISM DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Inherited disorders of amino acid metabolism, transportation, excretion ▪ Impaired enzymes → reactant accumulation → toxicity ▪ Inherited autosomal/X-linked recessive SIGNS & SYMPTOMS ▪ See individual disorders DIAGNOSIS LAB RESULTS ▪ Amino acids levels in blood, urine CAUSES ▪ Gene mutation TREATMENT RISK FACTORS ▪ Infants with central nervous system (CNS) disorders most commonly affected OTHER INTERVENTIONS ▪ Modified diet ALKAPTONURIA PATHOLOGY & CAUSES ▪ Inherited autosomal recessive disorder of tyrosine, phenylalanine metabolism with build-up of degradation product (homogentisic acid) in connective tissues ▪ Homogentisic acid transforms into polymer → deposition of polymer into collagen fibers of connective tissues (e.g. cartilage) → ochronosis CAUSES ▪ Mutation of homogentisic oxidase gene (HDG) → deficit of homogentisate oxidase → ↑ homogentisic acid COMPLICATIONS ▪ Coronary artery disease ▪ Arthritis ▪ Renal stones SIGNS & SYMPTOMS ▪ Usually asymptomatic in childhood/ adolescence ▪ In infants, urine in diapers darkens due to oxidation of homogentisic acid; “black nappies” ▪ Bluish pigmentation of sclera, ear, etc. ▪ Pain in spine, hip, knee joints OSMOSIS.ORG 231
DIAGNOSIS DIAGNOSTIC IMAGING Radiology ▪ Calcification of multiple intervertebral discs LAB RESULTS ▪ Dark brown/black color of urine on prolonged air exposition ▪ Chromatography ▫ ↑ homogentisic acid TREATMENT MEDICATIONS ▪ Herbicide nitisinone → inhibits enzyme which converts tyrosine to homogentisic acid → ↓ homogentisic acid OTHER INTERVENTIONS ▪ Tyrosine, phenylalanine restriction → ↓ homogentisic acid excretion Figure 40.2 Alkaptonuria leads to the accumulation of homogentisic acid giving the clinical appearance known as ochronosis. 232 OSMOSIS.ORG Figure 40.1 An X-ray image demonstrating calcification of the intervertebral discs in an individual with ochronosis.
Chapter 40 Amino Acid Metabolism Disorders CYSTINURIA PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; high levels of cystine in urine → kidney, ureter, bladder stones CAUSES ▪ Mutation of SLC3A1, SLC7A9 gene → defect of intestinal, renal amino acid transporter affecting positively charged amino acids (e.g. cysteine, arginine, ornithine) COMPLICATIONS ▪ Hydronephrosis, pyelonephritis, frequent urinary tract infections (UTIs) SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Flank pain, hematuria DIAGNOSIS LAB RESULTS ▪ Sodium cyanide-nitroprusside test ▫ Determination of cystine concentration ▪ Urinalysis ▫ Pathognomonic hexagonal crystals ▪ Stone analysis TREATMENT MEDICATIONS ▪ Chelation therapy with penicillamine ▫ Forming soluble disulfide complex OTHER INTERVENTIONS ▪ Sufficient hydration; urine alkalization ▪ Protein, sodium restriction ▪ Formed stones ▫ Renal: extracorporeal shock wave lithotripsy (ESWL) ▫ Ureteric: intracorporeal lithotripsy ▫ Bladder: cystolitholapaxy HARTNUP DISEASE PATHOLOGY & CAUSES ▪ Inherited autosomal recessive metabolic disorder affecting neutral amino acids (esp. tryptophan) CAUSES ▪ Intestinal, renal deficiency of neutral amino acid transporters → ↓ absorption from intestines, ↓ reabsorption from kidneys → less amino acids available to build proteins COMPLICATIONS ▪ Drop of tryptophan to niacin conversion → decrease of nicotinamide, NAD+ → pellagra-like symptomatology ▪ Hyper/hypopigmentation in repeated sunlight exposure OSMOSIS.ORG 233
SIGNS & SYMPTOMS Pellagra-like symptoms Photosensitivity Diarrhea Nervous system symptoms (e.g. ataxia, tremor, headaches; intellectual disability, mental abnormalities) ▪ Ocular manifestations (e.g. nystagmus, double vision) ▪ ▪ ▪ ▪ DIAGNOSIS LAB RESULTS ▪ Urine chromatography ▫ Increased levels of neutral amino acids (e.g. aminoaciduria) TREATMENT OTHER INTERVENTIONS ▪ High-protein diet, nicotinic acid supplements, sunlight protection HOMOCYSTINURIA PATHOLOGY & CAUSES ▪ Autosomal recessive disorder; high levels of homocysteine in blood, urine due to impaired methionine metabolism TYPES ▪ Type I ▫ Deficiency of cystathionine synthase ▪ Type II ▫ Deficiency of methionine synthase ▪ Type III ▫ Cystathionine synthase impairment → decreased affinity for pyridoxal phosphate COMPLICATIONS ▪ Increased risk for thrombotic strokes SIGNS & SYMPTOMS ▪ Ocular anomalies (e.g. myopia, ectopia lentis) ▪ Marfan-like presentation ▪ Intellectual disability ▪ Cardiovascular defects ▪ Osteoporosis 234 OSMOSIS.ORG DIAGNOSIS DIAGNOSTIC IMAGING CT scan, MRI ▪ Large-vessel/lacunar stroke LAB RESULTS ▪ Blood, urine quantitative test for homocystinuria ▪ Cyanide nitroprusside test ▫ Urine screening test for amino acids containing sulfur ▪ Measurement of cystathionine synthase activity in cultured fibroblasts TREATMENT OTHER INTERVENTIONS ▪ Vitamin B6, B12, folate acid supplements in cystathionine synthase deficiency ▪ Methionine in methionine synthase deficiency ▪ Cysteine, high doses of vitamin B6 in decreased affinity of cystathionine synthase for pyridoxal phosphate
