Metabolic Disorders in New Born Screening (Midterm Topic)

• 31 core conditions

• 25 secondary target conditions

• Procedure: tandem mass spectrophotometry

(MS/MS)

• Capable of screening infant blood specimens

for specific substances

- Congenital hypothyroidism (CH)

- Congenital adrenal hyperplasia (CAH)

- Phenylketonuria (PKU)

- Glucose-6- phosphate dehydrogenase (G6PD)

deficiency

- Galactosemia (GAL)

- Maple syrup urine disease (MSUD)

Newborn Screening Tests Summary

tandem mass spectrophotometry

(MS/MS)

What is the spectrophotometry procedure for newborn screening?

• 31 core conditions

• 25 secondary target conditions

• Procedure: tandem mass spectrophotometry

(MS/MS)

• Capable of screening infant blood specimens

for specific substances

- Congenital hypothyroidism (CH)

- Congenital adrenal hyperplasia (CAH)

- Phenylketonuria (PKU)

- Glucose-6- phosphate dehydrogenase (G6PD)

deficiency

- Galactosemia (GAL)

- Maple syrup urine disease (MSUD)

Newborn Screening Tests Summary

tandem mass spectrophotometry

(MS/MS)

What is the spectrophotometry procedure for newborn screening?

31 conditions

How many core conditions in NBS?

25 secondary target conditions

How many secondary target conditions?

disruption of normal metabolic PW

What is the cause of Overflow type?

Override the reabsorption ability of renal tubules

• Not reabsorbed from the filtrate

• Nonmetabolized substances in overflow type?

malfunctions in the tubular reabsorption mechanism

Cause of renal disorder?

Failure to inherit gene-producing enzymes

Cause of Inborn error of metabolism?

-Phenylketonuria

-Tyrosinemia

-Alkaptonuria

-Maple syrup urine disease

-Organic acidemias

-Cystinosis

-Porphyria

-Mucopolysaccharidoses

-Galctosemia

-Lesch - Nyhan disease

What are the Overflow inherited disorders? (examples)

-Infantile tyrosinemia

-Melanuria

-Indicanuria

-5-Hydroxyindoleacetic acid

-Porphyria

What are the metabolic disorders? (examples)

Hartnup disease

Cystinuria

What are the renal disorders? (examples)

Phenylalanine and tyrosine metabolic pathway

Tyrosyluria

What disorder?

Accumulation of excess tyrosine in the plasma (tyrosinemia)

• Inherited or metabolic defects

p-hydroxyphenylpyruvic acid

• p-hydroxyphenyllactic acid

Degradation products of tyrosine

Transitory tyosinemia

Most frequently seen in premature infants

• Underdevelopment of liver function

Acquired severe liver disease

Produces tyrosyluria

• Urinary crystals: Leucine and Tyrosine

Leucine and Tyrosine

Urinary crystals in acquired severe liver disease?

Nitroso-naphthol test

Test for tyrosyluria?

5 - Hydroxyindoleacetic Acid (5 - HIAA)

Degradation product of serotonin

• Used in the stimulation of muscles

•From tryptophan by the argentaffin cells

Elevated urinary 5 - HIAA

what is the cause of Carcinoid tumors (argentaffin cells)?

2-8 mg

Normal daily excretion of urinary 5 - HIAA?

> 25mg/24 h

Argentaffin cell tumor what amount?

Silver nitroprusside test

testing for tryptophan disorder?

HPLC and Fluorescence detection

plasma method for tryptophan testing?

Phenylketonuria (PKU)

Most well-known of the aminoacidurias

• 1 of every 10,000 to 20,000 births

Norway, 1924

Ivan Folling identified PKU in (country, year?)

mousy odor

Urine odor of PKU?

Failure to inherit the gene producing phenylalanine hydroxylase

cause of PKU?

• Blood: increased levels of phenylalanine

• Excretion of urinary pheny|pyruvic acid: 2 to 6 weeks

• Can be detected as early as 4 hours after birth

• Testing: 24 to 48 hours after birth

screening of PKU?

Test: Ferric chloride tube test

testing for PKU?

Maple Syrup Urine Disease (MSUD)

Accumulation of one or more early A degradation products

• Inborn error of metabolism

Leucine/Isoleucine/Valine

Amino acid disorder in MSUD?

a -ketoisovaleric

a-ketoisocaproic

a -keto-B-methylvaleric

keto acids in MSUD?

maple syrup

odor of MSUD?

2, 4 - DNPH Test for MSUD

• Plasma AA (PAA)

test for MSUD?

