A protein metabolism disorder where excess amino acids are present in the urine

Primary aminoaciduria

Secondary aminoaciduria

Primary aminoaciduria is due to the enzyme defect in the metabolism of aminoacids Eg. Phenylketonuria, Tyrosinemia

Secondary aminoaciduria is due to the defect in the amino acid transporter in the kidney and intestine Eg. Cystinuria, Hartnup disease

Major categories

Forms Amino acids involved

Acidic aminoacids

Acidic aminoaciduria

Glutamate, Aspartate

Basic amino acids and cystine

Cystinuria Cystine, lysine, arginine, ornithine

Lysinuric protein intolerance

Lysine, arginine, ornithine

Isolated cystinuria

Cystine

Lysinuria Lysine

Major categories

Forms Amino acids involved

Neutral amino acids

Hartnup disease Alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine

Blue diaper syndrome

Tryptophan

Iminoglycinuria Glycine, proline, hydroxyproline

Glycinuria Glycine

Methioninuria Methionine

Acidic aminoaciduria involves the transport of glutamate and aspartateIt results from a defect in the high-affinity sodium potassium– dependent glutamate transporterIt is a clinically benign disorder

Cystine actually is a neutral amino acid that shares a common carrier with the dibasic amino acids lysine, arginine, and ornithine.The transport of all four amino acids is disrupted in cystinuria

The rarer disorder, lysinuric protein intolerance, results from defects in the basolateral transport of dibasic amino acids but not cystine

Hartnup disease involves a neutral amino acid transport system in both the kidney and intestineBlue diaper syndrome involves a kidney-specific tryptophan transporter Methioninuria appears to involve a separate methionine transport system in the proximal tubuleIminoglycinuria and glycinuria are clinically benign disorders

Alanine

Children: 65 to 190

Adults: 160 to 690

Carnosine

Children: 34 to 220

Adults: 16 to 125

Hydroxyproline

Children: not measured

Adults: not measured

Alpha-aminoadipic acid

Children: 25 to 78

Adults: 0 to 165

Citrulline

Children: 0 to 13

Adults: 0 to 11

Isoleucine

Children: 3 to 15

Adults: 4 to 23

Arginine

Children: 10 to 25

Adults: 13 to 64

Cystine

Children: 11 to 53

Adults: 28 to 115

Leucine

Children: 9 to 23

Adults: 20 to 77

Asparagine

Children: 15 to 40

Adults: 34 to 100

Glutamic acid Children: 13 to 22

Adults: 27 to 105

Lysine

Children: 19 to 140

Adults: 32 to 290

Aspartic acid

Children: 10 to 26

Adults: 14 to 89

Glutamine

Children: 150 to 400

Adults: 300 to 1,040

Methionine Children: 7 to 20

Adults: 5 to 30

In micromoles per deciliter (micromol/dL)

Ornithine

Children: 3 to 16

Adults: 5 to 70

Proline

Children: not measured

Adults: not measured

Threonine

Children: 25 to 100

Adults: 80 to 320

Phenylalanine

Children: 20 to 61

Adults: 36 to 90

Serine

Children: 93 to 210

Adults: 200 to 695

Tyrosine

Children: 30 to 83

Adults: 38 to 145

Beta-alanine

Children: 0 to 42

Adults: 0 to 93

Glycine Children: 195 to 855

Adults: 750 to 2,400

1-methylhistidine Children: 41 to 300 Adults: 68 to 855

Beta-amino-isobutyric acid

Children: 25 to 96

Adults: 10 to 235

Histidine

Children: 46 to 725

Adults: 500 to 1,500

3-methylhistidine Children: 42 to 135 Adults: 64 to 320

Phosphoserine

Children: 16 to 34

Adults: 28 to 95

Taurine

Children: 62 to 970

Adults: 267 to 1,290

Valine

Children: 17 to 37

Adults: 19 to 74

Organic acidurias are a group of inheritable genetic metabolic disorders due to a defect in protein metabolism where an essential enzyme is absent or malfunctioningThis defect results in a build up of chemicals, in this case usually acids, on one side of the metabolic blockage and a deficiency of vital chemicals on the otherThis causes an over dosage of one chemical (often toxic) and the shortage of another which is essential to normal body functioning.

