Tyrosinemia Type I

CLINICAL CHARACTERISTICS

Untreated tyrosinemia type I usually 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 lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Newborn screening / early diagnosis and combined treatment with nitisinone and a low-tyrosine 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.

DIAGNOSIS/TESTING: The diagnosis of tyrosinemia type I can be established in a proband by identification of increased succinylacetone concentration in the blood and urine or biallelic pathogenic variants in by molecular genetic testing.

MANAGEMENT

Nitisinone; low-phenylalanine, low-tyrosine diet; liver transplantation for children with severe liver failure at presentation and failure to respond to nitisinone therapy or malignant changes in hepatic tissue. Additional treatment (especially for those not receiving nitisinone) includes: antihypertensive medications and/or referral to nephrologist for management of hypertension; correction of metabolic acidosis, restoring calcium and phosphate balance, and 25-hydroxyvitamin D supplementation for osteoporosis/rickets; management of liver disease per hepatologist; treatment of hepatocellular carcinoma per oncologist/hepatologist; nutrition support per metabolic dietician; frequent feeds and avoidance of fasting to prevent hypoglycemia; developmental services and educational support as needed; provide written protocols and letters for emergency management; transitional care plan. Acute inpatient treatment for neurologic crises includes intravenous glucose, antihypertensives, analgesics, correction of hyponatremia, and prompt nitisinone therapy, with crises prevented by strict long-term adherence and monitoring. Plasma concentrations of methionine, phenylalanine, and tyrosine, blood and urine succinylacetone concentrations, blood nitisinone concentration, complete blood count, serum alpha-fetoprotein, routine coagulation tests, liver enzymes, and bilirubin concentrations should be measured per age-related recommendations. Liver imaging annually or as clinically indicated to assess for hepatocellular carcinoma. Blood urea nitrogen and creatinine, urine phosphate, calcium, and protein-to-creatinine ratio, and kidney ultrasound as clinically indicated to evaluate for kidney disease. Wrist radiographs as clinically indicated to evaluate for rickets. Developmental assessment at each visit or as clinically indicated. Neuropsychological testing should be done before school age and then as indicated. Assess for ophthalmologic manifestations at each visit with slit lamp examination if symptomatic. Psychosocial assessment at each visit or as clinically indicated. Excessive dietary protein or protein malnutrition inducing catabolic state; prolonged fasting; catabolic illness (intercurrent infection, brief febrile illness post vaccination); inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia). Testing of at-risk sibs of any age is warranted to allow for early diagnosis and prompt initiation of treatment. Prenatal testing (if the familial pathogenic variants are known) may be performed via amniocentesis or chorionic villus sampling. If prenatal testing was not performed, then – in parallel with NBS – urine and blood succinylacetone should be analyzed as soon as possible after birth to enable the earliest possible diagnosis and initiation of therapy ( molecular genetic testing can be performed if the familial pathogenic variants are known). Limited data exist on the use of nitisinone during human pregnancy; however, at least two women have given birth to healthy infants while receiving therapeutic doses of nitisinone.

GENETIC COUNSELING

Tyrosinemia type I is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for tyrosinemia type I are possible.