Alkaptonuria

1 of the 6 original IEM (Garrod in 1902)

"alkali lover"

3rd major defect in the phenylalanine-tyrosine PW

Brown-stained/black-stained cloth diapers/reddish-

stained disposable diapers

failure to inherit the gene-producing

homogentisic acid oxidase

cause of alkaptonuria?

accumulates in the blood,

tissues, and urine

homogentisic acid accumulates where?

• Ferric chloride

• Clinitest

GC-MS

Homogentisic acid test

testing for alkaptunoria?

Alkaptonuria

Melanuria

Melanuria

2nd metabolic PW for tyrosine

• Melanin

• Thyroxine

• Epinephrine

• Protein

• Tyrosine sulfate

• Dark urine

• Proliferation of melanocytes

• Malignant melanoma

• 5, 6 - dihydroxyindole

Increased melanin in urine causes the following?

indicanuria

indicanuria

Increased amounts of tryptophan what disease?

Indole:

reabsorbed and circulated becomes indican?

indicanuria

colorless to indigo blue, what disease?

Hartnup disease

Blue diaper syndrome

• Affects the following:

• Intestinal reabsorption of tryptophan

• Renal tubular absorption of other amino

acids (generalized aminoaciduria)

isovaleric acidemia

propionic acidemia and methylmalonic acidemia

organic acidemias?

Isovaleric acidemia

Urine odor: sweaty feet

• Accumulation of isovalerylglycine: deficiency in isovaleryl coenzyme A

• Propionic acidemia and Methylmalonic acidemia

Errors in the metabolic PW converting the following to succinyl COA

• Isoleucine

• Valine

• Threonine

• Methionine

Propionic acid

the immediate precursor to methylmalonic acid

3 types of phenylalanine-tyrosine disorders

Hurler syndrome

Effect: Abnormal skeletal structure

Intellectual disability

Affects cornea

notes: fatal during childhood

what disease? (syndrome)

Acid-albumin turbidity test

• CAB turbidity test

• Metachromatic staining spot test

tests for mucopolysaccharide disorders?

porphyrin disorders

porphyrias

Inherited or acquired

• Porphyrinuria: red or port wine urine color

Ehrlich reaction

• Fluorescent technique

tests for porphyrin disorders?

hunter syndrome

cause: Abnormal skeletal structure

Intellectual disability

notes: Sex-linked recessive

Rarely seen in females

Fatal during childhood*

what disease?

sanfilippo syndrome

effects: Intellectual disability

notes: Tx: Bone marrow transplant**

Gene replacement therapy**

what disease?

- Defect in methionine metabolism

-Test for homocysteine is included in the NBS program.

Homocystinuria Cause:

Homocystinuria

Effects:

- Failure to thrive

- Cataracts

- Intellectual disability

- Thromboembolic problems

- Stroke

- Death

Increased urinary homocysteine

• (+) Cyanide - nitroprusside test

Additional test: Silver-nitroprusside

Only homocysteine will react, what additional test?

Cystinuria

Elevated amounts of cystine in the urine.

• Cause: the inability of the renal tubules to reabsorb cystine filtered by the

glomerulus.

• Amino acids: Cystine/Lysine/Arginine/Ornithine

Modes of inheritance:

• Reabsorption of all four amino acids is affected.

• Reabsorption of cystine and lysine is affected.

• Test: Cyanide

- Nitroprusside Test

types of cystinuria

Cystinosis

Genuine inborn error of metabolism

• Cause: defect in the lysosomal membranes

• PCT: affected by the cystine deposits

• Nephropathic cystinosis

• Infantile

• Late-onset

• Intermediate cystinosis

• Nonnephropathic cystinosis

• Types of Cystinosis:

Molecular testing

• Test for Cystinosis

porphyrin disorder table

Porphyrin

intermediate compounds in the

production of heme.

Uroporphyrins

Coproporphyrins

Protoporphyrins

Three primary porphyrins:

Alpha-aminolevulinic acid (ALA)

• Porphobilinogen

Porphyrin precursors:

Blood

Bile

Feces

Urine

Specimens: for porphyrin

Mucopolysaccharides/Glycosaminoglycans(GAGs)

• Large compounds in the connective tissues

• Protein core with polysaccharide branches

• Products found in the urine:

• Dermatan sulfate

• Keratan sulfate

• Heparan sulfate

• Hurler syndrome

• Hunter syndrome

• Sanfilippo syndrome

• Mucopolysaccharidoses (MPSs) what syndromes?