The Hyperphenylalaninemias

The abnormalities that lead to an increase in the blood level of phenylalanine, most notably PAH deficiency or PKU, illustrate almost every principle of biochemical genetics related to enzyme defects. The biochemical causes of hyperphenylalaninemia are illustrated in Fig. 1, and the principal features of the diseases associated with the biochemical defect at the six known hyperphenylalaninemia loci are presented in Table 1. All the genetic disorders of phenylalanine metabolism are inherited as autosomal recessive conditions and are due to loss-of-function variants, either in the gene encoding PAH or in genes required for the synthesis or reutilization of the PAH cofactor, tetrahydrobiopterin (BH4 ), or (rarely) in DNAJC12, which encodes a chaperone for PAH.

Fig1. The biochemical pathways affected in the hyperphenylalaninemias. BH4 , tetrahydrobiopterin; 4αOHBH4 , 4α-hydroxytetrahydrobiopterin; qBH2 , quinonoid dihydrobiopterin, the oxidized product of the hydroxylation reactions, which is reduced to BH4 by dihydropteridine reductase (DHPR); PCD, pterin 4α-carbinolamine dehydratase; phe, phenylalanine; tyr, tyrosine; trp, tryptophan; GTP, guanosine triphosphate; DHNP, dihydroneopterin triphosphate; 6-PT, 6-pyruvoyltetrahydropterin; l-dopa, l dihydroxyphenylalanine; NE, norepinephrine; E, epinephrine; 5-OH trp, 5-hydroxytryptophan.

Table1. Locus Heterogeneity in the Hyperphenylalaninemias

Phenylketonuria. Classic PKU is the epitome of the enzymopathies. It results from pathogenic variants in the gene encoding PAH, which converts phenylalanine to tyrosine (see Fig. 1 and Table 1). The discovery of PKU in 1934 marked the first demonstration of a genetic defect as a cause of intellectual disability. Because patients with PKU cannot degrade phenylalanine, it accumulates in body fluids and damages the developing central nervous system. A small fraction of phenyl alanine is metabolized to produce increased amounts of phenylpyruvic acid, the keto acid responsible for the name of the disease. Ironically, although the enzymatic defect has been known for many decades, the precise pathogenetic mechanism(s) by which increased phenyl alanine damages the brain is still uncertain. Importantly, the neurologic damage is largely avoided by reducing the dietary intake of phenylalanine. The management of PKU is a paradigm of the treatment of the many metabolic diseases whose outcome can be improved by pre venting accumulation of an enzyme substrate and its derivatives; this therapeutic principle is described further in Chapter 14.

Variant Phenylketonuria and Nonphenylketonuria Hyperphenylalaninemia. Classical PKU results from a virtual absence of PAH activity (<1 % of that in controls) and is defined by untreated phenylalanine (phe) levels of more than 1200 µmol/l. less severe phenotypes – designated mild or variant PKU (phe levels 400–1200 µmol/l), and non-PKU (or benign) hyperphenylalaninemia (phe levels <400 µmol/l) (see Table 1) – result when the mutant PAH enzyme has some residual activity. The fact that a very small amount of residual enzyme activity can have a large impact on phenotype is another general principle of the enzymopathies.

Variant PKU includes individuals who require only some dietary phenylalanine limitations, less restrictive than for classic PKU, because their blood phenyl alanine levels are more moderate and less damaging to the brain. With classic PKU, the plasma phenylalanine levels are more than 1200 μmol/l on a normal diet, whereas non-PKU hyperphenylalaninemia is defined by plasma phenylalanine concentrations above the upper limit of normal (120 μmol/l) but below those seen in classic PKU. If the increase in non-PKU hyperphenylalaninemia is small (<400 μmol/l, termed benign hyperphenylalaninemia), no treatment is required; these individuals come to clinical attention only through new born screening (see Chapter 19). They are followed to ensure that levels do not rise into the treatment range. Their normal phenotype has been the best indication of the safe target level of plasma phenylalanine in treating classic PKU. The association of these three clinical phenotypes with variants in the PAH gene is a clear example of allelic heterogeneity leading to clinical het erogeneity (see Table 1).

