Casein Glycomacropeptide: An Alternative Protein Substitute in Tyrosinemia Type I.

Tyrosinemia type I (HTI) is treated with nitisinone, a tyrosine (Tyr) and phenylalanine (Phe)-restricted diet, and supplemented with a Tyr/Phe-free protein substitute (PS). Casein glycomacropeptide (CGMP), a bioactive peptide, is an alternative protein source to traditional amino acids (L-AA). CGMP contains residual Tyr and Phe and requires supplementation with tryptophan, histidine, methionine, leucine, cysteine and arginine. AIMS: a 2-part study assessed: (1) the tolerance and acceptability of a low Tyr/Phe CGMP-based PS over 28 days, and (2) its long-term impact on metabolic control and growth over 12 months. METHODS: 11 children with HTI were recruited and given a low Tyr/Phe CGMP to supply all or part of their PS intake. At enrolment, weeks 1 and 4, caregivers completed a questionnaire on gastrointestinal symptoms, acceptability and ease of PS use. In study part 1, blood Tyr and Phe were assessed weekly; in part 2, weekly to fortnightly. In parts 1 and 2, weight and height were assessed at the study start and end. RESULTS: Nine of eleven children (82%), median age 15 years (range 8.6-17.7), took low Tyr/Phe CGMP PS over 28 days; it was continued for 12 months in n = 5 children. It was well accepted by 67% (n = 6/9), tolerated by 100% (n = 9/9) and improved gastrointestinal symptoms in 2 children. The median daily dose of protein equivalent from protein substitute was 60 g/day (range 45-60 g) with a median of 20 g/day (range 15 to 30 g) from natural protein. In part 2 (n = 5), a trend for improved blood Tyr was observed: 12 months pre-study, median Tyr was 490 µmol/L (range 200-600) and Phe 50 µmol/L (range 30-100); in the 12 months taking low Tyr/Phe CGMP PS, median Tyr was 430 µmol/L (range 270-940) and Phe 40 µmol/L (range 20-70). Normal height, weight and BMI z scores were maintained over 12 months. CONCLUSIONS: In HTI children, CGMP was well tolerated, with no deterioration in metabolic control or growth when studied over 12 months. The efficacy of CGMP in HTI needs further investigation to evaluate the longer-term impact on blood Phe concentrations and its potential influence on gut microflora.

Natural Protein Tolerance and Metabolic Control in Patients with Hereditary Tyrosinaemia Type 1.

In a longitudinal retrospective study, we aimed to assess natural protein (NP) tolerance and metabolic control in a cohort of 20 Hereditary Tyrosinaemia type I (HTI) patients. Their median age was 12 years ([3.2-17.7 years], n = 11 female, n = 8 Caucasian, n = 8 Asian origin, n = 2 Arabic and n = 2 Indian). All were on nitisinone (NTBC) with a median dose of 0.7 g/kg/day (range 0.4-1.5 g/kg/day) and were prescribed a tyrosine (Tyr)/phenylalanine (Phe)-restricted diet supplemented with Tyr/Phe-free L-amino acids. Data were collected on clinical signs at presentation, medical history, annual dietary prescriptions, and blood Phe and Tyr levels from diagnosis until transition to the adult service (aged 16-18 years) or liver transplantation (if it preceded transition). The median age of diagnosis was 2 months (range: 0 to 24 months), with n = 1 diagnosed by newborn screening, n = 3 following phenylketonuria (PKU) screening and n = 7 by sibling screening. Five patients were transplanted (median age 6.3 years), and one died due to liver cancer. The median follow-up was 10 years (3-16 years), and daily prescribed NP intake increased from a median of 5 to 24 g/day. Lifetime median blood Tyr (370 µmol/L, range 280-420 µmol/L) and Phe (50 µmol/L, 45-70 µmol/L) were maintained within the target recommended ranges. This cohort of HTI patients were able to increase the daily NP intake with age while maintaining good metabolic control. Extra NP may improve lifelong adherence to the diet.

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria.

Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700 µmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. Elevated tyrosine (813 µmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3, 274.8, and 144.3 µmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 µmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 µmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.

Biomarkers of Micronutrients in Regular Follow-Up for Tyrosinemia Type 1 and Phenylketonuria Patients.

