Are You Confident of the Diagnosis?

What you should be alert for in the history

Be alert for progressive mental deterioration, behavior disorders, hyperactivity, seizures, and skin changes.

Characteristic findings on physical examination

Characteristic findings include an IQ of 20-50, mousy body odor (phenylacetic acid in sweat), and microcephaly. Height and weight at average at birth, with variable developmental delay thereafter. Other findings include athetosis,exaggerated tendon reflexes. Cutaneous findings include fair skin and hair (due to impaired melanin synthesis), eczema-atopic variety, light sensitivity, increased incidence of pyogenic infections, scleroderma-like lesions with involvement of muscles, and lightly pigmented eyes.

Expected results of diagnostic studies

Newborn blood sample screening during the first week of life can be performed using either a semiquantitative microbiological procedure (Guthrie bacterial inhibition assay) or a quantitative chemical reaction (Quantase test)

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The phenotypes of phenylalanine hydroxlyase (PAH) defect are determined by measuring blood pheynlalanine (Phe) and tyrosine levels while infants are fed a normal diet containing at least 500mg/d of Phe for 5 consecutive days and are classified as as indicated in Table I

Table I.
Type of hyperphenylalaninemia (HPA) Blood phenylalanine levels (µmol/L) Hepatic phenylalanine hydroxylase residual activity (%)
Classical PKU >1200 <1
Atypical PKU 600-1200 1-5
Mild permanent HPA <600 >5

HPA, hyperphenylalaninemia; PKU, phenylkotinuria.

Other laboratory studies include high urinary phenylacetic and phenylpyruvic acid using 2,4-dinitrophenol, and mutational analysis of DNA extracted from leukocytes sequenced for phenylalanine hydroxylase gene.

Diagnosis confirmation

Hyperphenylalaninemia types IV and V are due to disorders of tetrahydobiopterin (BH4) metabolism. The patient has features of phenylketonuria (PKU) with low birth weight, extrapyramidal syndrome, and occasional hyperthermia. The diagnosis is excluded by:

  • Analysis of pteridine profile in urine: low neopterin and biopterin levels in GTP cyclohydrolase deficiency, high neopterin : biopterin ratio 6-pyruvoyl tetrahydrobiopterin synthase deficiency.

  • Measurement of dihydropteridine reductase activity in erythrocytes

  • Oral BH4 loading test: to rapidly screen for BH4 synthesis defects and test BH4 responsiveness in some PKU patients. For the purpose of screening, responsiveness was defined as a 30% decrease in plasma Phe after an 8-day trial of oral sapropterin at 10mg/kg. Recently a single BH4 loading test (20mg/kg) with monitoring of blood Phe at 0,8,12,24 hours was proposed for evaluation of responsiveness. If Phe dropped more than 20% in the short term, then a trial with BH4 is warranted.

Tyrosinemia II: Painful palmoplantar hyperkeratosis with mental retardation and eye changes presenting after 1 year of age. Confirmed by low serum tyrosine levels and normal Phe levels.

Who is at Risk for Developing this Disease?

The overall incidence is 1 in 8-12000 live births. A higher incidence has been found in whites and native Americans, with lower incidence in Blacks, Hispanics, and Asians.

What is the Cause of the Disease?
Etiology

Hyperphenylalaninemia is autosomal recessive, with usually over 400 mutations at the PAH locus on chromosome 12q22-q24.1 resulting in deficiency of phenylalanine hydroxylase. Most PKU patients are compound heterozygotes, accounting for the large phenotypic variability encountered in the patient population. Reduced tetrahydrobiopterin synthesis or recycling also causes hyperphenylalaninemia.

Pathophysiology

In PKU, accumulation of phenylalanine along with its metabolites such as phenylethylamine (formed by decarboxylation) and phenylpyruvate (formed by transamination) inhibits the transport of large, neutral amino acids into the brain, resulting in inhibition of protein synthesis and synthesis of neurotransmitters, such as dopamine and serotonin.

Also, tyrosine deficiency will reduce availability of its metabolites, which contribute to the pool of two-carbon metabolites and glucose, so it could contribute to impaired brain development. However, tyrosine supplementation in PKU makes no impact on cognitive function.

The reduction of melanin formation in the hair is due to inhibition of tyrosine-tyrosinase reaction by phenylalanine, and the hair will darken if large amounts of tyrosine are ingested. Disorders of BH4 recycling and synthesis in addition have pathological effects secondary to impaired tryptophan and tyrosine hydroxylation.

