Hepatorenal tyrosinaemia (HT1) is an autosomal recessive disorder of tyrosine degradation resulting in hepatic and renal dysfunction, neurological sequelae may occur in some patients. The use of nitisinone (NTBC) has revolutionised treatment and outcome of this disorder. NTBC has to be combined with a low protein diet. While NTBC modulates the disease course in HT1 patients, several issues are open. Optimal dosage, doses per day, therapeutic range of NTBC concentration, mode of protein restriction and biomarkers are not well defined. HCC and neurocognitive deficits are long-term sequelae. Early diagnosis and treatment are essential to minimise the risk for these complications. Clinical guidance for management of HT1-patients is required. Randomised clinical studies are difficult in the presence of therapeutic options. We discussed these issues in a consensus group of 10 paediatricians, 1 adult hepatologist, 1 geneticist, 2 dieticians, 2 newborn screening specialists with experience in HT1, 1 psychologist and 2 representatives of a patient group from the German-speaking countries (DACH). Recommendations were based on scientific literature and expert opinion, also taking into account recent experience with newborn screening. There was strong consensus that newborn screening using succinylacetone (SA) and early treatment are essential for a good outcome. The dose of NTBC should be as low as possible without losing metabolic control. This has to be accompanied by a low protein diet, in some patients a simplified diet without calculation of protein intake. Specific education and psychosocial support are recommended. Indications for liver transplantation were defined. Monitoring shall include clinical findings, levels of SA, tyrosine, phenylalanine and NTBC in (dried) blood.

• Keywords
• hepatorenal tyrosinaemia, newborn screening, nitisinone, succinylacetone, tyrosine,
• MeSH
• Cyclohexanones * therapeutic use   MeSH
• Heptanoates MeSH
• Consensus MeSH
• Humans MeSH
• Nitrobenzoates * therapeutic use   MeSH
• Diet, Protein-Restricted MeSH
• Infant, Newborn MeSH
• Neonatal Screening * methods   MeSH
• Liver Transplantation MeSH
• Tyrosinemias * diagnosis   therapy   MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• Germany MeSH
• Names of Substances
• Cyclohexanones * MeSH
• Heptanoates MeSH
• nitisinone MeSH Browser
• Nitrobenzoates * MeSH
• succinylacetone MeSH Browser

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism that leads to severe liver, kidney, and neurological dysfunction. Newborn screening (NBS) can enable a timely diagnosis and early initiation of treatment. We presented the follow up of the only two Slovenian patients diagnosed with HT1. Metabolic control was monitored by measuring tyrosine, phenylalanine and succinylacetone from dried blood spots (DBSs). Retrograde screening of HT1 was performed from DBSs taken at birth using tandem mass spectrometry. First patient was diagnosed at the age of 6 months in the asymptomatic phase due to an abnormal liver echogenicity, the other presented at 2.5 months with an acute liver failure and needed a liver transplantation. The first was a compound heterozygote for a novel FAH intronic variant c.607-21A>G and c.192G>T whereas the second was homozygous for c.192G>T. At the non-transplanted patient, 66% of tyrosine and 79% of phenylalanine measurements were in strict reference ranges of 200-400 μmol/L and >30 μmol/L, respectively, which resulted in a favorable cognitive outcome at 3.6 years. On retrograde screening, both patients had elevated SA levels; on the other hand, tyrosine was elevated only at one. We showed that non-coding regions should be analyzed when clinical and biochemical markers are characteristic of HT1. DBSs represent a convenient sample type for frequent amino acid monitoring. Retrograde diagnosis of HT1 was possible after more than three years of birth with SA as a primary marker, complemented by tyrosine.

• Keywords
• AFP, alpha-fetoprotein, ALP, alkaline phosphatase, ALT, alanine transaminase, AST, aspartate transaminase, DBS, dried blood spot, Dried blood spot, FAH, fumarylacetoacetate hydrolase, Fumarylacetoacetate hydrolase, GGT, gamma glutamyl transferase, HT1, tyrosinemia type 1, INR, international normalized ratio, Intronic variant, MS/MS, tandem mass spectrometry, NBS, newborn screening, NTBC, nitisinone, Nitisinone, PTT, partial thromboplastin time, RF, reference range, SA, succinylacetone, Succinylacetone, Tyrosinemia,
• Publication type
• Journal Article MeSH
• Case Reports MeSH