Phenylketonuria (PKU) is treated with dietary restrictions and sometimes tetrahydrobiopterin (BH4). PKU patients are at risk for developing micronutrient deficiencies, such as vitamin B12 and folic acid, likely due to their diet. Tyrosinemia type 1 (TT1) is similar to PKU in both pathogenesis and treatment. TT1 patients follow a similar diet, but nutritional deficiencies have not been investigated yet. In this retrospective study, biomarkers of micronutrients in TT1 and PKU patients were investigated and outcomes were correlated to dietary intake and anthropometric measurements from regular follow-up measurements from patients attending the outpatient clinic. Data was analyzed using Kruskal-Wallis, Fisher's exact and Spearman correlation tests. Furthermore, descriptive data were used. Overall, similar results for TT1 and PKU patients (with and without BH4) were observed. In all groups high vitamin B12 concentrations were seen rather than B12 deficiencies. Furthermore, all groups showed biochemical evidence of vitamin D deficiency. This study shows that micronutrients in TT1 and PKU patients are similar and often within the normal ranges and that vitamin D concentrations could be optimized.

Eficacia y seguridad de los suplementos nutricionales libres de tirosina y fenilalanina para el tratamiento de pacientes menores de 18 años con diagnóstico de tirosinemia tipo I / Efficacy and safety of tyrosine and phenylalanine free nutritional supplements for the treatment of patients under 18 years of age with diagnosis of tyrosinemia type I

INTRODUCCIÓN: La tirosinemia tipo 1 (HT-1) es una enfermedad genética infrecuente causada por la mutación del gen FAH. Esta mutación produce escasez de la enzima fumaril-aceto-acetato hidrolasa; responsable del último paso en la vía de degradación de la tirosina. El acúmulo de los metabolitos tóxicos de la tirosina interrumpe severamente el metabolismo intracelular del hígado y riñón; dañando estos órganos. La HT-1 se presenta en uno de cada 100.000 - 120.000 nacimientos alrededor del mundo. El tratamiento de los pacientes con HT-1 está dirigido a controlar los niveles plasmáticos de tirosina y evitar la formación de sus metabolitos tóxicos. El manejo nutricional reduce la ingesta de tirosina y fenilalanina mediante la dieta. El tratamiento farmacológico involucra el uso de nitisinona; la cual bloquea el segundo paso de la vía de degradación de la tirosina. De esta forma, se evita la formación de los metabolitos tóxicos de la tirosina; pero se incrementa el nivel plasmático de tirosina; lo cual produce, a su vez, molestias visuales debidas a la formación de cristales de tirosina. Para mantener el nivel de tirosina dentro del rango normal, la dieta debe estar reducida en tirosina y fenilalanina (precursor de la tirosina). Esto refuerza la importancia del manejo nutricional mediante la restricción de la ingesta de tirosina y fenilalanina en la dieta. Sin embargo, esta dieta podría no cubrir los demás requerimientos nutricionales, energéticos y proteicos de los pacientes con HT-1. Por lo tanto, los suplementos nutricionales serían necesarios para complementar la dieta. En EsSalud se dispone de suplementos nutricionales pediátricos. Sin embargo, estos no están libres de fenilalanina y tirosina. OBJETIVO: el presente dictamen preliminar expone la eficacia y seguridad de los suplementos nutricionales libres de fenilalanina y tirosina, junto con una dieta reducida en tirosina, comparado con una dieta reducida en tirosina para el tratamiento de los pacientes menores de 18 años, con diagnóstico de HT-1. METODOLOGÍA: Tras una búsqueda sistemática de literatura publicada hasta diciembre del 2018, no se encontró evidencia científica que evalúe el uso de suplementos nutricionales libres de fenilalanina y tirosina acompañados de una dieta reducida en tirosina, comparado con un manejo nutricional que involucre solo la dieta reducida en tirosina, en pacientes menores de 18 años con diagnóstico de HT-1. En su lugar, se hallaron tres artículos de recomendación tipo revisión que abordan el manejo nutricional de los pacientes con HT-1. Uno de ellos no menciona los suplementos libres de tirosina y fenilalanina. Los otros dos, mencionan que es necesario añadir estos suplementos a la dieta de todo paciente con HT-1. Sin embargo, esta afirmación no forma parte de las recomendaciones propiamente dichas, y no se mostraron las referencias de la evidencia utilizada para dar esta afirmación. RESULTADOS: Pese a la escasa evidencia científica disponible, la eficacia de los suplementos nutricionales libres de tirosina y fenilalanina tiene sustento biológico razonable. El requerimiento varía desde 3 g/kg/día, aproximadamente, en menores de 2 años hasta 1.5 g/Kg/día a los 10-14 años. Sin embargo, los requerimientos de tirosina y fenilalanina se alcanzan con pequeñas cantidades de proteína natural (0.5 a 1.0 g/Kg/día). Al restringir la ingesta de proteína natural (para evitar el exceso de tirosina y fenilalanina en pacientes con HT-1), se crea un déficit para cubrir el requerimiento proteico global. Si este déficit no se cubre, el paciente tendrá problemas en el crecimiento y desarrollo psicomotor. Por lo tanto, la inclusión de suplementos nutricionales libres de tirosina y fenilalanina en la dieta de los pacientes HT-1 ayuda a cubrir sus requerimientos proteicos, manteniendo las concentraciones plasmáticas de tirosina en el rango saludable. En línea con lo mencionado, el experto en pediatría de la institución, afirma que los suplementos nutricionales libres de tirosina y fenilalanina permiten el adecuado crecimiento y desarrollo neurológico mientras evita la aparición de problemas visuales. Por lo tanto, el experto en pediatría opina que estos suplementos nutricionales son un complemento terapéutico necesario para el tratamiento dietético. Esta posición coincide con la opinión de los expertos internacionales y las revisiones presentadas en el presente dictamen preliminar. CONCLUSIÓN: Con respecto a lo expuesto previamente, el equipo técnico del IETSI valoró los siguientes aspectos: i) La HT-1 es una enfermedad hereditaria, infrecuente, que afecta la calidad de vida del paciente desde edades muy tempranas y está asociada a una alta mortalidad si no es tratada adecuadamente ii) En el contexto de EsSalud existe un vacío terapéutico para la población objetivo, iii) Aunque la evidencia disponible actualmente es limitada, algunas guías mencionan el uso de suplementos nutricionales libres de tirosina y fenilalanina. Además, su uso cuenta con plausibilidad biológica, lo cual va en línea con lo recomendado por el experto clínico. Por todo lo mencionado, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI, aprueba el uso de suplementos libres de tirosina y fenilalanina para el manejo de pacientes menores de 18 años, con diagnóstico de HT-1, según lo establecido en el Anexo N° 1 La vigencia del presente dictamen preliminar es de dos años a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Dietary Considerations in Tyrosinemia Type I.

