Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids.

UNLABELLED: Tyrosine supplementation has not consistently been found to improve neuropsychologic function in phenylketonuria (PKU), possibly because of failure to achieve adequate levels of tyrosine in the brain. OBJECTIVES: To evaluate blood levels achieved after tyrosine supplementation in treated PKU and calculate brain influxes of tyrosine and other large neutral amino acids before and with tyrosine supplementation. STUDY DESIGN: Ten subjects with PKU receiving a phenylalanine-restricted diet were studied over 48 hours; each received tyrosine supplementation (300 mg/kg) on day 2. Plasma phenylalanine and tyrosine were measured every 2 hours, and all free amino acids were measured every 6 hours. Brain influxes of tyrosine and other large neutral amino acids were calculated. RESULTS: Plasma tyrosine levels were low normal at baseline. With supplementation there was a substantial but unsustained rise in plasma tyrosine. Calculated brain influx of tyrosine was 27% +/- 19% of normal before supplementation, increasing to 90% +/- 58% of normal with supplementation. Nevertheless, calculated influx remained less than 70% of normal at 50% of the time points. The calculated brain influxes of all other large neutral amino acids except tryptophan were 20% to 40% of normal before and with tyrosine supplementation. CONCLUSIONS: Tyrosine supplementation in the diet for PKU produces marked but nonsustained increases in plasma tyrosine levels, with calculated brain influx that often remains suboptimal. This could explain the lack of consistent neuropsychologic benefit with tyrosine supplementation.

Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very-long-chain acyl-coenzyme A dehydrogenase deficiency.

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is a disorder of fatty acid beta oxidation that reportedly has high rates of morbidity and mortality. We describe the outcome of a 5-year-old girl with VLCAD deficiency who was first seen at 5 months of age with severe hypertrophic cardiomyopathy, hepatomegaly, encephalopathy, and hypotonia. Biochemical studies indicated VLCAD deficiency caused by a stable yet inactive enzyme. Molecular genetic analysis of her VLCAD gene revealed a T1372C (F458L) missense mutation and a 1668 ACAG 1669 splice site mutation. After initial treatment with intravenous glucose and carnitine, the patient has thrived on a low-fat diet supplemented with medium-chain triglyceride oil and carnitine and avoidance of fasting. Her ventricular hypertrophy resolved significantly over 1 year, and cognitively, she is in the superior range for age. Clinical recognition of VLCAD deficiency is important because it is one of the few directly treatable causes of cardiomyopathy in children.

Infantile phosphofructokinase deficiency with arthrogryposis: clinical benefit of a ketogenic diet.

We report a 2-year-old boy with phosphofructokinase deficiency presenting in the newborn period with congenital arthrogryposis and severe myopathy, who has had significant improvement on a ketogenic diet since its institution at 4 months of age. We provide a rationale for use of this treatment and hypothesize it may be beneficial in other patients with phosphofructokinase deficiency and progressive muscular involvement. Confirmation awaits further clinical trials in carefully selected patients.

Oxidative phosphorylation defect associated with primary adrenal insufficiency.

An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.

Lethal neonatal deficiency of carnitine palmitoyltransferase II associated with dysgenesis of the brain and kidneys.

We describe neonatal onset of a lethal multiorgan deficiency of carnitine palmitoyltransferase II (CPT II) associated with dysmorphic features, cardiomyopathy, and cystic dysplasia of the brain and kidneys. Concentrations of long-chain acylcarnitines were evaluated in blood and multiple tissues, diffuse lipid accumulation was present at autopsy, and a profound deficiency of CPT II activity was evident in heart, liver, muscle, and kidney tissue. This disorder constitutes another recognizable malformation syndrome with a metabolic basis. Deficiency of CPT II should be included in the differential diagnosis of patients with cystic renal dysplasia, dysmorphism, central nervous system malformations, and early death, along with glutaric acidemia type II, Zellweger syndrome, and other disorders in which peroxisomal beta-oxidation is impaired. The clinicopathologic similarities among these disorders raise the possibility that a common biochemical mechanism, namely the disruption of beta-oxidation of fatty acids, is responsible for the abnormal organogenesis.

Neonatal-onset propionic acidemia: neurologic and developmental profiles, and implications for management.

OBJECTIVES: To document the clinical and neurodevelopmental profiles of a cohort of patients with neonatal-onset propionic acidemia and to determine the efficacy of current therapy with respect to outcome. METHOD: The clinical, neurologic, and developmental status of six patients was prospectively evaluated during a 15-month period. Previous clinical and biochemical data were ascertained from hospital records to determine longitudinal nutritional status, number of episodes of hyperammonemia with ketoacidosis, and developmental performance with respect to age. RESULTS: No deaths resulted from propionic acidemia since the identification of the oldest patient in the series in 1980. Therapeutic intervention (e.g., gastrostomy tube feeding) resulted in improved nutritional status and possibly contributed to improved survival. All children had hypotonia, resulting in a significant effect on motor development; however, focal neurologic deficits and evidence of movement or seizure disorder were absent. Mild cortical atrophy was evident on cranial magnetic resonance imaging in four patients. All children, including two patients with no significant episodes of hyperammonemia and normal growth since the neonatal period, had a mild to moderate degree of intellectual impairment. CONCLUSIONS: The results of our study suggest that current therapy for neonatal-onset propionic acidemia is associated with improved survival and nutritional status, and an absence of focal neurologic deficits. However, hypotonia and cognitive delay were still present, even in children with "optimal" metabolic control. Additional therapeutic advances are required to improve the developmental and cognitive outcome.