Systemic Implications and Complications

Maternal phenylketonuria (PKU) syndrome: This term defines the embryopathy that affects the infants born to untreated PKU mothers despite the fact that usually the children do not themselves have PKU. It is characterized by low birthweight, microcephaly, dysmorphism, congenital heart defects, and developmental retardation.

An increased risk is directly correlated to maternal phenylalanine levels during pregnancy. The frequency of phenylalanine monitoring during pregnancy is twice weekly.

It is recommended that Phe levels <6mg/dl be achieved at least 3 months before conception. Therefore, educational programs for adolescents and women of childbearing age that focus on information on managing maternal PKU should be offered.

Therapy with L-tyrosine in conjunction with a phenylalanine-restricted diet would be effective in maternal PKU. Focusing on overall nutritional status of pregnant mothers including intake of vitamins (folic acid, vitamin B12) is essential.

Treatment Options

The goal in the treatment of PKU is to maintain metabolic control of phenylalanine for optimal adaptation and outcome.

Diet

A phenylalanine-controlled diet allows the reduction of systemic phe concentration, satisfactory tyrosine provision and optimal growth and development. This amount of Phe intake, called tolerance, is individually determined depending on the phenylalanine hydroxylase residual activity, anabolism, and rate of growth. Infants with PKU who have blood Phe levels>10 mg/dl should be started on treatment ideally by the time the neonate is 7 days old. Before treatment is started, tetrahydrobiopterin (BH4) deficiency should be excluded.

Reducing Phe solely by restricting dietary protein from natural food would cause protein malnutrition and nutrient deficiency. Thus such diets necessitate use of Phe-free amino acid formula containing adequate amounts of nitrogen, vitamins, minerals and micronutrients. These dietary products have progressively been refined but remain unpalatable.

At the start of treatment in infants, a period of Phe-free milk brings blood levels down. As the levels approach therapeutic range, Phe is added using measured amounts of normal milk and then adjusted until serial blood controls have stabilized. Once addition of solids begin, the diet is progressively adapted with the following main principles explained to parents and later to the patients.

–High-protein foods like meat, fish, eggs, dairy and wheat products: excluded

–Foods with low protein content like milk, vegetables, fruits: used to meet required amount of Phe.

To allow diversification of diet, serving lists were established in which one weighed portion is equivalent to a previously determined amount of Phe (usually 15-20mg).

Life-long dietary treatment is universally recommended, but because of the practical difficulties involved in sustaining a strict diet, many allow a relaxation at some point between adolescence and adulthood. Whatever the decision regarding diet discontinuation, sustained follow-up is essential for affected females who are at risk for maternal PKU.

With appropriate dietary restriction, the blood levels of Phe should be maintained below the following values in different age groups as given below in Table II.

Table II.
Age (years) Blood Phe levelsmg/dl (µmol/L)
<10 2-5 (120-300)
15-18 2-15 (120-900)
Thereafter <20 (1200)

Tyrosine supplementation has not been adequately studied to provide any recommendation.Tyrosine supplementation along with a Phe-restricted diet is effective in maternal PKU.

Drugs

Tetrahydrobiopterin (BH4) may reduce blood Phe levels in mild cases of PKU and hyperphenylalaninemia due to defects in biosynthesis of BH4. It acts by the following ways:

– High-dose BH4 treatment may compensate for the decresed affinity of the mutant phenylalanine hydroxylase (PAH) for BH4.

– BH4 may upregulate the expression of PAH gene, stabilize PAH messenger mRNA, facilitate formation of functional PAH tetramers or protect a misfolded enzyme from proteolytic cleavage.

– Dose: 7.1 to 10.7mg/kg daily used in trials.

Sapropterin dihydrochloride: (Kuvan, Biomarin Corporation, Tiburon) a synthetic version of tetrahydrobiopterin, is FDA approved for reducing blood Phe levels in patients with hyperphenylalaninemia due to BH4-responsive PKU. The starting dose is 10mg/kg once daily (range, 5-20 mg/kg). It is available as 100mg off-white to light yellow tablets (equivalent to 76.8mg sapropterin base). Tablets should be dissolved in 4-8 ounces (120-240ml) of water or apple juice and taken within 15 minutes to increase absorption.

