Metabolic Disorders and Semen Analysis

What are the two main categories of disorders that cause abnormal substances in urine?

overflow disorders and renal disorders.

What causes overflow disorders?

by disruptions in metabolic pathways, leading to increased plasma levels of substances that the kidneys cannot reabsorb or only absorb in small amounts.

How do renal disorders differ from overflow disorders?

They occur when the kidneys malfunction in reabsorbing substances, leading to abnormal substances in the urine, while overflow disorders involve excess substances in the blood that overwhelm the kidneys' ability to reabsorb them.

What types of metabolic disturbances commonly lead to abnormal urine substances?

1. Proteins

2. Fats

3. Carbohydrates

How many tests do the state mandate for Newborn screening for Inborn Errors of metabolism

31 core conditions and 25 secondary target conditions

Why is newborn screening important for IEMs?

because it helps detect IEMs early, preventing the buildup of harmful substances that could cause serious health problems, such as developmental delays and intellectual disabilities.

How are IEMs detected in newborns?

through blood tests, often using tandem mass spectrometry (MS/MS)

What are amino acid disorders?

involve abnormalities in the metabolism of amino acids. Conditions like phenylketonuria, tyrosyluria, and maple syrup urine disease

What can cause the disruption of enzyme function?

either failure to inherit the gene for a specific enzyme or by organ malfunction due to disease or toxic reactions.

What is an inborn error of metabolism (IEM)?

condition where a person fails to inherit the gene needed to produce a specific enzyme, leading to enzyme dysfunction.

What is phenylketonuria (PKU)?

an inherited disorder where the body cannot break down phenylalanine, an amino acid, due to a deficiency in the enzyme phenylalanine hydroxylase. This leads to the accumulation of phenylalanine, causing intellectual disability if untreated.

How is Phenylketonuria diagnosed?

through a blood test taken from newborns, typically 24 to 48 hours after birth. The test measures levels of phenylalanine, which if elevated, indicate PKU.

What treatment is available for PKU?

by eliminating phenylalanine from the diet, which is mainly found in protein-rich foods like milk. Special formula and foods low in phenylalanine are used to manage the condition.

What are the symptoms of PKU if not treated?

1. Intellectual disability

2. Seizures

3. Developmental delays

4. Psychiatric disturbances

5. Lighter skin and hair color

What is tyrosyluria?

a condition where there is an excess of tyrosine in the urine, which may result from various causes, including enzyme deficiencies in the metabolic pathway of tyrosine.

What causes tyrosyluria?

1. Premature birth

2. Liver disease

3. Inherited genetic defects

What is the significance of tyrosinemia?

the excess accumulation of tyrosine in the blood, often leading to the condition tyrosyluria, which can cause serious liver and kidney issues if untreated.

What is melanuria?

The presence of melanin in the urine, which can darken the urine. It is associated with malignant melanoma, a type of skin cancer.

How is melanuria detected?

when the urine darkens after exposure to air, indicating the presence of melanin, which is often produced in excess by melanoma tumors.

What is alkaptonuria?

a metabolic disorder where homogentisic acid accumulates in the body due to a deficiency of the enzyme homogentisic acid oxidase. This condition leads to darkening of the urine and the deposition of dark pigment in tissues, particularly in the cartilage.

What are the symptoms of alkaptonuria?

1. Dark urine

2. Joint pain

3. Deposition of dark pigment in tissue

4. Arthritis

5. Potential liver and heart issues

How is alkaptonuria diagnosed?

by observing the darkening of urine after it is exposed to air or using specific tests like the ferric chloride test, which produces a blue color in the presence of homogentisic acid.

What is the treatment for alkaptonuria?

1. Vitamin C

2. Pain management

3. Surgery

What is maple syrup urine disease (MSUD)?

a disorder where the body cannot break down certain amino acids (leucine, isoleucine, and valine) due to an enzyme deficiency, leading to a buildup of these amino acids in the blood and urine, which can cause severe brain damage if untreated.

What enzymes can the body not break down in maple syrups disease

1. Leucine

2. Isoleucine

3. Valine

What is the significance of ketonuria in newborns with MSUD?

can be a sign of MSUD, as these babies often cannot metabolize certain amino acids properly, leading to the accumulation of ketones.

What are organic acidemias?

are a group of metabolic disorders where the breakdown of amino acids or fatty acids produces toxic organic acids, leading to various health issues.

What symptoms might a child with PKU have?

1. Mousy odor in urine and sweat

2. Fair skin

3. Lighter hair and eyes

4. seizures

5. Hyperactivity

6. Developmental delay

7. Psychiatric disturbances

How is Phenylketonuria inherited?

as an autosomal recessive trait, meaning a child must inherit two defective genes (one from each parent) to develop the disorder. Carriers (heterozygous individuals) do not show symptoms.

What foods contain phenylalanine?

1. Milk

2. Aspartame

3. Diet sodas

4. Meds

5. Diet foods

How does the ferric chloride test work for PKU?

the addition of ferric chloride to urine containing phenylpyruvic acid causes a permanent blue-green color change, indicating the presence of phenylpyruvic acid.

