A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report.

A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (<720), total bilirubin was 2.53 mg/dl (<1.0), ammonaemia 69 microM (<32), prothrombin time less than 10%, thromboplastin time >180 s (<60) and alpha-fetoprotein 29723 microg/L (<186). Plasma tyrosine (651 microM) and methionine (1032 microM) were strongly increased. In urine, tyrosine metabolites and 4-oxo-6-hydroxyheptanoic acid were increased, but succinylacetone and succinylacetoacetate--pathognomonic for tyrosinemia type I--were repeatedly undetectable. Delta-aminolevulinic acid was normal, which is consistent with the absence of succinylacetone. Abdominal ultrasound and brain CT were normal.Fumarylacetoacetase (FAH) protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression.Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development.This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate.

[Individualized pharmacotherapy based on cytochrome P-450 (CYP) genotyping]. / Individualisert farmakoterapi basert på cytokrom P-450 (CYP)-genotyping.

BACKGROUND: Genetic polymorphisms of the drug-metabolising cytochrome P-450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6 have been characterized, and several of these variants lead to reduced or absent activity. This is of clinical importance mainly in patients having two non-functional alleles, phenotypically characterised as "poor metabolisers" (1-10% of Caucasians). Since most drugs are transformed into inactive or less active metabolites, "poor metabolisers" are at increased risk of developing drug induced adverse reactions. MATERIAL AND METHODS: Studies of relevant literature (MedLine search) in addition to our own experiences, show that CYP genotyping can predict the phenotype and thereby explain some abnormal drug responses and may be used to individualize pharmacotherapy. RESULTS: At present, CYP genotyping (CYP2C9/2C19/2D6) is most frequently requested in psychiatry and anticoagulant therapy, but the field is expanding. Important factors for implementation of pharmacogenetic methods are accuracy of diagnosis, quality of reports, response time, and cost. INTERPRETATION: Pharmacogenetic analyses will significantly contribute to reducing treatment costs for drug-induced adverse reactions and costs of sick leave, by predicting the best drug and the most effective and safest dosage. The expenses of full genotyping (CYP2C9/2C19/2D6) are equivalent to one day of sick leave. One might ask: Are pharmacogenetic analyses coming to the point where they drive down costs incurred by illness?

Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene.

Phosphorylase kinase-deficient liver glycogenosis manifests in infancy with hepatomegaly, growth retardation, and elevated plasma aminotransferases and lipids. It can be caused by mutations in three different genes of phosphorylase kinase subunits: PHKA2, PHKB, and PHKG2. It is usually a benign condition, often with complete resolution of symptoms during puberty. A minority of patients displays a more severe phenotype with symptomatic fasting hypoglycemia and abnormal liver histology that may progress to cirrhosis. Three patients with liver cirrhosis in childhood analyzed previously all had PHKG2 mutations. This suggested that this genotype may generally cause a more severe clinical manifestation, but to date PHKG2 mutations have been identified in only seven patients. Here, we report mutation analysis in three new patients with liver phosphorylase kinase deficiency and recurrent hypoglycemia, liver fibrosis, and lack of glucagon response but no overt cirrhosis. In all three patients, PHKG2 mutations were found (H89fs[insC], E157K, D215N, W300X). Three of these mutations are novel, bringing the total number of distinct human PHKG2 mutations to 11, found in 10 patients. We conclude that liver phosphorylase kinase deficiency with a severe phenotype, with or without cirrhosis, is indeed often caused by PHKG2 mutations. These patients require active measures to maintain normoglycemia (raw cornstarch, nocturnal tube feeding), which may also alleviate growth retardation and the development of abnormal liver histology.