Tyrosinemia type 1: a rare and forgotten cause of reversible hypertrophic cardiomyopathy in infancy

Abstract

BackgroundTyrosinemia type 1 (TT1) is an autosomal recessive disorder caused by deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). TT1 usually presents in infancy with features suggestive of liver disease or with sepsis-like symptoms.Case presentationWe report two Saudi siblings with TT1. Case 1 was a male infant who presented at 2 months old with fever, vomiting and refusal of feeding. Examination revealed a sick-looking infant with signs of severe dehydration and hypovolemic shock. He was jaundiced, and had hepatomegaly and elevated liver enzymes. Echocardiography was performed in light of a lack of response to inotropes, and revealed biventricular and interventricular septal hypertrophies. The ventricular ejection fraction was 65%. Urine organic acid analysis showed elevated succinylacetone, consistent with a diagnosis of TT1. An FAH gene study identified a c.1 A > G homozygous mutation. This patient responded well to intensive cardiorespiratory therapy, tyrosine-free formula, and oral 2-nitro-4- trifluoromethylbenzyl 1, 3 cyclohexanedione (NTBC). Echocardiographic findings reverted to normal after 4 weeks. Case 2 was the younger brother of Case 1, and was born 6 months after his brother had been confirmed with tyrosinemia. Pregnancy and delivery were uneventful. Serum amino acid and organic acid analyses 4 days after birth confirmed tyrosinemia. DNA analysis identified a c.1 A > G homozygous mutation, as in his brother. Echocardiography was normal. Special formula and NTBC were commenced on day 7 of life. The infant remained asymptomatic after 9 months of follow-up.ConclusionsThese cases highlight TT1 as a treatable cause of cardiomyopathy in children. It also supports the idea that early diagnosis and treatment may prevent the development of cardiomyopathy associated with tyrosinemia.

Clinical Features of 29 Patients with Hereditary Tyrosinemia I in Western Turkey

“…Other clinical manifestations that less frequently observed are hypoglycemia due to hyperinsulinism (6) and hypertrophic cardiomyopathy (7,8).…”

Nitisinone: a review

“…40 Cardiomyopathy resolves in the patients treated with nitisinone. 39,40,80 Nitisinone and alkaptonuria Alkaptonuria (AKU; OMIM 203500) is a rare autosomal recessive disease caused by a deficiency of homogentisate 1,2-dioxygenase (HGD) that converts intermediate HGA to MAA in the Tyr metabolism pathway (Figure 1). The singlecopy human HGD gene maps to chromosome 3q13.33, encompassing 14 exons and encoding a 445-mer protein.…”

“…26,32,[34][35][36][37] Cardiomyopathy and hyperinsulinism have also been described. [38][39][40] Most patients present with the acute and subacute form of the disease characterized by clinical findings of acute-subacute liver failure with poor growth, vomiting, ascites, coagulopathy, hypoglycemia, hypoalbuminemia, and hyperbilirubinemia. Patients with the chronic form have growth failure; renal tubular dysfunction including Fanconi syndrome; and neurologic crises with pain and paresthesias associated with evidence of liver dysfunction, including hepatomegaly, transaminasemia, hyperbilirubinemia, and coagulopathy.…”

“…64,78,79 Cardiomyopathy is a rare complication of HT1 and usually reported at the initial presentation as hypertrophic cardiomyopathy involving hypertrophy of the interventricular septum. 39,40 The pathogenesis is poorly understood and is thought to be related to the accumulation of toxic FAA in the cardiac tissues or to the elevated Tyr levels. 40 Cardiomyopathy resolves in the patients treated with nitisinone.…”

“…39,40 The pathogenesis is poorly understood and is thought to be related to the accumulation of toxic FAA in the cardiac tissues or to the elevated Tyr levels. 40 Cardiomyopathy resolves in the patients treated with nitisinone. 39,40,80 Nitisinone and alkaptonuria Alkaptonuria (AKU; OMIM 203500) is a rare autosomal recessive disease caused by a deficiency of homogentisate 1,2-dioxygenase (HGD) that converts intermediate HGA to MAA in the Tyr metabolism pathway (Figure 1).…”