For a subset of patients with PKU, Kuvan will be sufficient as sole therapy; for others, Kuvan treatment may not completely eliminate the need for dietary therapy, but may increase patient’s dietary protein tolerance, allowing a significant improvement in daily quality of life.

Optimal Therapeutic Approach for this Disease

The objective is to specify the diagnosis and institute treatment as early as possible. The plasma level at screening indicates severity: Infants with blood Phe levels between 150-300µmol/L are retested; between 300-600µmol/L are controlled, investigated and monitored at outpatient clinic; those with levels>600µmol/L are hospitalized for further investigations, treatment and education. Secondary hyperphenylalaninemia due to various liver diseases (eg,, cirrhosis of liver, hemochromatosis) need to be excluded. Premature or small-for-gestational-age babies may have transient hyper Phe, especially those on parenteral nutrition. Disorders of BH4 metabolism should be excluded systematically.

Patients with both classical and atypical PKU require a (lifelong) dietary phenylalanine restriction, whereas patients affected with mild permanent HPA develop normally without treatment. A Phe-restricted diet lowered blood Phe levels at 3 months compared with a less restricted diet, with an improved intelligence quotient after 12 months compared with those who stopped the diet in trials.

Individuals with mental retardation caused by PKU who are experiencing severe behavioral disturbances should be considered for dietary treatment lasting for at least 6 months because metabolic control has been reported to improve behavior in such patients. Tyrosine supplementation in diet improves hair color with no significant effect on neurological outcomes, but tyrosine supplementation in conjunction with Phe-restricted diet is effective in maternal PKU.

Those with BH4-responsive disease may benefit from a trial of sapropterin dihydrochloride (Kuvan) initiated at dose of 10mg/kg once daily (adjust doses in range of 5-20mg/kg).

Use of Kuvan, may help maintain reduced Phe levels as an adjunct to Phe-controlled diet. Few patients were able to discontinue restricted diets with long-term tetrahydrobiopterin. Patients with liver impairment should be carefully monitored while receiving Kuvan because hepatic damage has been associated with impaired Phe metabolism. The most common side effects of kuvan (>4% of treated patients are headache, diarrhea, abdominal pain, upper respiratory tract infection, pharyngolaryngeal pain, vomiting. Serious but rare side effects include gastritis, spinal cord injury, urinary tract infection, neutropenia and testicular carcinoma.

Drug interactions due to coadministratrion with drugs affecting folate metabolism include

–methotrexate: decrease BH4 levels

–phosphodiesterase-5 inhibitors (sildenafil): additive vasorelaxation

–levodopa: exacerbation of convulsions, irritability

–Pregnancy category C: may be used when clearly needed.

Patient Management

Monitoring

  • Screening of newborn with automated capillary blood tests; if tested before 24 hours, should be retested at 2-7 days because of high false negative rates.

  • Serial monitoring of blood Phe levels, weekly for the first 2 or 3 years of life, declining to monthly by the age of 7-8 years. The aim is to maintain the blood Phe levels below 5mg/dl in children < 10 years of age and below 15mg/dl up to 18 years of age.

  • Monitoring done twice weekly during pregnancy.

  • Screening of individuals with mental retardation or severe behavioral disturbances of undetermined cause such as hyperactivity, aggression, self-injurious behavior- screened for PKU regardless of age.

  • The targeted blood levels of Phe varies with age with some relaxation by adolescence. However, it is recommended that Phe levels <6mg/dl be achieved at least 3 months before conception to prevent maternal PKU.

Education

Family members should be instructed to strictly adhere to the Phe-restricted diet, failing which the intellectual development of the child will be affected. Patients should avoid high-protein foods like meat, fish, eggs, dairy, and wheat products. In case of unpalatability or unaffordability of Phe-restricted supplements, parents may be instructed to give low-protein foods like fruits and vegetables. Parents should be counseled that there is about a 25% risk of the next offspring being affected with a similar problem.

Recommend outreach and educational programs for adolescents and women of childbearing age- focusing on social support, positive attitudes towards metabolic control of Phe, family planning, and information on maternal PKU

Unusual Clinical Scenarios to Consider in Patient Management

Reduction of blood Phe levels through dietary protein restriction prevents the major manifestations of the disease (mental retardation, seizure and growth failure). Shortcomings in this strategy exist, such as the need to adhere consistently to an unpalatable and expensive diet, persistent mild cognitive deficits in some treated children and severe teratogenic effects upon fetuses of mothers who cannot maintain dietary control.Therefore, cell-directed treatments including gene therapy like liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine PKU are being explored.