Allelic and Locus Heterogeneity in the Hyperphenylalaninemias

Allelic Heterogeneity in the PAH Gene. A striking degree of allelic heterogeneity at the PAH locus – more than 1200 different variants worldwide – has been identified among individuals with hyperphenylalaninemia associated with classic PKU, variant PKU, or benign hyperphenylalaninemia (see Table 1). Seven variants account for a majority of known pathogenic alleles in populations of European descent, whereas six others represent the majority of PAH pathogenic variants in Asian populations. The remaining disease-causing variants are individually rare. To record and make this information publicly available, a PAH variant database has been developed by an international consortium.

The allelic heterogeneity at the PAH locus has major clinical consequences. Most important is that most individuals with hyperphenylalaninemia are compound heterozygotes (i.e., they have two different disease-causing alleles). This allelic heterogeneity accounts for much of the enzymatic and phenotypic het erogeneity among affected individuals. Thus pathogenic variants that eliminate or dramatically reduce PAH activity generally cause classic PKU, whereas greater residual enzyme activity is associated with milder phenotypes. However, homozygous patients with certain PAH variants have phenotypes ranging all the way from classic PKU to non-PKU hyperphenylalaninemia. Accordingly, other unidentified biologic variables – undoubtedly including modifier genes – generate variation in the phenotype for a given genotype. This lack of a strict genotype-phenotype correlation, initially somewhat surprising, is now recognized as a feature of most single-gene diseases, highlighting that even monogenic traits like PKU are not genetically simple disorders.

Defects in Tetrahydrobiopterin Metabolism. In 1% to 3% of individuals with elevated phenylalanine, the PAH gene is normal, and the hyperphenylalaninemia results from a defect in one of the steps in the biosynthesis or regeneration of BH4 – the cofactor for PAH (see Table 1 and Fig. 1). The association of a single biochemical phenotype, such as hyperphenylalaninemia, with variants in different genes, is an example of locus heterogeneity (see Table 1). The proteins encoded by genes that manifest locus heterogeneity generally act at different steps in a single biochemical pathway: another principle of genetic disease illustrated by hyperphenylalaninemia (see Fig. 1). BH4-deficient patients were first recognized because they developed profound neurologic problems in early life, despite the successful administration of a low-phenylalanine diet. This poor outcome is due in part to the requirement for the BH4 cofactor by two other enzymes: tyrosine hydroxylase and tryptophan hydroxylase. These hydroxylases are critical for the synthesis of the monoamine neurotransmitters, dopamine, norepinephrine, epinephrine, and serotonin (see Fig. 1).

The locus heterogeneity of hyperphenylalaninemia is significant because the treatment of patients with a defect in BH4 metabolism differs markedly from that for subjects with pathogenic variants in PAH, in two ways. First, because the PAH enzyme is itself normal in individuals with BH4 defects, its activity can be restored by large doses of oral BH4 , leading to reduction in plasma phenylalanine levels. This practice highlights the principle of product replacement in the treatment of some genetic disorders. Consequently, phenylalanine restriction can be significantly relaxed for those with defects in BH4 metabolism, and some actually tolerate an unrestricted diet. Second, one must try to normalize the neurotransmitters in the brains of these patients by administering the products of tyrosine hydroxylase and tryptophan hydroxylase: l-dopa and 5-hydroxytryptophan, respectively (see Fig. 1 and Table 1).

A novel form of hyperphenylalaninemia with movement disorder and sometimes with cognitive impairment is caused by biallelic pathogenic variants in DNAJC12, which codes for a member of the HSP40 family of proteins. It functions as a cochaperone (with members of the HSP70 family of proteins) of the aromatic hydroxylases, including PAH, tyrosine hydroxylase, and tryptophan hydroxylases 1 and 2. So far, more than 20 patients have been described. This condition will be identified by elevated phenylalanine on newborn screening and requires sequencing of the gene for diagnosis.

Remarkably, pathogenic variants in sepiapterin reductase, an enzyme in the BH4 synthesis pathway, do not cause hyperphenylalaninemia. Only dopa- responsive dystonia is seen, due to impaired synthesis of dopamine and serotonin (see Fig. 1). Alternative pathways may exist for the final step in BH4 synthesis, bypassing the sepiapterin reductase deficiency in peripheral tissues, an example of genetic redundancy.

