11 urine screening for Metabolic disorders

Overflow disorders

• Caused by an inborn error of metabolism (IEM)

• disruption of metabolic pathway causing plasma concentration of specific metabolite to rise

• Metabolite surpass renal threshold and appear in urine

• Now screened via Tandem mass spec new born screen

Inborn error of metabolism (IEM)

failure to inherit gene that produces necessary enzyme in a metabolic pathway

Renal disorders

Malfunction in tubular reabsorption causing metabolites to enter urine

Amino acid disorder catagories

• phenylalanine-tyrosine disorder

• branched chain amino acid disorder

• tryptophan disorder

• cystine disorder

Phenylalanine tyrosine disorders

• phenylketonuria

• tyrosyluria

• alkaptonuria

• melanuria

Branched chain amino acid disorders (2 catagories)

• Accumilation of early amino acid metabolism products:

  • maple syrup urine disease

• Accumulation of later amino acid metabolism products:

  • organic acidemias

Typtophan disorder

• indicanuria

• 5-hydroxyindoleacitic acid

cystine disorders

• cystinuria

• cystinosis

• homocystinuria

Phenylketonuria (PKU)

Phenylalanine tyrosine disorder

• cannot convert phenylalanine → tyrosine

• No melanin bc tyrosine is needed to produce melanin

  • → albinism common

• Can cause neurological symptoms if phenylalanine builds up too much

• Treatment

  • decreased food intake of phenylalanine and aspartame

    • aspartame converts into phenylalanine

    • Babies need special milk!

  • Children can form alternative pathways to metabolize phenylalanine

Phenylketonuria (PKU) UA

• Mousy urine smell

• increased keto acids

• Ferric chloride test

  • nonspecific reaction with amino acids

  • Permanent blue green color

• Not used for diagnosis bc screen is used

  • used for monitoring dietary control

  • follow up if screen is questionable

Phenylketonuria Blood testing

• Tandem mass spec for phenylalanine

  • can have high false negatives if heel stick screen is too early. best taken after ingestion of milk (containing pheylalanine)

• Required by all 50 states, included in all newborn screens

• Can also do bacterial inhibition test (Guthrie test)

Guthrie test

Bacterial inhibition test to detect high phenylalanine in blood

• heel stick blood is absorbed on paper

• paper is incubated on plate with bacillus subtitles and inhibitor in media

• If enough phenylalanine is in the blood, the bacteria can overcome the inhibitor and grow around blood disk

• can detect serum phenylalanine levels of 180 - 240μmol/L

  • normal is under 120μmol/L

Tyrosyluria

Phenylalanine tyrosine disorder

• excess tyrosine, hydroxyphenylpyruvic acid, hydroxypheylacitic acid

• IEM or transient or aquired

  • transient in premature babies bc liver not mature enough to make enzymes to metabolize tyrosine

  • aquired liver disease from cirrhosis, alcohol damage, etc can also cause

Tyrosyluria UA

• tyrosine and leucine crystal

  • if cause is liver damage

• Ferric chloride test

  • fading green

• Nitroso-napthol test

  • orange red

Melanuria

Phenylalanine tyrosine disorder

• overproduction of melanogin → oxidized into melanin

  • black urine

• overproliferation of melanocytes: usually melanoma

Melanuria UA

• Ferric chloride

  • grey or black precipitate

• sodium nitroprusside

  • red

• Ehrlich reagent

  • red

Alkaptonuria

Phenylalanine tyrosine disorder

• accumulation of homogentisic acid in blood, tissue, urine

• children: brown, black stained diapers

• adults: pigment deposits on body, ear and hands. arthritis from deposits

Alkaptonuria UA

• ferric chloride

  • blue

• clintitest

  • yellow precipitate

• alkalization of urine → dark color

  • add silver nitrate, ammonium hydroxide → black urine

Maple Syrup Urine Disease

Branched chain amino acid disorder

• IEM

• Leucine, isoleucine, valine converted into keto acid

  • unable to decarboxylate the ketoacid

  • accumulation of ketoacids

• Must detect before d11 birth and restrict diet or else the newborn will fail to thrive

Maple syrup urine disease UA

• maple syrup smell

• High ketones

• DNPH (2,4- dinitrophenylhydrazine)

  • yellow precipitate

• Amino acid chromatography

Organic acidemias

Branched amino acid disorder

• symptoms: vomiting, metabolic acidosis, hypoglycemia, ketonuria, increased serum ammonia

