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

Abstract

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.

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

“…THcy concentrations are highly elevated with mean (median) concentrations between 119 ± 43 (109) and 131 ± 69 (123) μmol/l in Cbl‐dependent remethylation disorders and even higher (mean 182 ± 91; median 179 μmol/L) in MTHFR deficiency. In MTHFD1 deficiency normal or moderately elevated (up to 50 μmol/L) tHcy concentrations have been observed.…”

“…Current knowledge, based on the small number of reported cases, suggests that the clinical patterns of cblF and cblJ disease are very similar. Feeding problems and failure to thrive often with onset in the first year accompanied by developmental delay, macrocytic anemia and in single cases pancytopenia, respiratory failure, congenital heart defects and progressive hyperpigmentation or stomatitis have been reported.…”

“…The cblC defect is the most frequent combined remethylation disorder with more than 500 reported patients. Early‐onset cblC disease (present in up to 89% of cases) has been defined as disease onset before 12 months; 75% of children manifest within their first 4 months and many in their first days of life.…”

“…The cblC defect is the most frequent combined remethylation disorder with more than 500 reported patients. Early‐onset cblC disease (present in up to 89% of cases) has been defined as disease onset before 12 months; 75% of children manifest within their first 4 months and many in their first days of life. Early‐onset disease is associated with the c.271dupA mutation, which occurs with frequencies between 40% and 55% in most and 85% in the Italian‐Spanish‐Portuguese cohort described by Richard et al.…”

“…In late‐onset disease, eye disease is generally absent. Acute or chronic microangiopathic renal or pulmonary disease, behavioral or psychiatric problems, insidious cognitive impairment, peripheral neuropathy and ataxia, combined degeneration of the spinal cord, macrocytic anemia, stroke and thrombosis are characteristic presentations.…”