What is the Evidence?

Sarkany, RPE, Breathnach, SM, Morris, AAM, Weismann, K, Flynn, PD, Burns, T, Breathnach, S, Cox, N, Griffiths, C. “Metabolic and nutritional disorders”. Rook's textbook of dermatology. 2010. pp. 59.94-59.97. (The authors provide a comprehensive idea on the pathogenesis, clinical features and management of phenylketonuria and help us understand the other hyperphenylalaninemias due to defect in tetrahydrobiopterin pathway.)

de Klerk, JBC, Oranje, AP, Harper, J, Oranje, A, Prose, N. “Inherited metabolic disorders and the skin”. Textbook of pediatric dermatology. 2006. pp. 1964-68. (The authors describe the key symptoms of phenylketonuria and other inborn errors of metabolism related to skin and hair.)

“National Institutes of Health Consensus Development Conference Statement:Phenylketonuria:screening and management, October 16-18,2000”. Pediatrics. vol. 108. 2001. pp. 972-82. (The experts from various fields provide a consensus statement based on scientific evidence to provide health care providers, public and patients with a responsible assessment of currently available data regarding screening and management of phenylketonuria. This article emphasises the need for multidisciplinary system for delivery of care to individuals with phenylketonuria and the stringent metabolic control needed across the lifespan of such patients.)

de Baulny, HO, Abadie, V, Feillet, F, de Parscau, L. “Management of phenylketonuria and hyperphenylalaninemia”. J Nutr. vol. 137. 2007. pp. 1561S-63S. (The authors present the French guidelines to specify the minimal diagnostic procedures and optimal treatment of patients with phenylketonuria with a special note on maternal phenylketonuria.)

Muntau, A, Roschinger, W, Habich, M, Demmelmair, H, Hoffman, B, Sommerhoff, C. “Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria”. N Engl J Med. vol. 347. 2002. pp. 2122-32. (The authors explore the therapeutic efficacy of tetrahydrobiopterin in patients with mild hyperphenylalaninemia and observed a significant fall in blood phenylalanine levels in 87% (27 of 31) patients. They have also assessed whether responsiveness to tetrahydrobiopterin was associated with specific genotypes.)

Harding, C. “New era in treatment for phenylketonuria: pharmacologic therapy with sapropterin dihydrochloride”. Biologics: Targets&Therapy. vol. 4. 2010. pp. 231-36. (The authors provide an understanding of the biology of phenylketonuria and tetrahydrobiopterin, clinical trials of sapropterin in phenylketonuria, and how in a subset of individuals with phenylalanine hydroxylase deficiency sapropterin administration can lead to reduction in blood phenylalanine levels independant of dietary protein.)

Rohr, FJ, Lobbregt, D, Levy, HL. “Tyrosine supplementation in the treatment of maternal phenylketonuria”. Am J Clin Nutr. vol. 67. 1998. pp. 473-76. The authors study the response to supplementation with L-tyrosine in five maternal phenylketonuria pregnancies to support normal protein and catecholamine synthesis in the fetus by crossing the placenta and thus overcoming the fetal damage that would otherwise occur in a tyrosine-poor environment.)

Webster, D, Wildgoose, J. “Tyrosine supplementation for phenylketonuria (Review)”. Cochrane Database of Systematic Reviews. vol. 8. 2010. pp. CD001507(Detailed literary search to include randomized or quasi-randomized trials investigating use of tyrosine supplementation vs placebo in people with phenylketonuria in addition to, or instead of, a phenylananine-restricted diet was done. From the available evidence, the authors could not come up with any recommendations as to whether tyrosine supplementation should be introduced into routine clinical practice.)

(This prescribing information provides the practical concerns in the prescription of sapropterin (Kuvan) like formulation, dosing and drug interactions.)

Harding, CO, Gillingham, MB, Hamman, K, Clark, H, Goebel-Daghighi, E, Bird, A. “Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria”. Gene Tther. vol. 13. 2006. pp. 457-62. (The authors have produced a novel recombinant adeno-associated virus vector pseudotyped with serotype 8 capsid (rAAV2/8) expressing phenylalanine hydroxylase cDNA,, a liver-directed gene therapy, as a promising treatment approach for phenylketonuria and other allied inborn errors of metabolism.)

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