Pancreaticinsufficiencyisextremelycommon;infertilitycausedbycongenitalbilateralabsenceofvasdeferensisacharacteristicfindinginadultpatientswithCF.
Liverdisease,includingcirrhosis,isincreasinginfrequencyaslifeexpectancyincreases.
MoleculartherapiesthatenhancethetransportorstabilityofmutantCFTRproteinareusefulinpatientswhoharborcertainCFTRalleles.
PKU results from mutations that cause a severe lack of the enzyme phenylalanine hydroxylase (PAH). It affects 1 in 10,000 live-born white infants and there are several variants of this disease. The most common form, referred to as classic phenylketonuria, is common in persons of Scandinavian descent and is distinctly uncommon in African-American and Jewish populations.
Homozygotes with this autosomal recessive disorder classically have a severe lack of PAH, leading to hyperphenylalaninemia and PKU. Affected infants are normal at birth but within a few weeks exhibit a rising plasma phenylalanine level, which impairs brain development. Usually, by 6 months of life, severe mental retardation becomes all too evident; less than 4% of untreated phenylketonuric children have intelligence quotients (IQs) greater than 60. About one-third of these children are never able to walk, and two-thirds cannot talk. Seizures, other neurologic abnormalities, decreased pigmentation of hair and skin, and eczema often accompany the mental retardation in untreated children. Hyperphenylalaninemia and the resultant mental retardation can be avoided by restricting phenylalanine intake early in life. Hence, several screening procedures are routinely performed to detect PKU in the immediate postnatal period.
Many female patients with PKU who receive dietary treatment beginning early in life reach childbearing age and are clinically normal. Most of them have marked hyperphenylalaninemia, because dietary treatment is discontinued after they reach adulthood. 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. This syndrome, termed maternal PKU, results from the teratogenic effects of phenylalanine or its metabolites that cross the placenta and affect specific fetal organs during development. The presence and severity of the fetal anomalies directly correlate with the maternal phenylalanine level, so it is imperative that maternal dietary restriction of phenylalanine be initiated before conception and continued throughout pregnancy.
The biochemical abnormality in PKU is an inability to convert phenylalanine into tyrosine. In normal children, less than 50% of the dietary intake of phenylalanine is necessary for protein synthesis. The remainder is converted to tyrosine by the phenylalanine hydroxylase system (
Fig.
7.7 ). When phenylalanine metabolism is blocked because of a lack of PAH enzyme, shunt pathways come into play, yielding several intermediates that are excreted in large amounts in the urine and in the sweat. These impart a strong musty or mousy odor to affected infants. It is believed that excess phenylalanine or its metabolites contribute to the brain damage in PKU. Concomitant lack of tyrosine (
Fig. 7.7 ), a precursor of melanin, is responsible for the light color of hair and skin.