What are the treatment options for a child with tyrosine deficiency, presenting with hypotonia, developmental delays, and seizures?

Treatment of Tyrosinemia Type 1 (Not Tyrosine Hydroxylase Deficiency)

For a child with tyrosinemia type 1 presenting with hypotonia, developmental delays, and seizures, immediately initiate NTBC (nitisinone) combined with dietary restriction of phenylalanine and tyrosine—this combination prevents progression of hepatic and renal failure, avoids liver transplantation, and dramatically improves survival from 29% to 88% at 2-4 years when started early. 1, 2

Immediate Management Algorithm

First-Line Therapy: NTBC + Dietary Restriction

NTBC (Nitisinone) is the cornerstone of treatment and must be started immediately upon diagnosis without waiting for genetic confirmation. 2 This medication blocks the tyrosine catabolic pathway upstream of the toxic metabolite accumulation, preventing formation of fumarylacetoacetate and succinylacetone—the compounds directly responsible for hepatic, renal, and neurological damage. 1

Dietary Management Protocol

Restrict both phenylalanine AND tyrosine since approximately 75% of dietary phenylalanine converts to tyrosine. 1 The dietary approach requires:

• Reduced intact protein intake appropriate for age 1
• Medical foods (amino acid mixtures devoid of phenylalanine and tyrosine, such as Tyrex 1, Tyros 1, or Tyr coolers) 1
• High energy intake: 130 kcal/kg/day 1
• High protein intake from medical foods: 3.5-4 g/kg/day to prevent catabolism 1
• Modified low-protein foods for energy, variety, and satiety 1

Target Blood Levels

Maintain plasma tyrosine at 200-600 μmol/L (normal range: 35-90 μmol/L) and plasma phenylalanine at 20-80 μmol/L. 1 These targets balance preventing toxic tyrosine accumulation while avoiding phenylalanine deficiency.

Critical Monitoring for Phenylalanine Deficiency

A major pitfall is hypophenylalaninemia, which can cause growth retardation, neurological impairments, and skin problems. 3 If phenylalanine falls below 20 μmol/L:

• Add intact protein from milk or foods 1
• Consider phenylalanine supplementation (20-30 mg/kg/day) if levels remain low despite increased intact protein 1, 3
• Monitor closely during the first months of life, as hypophenylalaninemia rather than hypertyrosinemia may be the primary cause of neurocognitive impairment in young infants 3

Addressing Presenting Symptoms

For the specific symptoms mentioned (hypotonia, developmental delays, seizures):

• Neurological complications in tyrosinemia type 1 result from succinylacetone accumulation, which inhibits heme synthesis and causes porphyric-like crises 1
• NTBC therapy directly reduces succinylacetone levels, ameliorating neurological symptoms 1
• Seizures and developmental delays should improve with NTBC and dietary therapy, though early symptomatic presentation may indicate more severe disease 1

Long-Term Monitoring Requirements

Obtain periodic plasma amino acids (PAAs) with focus on phenylalanine and tyrosine to prevent deficiencies. 1 Monitor:

• Comprehensive nutrient intake to prevent vitamin and mineral deficiencies that accompany low-protein diets 1
• Growth parameters regularly 1
• Hepatic function including coagulopathy (an early sign even without other hepatic dysfunction) 1
• Renal function for Fanconi syndrome 1
• Ophthalmologic examination for keratitis, which can occur when NTBC elevates tyrosine levels 1

When Liver Transplantation is Required

Despite NTBC therapy, transplantation remains necessary for: 1

• Incomplete response to NTBC and dietary restrictions 1
• Hepatocellular carcinoma (HCC) at presentation 1
• Development of HCC during treatment 1
• Progressive liver failure 1

Children with tyrosinemia who develop HCC and meet transplant criteria should be high-priority candidates. 1

Multidisciplinary Team Requirements

Management requires a specialized team including biochemical genetics physicians and certified registered dietitians with expertise in metabolic disorders. 1, 4 This is not optional—the complexity of balancing NTBC therapy with precise dietary management of two amino acids while ensuring adequate nutrition for growth demands expert oversight.

Critical Distinction: This is NOT Tyrosine Hydroxylase Deficiency

The question specifically asks about "tyrosine deficiency" (tyrosinemia), not tyrosine hydroxylase deficiency. Tyrosine hydroxylase deficiency is an entirely different disorder causing progressive infantile encephalopathy with dopa-responsive (or non-responsive) dystonia, treated with L-dopa ± selegiline. 5, 6 The presenting symptoms and treatment are completely different from tyrosinemia type 1.