Characteristics of the conditions include general malaise, reluctance to feed, breathing problems, vomiting, hypotonia (floppiness) and/or spasticity

2-Methyl-3-Hydroxybutyrl CoA Dehydrogenase deficiency (MHBD)• 2-Methylbutyrl CoA Dehydrogenase deficiency (2-MBCD)• 3-Hydroxy-3-Methylglutaryl CoA Lyase deficiency (HMG)• 3-Methylcrotonyl CoA Carboxyl deficiency (3-MCC)• 3-Methylglutaconyl CoA Hydratase deficiency (3-MGA)• Glutaric Aciduria Type I (GA-1)• Isobutyryl CoA Dehydrogenase deficiency (ICBD)• Isovaleric Acidemia (IVA)• Malonic Aciduria (MA)• Methylmalonic Acidemia (MMA)• Mitochondrial Acetoacetyl CoA Thiolase – (3-Ketothiolase) (BKT)• Multiple CoA Carboxylase (MCD)• Propionic Acidemia (PA)

Selected Organic Acidurias and Associated Organic Acid ElevationsSelected Organic Acidurias and Associated Organic Acid Elevations

Organic AciduriaOrganic Aciduria Elevated Organic AcidElevated Organic Acid

Methylmalonic acidemiaMethylmalonic acidemia Methylmalonic acid, methylcitric acid,Methylmalonic acid, methylcitric acid,3-hydroxypropionic acid, propionylglycine,3-hydroxypropionic acid, propionylglycine,3-hydroxyvaleric acid3-hydroxyvaleric acid

Fatty oxidation defects (medium chain acyl-Fatty oxidation defects (medium chain acyl-CoA dehydrogenase deficiency [MCAD])CoA dehydrogenase deficiency [MCAD])

Adipic acid, suberic acid, sebacic acid, octanoic Adipic acid, suberic acid, sebacic acid, octanoic acid, suberylglycine, hexanoylglycine, acid, suberylglycine, hexanoylglycine, octenedioic acid, phenylpropionylglycine, octenedioic acid, phenylpropionylglycine, 5-hydroxyhexanoic acid5-hydroxyhexanoic acid

Propionic acidemiaPropionic acidemia Propionylglycine, methylcitric acid,Propionylglycine, methylcitric acid,3-hydroxypropionic acid, 3-hydroxyvaleric 3-hydroxypropionic acid, 3-hydroxyvaleric acidacid

Glutaric aciduria, type 1Glutaric aciduria, type 1 Glutaric acid, glutaconic acid, 3-hydroxyglutaric Glutaric acid, glutaconic acid, 3-hydroxyglutaric acidacid

Multiple acyl-CoA dehydrogenase Multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria, type II)deficiency (glutaric aciduria, type II)

Glutaric acid, adipic acid, suberic acid,Glutaric acid, adipic acid, suberic acid,2-hydroxyglutaric acid, ethylmalonic acid, 2-hydroxyglutaric acid, ethylmalonic acid, isovalerylglycineisovalerylglycine

Isovaleric acidemiaIsovaleric acidemia Isovalerylglycine, 3-hydroxyisovaleric acidIsovalerylglycine, 3-hydroxyisovaleric acid

Multiple carboxylase deficiencyMultiple carboxylase deficiency 3-Methylcrotonylglycine, methylcitric acid, 3-Methylcrotonylglycine, methylcitric acid, lacticlacticacid, 3-hydroxyisovaleric acid, tiglylglycine,acid, 3-hydroxyisovaleric acid, tiglylglycine,3-hydroxypropionic acid3-hydroxypropionic acid

Urea cycle defectsUrea cycle defects Orotic acidOrotic acid

Maple syrup urine disease (MSUD)Maple syrup urine disease (MSUD) 2-Oxoisocaproic acid, 2-hydroxyisocaproic 2-Oxoisocaproic acid, 2-hydroxyisocaproic acid,acid,2-hydroxyisovaleric acid, 2-oxoisovaleric 2-hydroxyisovaleric acid, 2-oxoisovaleric acid,acid,2-hydroxy-3-methylvaleric acid,2-hydroxy-3-methylvaleric acid,2-oxo-3-methylvaleric acid2-oxo-3-methylvaleric acid

Lactic acidosisLactic acidosis Lactic acid, pyruvic acid, 2-hydroxybutyric acid,Lactic acid, pyruvic acid, 2-hydroxybutyric acid,4-hydroxyphenyllactic acid4-hydroxyphenyllactic acid

TyrosinemiaTyrosinemia 4-Hydroxyphenyllactic acid, 4-4-Hydroxyphenyllactic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenylpyruvic acid, N-hydroxyphenylpyruvic acid, N-acetyltyrosine, succinylacetone (type I only)acetyltyrosine, succinylacetone (type I only)

