What is the management approach for hereditary metabolic diseases, such as phenylketonuria (PKU) and disorders of fatty acid oxidation?

From the Guidelines

The management of hereditary metabolic diseases, such as phenylketonuria (PKU) and disorders of fatty acid oxidation, primarily involves dietary modifications, supplementation, and careful monitoring to reduce morbidity, mortality, and improve quality of life. For PKU, treatment centers on a phenylalanine-restricted diet that limits natural protein intake while providing phenylalanine-free protein supplements to maintain adequate nutrition, as recommended by the American College of Medical Genetics and Genomics 1. Patients typically need to maintain this diet lifelong, with blood phenylalanine levels monitored regularly (weekly in infants, monthly in stable patients). Sapropterin (Kuvan) at 5-20 mg/kg/day can be prescribed for BH4-responsive PKU patients, allowing some dietary liberalization.

Key aspects of management include:

• Dietary intervention: a low-protein (Phe-restricted) diet, supplemented with Phe-free formula containing Tyr, and the frequent monitoring of plasma Phe, plasma Tyr, and micronutrients 1
• Pharmaceutical agents: sapropterin (a derivative of BH4) and pegvaliase (pegylated derivative of phenylalanine ammonia lyase) can be used to allow individuals with PAH deficiency to reduce Phe levels and relax their diet to a certain extent 1
• Monitoring: regular monitoring of plasma Phe levels, with targets of 2-6 mg/dL in children up to 12 years old and 2-15 mg/dL in children older than 12 years 1
• Multidisciplinary follow-up: regular follow-up with metabolic specialists, dietitians, and neuropsychological assessment is essential for optimal outcomes and adjustment of treatment plans as patients grow 1

For fatty acid oxidation disorders, management includes:

• Avoiding fasting with frequent feeding schedules (every 2-4 hours for infants, 4-6 hours for older children)
• A low-fat/high-carbohydrate diet
• Medium-chain triglyceride (MCT) oil supplementation
• L-carnitine supplementation (50-100 mg/kg/day) to help transport fatty acids
• Emergency protocols including glucose-containing fluids to prevent metabolic decompensation during illness

Early diagnosis through newborn screening is crucial, allowing prompt intervention before irreversible damage occurs 1. Regular multidisciplinary follow-up and careful monitoring are essential to adjust treatment plans as patients grow and to prevent long-term complications. By prioritizing these management strategies, individuals with hereditary metabolic diseases can achieve optimal outcomes and improved quality of life.

From the FDA Drug Label

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations Prior to JAVYGTOR Treatment Treatment with JAVYGTOR should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with JAVYGTOR should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.

The management approach for hereditary metabolic diseases, such as phenylketonuria (PKU), involves:

• Treatment with JAVYGTOR (sapropterin dihydrochloride) under the direction of physicians knowledgeable in the management of PKU
• A Phe-restricted diet, including dietary protein and Phe restriction, in addition to JAVYGTOR treatment
• Periodic blood Phe monitoring to assess blood Phe control, especially in pediatric patients 2 Key points to consider:
• The recommended starting dosage of JAVYGTOR is 10 mg/kg (actual body weight) administered orally once daily for pediatric patients 1 month to 6 years
• Patients 7 years and older should receive 10 to 20 mg/kg (actual body weight) administered orally once daily
• Dosage adjustment may be necessary based on biochemical response to therapy (blood Phe) 2

From the Research

Management Approach for Hereditary Metabolic Diseases

The management approach for hereditary metabolic diseases, such as phenylketonuria (PKU) and disorders of fatty acid oxidation, involves a combination of dietary restrictions and pharmacological interventions.

• Dietary Restrictions: Patients with PKU are required to follow a lifelong phenylalanine-restricted diet to reduce the intake of saturated and unsaturated fatty acids, especially long-chain polyunsaturated fatty acids (LC-PUFA) 3.
• Pharmacological Interventions: Sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), is approved for the treatment of PKU in patients who are BH4-responsive 4, 5. Sepiapterin, an oral synthetic form of a natural precursor of BH4, has also been shown to reduce hyperphenylalaninemia in some patients with PKU 6.

Treatment Options for PKU

Treatment options for PKU include:

• Sapropterin Dihydrochloride: Decreases blood phenylalanine concentration and increases dietary phenylalanine tolerance in some patients with PKU on a low-phenylalanine diet 4, 5.
• Sepiapterin: Reduces hyperphenylalaninemia in some patients with PKU, allowing for more patients to attain phenylalanine treatment targets or easing dietary phenylalanine restrictions 6.

Future Directions

Gene therapy is a potential future direction for the treatment of metabolic disorders, including PKU 7. However, more research is needed to assess the long-term safety and efficacy of current treatments and to develop new therapeutic options.