Metabolic disorders

Question 1

Introduction to metabolic disorders

Answer 1

Inherited genetic mutations can result in disruption of some metabolic pathways
The biochemical abnormalities can be detectable before symptoms underscoring the
importance of newborn screening
Blood is collected from newborn before leaving the hospital. Samples are submitted to the
state public health department for testing and data compilation. The National Newborn
Screening and Genetics Resource Center is a national repository for results and more
information on disorders.
Most newborn screening tests use mass spectroscopy, but genetic tests continue to be
developed.

Question 2

Cystinuria

Defective what

and what builds up and forms what

Answer 2

Defective carrier protein for reabsorption of cysteine (and
other amino acids) so they are not reabsorbed from tubules.

Amino acids build up in urine and can form renal calculi.
Cystine crystals seen in urine.

Question 3

Cystinuria defective proteins

Answer 3

Cysteine, Ornithine, Lysine, and Arginine

Question 4

Cystinosis

A blank what because

Answer 4

A lysosomal storage disease because can’t transport cystine and other
amino acids across lysosomal membranes – results in accumulation in
kidneys, eye, bone marrow, liver, spleen, and macrophages

Question 5

Cystinosis

Most common- type

other types

Answer 5

Most common: Nephropathic cystinosis - Renal tubules are affected by
crystalized deposits causing Fanconi syndrome (aminoaciduria and
isothenuria)
Infantile: rapid progression to renal failure
Late-onset: gradual progression to renal failure and ocular impairment

Question 6

Non-nephropathic cystinosis

Answer 6

Non-nephropathic: benign, some ocular problems

Question 7

Laboratory diagnosis of Cystinosis

Treatment

Answer 7

Laboratory: aminoaciduria, glucosuria, proteinuria, cystine crystals, low
specific gravity,
No renal calculi seen.
May require kidney transplant.

Question 8

Phenylketonuria PKU

Inborn error of metabolism causing what

Answer 8

Inborn error of metabolism: deficient in the enzyme phenylalanine dehydroxylase. This
the enzyme is needed to convert phenylalanine to tyrosine

Question 9

Phenylketonuria symptoms

testing

treatment

Answer 9

Symptoms: Damage to child’s mental capacity, mousy odor, lighter skin pigmentation
Testing: tandem mass spectrophotometry, MS/MS
Treatment: Eliminate phenylalanine from diet (milk) Avoid ↑ phenylalanine foods (aspartame)

Question 10

Phenylalanine causes a buildup of

Answer 10

Glutamic acid

Question 11

Tyrosinemia defect

Answer 11

Defect in enzymes needed for tyrosine metabolism. Three types depending on enzyme
involved

Question 12

Tyrosinemia an error of

Answer 12

an error of metabolism, in which the body cannot effectively break down the amino acid
tyrosine

Question 13

Tyrosinemia results in

Answer 13

Results in accumulation of tyrosine in kidney and liver. Very toxic

Question 14

Tyrosimemia detected by

Testing

Treatment

Answer 14

Detected by newborn screening before symptoms appear.
Testing: detect tyrosine in urine, plasma, or CSF. Possible tyrosine crystals in urine.
Treatment: low protein diet and nitisinone, possible liver transplant

Question 15

Melanuria

Answer 15

Melanin is produced from tyrosine by melanocytes and is the pigment responsible
for the color of hair, skin, and eyes.
When inherited defects result in defective melanin production, hypomelanosis or
albinism results
Overproduction of melanin indicates malignant neoplasms of melanocytes (some
melanomas). Urine will darken upon exposure to air.

