Tyrosinemia Type I: FAH Gene Deletion/Duplication

Tyrosinemia Type I is an autosomal recessive inborn error of tyrosine metabolism [1]. In untreated children, it presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises that can include:

• changes in mental status
• abdominal pain
• peripheral neuropathy

This may lead to liver failure, hepatocellular carcinoma, and potentially death before the age of ten years.

Inclusion of tyrosinemia in the newborn screening panel has improved diagnosis of this condition and initiation of crucial therapy [2]. Combined treatment with nitisinone (orfadine) and a low-tyrosine/phenylalanine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.

Tyrosinemia Type I results from deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). Typical biochemical findings include increased plasma and urine concentration of succinylacetone, elevated plasma concentrations of tyrosine, methionine, and phenylalanine, and elevated urinary concentration of tyrosine metabolites.

The FAH enzyme is encoded by the FAH gene located at 15q23, and mutations to this gene are responsible for tyrosinemia by leading to reduced or absent FAH enzyme activity. The four common FAH mutations (IVS12+5 G&A, IVS6-1 G&T, IVS7-6 T&G, and P261L) account for approximately 60% of mutations in tyrosinemia type I in the general US population. The P261L mutation accounts for nearly 100% of mutations responsible for tyrosinemia type I in the Ashkenazi Jewish population [3]. IVS12+5 G&A accounts for 87.9% of mutations in the French Canadian population [4]. However, no genotype/phenotype correlation has been established [5]. Gene sequence analysis is available to test for mutations in the FAH gene.

This test is indicated for:

• Confirmation of a clinical/biochemical diagnosis of Tyrosinemia Type I.
• Carrier testing in adults with a family history of Tyrosinemia Type I.

DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.

Please note that a "backbone" of probes across the entire genome are included on the array for analytical and quality control purposes. Rarely, off-target copy number variants causative of disease may be identified that may or may not be related to the patient's phenotype. Only known pathogenic off-target copy number variants will be reported. Off-target copy number variants of unknown clinical significance will not be reported.

Submit only 1 of the following specimen types

Preferred specimen type: Whole Blood

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

Oragene^TM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

• Amino Acid Analysis - Plasma (AA) and Organic Acids - Urine (OA) including succinylacetone and tyrosine metabolites.
• Sequence analysis of the FAH gene is available and is required before deletion/duplication analysis.
• Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

Requisition Forms

• Comprehensive Molecular Test Requisition Form
• Metabolic/Newborn Screening Follow-up Test Requisition Form

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