Inborn Errors Flashcards
Ethology of inborn error of
metabolism
Etiology : inherited or due to spontaneous
mutation.
INBORN ERRORS OF METABOLISM
Effects are due to:
1 - Toxic accumulations of substrates before the block,
2 = Intermediates from alternative metabolic pathways, and/or
3-• Defects in energy production and utilization caused
by a deficiency of|products beyond the block.
Phenylketonuria PKU
Are ?
Autosomal recessive
PHENYL-KETONURIA
It is due to a deficiency of the enzyme
phenylalanine hydroxylase.
CHARACTERISTICS OF CLASSIC PKU
- Phenylalanine elevated amounts in tissues,
plasma & urine.
Phenyl-pyruvate, phenyl-lactate ,acetate are also elevated in PKU.and phenyl- - CNS symptoms:
Mental retardation, failure to walk or talk, hyperactivity, tremor, microcephaly and failure to arow.
Symptoms of mental retardation by the age of(( one ))year. - Hypopigmentation:
Patients often show a deficiency of pigmentation.
Hydroxylation of the tyrosine by tyrosinase enzyme, is the first step in the formation of the melanin pigment. Patient has fair hair, light skin color and blue eyes.
DIAGNOSIS OF PKU
Urine examination by Ferric Chlorid (detects presence of phenyl-pyruvate) → Green color in positive cases that lasts for 30 min
Blood test, blood is obtained by “heel “heel stick”
collected on a special blotter paper.
Restricted Fragment Length Polymorphism is used for DNA analysis of cases of PKU. Carriers could also be
Normal levels of phenylalanine may persist until the
For newborns with a positive screening test, diagnosis
is confirmed through …………….
newborn is exposed to of 24 - 48h protein feeding.
Screening tests are typically done after this time to avoid
False negatives.
quantitative determination of
“phenylalanine levels”.
TREATMENT OF PKU
must begin during the …… days of life
first 7-10
TREATMENT OF PKU
Milk formula low in phenylalanine and rich in
tyrosine.
Lifelong restriction of dietary phenylalanine.
Some phenylalanine is needed for normal growth. So, diet containing some phenylalanine in much lower amounts than normal is the recommended treatment.
High-protein foods are avoided, as meat, fish, eggs,
cheese & milk.
Calculated amounts of cereals, starches, fruits and
vegetables, along with a milk substitute are usually -
recommended.
Dietary supplements with large neutral amino acids
(LNAA)as valine ,leucine and isoleucine, because they
compete with phenylalanine for specific carrier in blood brain barrier.
Kuvan is effective only in patients who have some PAH activitv and who continue to follow a phenylalanine- restricted diet and have their phenylalanine levels monitored.
ALKAPTONURIA: It is a metabolic “…….” disease.
autosomal recessive
ALKAPTONURIA:
It is due to a deficiency in “………. ………. “ enzyme which is needed for metabolism
of tyrosine and phenylalanine.
meis
This results in accumulation of…..
homogentisic acid oxidase
homosentisic acid.
ALKAPTONURIA:
Other names for AKU include
Other names for AKU include
Disease or urine Disease. Black Bone
ALKAPTONURIA:
* Alkaptonuric patients have no immediate problems.
• Late in the disease?
Late in the disease, the high level of homogentisic acid gradually accumulates in connective tissues, causing their pigmentation (ochronosis).
Arthritis-like degeneration homogentisic acid in the cartilage.
Deposition of pigment in the cartilage of the ears, nose and tendons of the extremities.
Addition of ferric chloride to urine, will turn it black in patients with alkaptonuria.
ALKAPTONURIA:
Treatment:
Treatment: high-dose of vitamin Chas been shown to decrease the buildup of the dark pigment in cartilage and may slow the developmen tota chriti decreases homogentiste acidia
Nitisinone is a drug that decreases homogentisic acid
production.
USES OF NADPH:
- Role in fatty acid biosynthesis, reductive agent.
- Role in antioxidant metabolism (part of glutathione
system). - Role in oxygen-dependant phagocytosis by WBCs.
- Role in the synthesis of nitric oxide.)
Precipitating factors in G6PD deficiency:
Oxidant drugs: antibiotics (as chloramphenicol),
antimalarials (as primaquine) and antipyretics as acetaminophen).
Fava beans: Some forms of G6PD are susceptible to
the haemolytic effect of fava beans Favism).
• Infection: is the common precipitating factor of
haemolysis in G6PD deficiency.
• Neonatal jaundice: neonates with G6PD deficiency
→ neonatal jaundice appearing 1-4 days after birth.
Almost all G6PD variants
mutations in the G6PD gene.
are caused by
point mutation
VARIANTS OF G6PD DEFICIENCY
(Type)
G6PD A (class3 is the prototype of the moderate. form of the disease. RBCs contain an !stable, but kinetically normal G6PD, with most of the enzyme activity present in the reticulocytes
and younger erythrocytes.
G6PD Mediterranean (class2
the prototype of a more severe deficiency. The enzyme shows normal stability but rarely detectable activity in all RBCS.
Class 1 mutations are often associated with chronio; non-spherocytic anaemia, which occurs even in the absence of oxidative stress!!!!!
