M I o C BSMT 3B

AMINO ACID DISORDERS

The amino acid disorders with urinary screening tests include phenylketonuria (PKU), tyrosyluria, alkaptonuria, melanuria, maple syrup urine
disease, organic acidemias, indicanuria, cystinuria, and cystinosis.

Phenylalanine-Tyrosine Disorders

Major inherited disorders include PKU, tyrosyluria, and alkaptonuria. Metabolic defects cause overproduction of melanin.

PHENYLKETONURIA (PKU)
Definition Inherited metabolic disorder caused by lack of phenylalanine hydroxylase enzyme
Prevalence 1 in every 10,000 to 20,000 births
Cause Autosomal recessive trait; deficiency of phenylalanine hydroxylase enzyme
Symptoms Mousy odor in urine
Fair complexion (due to decreased melanin)
Screening Mandatory newborn screening in all U.S. states
Blood test 24 hours after birth, may need repeat testing
Treatment Dietary restriction of phenylalanine to prevent intellectual disability
Diet may be relaxed as the child ages
Urine Test (Ferric Chloride) Used as a follow-up for diagnosed cases or monitoring
Blue-green color indicates the presence of phenylpyruvic acid in urine
Dietary Monitoring Ferric chloride urine test helps ensure proper dietary control and monitor intake in PKU patients, including
pregnant women lacking phenylalanine hydroxylase

TYROSYLURIA
Definition Excess tyrosine in blood (tyrosinemia) causing urinary excretion of tyrosine.
Common Causes Transient Tyrosinemia in premature infants
Severe liver disease
Type 1 FAH deficiency; causes renal and liver failure
Type 2 Tyrosine aminotransferase deficiency; causes corneal and skin lesions
Type 3 p-Hydroxyphenylpyruvic acid dioxygenase deficiency; may cause mental retardation
Symptoms Tyrosine and leucine crystals in urine sediment
Liver and kidney complications in severe cases
Screening Tests MS/MS for tyrosinemia types 1, 2, and 3
Urine Test for Tyrosine Nitroso-Naphthol Test: Detects tyrosine presence in urine

MELANURIA
Definition Condition with increased melanin in the urine, affecting urine color.
Melanin is responsible for the pigmentation of hair, skin, and eyes.
Tyrosine Pathway Products Melanin, thyroxine, epinephrine, protein, tyrosine sulfate
Associated Conditions Albinism: Deficient melanin production
Malignant Melanoma: Excess melanin in urine
Urine Characteristics Darkening upon air exposure due to oxidation of 5,6-dihydroxyindole, precursor to melanin
Diagnostic Importance High urinary melanin suggests malignant melanoma

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AMINO ACID DISORDERS

ALKAPTONURIA
Definition an inborn error of metabolism characterized by the accumulation of homogentisic acid due to the
deficiency of the enzyme homogentisic acid oxidase.
Third major defect in the phenylalanine-tyrosine pathway
Historical Context Identified by Garrod in 1902; name derived from urine darkening in alkaline conditions. (term “alkali
lover”)
Pathophysiology Defect in phenylalanine-tyrosine pathway causes accumulation of homogentisic acid in blood and tissues.
Clinical Presentation Brown/black stains on diapers
Pigment deposits in tissues
Arthritis from cartilage deposits
Liver and cardiac disorders
Diagnostic Testing Ferric Chloride Test: Blue color indicates homogentisic acid
Clinitest: Yellow precipitate
Alkaline Reaction: Color darkening upon adding alkali
Chromatography: Quantification of homogentisic acid

Branched-Chain Amino Acid Disorders

Branched-chain amino acids (BCAAs) are characterized by having a methyl group that branches from the main aliphatic carbon chain.
There are two major groups of disorders associated with errors in the metabolism of these amino acids:

1. Accumulation of Early Degradation Products: This group includes disorders such as maple syrup urine disease (MSUD), where one
or more of the early amino acid degradation products accumulate due to enzyme deficiencies.

2. Organic Acidemias: These disorders result in the accumulation of organic acids produced further down in the amino acid
metabolic pathway.