What does the Guthrie blood test detect?

detects inborn errors of metabolism (IEM) by using bacterial inhibition.

What is used in the Guthrie test to inhibit Bacillus subtilis?

Media containing beta-2-thienylalanine

What happens when phenylalanine is present in the Guthrie test?

Phenylalanine counteracts the beta-2-thienylalanine inhibitor, allowing Bacillus subtilis to grow around the blood disc.

What substances may be found in the urine in Tyrosyluria?

1. tyrosine

2. p-hydroxyphenylpyruvic acid

3. p-hydroxyphenyllactic acid

What is Type 3 Tyrosinemia?

a deficiency of the enzyme p-hydroxyphenylpyruvic acid dioxygenase, which can lead to intellectual disability, seizures, and ataxia if not managed with dietary restrictions.

How is Type 3 Tyrosinemia diagnosed?

1. elevated levels of plasma tyrosine

2. 4-hydroxyphenylpyruvic acid

3. 4-hydroxyphenyllactic acid

4. 4-hydroxyphenylacetic acid

What genetic test is used to diagnose Type 3 Tyrosinemia?

testing for mutations in the gene responsible for the enzyme p-hydroxyphenylpyruvic acid dioxygenase.

What is the qualitative urine screening test for Tyrosyluria?

using nitroso-naphthol, which detects excess tyrosine and its metabolites in the urine.

What is Type 1 tyrosinemia?

a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). It leads to a generalized renal tubular disorder and progressive liver failure in infants shortly after birth.

How is Type 1 tyrosinemia diagnosed?

by detecting tyrosine and succinylacetone in the urine and blood.

What is Type 2 tyrosinemia?

a lack of the enzyme tyrosine aminotransferase. It results in corneal erosions and lesions on the palms, fingers, and soles of the feet, due to crystallization of tyrosine in the cells.

How is Type 2 tyrosinemia diagnosed?

by testing for the lack of tyrosine aminotransferase and identifying the presence of symptoms like corneal erosions and skin lesions.

What does melanin do in the body?

the pigment responsible for the color of hair, skin, and eyes. It helps protect the skin from UV radiation.

What happens when there is deficient production of melanin?

albinism, a condition where a person has little to no pigmentation in their skin, hair, and eyes.

Why is increased urinary melanin a concern?

indicates the proliferation of melanin-producing cells (melanocytes), often caused by malignant melanoma, a type of skin cancer.

How does malignant melanoma affect melanin production?

causes melanocytes to produce a colorless melanin precursor called 5,6-dihydroxyindole, which then oxidizes into melanogen and melanin, darkening the urine.

When do symptoms of alkaptonuria typically appear?

Symptoms of alkaptonuria do not usually appear in early childhood, but brown or black stains in cloth diapers or reddish stains in disposable diapers may be observed in infants.

What are some common signs of alkaptonuria in later life?

patients may develop ochronosis, which is the deposition of dark pigment in connective tissues, leading to joint problems like arthritis. Liver and cardiac disorders are also common.

How is alkaptonuria diagnosed?

by testing for the presence of homogentisic acid in the urine, which can be done through the ferric chloride test or gas chromatography-mass spectrometry (GC-MS).

What is the Clinitest used for in alkaptonuria diagnosis?

detects a reducing substance in the urine, which forms a yellow precipitate when homogentisic acid is present.

What effect does adding alkali to urine have in diagnosing alkaptonuria?

can cause it to darken, indicating the presence of homogentisic acid, although high levels of ascorbic acid can interfere with this reaction.

What is the result of the Ferric chloride test for melanuria?

The Ferric chloride test produces a gray or black precipitate if melanin is present.

What color indicates a positive result in the Sodium nitroprusside (Acetest) test for melanuria?

red color

What interferences should be considered when performing melanuria testing?

Acetone and creatinine

How can melanuria be differentiated from homogentisic acid?

Both melanin and homogentisic acid can turn urine dark, but homogentisic acid will turn the urine dark after becoming alkaline, while melanin causes the urine to darken upon exposure to oxygen.

How is MSUD inherited?

an autosomal recessive trait, meaning both parents must carry the defective gene for a child to develop the disease.

What are the common symptoms of MSUD in newborns?

1. Failure to thrive

2. Poor feeding

3. Vomiting

4. Lethargy

How might MSUD be detected in a newborn?

if the urine has a strong odor resembling maple syrup, which is due to the accumulation of keto acids.

How important is early detection of MSUD?

because if detected by the 11th day, dietary regulation and monitoring of urinary keto acid levels can prevent severe intellectual disability and death.

What test is used to screen for MSUD?

The 2,4-dinitrophenylhydrazine (DNPH) urine screening test

What plasma tests are used to diagnose MSUD?

Plasma amino acid (PAA) testing is used to detect elevated levels of branched-chain amino acids (BCAAs) and alloisoleucine.

What is the most specific and sensitive marker for MSUD?

