Nitisinone treatment during two pregnancies and breastfeeding in a woman with tyrosinemia type 1 – a case report

Objectives Tyrosinaemia type 1, an inherited disorder of tyrosine metabolism, is usually treated with a tyrosine-defined diet and since 2000 with nitisinone. So far, data about effects of nitisone during pregnancy and breastfeeding are rare. This is the first report of two pregnancies in a patient with tyrosinaemia type 1 while under treatment with nitisinone. Case presentation We here present a 20-year-old female patient with tyrisonemia type 1 receiving treatment with nitisinone and a tyrosine-defined diet since she was diagnosed with tyrosinaemia type 1 at the age of 18 months. During two pregnancies blood concentrations of tyrosine, succinylacetone and nitisinone were measured regularly. Neither infant has tyrosinaemia type 1 and both showed an initial increase in concentrations of tyrosine, succinylacetone and nitisinone. All three metabolites dropped within two weeks after birth. Both were exclusively breastfed for about two weeks. Both children show age-appropriate physical and mental development. Conclusions Nitisinone therapy during pregnancy and the short breastfeeding period did not result in adverse events in our patient or her children. Regular assessments of tyrosine, succinylacetone and nitisinone should be made during pregnancy and the breastfeeding period in both the mother and the infant. For better understanding, in principle, all cases of pregnancy and breastfeeding with tyrosinemia type 1 should be assessed and followed to further evaluate the implications of tyrosinaemia type 1 and its treatment during pregnancy. Additionally, even though experience with breastfeeding is limited, medication with nitisinone is safe and there is no reason to consider breastfeeding unsafe or to not recommend it.

Physical Growth of Patients with Hereditary Tyrosinaemia Type I: A Single-Centre Retrospective Study

In a retrospective review, we aimed to assess long-term growth in 17 patients (n = 11 males) with hereditary tyrosinaemia type I (HTI). Median age at assessment was 15.6 years (5.7–26.6 years) and median age at diagnosis was 1 month (range: 0–16 months), with 35% (n = 6/17) symptomatic on presentation. From the age of 8 years, there was a noticeable change in median height, weight, and body-mass-index [BMI]-z-scores. Median height-for-age z-scores were consistently ≤ −1 (IQR −1.6, −0.5) during the first 8 years of life but increased with age. Weight-for-age z-scores ranged between −1 to 0 (IQR −1.2, 0.1) in the first 8 years; then increased to > 0.5 (IQR −0.3, 1.3) by age 16 years, and BMI-for-age z-scores ranged from 0 to 1 (IQR −0.7, 1.3) up to 8 years, and >1 (IQR −0.2, 1.9) until 16 years. The percentage of overweight and obesity was lowest in children aged < 5 years, and consistently > 40% in patients aged between 7 to 16 years. The prescribed total protein intake was associated with improved height growth (p < 0.01). Impaired growth in early life improved with age achieving normal population standards. Further studies are needed to investigate factors that influence growth outcome in HTI patients.

Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Patient with Uncontrolled Tyrosinaemia Type 1

Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a recognisable complication of acute porphyria. We report a nine-year-old female patient with hereditary tyrosinaemia type 1 and poor adherence to nitisinone therapy who presented with acute abdominal pain, vomiting and lethargy at Sultan Qaboos University Hospital, Muscat, Oman in 2016. She subsequently developed generalised tonic-clonic seizures attributable to severe hyponatremia that met the diagnostic criteria of SIADH. The acute porphyria screen also appeared positive. The patient responded well to fluid restriction and was discharged home without immediate neurological sequelae. Although acute porphyria is also a recognised complication of uncontrolled tyrosinaemia type 1, to the best of the authors’ knowledge, no patient with tyrosinaemia type 1 has been reported to present with SIADH. Keywords: Tyrosinemia Type 1; Hyponatremia; Inappropriate ADH Syndrome; Case Report; Oman.

Diazoxide-responsive hyperinsulinaemic hypoglycaemia in tyrosinaemia type 1

Summary Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5–12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1. Learning points Every child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia. If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected. Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects. The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Hepatorenal Tyrosinaemia: Impact of a Simplified Diet on Metabolic Control and Clinical Outcome

Background: Tyrosinaemia type 1 is a rare inherited metabolic disease caused by an enzyme defect in the tyrosine degradation pathway. It is treated using nitisinone and a low-protein diet. In a workshop in 2013, a group of nutritional specialists from Germany, Switzerland and Austria agreed to advocate a simplified low-protein diet and to allow more natural protein intake in patients with tyrosinaemia type 1. This retrospective study evaluates the recommendations made at different treatment centers and their impact on clinical symptoms and metabolic control. Methods: For this multicenter study, questionnaires were sent to nine participating treatment centers to collect data on the general therapeutic approach and data of 47 individual patients treated by those centers. Results: Dietary simplification allocating food to 3 categories led to increased tyrosine and phenylalanine blood concentrations without weighing food. Phenylalanine levels were significantly higher in comparison to a strict dietary regimen whereas tyrosine levels in plasma did not change. Non-inferiority was shown for the simplification and liberalization of the diet. Compliance with dietary recommendations was higher using the simplified diet in comparison to the stricter approach. Age correlates negatively with compliance. Conclusions: Simplification of the diet with increased natural protein intake based on three categories of food may be implemented in the diet of patients with tyrosinaemia type 1 without significantly altering metabolic control. Patient compliance is strongly influencing tyrosine blood concentrations. A subsequent prospective study with a larger sample size is necessary to get a better insight into the effect of dietary recommendations on metabolic control.

Clinical utilization of dried blood spot nitisinone (NTBC) and succinylacetone (SA) concentrations in hereditary tyrosinaemia type 1 – A UK centre experience

Background Dried blood spot monitoring of nitisinone and succinylacetone in hereditary tyrosinaemia type 1 patients is not widely available in the United Kingdom. Currently, biochemical monitoring utilizes urinary succinylacetone, blood spot tyrosine and phenylalanine monitoring, which can lack in convenience and accuracy, respectively. Methods We report the development of a dried blood spot assay for nitisinone and succinylacetone and analysed retrospective clinical and biochemical data for hereditary tyrosinaemia type 1 patients from a single UK centre. Results A total of 13 hereditary tyrosinaemia type 1 patients were evaluated. Eleven presented with liver dysfunction (two with associated renal tubulopathy) and two were detected by early sibling screening. All patients (age 0.03–22 months) were commenced on a tyrosine-/phenylalanine-restricted diet and nitisinone at diagnosis. Ten patients were on twice daily dosing and three were on single daily dosing at the start of monitoring. One patient from each dosing group swapped between dosing regimens at 20 years of age and 8 months of age, respectively. A total of 684 dried blood spot samples were analysed; 80% of nitisinone concentrations were between 9.2 and 27 µmol/L when succinylacetone was <0.3 µmol/L. Patients on twice daily dosing regimens had significantly higher nitisinone concentration compared with those on once daily dosing ( P < 0.0001). The median dose required in the twice daily doing group was significantly lower when compared with once daily dosing. Conclusions Dried blood spot monitoring for nitisinone and succinylacetone concentrations in hereditary tyrosinaemia type 1 patients is a rapid and convenient method which allows physicians to individualize treatment plans and observe adherence to treatment.

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.