Hyperphenylalaninemia

Hyperphenylalaninemia is broadly defined as the presence of blood phenylalanine levels that exceed the limits of the upper reference range (2 mg/dL or 120 µmol/L) without treatment but that are below the level found in patients with phenylketonuria (PKU). Phenylalanine levels that exceed 20 mg/dL (1200 µmol/L) are considered typical of classic PKU (see Phenylketonuria). In 2014, the American College of Medical Genetics and Genomics released a practice statement that recommended that PKU and hyperphenylalaninemia both be considered part of the spectrum of phenylalanine hydroxylase (PAH) deficiency.

Phenylalanine levels of 6 mg/dL (360 µmol/L) or less in patients consuming an unrestricted diet are generally considered to be a benign condition. No dietary phenylalanine restrictions are usually recommended in this instance. In contrast, dietary restriction is generally indicated among patients whose phenylalanine levels are more than 12 mg/dL (725 µmol/L); chronic phenylalanine levels in this range reportedly cause measurable intellectual impairment in children.

Practices of dietary treatment vary in children with phenylalanine levels in the intermediate range of 7-11 mg/dL (425-660 µmol/L). Most centers in the United States recommend restricting dietary phenylalanine when levels exceed 10 mg/dL (600 µmol/L). Some also recommend treatment for levels that exceed 8-9 mg/dL (480-545 µmol/L). The British Medical Research Council Working Party on PKU recommends dietary phenylalanine restriction when levels consistently exceed 6.6-10 mg/dL (400-600 µmol/L).

Hyperphenylalaninemia is the term used to describe the mildest manifestation of phenylalanine hydroxylase deficiency, with classic PKU representing the more severe end of this spectrum.[15] Broad genotype/phenotype correlations have been made for mild versus severe disease, although phenylalanine tolerance may vary in unrelated individuals with identical mutations. A small percentage of individuals with elevated phenylalanine levels have normal phenylalanine hydroxylase activity but lack tetrahydrobiopterin, a crucial cofactor. These patients generally have a more severe phenotype with more pronounced neurological involvement and a less consistent response to therapy. See the image below.

Frequency

United States

Frequency is approximately 15-75 cases per 1,000,000 births.

International

The condition is less prevalent than classic PKU and shows less variation in incidence among populations.

Mortality/Morbidity

Most individuals with hyperphenylalaninemia have normal life expectancy. Several studies have identified a linear relationship between the phenylalanine level and intelligence testing and performance. Intelligence quotients seem less affected by benign hyperphenylalaninemia than by PKU, even at the same levels of serum phenylalanine. This effect may be due to smaller fluctuations of serum phenylalanine concentration.

Race

Hyperphenylalaninemia occurs in all races.

Sex

Both sexes are equally affected because deficiency in phenylalanine hydroxylase activity is inherited as an autosomal-recessive trait. Pregnant women with phenylalanine levels that exceed 6 mg/dL risk having children with microcephaly, mental retardation, and birth defects (eg, maternal hyperphenylalaninemia).[1]

Age

Hyperphenylalaninemia most is commonly diagnosed by newborn screening and must be distinguished from classic PKU by confirmatory testing at an experienced center.[2] Some cases in adult women have been detected using maternal screening programs or following birth of children with birth defects. Elevated phenylalanine levels are associated with neuropsychological effects.

Prognosis is excellent for normal development when treated as indicated.

Teach patients and parents about proper diet. Children should participate in their dietary planning as soon as they have that ability.

An abnormal newborn screen is the most common history in patients with hyperphenylalaninemia. Infants are screened for elevated phenylalanine in every US state and in Puerto Rico. Several other countries also have established screening programs.

Affected individuals missed by screening may have mild-to-moderate performance deficits, depending on the degree of phenylalanine elevation.

Measurable IQ deficits can be seen at phenylalanine levels in the hyperphenylalaninemia range, particularly as levels exceed 10 mg/dL (600 µmol/L). At phenylalanine levels near 20 mg/dL (1200 µmol/L), phenylketonuria (PKU)-like symptoms may emerge, including more pronounced developmental abnormalities, eczema, and vomiting. Preliminary evidence indicates milder attention and organizational problems may arise when levels exceed 6 mg/dL.

Most children have few abnormal findings on physical examination.

Some physical stigmata of PKU may be present in individuals who have phenylalanine levels near 20 mg/dL. PKU-like symptoms include eczema and fair hair and skin coloring.