A plasma alloisoleucine level greater than 5 µmol/L

What is the primary treatment for MSUD?

the dietary restriction of foods containing branched-chain amino acids (BCAAs).

What does the black color in the homogentisic acid test indicate?

indicates the presence of homogentisic acid, which is linked to certain metabolic disorders.

What are the generalized symptoms of organic acidemias?

1. Severe illness

2. Vomiting

3. Metabolic acidosis

4. Hypoglycemia

5. Ketonuria

6. Increased serum ammonia

What are the three most common types of organic acidemias?

1. Isovaleric acidemia

2. Propionic Acidemia

3. Methylmalonic acidemia

What is a key identifying characteristic of isovaleric acidemia?

a characteristic odor of “sweaty feet” in urine specimens or the patient.

What causes the "sweaty feet" odor in isovaleric acidemia?

the accumulation of isovalerylglycine due to a deficiency of isovaleryl coenzyme A in the leucine metabolic pathway.

What are the two main tryptophan metabolites involved in urinalysis?

indican and 5-hydroxyindoleacetic acid (5-HIAA).

What happens to tryptophan under normal conditions in the intestine?

either reabsorbed for protein production or converted to indole by intestinal bacteria and excreted in feces.

What causes increased conversion of tryptophan to indole?

1. Obstruction

2. Abnormal bacteria

3. Malabsorption syndromes

4. Hartnup disease

What is indicanuria?

a condition where excess indole is absorbed into the bloodstream, converted to indican in the liver, and excreted in urine.

How is indican in the urine detected?

is colorless in urine but turns blue upon exposure to air due to oxidation, forming the dye indigo blue.

What is the "blue diaper syndrome"?

In Hartnup disease, indican in the urine oxidizes, staining infants’ diapers blue, helping in early diagnosis.

How is urinary indican returned to normal levels in most cases?

Treating the underlying intestinal disorder usually normalizes urinary indican levels, except in Hartnup disease.

What happens in Hartnup disease besides increased indican excretion?

defective reabsorption of tryptophan and other amino acids in the intestine and renal tubules, causing generalized aminoaciduria. (Fanconi Syndrome)

What is the treatment for Hartnup disease?

Proper dietary supplements, including niacin

What is serotonin, and where is it produced?

a substance that stimulates smooth muscles. It is produced from tryptophan by argentaffin cells in the intestine

What happens to serotonin in the body under normal conditions?

Most serotonin is used by the body, and only small amounts of its degradation product, 5-HIAA, are excreted in the urine.

What are carcinoid tumors, and how do they affect serotonin production?

involve argentaffin cells and cause excessive serotonin production, leading to high levels of urinary 5-HIAA.

How is 5-HIAA detected in the urine?

Adding nitrous acid and 1-nitroso-2-naphthol to urine containing 5-HIAA turns the urine purple to black, depending on the 5-HIAA amount.

What types of urine specimens are used for 5-HIAA testing?

1. Random

2. First morning

3. 24 hour

What food restrictions must be followed before 5-HIAA testing?

1. Avocados

2. Bananas

3. Tomatoes

What is the dietary restriction timeline for 5-HIAA testing?

Patients must avoid serotonin-rich foods for 3 days before and during the urine collection period.

What are the two cystine metabolism disorders?

cystinuria and cystinosis.

What is Cystinuria

a defect in the renal tubular transport of amino acids.

What is Cystinosis

an inborn error of metabolism (IEM) involving cystine storage in cells.

What is the main cause of confusion between the two disorders?

Both disorders involve renal manifestations, including cystine in urine and renal calculi.

Why is cystine significant in these disorders?

much less soluble than other amino acids, and its presence leads to crystals and calculi formation.

How is urinary cystine detected in the laboratory?

• Observing cystine crystals in sediment.

• Using the cyanide–nitroprusside test, which produces a red-purple color if cystine is present.

What can cause false positives in the cyanide–nitroprusside test?

the presence of ketones or homocysteine.

What test is used to confirm elevated cystine levels after a positive cyanide–nitroprusside test?

Quantitative analysis using ion-exchange chromatography of a 24-hour urine specimen.

What causes cystinuria?

Cystinuria is caused by the inability of renal tubules to reabsorb cystine, leading to its accumulation in urine.

Which amino acids are affected in cystinuria?

1. Cystine

2. Lysine

3. Arginine

4. Ornitine

What are the forms of Cystinosis

• Severe infantile nephropathic form.

• Milder late-onset nephropathic form.

• Benign nonnephropathic form.

What causes cystinosis?

A defect in the lysosomal membranes prevents cystine release into the cytoplasm, leading to deposits in tissues.

Which tissues are affected in cystinosis?

1. Cornea

2. Bone marrow

3. Lymph Nodes

4. Internal Organs

5. Renal tubules

How does cystinosis affect the kidneys?

• Cystine deposits damage the renal tubular reabsorption mechanism, leading to Fanconi syndrome.

• Progression leads to renal failure if untreated.

What treatments extend life in cystinosis?

Renal transplants and cystine-depleting medications reduce cystine buildup and improve outcomes.