Abstract
BackgroundCobalamin (cbl)-related remethylation disorders are a heterogeneous group of inherited disorders comprising the remethylation of homocysteine to methionine and affecting multiple organ systems, most prominently the nervous system and the bone marrow. To date, the parenteral, generally intramuscular, lifelong administration of hydroxycobalamin (OHCbl) is the mainstay of therapy in these disorders. The dosage and frequency of OHCbl is titrated in each patient to the minimum effective dose in order to account for the painful injections. This may result in undertreatment, a possible risk factor for disease progression and disease-related complications.ResultsWe describe parenteral administration of OHCbl using a subcutaneous catheter together with a portable infusion pump in a home therapy setting in four pediatric patients with remethylation disorders, two patients with cblC, one patient with cblG, and one patient with cblE deficiency, in whom intramuscular injections were not or no longer feasible. The placement of the subcutaneous catheters and handling of the infusion pump were readily accomplished and well accepted by the patients and their families. No adverse events occurred. The use of a small, portable syringe driver pump allowed for a most flexible administration of OHCbl in everyday life. The concentrations of total homocysteine levels were determined at regular patient visits and remained within the therapeutic target range. This approach allowed for the continuation of OHCbl therapy or the adjustment of therapy required to improve metabolic control in our patients.ConclusionsSubcutaneous infusion using a subcutaneous catheter system and a portable pump for OHCbl administration in combined and isolated remethylation disorders is safe, acceptable, and effective. It decreases disease burden in preventing frequent single injections and providing patient independence. Thus, it may promote long-term adherence to therapy in patients and parents.
Highlights
Cobalamin-related remethylation disorders are a heterogeneous group of inherited disorders comprising the remethylation of homocysteine to methionine and affecting multiple organ systems, most promi‐ nently the nervous system and the bone marrow
Dried blood spots for newborn screening were collected at 35 h of age and revealed slightly elevated concentrations of propionylcarnitine (8.9 μmol/l; cut-off < 5.9) and methylmalonic acid (MMA) (59.5 μmol/l; cut-off < 5), whereas the concentration of methionine (7 μmol/l; cut-off > 8) was decreased, and 3-hydroxy-propionic acid (26.7 μmol/l; cut-off < 30) was normal
The concentrations of ammonia (82 μmol/l; reference range < 110), lactate (1.7 mmol/l; reference range < 2.1), vitamin B12 (1780 pg/ml; reference range 197–771), and folic acid (19.8 ng/ml; reference range 3.9–26.8) were unremarkable. These findings are highly indicative for an inborn error of cobalamin metabolism, and supplementation of OHCbl 1 mg IV, folic acid 20 mg Per os (PO), betaine 250 mg/ kg PO, and initially methionine 25 mg PO per day were started
Summary
Cobalamin (cbl)-related remethylation disorders are a heterogeneous group of inherited disorders comprising the remethylation of homocysteine to methionine and affecting multiple organ systems, most promi‐ nently the nervous system and the bone marrow. The dosage and frequency of OHCbl is titrated in each patient to the minimum effective dose in order to account for the painful injections. This may result in undertreatment, a possible risk factor for disease progression and disease-related complications. Some disorders of intracellular cobalamin metabolism (cblC, cblD-MMA/Hcy, cblF, and cblJ) do compromise the synthesis of methylcobalamin, and the synthesis of adenosylcobalamin, cofactor of the enzyme methylmalonyl-CoA mutase, leading to elevated concentrations of both tHcy and methylmalonic acid (MMA). Juvenile or adult onset manifestations characterized mainly by ataxia, dementia, and psychosis have been described [2, 4]
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