Canavan diseaseCanavan disease N-acetylaspartic acidN-acetylaspartic acid

KetosisKetosis Acetoacetic acid, 3-hydroxybutyric acid, adipic Acetoacetic acid, 3-hydroxybutyric acid, adipic acid, suberic acid, 3-hydroxyisobutyric acid, suberic acid, 3-hydroxyisobutyric acid,acid,3-hydroxyisovaleric acid, 3-hydroxy-2-3-hydroxyisovaleric acid, 3-hydroxy-2-methylbutyric acidmethylbutyric acid

Phenylketonuria (PKU)Phenylketonuria (PKU) Phenyllactic acid, phenylpyruvic acid,Phenyllactic acid, phenylpyruvic acid,2-hydroxyphenylacetic acid2-hydroxyphenylacetic acid

2-Oxoadipic aciduria2-Oxoadipic aciduria 2-Oxoadipic acid, 2-hydroxyadipic acid2-Oxoadipic acid, 2-hydroxyadipic acid

3-Hydroxy-3-methylglutaric aciduria 3-Hydroxy-3-methylglutaric acid, 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-methylglutaconicacid, 3-methylglutaric acid

3-Methylcrotonyl-CoA carboxylase deficiency

3-Hydroxyisovaleric acid, 3-methylcrotonylglycine

3-Methylglutaconic aciduria 3-Methylglutaconic acid, 3-hydroxyisovaleric acid,3-methylglutaric acid

3-Oxothiolase deficiency 3-Hydroxy-2-methylbutyric acid, tiglylglycine,

2-methylacetoacetic acid, acetoacetic acid,

3-hydroxybutyric acid

5-Oxoprolinuria 5-Oxoproline

Dihydrolipoyl dehydrogenase deficiency (lipoamide dehydrogenase, E3)

Lactic acid, 2-hydroxyisocaproic acid,2-hydroxyisovaleric acid, 2-hydroxy-3-methylvaleric acid, 2-oxoglutaric acid, 2-oxoisocaproic acid,2-oxoisovaleric acid, 2-oxo-3-methylvaleric acid

 

Tandem MS Spectrophotometry Ascending and descending chromatography on

paper, Thin-layer chromatography (TLC) (Ortho Dianisidine stain for organic acids and

Ninhydrin stain for Aminoacids ) High voltage electrophoresis (HVE) on paper Colorimetric methods Gas chromatography (GC) HPLC Enzyme assays

PorphyriasPorphyrias

IntroductionIntroduction

The porphyrias are caused by deficiencies The porphyrias are caused by deficiencies of enzymes involved in heme biosynthesis of enzymes involved in heme biosynthesis which lead to blockade of the porphyrin which lead to blockade of the porphyrin pathway and subsequent accumulation of pathway and subsequent accumulation of porphyrins and their precursors.porphyrins and their precursors.

Classification of porphyriasClassification of porphyrias

Cutaneous features are not seen in acute Cutaneous features are not seen in acute intermittent porphyria (AIP) or the very rare intermittent porphyria (AIP) or the very rare aminolevulinic acid dehydratase (ALA-D) aminolevulinic acid dehydratase (ALA-D) deficient porphyria. deficient porphyria.

Erythropoietic protoporphyria and congenital Erythropoietic protoporphyria and congenital erythropoietic porphyria are characterized erythropoietic porphyria are characterized by porphyrins produced mainly in the bone by porphyrins produced mainly in the bone marrow. The reminder are primarily marrow. The reminder are primarily hepatic porhyrias. hepatic porhyrias.

Excessive concentrations of porhyrins Excessive concentrations of porhyrins exposed to day-light generate free exposed to day-light generate free radicals, leading to cell membrane radicals, leading to cell membrane damage and cell death. damage and cell death.

The type of cellular damage depends on The type of cellular damage depends on the solubility and tissue distribution of the the solubility and tissue distribution of the porphyrins. Two main patterns of skin porphyrins. Two main patterns of skin damage are seen in the porphyries:damage are seen in the porphyries:

1.1. accumulation of water soluble uro- and accumulation of water soluble uro- and coproporphyrins leads to blistering.coproporphyrins leads to blistering.

2.2. accumulation of the lipophilic protoporphyrins accumulation of the lipophilic protoporphyrins leads to burning sensations in the exposed leads to burning sensations in the exposed skin. skin.

InvestigationInvestigation