Since the introduction of 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione (NTBC), life expectancy of HT1 patients greatly improved. However, due to treatment with NTBC, tyrosine concentrations greatly increase. As a consequence to possible neurocognitive problems, the main objective of dietary therapy in HT1 is to provide adequate nutrition allowing normal growth and development while strictly controlling tyrosine levels in blood (and tissues). Although no well-defined target levels exist, tyrosine concentrations below 400 µmol/L are considered to be safe. To achieve this aim a diet restricted in natural protein and supplemented with a special tyrosine and phenylalanine-free amino acid mixture is necessary.Dietary management could be strenuous at diagnosis due to several different problems. If vomiting and diarrhea are a major issue at diagnosis, frequent feeding with additional energy from low protein food is needed for catch-up growth. Initiation of dietary treatment is usually easier if diagnosis is directly after birth. Based on newborn screening when infants are still reasonable healthy. If presenting clinically infants may experience serious difficulties in taking the amino acid mixtures probably due to feeding problems while when presenting after some 2-3 months taste development and the difference in the taste of amino acid mixtures compared to regular formula and breast milk increase difficulties with the treatment.Following a dietary treatment is even harder than taking some medicine. Older children and adolescents often relax the diet and at some age become reluctant to stick to a strict regimen. Therefore, adequate training and information should be given to the patients and the family at regular intervals. To achieve this, a multidisciplinary approach involving pediatricians/physicians, dieticians, psychologists and social workers is an asset for the care of patients with HT1.

Experience with NTBC therapy in hereditary tyrosinaemia type I: an alternative to liver transplantation.

We present the clinical data of five infants with type I (hepato-renal) tyrosinaemia on NTBC therapy. All presented initially at the local hospital in the 1st year of life with progressive abdominal distension owing to hepato-splenomegaly and with radiological evidence of liver cirrhosis, except for one child who was diagnosed during screening because of an affected sibling. Age at commencement of NTBC therapy ranged from 6 to 30 months. All infants showed remarkable improvement within 2-6 months of starting NTBC treatment, except one who died 2 months after commencement of therapy from uncontrolled liver failure, severe coagulopathy and Streptococcus pneumoniae septicaemia. NTBC treatment along with a phenylalanine- and tyrosine-restricted diet has effectively reversed most clinical manifestations of this disease. To date, none of our patients has developed hepatic carcinoma and NTBC was well tolerated without side-effects. NTBC is costly but life-saving and is an obvious alternative to more hazardous liver transplantation.