For these reasons, all hyperphenylalaninemia infants must be evaluated to determine whether their hyperphenylalaninemia is the result of an abnormality in PAH, in BH4 metabolism, or in the chaperone. The hyperphenylalaninemias thus illustrate the critical importance of obtaining a specific molecular diagnosis in all patients with a genetic disease phenotype. The underlying genetic defect may not be what one first suspects, and the treatment can vary accordingly.

Tetrahydrobiopterin Responsiveness With PAH Variants. Many individuals with variants in the PAH gene (rather than in BH4 metabolism) will also respond to large oral doses of BH4 cofactor, with a substantial decrease in plasma phenylalanine. BH4 supplementation is therefore an important adjunct therapy for PKU patients of this type, allowing a less restricted dietary intake of phenylalanine. The affected individuals most likely to respond are those with significant residual PAH activity (i.e., those with variant PKU and non-PKU hyperphenylalaninemia), but a minority of individuals with classic PKU are also responsive. The presence of residual PAH activity does not, however, guarantee an effect of BH4 administration on plasma phenylalanine levels. Rather, the degree of BH4 responsiveness will depend on the specific properties of each altered PAH protein, reflecting the allelic heterogeneity underlying PAH variants.

The provision of increased amounts of a cofactor is a strategy that has been used for the treatment of many inborn errors of enzyme metabolism. In general, a cofactor comes into contact with the protein component of an enzyme (termed an apoenzyme) to form the active holoenzyme, which consists of both the cofactor and the otherwise inactive apoenzyme. Illustrating this strategy, BH4 supplementation exerts its beneficial effect through one or more mechanisms, all of which result from increased cofactor in contact with the altered PAH apoenzyme. These mechanisms include stabilization of the enzyme, protection of the enzyme from degradation by the cell, and increase in cofactor supply for an altered enzyme with low affinity for BH4 .

Newborn Screening. PKU is the prototype of genetic diseases for which mass newborn screening is justified because (1) it is relatively common in some populations (up to ~1 in 2900 live births), (2) mass screening is feasible, (3) failure to treat has severe consequences (profound intellectual disability), and (4) treatment is effective if begun early in life. To allow time for the postnatal increase in blood phenylalanine levels, the test is performed after 24 hours of age. Central laboratories assay blood from a heel prick for blood phenylalanine levels and phenylalanine-to-tyrosine ratio. Positive test results must be confirmed quickly because delays in treatment beyond 4 weeks postnatally have profound effects on intellectual outcome. The current recommendation is to initiate treatment within the first week of life.

Maternal Hyperphenylalaninemia. Originally, the low- phenylalanine diet was discontinued in mid-childhood for most individuals with PKU. It was later found, however, that almost all offspring of women with PKU not on treatment are clinically abnormal; most are severely delayed developmentally, and many have microcephaly, growth impairment, and malformations, particularly of the heart. As predicted by principles of mendelian inheritance, these children are heterozygotes; their neurodevelopmental delay is not due to their own genetic constitution but to the highly teratogenic effect of elevated phenylalanine in the maternal circulation. Accordingly, women with PKU who are planning pregnancies must achieve tight metabolic control with a low-phenylalanine diet and BH4 supplementation (if responsive) prior to conception.

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جامعة الكفيل تكرِّم طلبتها المتميزين من ذوي الاحتياجات الخاصة

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المجمع العلمي يقيم محاضرة متخصِّصة في فنِّ الإقراء بمحافظة صلاح الدين

جامعة الكفيل تنظم سلسلة محاضرات عن التعليم الطبي لملاكاتها التدريسية

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مواضيع ذات صلة

Lysosomal Storage Diseases: A Unique Class of Enzymopathies

Diseases due to pathogenic variants in different classes of proteins

Renal cysts and diabetes (HNF1B MODY)

Maternally inherited diabetes and deafness

Genetic testing in neonatal diabetes

Human Hemoglobin and Associated Diseases

The Relationship Between Genotype and Phenotype in Genetic Disease

Effect of Pathogenic Variants on Protein Function

HNF1A and HNF4A (Transcription factor MODY)

Categories of Epigenetic disorders

Epigenetics in Development

Mosaicism