MAPLE SYRUP URINE DISEASE (MSUD)

Type Inborn Error of Metabolism (IEM)
Inheritance Autosomal recessive
Amino Acids Involved Leucine, Isoleucine, Valine
Metabolic Pathway Transamination to keto acids; oxidative decarboxylation failure
Symptoms Onset After approximately 1 week of life
Clinical Symptoms Failure to thrive, abnormal urine odor resembling maple syrup due to keto acid accumulation.
Laboratory Detection Unusual odor in urine; DNPH test (2,4-dinitrophenylhydrazine)
Importance of Early Prevents severe mental retardation and death
Detection
Intervention Dietary regulation and monitoring if detected by the 11th day

ORGANIC ACIDEMIAS
Definition Metabolic disorders with organic acid accumulation
General Symptoms Early severe illness, vomiting, metabolic acidosis, hypoglycemia, ketonuria, increased serum ammonia
Common Disorders 1. Isovaleric Acidemia - Distinctive "sweaty feet" odor in urine and sometimes the patient.
Deficiency of isovaleryl coenzyme A in the leucine metabolic pathway, leading to the
accumulation of isovalerylglycine.
2. Propionic Acidemia - Errors in the metabolic pathway that converts isoleucine, valine, threonine,
and methionine to succinyl coenzyme A. Propionic acid is the immediate precursor to
methylmalonic acid.
3. Methylmalonic Acidemia - Similar errors in the same metabolic pathway as propionic acidemia.
Newborn Screening Detection via MS/MS
Method

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AMINO ACID DISORDERS

Tryptophan Disorders - The major concern of the urinalysis laboratory in the metabolism of tryptophan is the increased urinary excretion of
the metabolites indican and 5-hydroxyindoleacetic acid (5-HIAA).

INDICANURIA
Definition Presence of indican in the urine, usually resulting from increased conversion of tryptophan to indole due to
intestinal disorders.
Normal Tryptophan Reabsorbed or converted to indole and excreted in feces
Metabolism
Conditions Leading to Intestinal obstruction
Indicanuria Abnormal bacteria
Malabsorption syndromes
Hartnup disease (rare inherited disorder)
Mechanism Indole reabsorbed, converted to indican in the liver, excreted in urine
Color Change Indican is colorless until oxidized to indigo blue by air exposure
Clinical Significance "Blue diaper syndrome" indicates Hartnup disease
Correction of intestinal disorders normalizes indican levels
Prognosis for Hartnup Good with dietary supplements, including niacin
Disease

5-HYDROXYINDOLEACETIC ACID (5-HIAA)

Definition Degradation product of serotonin, normally excreted in small amounts in urine
Metabolic Pathway Derived from tryptophan converted to serotonin by argentaffin cells
Normal Function Serotonin utilization leads to minimal 5-HIAA in urine
Conditions Increasing 5- Carcinoid tumors producing excess serotonin
HIAA
Color Reaction Turns purple to black with nitrous acid and 1-nitroso-2-naphthol
Normal Excretion Levels 2 to 8 mg/day; >25 mg/24 h indicates possible tumors

Specimen Collection Can use random or first morning urine; 24-hour samples must be preserved

False Negatives Variability due to concentration and diurnal changes

Dietary Restrictions Avoid foods high in serotonin before collection (e.g., bananas, pineapples, tomatoes)
Medication Interference Certain medications should be withheld for 72 hours before testing

Cystine Disorders - It is now known that although both disorders are inherited, one is a defect in the renal tubular transport of amino acids
(cystinuria) and the other is an IEM (cystinosis). A noticeable odor of sulfur may be present in the urine of people with cystine metabolism
disorders.

CYSTINURIA
Definition Marked by high cystine levels in urine.
Cystinuria is due to renal tubules' inability to reabsorb cystine, rather than a metabolic defect.
Affected Amino Acids Cystine, lysine, arginine, and ornithine are not reabsorbed, leading to their increased presence in urine.
Inheritance Patterns Type 1 affects all four amino acids
Type 2 affects only cystine and lysine.
Clinical Manifestation Around 65% of individuals with complete amino acid impairment develop cystine calculi early in life.
Laboratory Diagnosis Cystine crystal observation in urine sediment; cyanide-nitroprusside test turns red-purple if excess cystine is
present.

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AMINO ACID DISORDERS

CYSTINOSIS
Definition and Types Cystinosis is an inborn error of metabolism (IEM) with nephropathic (infantile and late-onset) and non-
nephropathic types.
Pathophysiology Lysosomal membrane defect prevents cystine metabolism, leading to cystine crystal deposits in multiple
organs.
Renal Impact Causes Fanconi syndrome due to cystine deposits in renal tubules, potentially leading to renal failure.
Clinical Manifestations Infantile nephropathic progresses rapidly to renal failure; late-onset is gradual; nonnephropathic is relatively
benign but may affect eyes
Treatment Managed with cystine-depleting medications and renal transplants to prevent buildup and extend life.
Laboratory Findings Polyuria, generalized aminoaciduria, positive Clinitest, and poor urine concentration ability.

