Tyrosinaemia type Ia without excess of urinary succinylacetone

Tyrosinaemia type I (McKusick 276700) (Kvittingen 1991) is an autosomal recessively inherited metabolic disorder due to two enzymatic deficiencies: fumarylacetoacetase (FAH) (type Ia) and maleylacetoacetate isomerase (type Ib) (Berger et al 1988). Elevation of urinary succinylacetone (SA) is usually deemed to be specific for tyrosinaemia type I. Diagnosis is made by assessing plasma tyrosine levels and urinary SA and by determining the activity of FAH in fibroblasts or lymphocytes. We report the case of a 3-year-old female child affected by tyrosinaemia type Ia, with persistent low levels of plasma tyrosine and no excess of urinary SA. Maria M. was born to first-degree cousins; the postnatal period is reported as uneventful. At 7 months of age hepatomegaly was noted and the child was hospitalized. At that time plasma tyrosine was slightly elevated (425 #mol/L by ion exchange chromatography), with moderate tyrosinuria. No excess of SA was detectable in urine by GC-MS. c~-Fetoprotein serum level was > 300 IU/ml. Liver ultrasound and CT scans showed hepatomegaly and multifocal micronodular structural abnormalities. Tyrosinaemia type I was then suspected despite the absence of SA and a dietary regimen with low phenylalanine and tyrosine intake (25mg/kg per day) wasintroduced. One month later, plasma tyrosine level was in the normal range (100/~mol/L). The clinical picture has always been good, including adequate psychomotor development, except for a marked hepatomegaly (4 cm below the costal arch); plasma tyrosine was steadily below l l0/tmol/L with only a slight elevation of plasma methionine; a major biochemical abnormality was c~-fetoprotein 4232 IU/ml (normal 0.01-7.00). On the basis of the good metabolic control, diet was then progressively relaxed in order to assess her dietary tyrosine tolerance (up to 100mg/kg per day). Plasma tyrosine levels remained constantly below 160 #mol/L, even 3 h after a meal. Urinary SA was still absent. Tyrosinaemia was then monitored for 1 year on a relaxed diet, being continuously below l l0#mol/L even after a protein load test providing 100mg/kg body weight, with no detectable urinary SA and only slight increase of 6-aminolaevulinic acid (600 ~mol/L; normal < 500/~mol/L). Hepatomegaly was the only clinical abnormality ever reported. The child stayed on a relaxed diet until the diagnosis of tyrosinaemia type Ia was confirmed by enzymatic activity determination on cultured skin fibroblasts (FAH 0.19nmol/min per mg protein; normal 0.67) performed at Professor R. Berger's Metabolic Laboratory, Wilhelmina Kinderziekenhuis, Utrecht. In the meantime her younger sister, aged 2 months, was admitted to another centre for recurrent vomiting, diarrhoea and jaundice. She had hepatomegaly (4 cm below costal arch) and elevation of serum total and conjugated bilirubin, ammonia, AST and ALT. Plasma tyrosine was 510#mol/L. In 24h her clinical picture worsened acutely with occurrence of seizures, dyspnoea, cyanosis and haematemesis, until death. Post-mortem liver histology showed a diffuse cirrhosis and features suggestive of tyrosinaemia type I. Maria was referred again to our department for progressive restriction of the dietary tyrosine intake. At that time liver ultrasound scan showed no modification of the previous picture of cirrhosis. Serum c~-fetoprotein level was 795 IU/ml. Three months later she remained in very good clinical condition, with adequate psychomotor development; plasma tyrosine was 70#mol/L and urinary SA still present in undetectable or trace amounts. We report this case of tyrosinaemia type Ia to encourage consideration of this disease even when the biochemical picture is not properly suggestive of it. Furthermore, the family history confirms the possible occurrence of acute and chronic forms of this disease in one family. Also, we believe that it demonstrates that no biochemical parameter by itself is pathognomonic for this disease, and that any slight elevation of plasma tyrosine levels even without SA urinary excess is worth further investigation