Inborn Errors Flashcards
PHENYLKETONURIA (PKU)
Ethnic distribution
Common in persons of Scandinavian descent
uncommon in persons of African-American and Jewish descent
Autosomal recessive, 1:10 000-20 000
Phenylalanine hydroxylase (PAH, in 98%) or dihydropteridine reductase (in 2%) deficiency leads to hyperphenylalaninemia, brain damage, and mental retardation
Phenylananine metabolites are excreted in the urine
Variant forms exist (Classic, Malignant, Benign)
Normal level phenylalanine <120microM
Most inborn errors of metabolism are
autosomal recessive or X-linked
Etiology of classic PHENYLKETONURIA-PKU
complete or near-complete deficiency of phenyl-alanine hydroxylase. Excess phenylalanine is transaminated to phenylpyruvic acid or decarboxylated to phenyl-ethylamine.
These and subsequent metabolites, along with excess phenylalanine, disrupt normal metabolism and cause brain damage.
Etiology of malignant PKU
Hyperphenylalaninemia due to cofactor tetrahydrobiopterin (BH4) gene mutation
The defect resides in one of the enzymes necessary for production or recycling of the cofactor BH4. BH4 was then shown to be a cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. The latter two hydroxylases are essential for biosynthesis of the neurotransmitters dopamine and serotonin .
BH4 is a cofactor for…..
nitric oxide synthase, which catalyzes the generation of nitric oxide from arginine. Today, patients with BH4 deficiency are diagnosed very early in life because all patients with hyperphenylalaninemia are tested for the possibility of this cofactor deficiency.
Maternal PKU
Clinically normal female with PKU who are treated with dietary control early in life reach childbearing age
If mother with PKU does not follow dietary regimen then between 75% and 90% of children born to such women are mentally retarded and microcephalic, and 15% have congenital heart disease, even though the infants themselves are heterozygotes.
Mechanism: teratogenic effects of phenylalanine or its metabolites that cross the placenta and affect specific fetal organs during development.
$$ It is imperative that maternal dietary restriction of phenylalanine be initiated before conception and continue throughout pregnancy.
Clinical manifestation of classic PKU
normal at birth
- Mental retardation may develop gradually, hyperactive with purposeless movements, rhythmic rocking, and athetosis.
- Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis
- infants are blonder than unaffected siblings, have fair skin and blue eyes, eczema
- unpleasant odor of phenylacetic acid, which has been described as musty or mousey.
- seizures, microcephaly, growth retardation
Clinical Manifestations of Malignant PKU (Hyperphenylalaninemia due to cofactor tetrahydrobiopterin (BH4)
> similar and usually indistinguishable from those of classic PKU
loss of head control, hypertonia, swallowing difficulties, myoclonic seizures
Plasma phenylalanine levels may be as high as those in classic PKU or in the range of benign.
Diagnosis of PKU
- Blood phenylalanine
- Urine for phenylpyruvic acid
- BH4 loading test
- Gene study
The criteria for diagnosis of classic PKU are:
(1) a plasma phenylalanine level above 20 mg/d L (600microM);
(2) a decreased plasma tyrosine level;
(3) increased urinary levels of metabolites of phenylalanine (phenylpyruvic and hydroxyphenylacetic acids)
(4) a decreased concentration of the cofactor tetrahydrobiopterin (BH4)
Treatment for classic PKU
> diet low in phenylalanine: The optimal serum level to be maintained probably lies between 3 mg/d L (0.18 mM) and 15 mg/dL (0.9 mM). rigid diet control may be relaxed after 6 yr of age
BH4 administration (50% efficacy)
Gene therapy
Maternal PKU
Pregnant PKU patients if discontinue diet regimen will expose child to high serum levels of phenylalanine and its metabolites
75-90% of children will have mental retardation, microcephaly
15% -congenital heart defects
!!! Maternity dietary restriction should be strict and started before conception
Galactosemia
> Autosomal recessive
Lactose (major carbonhydrate of milk) → glucose + galactose
Galactose-1-phosphate uridyl transferase (GALT)
GALT is involved in the second step in the transformation of galactose to glucose
absence of GALT (MC variant) or Galactokinase activity (rare variant, no CNS damage)→ galactosemia
Alternative pathway metabolites:
Galactocemia
Galactitol
Galactonate
Induce cell swelling and cell death
Galatosemia
Alternative pathway metabolites:
Galactitol
Galactonate both are toxic for liver, eyes and brain cells
> Clinical Picture:
Symptoms appear with milk ingestion (a few days after that):
1.Vomiting,
2.Diarrhea,
3.Jaundice,
4.Hepatomegaly (fatty change and fibrosis),
5.Cataracts (3-6 weeks),
6.Brain damage (mental retardation – in 1 year, not so severe as in PKU!),
7.Aminoaciduria (impaired aminoacid transport in kidneys),