HOMOCYSTINURIA
Definition and Types results from methionine metabolism defects, leading to elevated homocystine levels.
Clinical Manifestations Includes failure to thrive, cataracts, mental retardation, thromboembolic issues, and potential death.
Early Detection and Early detection through newborn screening can improve outcomes; dietary changes can alleviate
Management symptoms.
Laboratory Testing Initial screening via MS/MS; positive cyanide-nitroprusside test indicates elevated homocystine levels.
Testing Protocols Confirmatory silver-nitroprusside test required; fresh urine samples must be used for testing accuracy.

Porphyrin Disorders - Porphyrins are the intermediate compounds in the production of heme. three primary porphyrins (uroporphyrin,
coproporphyrin, and protoporphyrin) and the porphyrin precursors (α -aminolevulinic acid [ALA] and porphobilinogen). Disorders of
porphyrin metabolism are collectively termed porphyrias.

PORPHYRIN DISORDERS
Overview Porphyrins are intermediates in heme synthesis; blockages in synthesis cause accumulation and aid
diagnosis.
Solubility and Specimen ALA, porphobilinogen, and uroporphyrin are highly soluble and found in urine;
Types coproporphyrin in urine, protoporphyrin in blood or feces.
Porphyria Types and Inherited or acquired disorders; inherited from enzyme deficiencies, acquired from toxic exposures and
Causes diseases (e.g., lead poisoning, liver disease).
Diagnostic Indicators Red or "port wine" urine color after exposure to air; symptoms include neurological/psychiatric effects or
photosensitivity; congenital cases stain diapers.
Screening Tests Ehrlich Reaction: Detects ALA and porphobilinogen
Fluorescent Screening: Detects other porphyrins via UV light.
Specific Diagnostic Differentiation requires additional fecal and blood analyses to identify individual porphyrins.
Techniques

MUCOPOLYSACCHARIDE DISORDERS
Overview Mucopolysaccharides (glycosaminoglycans) are found in connective tissues; metabolic disorders cause
accumulation in lysosomes.
Types and Urinary Accumulated and excreted products include dermatan sulfate, keratan sulfate, and heparan sulfate;
Products enzyme deficiency diagnosis needed.
Notable Disorders Hurler Syndrome: Skeletal abnormalities, mental retardation, corneal deposits.
Hunter Syndrome: Similar to Hurler but sex-linked.
Sanfilippo Syndrome: Mental retardation only. Treatments involve bone marrow transplants or gene
therapy.
Screening Tests Acid-Albumin and CTAB Turbidity Tests: Detect mucopolysaccharides by white turbidity in urine.
Metachromatic Staining Spot Tests: Detect specific mucopolysaccharides.

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AMINO ACID DISORDERS

PURINE DISORDERS
Disease Name Lesch-Nyhan Disease
Cause Sex-linked recessive disorder; lack of enzyme hypoxanthine guanine phosphoribosyltransferase.
Symptoms Severe motor defects, mental retardation, self-destructive tendencies, gout, renal calculi.
Initial Signs Uric acid crystals resembling "orange sand" in infant diapers, typically appearing around 6-8 months of
age.
Laboratory Detection Observation of increased uric acid crystals in pediatric urine specimens.

CARBOHYDRATE DISORDERS
Condition Name Carbohydrate Disorders (Melituria)
Overview Increased urinary sugar, typically from inherited disorders.
Most types are benign, except for certain carbohydrate metabolism disorders.
Primary Detection Method Clinitest for reducing substances in pediatric urine specimens.
Main Concern Galactosuria (inability to metabolize galactose) leading to galactosemia with potential toxic effects.
Symptoms Infant failure to thrive, liver issues, cataracts, mental retardation.
Cause of Galactosuria Deficiencies in GALT (most severe), galactokinase, or UDP-galactose-4-epimerase enzymes.
Newborn Screening GALT enzyme measured in red blood cells as part of newborn protocol.
Other Forms of Melituria Lactosuria: Linked with pregnancy and lactation.
Fructosuria: Associated with parenteral feeding.
Pentosuria: Related to high fruit intake. Was one of Garrod’s original six IEMs
Additional Testing Chromatography for identifying specific non-glucose reducing substances.

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