Chapter 40 Amino Acid Metabolism Disorders MAPLE SYRUP URINE DISEASE PATHOLOGY & CAUSES ▪ Disease caused by impaired metabolism of branched amino acids (e.g. isoleucine, leucine, valine); AKA branched-chain ketoaciduria ▪ Autosomal recessive inheritance ▪ Impaired metabolism → accumulation of byproducts with toxicity in brain, other organs TYPES Classic MSUD ▪ Most common; occurs soon after birth Non-classic MSUD ▪ Later onset, less severe symptoms CAUSES ▪ Mutation of genes BCKDHA, BCKDHB, DBT → dysfunction of enzyme complex COMPLICATIONS DIAGNOSIS LAB RESULTS ▪ Plasma amino acid test ▫ Alloisoleucine detection ▪ Prenatal diagnostic by measuring enzyme activity in cultured amniocytes OTHER DIAGNOSTICS ▪ Genetic testing ▫ BCKDHA, BCKDHB, DBT ▪ Physical examination, newborn screening TREATMENT SURGERY ▪ Liver transplant OTHER INTERVENTIONS ▪ Regular metabolism check ▪ Regulation of isoleucine, leucine, valine intake ▪ Possible permanent brain damage ▪ Fatal if not treated in first five months SIGNS & SYMPTOMS ▪ Sweet (maple syrup-like) smelling urine Classic MSUD ▪ Healthy-looking infants at birth, quick deterioration; feeding difficulties, failure to thrive (FTT), vomiting, seizures Non-classic MSUD ▪ Vomiting, diarrhea, rapid neurological decline, ataxia, seizures, coma OSMOSIS.ORG 235
ORNITHINE TRANSCARBAMYLASE DEFICIENCY PATHOLOGY & CAUSES DIAGNOSIS ▪ X-linked disorder affecting ornithine transcarbamylase enzyme ▪ Disorder of urea cycle → accumulation nitrogen in form of ammonia ▪ Defect of ornithine transcarbamylase enzyme → carbamoyl phosphate accumulation → conversion of carbamoyl phosphate into orotic acid ▪ Presents often in neonatal form, may present later LAB RESULTS RISK FACTORS ▪ Ornithine transcarbamylase only expresses in liver; liver biopsy needed to confirm diagnosis ▪ Newborn screening ▪ Individuals who are biologically male fully affected due to X-recessive transmission ▪ Individuals who are biologically female usually asymptomatic SIGNS & SYMPTOMS ▪ Neonatal form ▫ Lethargy, irritability, poor feeding, seizures, impaired thermoregulation; hyperventilation → respiratory alkalosis; cerebral edema, possible progression into coma, death ▪ Later presentation ▫ Headaches, nausea, vomiting, psychiatry disorders 236 OSMOSIS.ORG ▪ Plasma, urine amino acid analysis ▫ Elevated arterial/venous ammonia (hallmark finding), orotic acid, glutamine ▫ Decreased blood urea nitrogen (BUN), citrulline concentrations ▪ Urine organic acid analysis ▫ Orotic acid in urine OTHER DIAGNOSTICS TREATMENT SURGERY ▪ Liver transplant OTHER INTERVENTIONS ▪ Low-protein diet ▪ Nitrogen scavenging agents ▫ Sodium benzoate, arginine
Chapter 40 Amino Acid Metabolism Disorders PHENYLKETONURIA PATHOLOGY & CAUSES DIAGNOSIS ▪ Genetic disorder characterized by high levels of phenylalanine ▪ Autosomal recessive inheritance LAB RESULTS CAUSES Chromatography/tandem mass spectrometry ▪ ↑ phenylalanine ▪ PAH gene mutation → hepatic phenylalanine hydroxylase deficiency → defect in metabolism of phenylalanine → activation of alternative pathways → accumulation of phenylalanine, byproducts ▪ Mutation of HPABH4 genes → impairment in synthesis, recycling of tetrahydrobiopterin cofactor (BH4) → impaired function of phenylalanine hydroxylase enzyme COMPLICATIONS ▪ If untreated ▫ Severe intellectual disability ▪ Seizures ▪ Increased risk of anxiety, inattention, depression, other neuropsychiatric disorders ▪ Phenylalanine embryopathy ▫ Inappropriate diet during pregnancy in individuals with phenylketonuria → elevated levels of phenylalanine concentration in serum → teratogenic effects of phenylalanine passing placenta → newborn with microcephaly, mental disorders, congenital heart defects SIGNS & SYMPTOMS ▪ Skin, hair pigmentation disorders (lack of melanin pigment) ▪ Eczema ▪ Musty odor Cranial magnetic resonance spectrometry ▪ Brain phenylalanine levels Guthrie test ▪ Formerly used; replaced with tandem mass spectrometry Ferric chloride urine test ▪ Rarely used; results may be negative in first months of life OTHER DIAGNOSTICS ▪ Newborn screening Figure 40.3 The heelprick test is performed on all newborn babies and screens for phenylketonuria. TREATMENT MEDICATIONS ▪ Sapropterin OTHER INTERVENTIONS ▪ Lifelong low-phenylalanine diet with tyrosine supplements ▪ Avoid artificial sweeteners containing phenylalanine (e.g. aspartame) OSMOSIS.ORG 237

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