Question 16

Alkaptonuria

Answer 16

Alkaptonuria is a rare disease characterized by the
excretion of homogentisic acid (HGA) in the urine. It is
due to the congenital lack of the enzyme homogentisic
acid oxidase, which mediates an essential step in the
catabolism of phenylalanine and tyrosine
Results in accumulation of HGA in urine and tissues.
Develop arthritis of the spine and joints at age 30 – 40
Urine is brown

Question 17

Maple syrup urine disease

Lack the enzymes that break down what

symptoms

Therapy

Answer 17

Lack the enzyme to break down branched chain amino acids (valine, leucine, isoleucine)
Symptoms: Soon after birth, urine smells like maple syrup, spasms, developmental delay,
seizures, coma, respiratory failure as disease progresses.
◦ Depends on type of MSUD
Therapy: reduce toxic metabolites by restricting dietary branched chain amino acids
(restricted protein intake with synthetic formulation supplements and administration of BCAA
depending on plasma level).
◦ Liver transplant

Question 18

Galactosemia

Answer 18

Galactosemia (a high blood level of galactose) is a carbohydrate metabolism disorder that is
caused by a lack of one of the enzymes necessary for metabolizing galactose. A toxic
metabolite builds up in liver, kidney and eyes and kidneys causing cirrhosis, kidney failure,
cataracts.
Even with adequate treatment, affected children still develop mental and physical problems.
Symptoms: vomiting, jaundice, diarrhea, and abnormal growth. Depends on type.
Treatment: involves completely eliminating galactose: no milk and milk products.

Question 19

Diabetes mellitus

Answer 19

Defects in insulin production or action. Results in chronic glucosuria and hyperglycemia
◦ Type I juvenile onset
◦ Type II adult onset (90 – 95% of cases): leading cause of blindness, ESRD and limb amputations
Symptoms: complications include retinopathy, neuropathy, nephropathy
Treatment: diet and exercise and sometimes insulin injections (type I). Other medications available.

Question 20

Diabetes insipidus

Answer 20

Diabetes insipidus is a rare condition that occurs when the kidneys are unable to conserve
water during the process of filtering blood.
Diabetes insipidus is caused by a lack of antidiuretic hormone (ADH) which prevents
dehydration, or the kidney’s inability to respond to ADH. ADH normally enables the kidneys
to retain water in the body.
Symptoms: Urine appears dilute and has a low specific gravity (unlike diabetes mellitus),
thirst, dehydration can be life-threatening.
Treatment: maintain hydration through water consumption, drugs that act like ADH

Question 21

Porphyrias

Answer 21

Porphyrins are heme precursors.
Variety of disorders, some of which are inherited (congenital erythropoietic porphyria) and
some are acquired (lead intoxication).
Symptoms: toxicity from build-up. Two major clinical manifestations occur:
◦ neurovisceral abnormalities (the acute porphyrias) abdominal distress and mental changes
◦ cutaneous photosensitivity (the cutaneous porphyrias).
Testing: urine will have a red or port wine color upon standing (photooxidation).
Test for porphyrin precursor α - aminolevulinic acid. If positive, can be further analyzed to
determine specific type of porphyria.

Question 22

Lesch-Nyhan

Answer 22

Purines are a group of molecules that are found naturally occurring in all living things and provide
the basic building blocks for DNA and RNA. A deficiency of the enzyme hypoxanthine guanine
phosphoribosyltransferase (HPRT) prevents the body from recycling purines causing the body to
produce more purines “from scratch” to keep up with its needs. Because the purines are not
recycled, the purine wastes are turned into uric acid.
Lesch–Nyhan disease is an inherited disorder of purine metabolism that results in excessive uric
acid in urine. When too much uric acid accumulates, it clumps together to form tiny crystals or
stones.
Symptoms: see orange sand or red brick dust in a diaper.
Later (if Lesch-Nyhan): mental
retardation, severe motor defects, gout, renal calculi, and a tendency toward self-destruction
No specific treatment.

Question 23

Lesch Nyhan symptoms

Answer 23

mental
retardation, severe motor defects, gout, renal calculi, and a tendency toward self-destruction

Question 24

Hartup syndrome

Answer 24

Lack of reabsorption of amino acids: Inherited disorder affects intestinal
reabsorption of indole and renal tubular reabsorption = Fanconi syndrome
Example: Newborns that cannot reabsorb tryptophan. Excess
tryptophan converted to indole in by intestinal bacteria. Some goes into
circulation and is converted to indican in the liver and excreted in the urine.
Indican oxidizes upon exposure to air and turns blue.
Testing: evaluate amino acids in urine using mass spectroscopy
Treatment:
if symptoms, maintain a high protein diet, niacin supplements