Genetic defects in phenylalanine hydroxylase cause most cases of hyperphenylalaninemia. In a few cases, defective synthesis or recycling of the biopterin cofactor is the cause (see Tetrahydrobiopterin Deficiency).[3]

In some children with mild enzyme deficits, excessive protein intake may elevate phenylalanine levels to a range requiring treatment. The problem may resolve when protein intake is reduced to more ordinary levels. For example, infants with nonphenylketonuric hyperphenylalaninemia who consume excessive infant formula (60-70 oz/d or 1800-2100 mL/d) may demonstrate phenylalanine levels exceeding 10-12 mg/dL. Levels may fall when formula intake is restricted to 32-40 oz/d.

Screening for hyperphenylalaninemia includes the following:

• Newborns with abnormal screening findings should be monitored in accordance with local regulations. Different states or authorities may have various protocols regarding result interpretation and follow-up. Do not restrict dietary phenylalanine or interrupt breastfeeding based on screening results unless instructed by a health official or treatment center. However, immediately refer the patient to a treatment center for confirmatory testing.

• Low-grade elevations may require repeat screening. Phenylalanine levels can rise for several weeks after birth in children with hyperphenylalaninemia or phenylketonuria (PKU). A low-grade elevation 24-72 hours following birth might signal true PKU, not merely hyperphenylalaninemia.

Measure plasma phenylalanine and tyrosine levels as soon as possible after an abnormal screening result. An elevated phenylalanine level with low or normal tyrosine level is expected. Hepatic insufficiency and tyrosinemia can feature elevated phenylalanine levels, although typically in the context of elevated tyrosine.

Obtain blood and urine biopterins assays through a qualified laboratory to exclude a tetrahydrobiopterin defect.

Diagnostic procedures, such as phenylalanine or biopterin loading tests, are rarely indicated.

If available, patients should be evaluated at a phenylketonuria (PKU) treatment center. The extent of the hyperphenylalaninemia determines the nature and frequency of follow-up.[4]

In one study, 54% of patients with phenylalanine levels less than 600 µmol/L (10 mg/dL) demonstrated a decline of 30% or more in plasma phenylalanine levels when sapropterin (commercial tetrahydrobiopterin cofactor) was administered at a dose of 10 mg/kg/d.[5] The percentage of patients who responded declined with increasing plasma phenylalanine levels. Response to sapropterin may improve at a dose of 20 mg/kg/d.[6]

Preliminary studies are underway for injectable phenylalanine ammonium lyase, an enzyme substitute. This shows promise in animal studies as an alternative treatment to control phenylalanine levels.[7]

If dietary treatment is necessary, refer the patient to a dietitian experienced with PKU (usually a member of a PKU treatment team).

Refer families of affected infants to a medical geneticist or genetic counselor to review the inheritance of hyperphenylalaninemia.

Determine the degree of dietary phenylalanine restriction for each patient based on untreated phenylalanine levels. For more detailed information on a phenylalanine-restricted diet, see Phenylketonuria.

Breastfeeding is usually possible and should not be stopped unless instructed by a local health official or treatment center.

Aspartame should be restricted from diet. Phenylalanine is a primary component of aspartame.

Aspartame may be present in many artificially sweetened substances, including medicines, vitamins, beverages, and foods. A pharmacist can help determine if a medication has a significant amount of aspartame.

The amount of aspartame in a children's vitamin or in a teaspoon of antibiotic may be significant for a child who can tolerate only 200 mg/d of phenylalanine, yet such a dose may be insignificant for a child who can tolerate more than 1000 mg/d.

Stringent phenylalanine-restricted diets have been reported to cause deficiencies of iron, zinc, selenium, and other nutrients and essential amino acids in patients with PKU. The diet requires careful monitoring by a professional trained in PKU management.

Do not restrict activities.

In general, patients should avoid consuming aspartame because phenylalanine is a primary component of aspartame.

Phenylalanine levels determine the need for further outpatient care in patients with hyperphenylalaninemia.

Sapropterin may decrease plasma phenylalanine levels.

Class Summary

Some children respond to BH4 supplementation. Synthetic BH4 (sapropterin) is now approved by the US Food and Drug Administration. Also consider restricting use of drugs and food that contain aspartame.

Sapropterin (Kuvan)

Synthetic form of tetrahydrobiopterin (BH4), the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates phenylalanine through an oxidative reaction to form tyrosine. PAH activity is absent or deficient in patients with PKU. Treatment with BH4 can activate residual PAH enzyme, improve normal oxidative metabolism of phenylalanine, and decrease phenylalanine levels in some patients. Indicated to reduce blood phenylalanine levels in patients with hyperphenylalaninemia caused by BH4-responsive PKU. Used in conjunction with a phenylalanine-restricted diet.