• IEM, with later metabolite accumilation

• Common disorders

  • isovaleric acedemia

  • propinoic acedimia

  • methylmalonic acidemia

Isovaleric acedemia

organic acedemia

• branched chain amino acid disorder

• urine smells like sweaty feet

Indicanuria

Tryptophan disorder

• Intestinal disorders disrupt tryptophan metabolism

  • normal: tryptophan converted to indole by intestinal bacteria and excreted

  • Abnormal: obstruction, increased bacteria, malabsorption, IEM can cause excess conversion of tryptophan to indole

    • Indole reabsorbed → converted to indican in liver → increased indican in blood → indican in urine

• Indican colorless → oxidizes to indigo blue

  • blue diaper sydrome

Hartnup disease

Indicanuria - tryptophan disorder

• IEM that effects intestinal reabsorption of tryptophan

• Causes abnormalities of renal tubules

  • Acquired Fanconi syndrome (other aa affected)

• Dry red scaly rash, as it oxidized will turn blueish

• Muscular incoordination

• Treatment with niacin, eat less tryptophan

5-hydroxyindoleacetic acid (5HIAA)

Tryptophan disorder - carcinoid tumor

• malignant tumor can convert tryptophan into seratonin

• seratonin broken down into 5HIAA

• Increased 5HIAA seen in urine of patients with carcinoid tumors

Cystinuria

cystine disorder

• elevated cystine in urine from inability of renal tubules to reabsorb cystine

  • NOT IEM

  • Renal disorder

• Lysine, arginine, ornathine also not reabsorbed

Cystinuria UA

• cystine crystal

• renal calculi (most common cause in children)

• cyanide nitroprusside

  • red purple

• Amino acid chromatography for lysine, arginine, ornathine

Cystinosis

Cystine disorder

• IEM - OVERFLOW DISORDER

• Crystalline cystine deposits in cornea (blindness), bone marrow, lymph node, RTE (acquired fanconi)

• Bad prognosis compared to cystinuria

  • renal failure possible

Cystinosis UA

• polyuria (decreased reabsorption)

• aminoaciduria (decreased reabsorption)

• Decreased urine concentration

Homocystinuria

• IEM, increase in homocystine

• Cataracts, mental retardation, thromboembolic problems, death

Homocystinuria UA

• screen: cyanide nitroprusside test

  • red

• Confirmatory: silver nitroprusside test

  • red

  • not red for cystinuria

Porphyrins

intermediate compounds in heme production

• 3 main porphyrins

  • uroporphyrin

  • coproporphyrin

  • protoporphyrin

Porphyria

• porphyrin metabolism disorder

• IEM or acquired (RBC dysfunction, liver dysfunction, toxins)

• symptoms: neurologic, psychiatric, cutaneous photosensitivity

• Port red wine colored urine

Porphyria UA

• Ehrlich reaction: porphobilinogen

• Hoesch test: porphobilinogen

• Fluorescence screen

  • blue - NEG

  • purple, pink red - POS

Mucopolysacchride disorders

• Glycosaminoglycan metabolism issue - IEM

• accumulation of GAG in lysosome of connective tissue and excreted in urine

Hurler’s syndrome

Mucopolysacchride disorder

• gargoylism

• usually fatal in childhood

Hunter’s syndrome

Mucopolysaccharide disorder

• affects skeleton structure and causes mental retardation

• Usually fatal in childhood

Sanfilippo’s syndrome

Mucopolysaccharide disorder

• causes mental retardation

• not as fatal as others

Mucopolysaccharide disorder UA

• CTAB (cety-trimethyl-ammonium bromide) 

  • forms white turbidity

• Acid-albumin turbidity test

  • forms white turbidity

• Metachromatic staining spot test 

  • blue spot

Lesch Nyhan disease

Purine disorder

• IEM

• Increased uric acid

• severe motor defects, mental retardation, mental dysfunction, self destruction, gout, and renal calculi

Lesch Nyhan disease UA

• orange sand in diaper

• uric acid crystals HIGH

• renal calculi

Melituria

Increase of any urinary sugar, usually IEM

Galactosuria

Melituria

• IEM, deficient in enzyme to convert galactose to glucose

• galactosemia

  • liver disorder, cataracts, severe mental retardation in babies

• Treatment

  • remove galactose and lactose(breaks down into galactose) from diet

Galactosuria UA

• screen

  • clintitiest + glucose strip =

  • chromatographt