At the molecular level, approximately 500 mutant alleles of the PAH gene have been identified, only some of which cause a severe deficiency of the enzyme. Infants with mutations resulting in a severe lack of PAH activity present with the classic features of PKU, whereas those with some residual activity present with milder disease or may be asymptomatic, a condition referred to as benign hyperphenylalaninemia. Because the numerous disease-causing alleles of the PAH gene, complicate molecular diagnosis, measurement of serum phenylalanine levels is used to differentiate benign hyperphenylalaninemia from PKU; the levels in the latter disorder typically are ≥5 times higher than normal. After a biochemical diagnosis is established, the specific mutation causing PKU can be determined. With this information, carrier testing of at-risk family members can be performed. Currently, enzyme replacement therapy is being tried as a method for reducing circulating phenylalanine levels in patients with classic PKU. The replacement enzyme, known as phenylalanine ammonia lyase (or PAL), converts excess phenylalanine to ammonia and other nontoxic metabolites.
Although 98% of cases of hyperphenylalaninemia are attributable to mutations in PAH, approximately 2% arise from abnormalities in synthesis or recycling of the cofactor tetrahydrobiopterin (
Fig. 7.7 ). Clinical recognition of these variant forms is important because these patients cannot be treated by dietary restriction of phenylalanine alone, but also require supplementation with tetrahydrobiopterin, certain neurotransmitter precursors, and folic acid.
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Fig. 7.7 Thephenylalaninehydroxylasesystem.NADH, Nicotinamideadeninedinucleotide,reducedform.
PKUisanautosomalrecessivedisordercausedbyalackoftheenzymephenylalaninehydroxylaseandaconsequentinabilitytometabolizephenylalanine.
ClinicalfeaturesofuntreatedPKUmayincludeseverementalretardation,seizures,anddecreasedpigmentationofskin,whichcanbeavoidedbyrestrictingtheintakeofphenylalanineinthediet.
FemalepatientswithPKUwhodiscontinuedietarytreatmentcangivebirthtochildrenwithmalformationsandneurologicimpairmentresultingfromtransplacentalpassageofphenylalaninemetabolites.
Galactosemia is an autosomal recessive disorder of galactose metabolism resulting from a mutation in the gene encoding the enzyme galactose-1-phosphate uridyltransferase (GALT). It affects 1 in 60,000 live-born infants. Normally, lactase splits lactose, the major carbohydrate of mammalian milk, into glucose and galactose in the intestinal microvilli. Galactose is then converted to glucose in several steps, in one of which the enzyme GALT is required. As a result of this transferase deficiency, galactose-1-phosphate and other metabolites, including galactitol, accumulate in many tissues, including the liver, spleen, lens of the eye, kidney, and cerebral cortex.
The liver, eyes, and brain bear the brunt of the damage. The early-onset hepatomegaly results largely from fatty change, but in time widespread scarring that closely resembles the cirrhosis of alcohol abuse may supervene (Chapter 16). Opacification of the lens (cataract) develops, probably because the lens absorbs water and swells as galactitol, produced by alternative metabolic pathways, accumulates and increases its tonicity. Nonspecific alterations appear in the central nervous system (CNS), including loss of nerve cells, gliosis, and edema. There is still no clear understanding of the mechanism of injury to the brain, although elevated galactitol levels in neuronal tissues suggests that this may contribute to the damage.