Inborn Errors Flashcards
(36 cards)
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),
Symptoms of galactocemia
Cataracts Jaundiced Enlarged liver Brain damage Kidney damage If a galatocemic infant is given milk, unmetabolized milk products build up and damage the liver, eyes, brain and kidneys
Diagnosis of galactosemia
> Postnatal diagnosis suggested by presence of galactose in urine
GALT assay with erythrocytes or leukocytes
Prenatal diagnosis: GALT assay in cultured amniotic tissue, measuring level of Galactitol in amniotic fluid
Treatment for Galactosemia
> Treatment is removal of galactose from diet for at least the two first years of life
Even with strict diet patients still suffer due to increased incidence of speech disorders and gonadal failure, ataxia
Cystic Fibrosis (Mucoviscidosis)
> Autosomal recessive
Most common lethal genetic disease affecting Caucasians (1 in 2,500 live births)
2-4% of population are carriers
Uncommon in Asians and African-Americans
Widespread disorder in epithelial chloride transport affecting fluid secretion in exocrine glands
epithelial lining of the respiratory, gastrointestinal, and reproductive tracts
Abnormally viscid mucus secretions
CFTR Gene: Normal
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
> CFTR → epithelial chloride channel protein interacts with epithelial sodium channels (ENaC)
SWEAT GLAND
> CTFR activation increases luminal Cl− resorption
> ENaC increases Na+ resorbtion
> sweat is hypotonic
Respiratory and Intestinal epithelium
> CTFR activation increases active luminal secretion of chloride
> ENaC is inhibited
CFTR Gene mutated: Cystic Fibrosis
Sweat gland
> CTFR absence decreases luminal Cl− resorption
> ENaC decreases Na+ resorption
> sweat is hypertonic
Respiratory and Intestinal epithelium
> CTFR absence decreases active luminal secretion of chloride
> Lack of inhibition of ENaC is opens sodium channel with active resorption of luminal sodium
> secretions are decreased but isotonic
CFTR Gene: Mutational Spectra
> More than 1300 mutations are known
These are grouped into six classes
mild to severe
Phenotype is correlated with the combination of these alleles
correlation is best for pancreatic disease
genotype-phenotype correlations are less consistent with pulmonary disease
Other genes and environment further modify expression of CFTR
6 classes of CFTR mutations
I – Defective protein synthesis
II- Abnormal protein folding and trafficking
III- Defective regulation
IV – Decreased conductance
V- Reduced abundance
VI- Altered regulation of separate ion channels
1st 3 are the most severe forms
Genetics and environmental modifier for CF
There are variations in other genes which in combination with CFTR gene mutations modify frequency and severity of organ-specific manifestations:
n-mannose binding lectin 2 gene and TGFbeta1 gene polymorphism increases risk of lung damage
Environmental modifiers:
Infection with specific type of Pseudomonas Aeruginosa which produces alginate capsule which resistant to ABT and influence the severity of lung disease (Pseudomonas, Staph. aureus, Hemophilus influenzae and Burkholderia cepacia (fulminant spread) are the MC infections in CF!!!!!)
