Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

Transient phenylketonuria in premature infants.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (phe) metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase that converts phe into tyrosine. If left untreated, PKU results in increased phe concentrations in the blood and in the brain, which cause severe intellectual disability, epilepsy, and behavioral problems. These disorders can be prevented if a diet low in phe is introduced. This report focuses on a preterm newborn (gestational age 29 wk) with adequate weight (1290 g) and no family history of PKU. His parents had not received metabolic neonatal screening. A blood sample at 16 d of age and a weight of 1430 g showed phe 420 µmol/L, compatible with mild PKU. Mixed feeding was initiated with a formula free of phe (X-Phe), and breastfeeding was fortified with a contribution of 3.5 g/kg daily (2.5 g X-Phe and 1 g of high-value biological proteins). The next measurements of amino acid levels in the blood and urine were normal, and the progenitors study for PKU was negative. Normal feeding was reintroduced with normal neurologic and metabolic later evolution. The disorders of the metabolism of phe, in most cases, are due to a genetic condition. However, there are infrequent cases of transient hyperphenylalaninemia secondary to delayed maturation of the hydroxylation enzyme system. They are especially significant in premature infants. Although these forms have not been shown to cause sequelae, in view of high levels of phe in the blood, phe consumption must be restricted.