Outcomes of patients with cobalamin C deficiency: A single center experience

Abstract

Biallelic variants in MMACHC results in the combined methylmalonic aciduria and homocystinuria, called cobalamin (cbl) C (cblC) deficiency. We report 26 patients with cblC deficiency with their phenotypes, genotypes, biochemical parameters, and treatment outcomes, who were diagnosed and treated at our center. We divided all cblC patients into two groups: group 1: SX group: identified after manifestations of symptoms (n = 11) and group 2: NB group: identified during the asymptomatic period via newborn screening (NBS) or positive family history of cblC deficiency (n = 15). All patients in the SX group had global developmental delay and/or cognitive dysfunction at the time of the diagnosis and at the last assessment. Seizure, stroke, retinopathy, anemia, cerebral atrophy, and thin corpus callosum in brain magnetic resonance imaging (MRI) were common in patients in the SX group. Global developmental delay and cognitive dysfunction was present in nine patients in the NB group at the last assessment. Retinopathy, anemia, and cerebral atrophy and thin corpus callosum in brain MRI were less frequent. We report favorable outcomes in patients identified in the neonatal period and treated pre‐symptomatically. Identification of cblC deficiency by NBS is crucial to improve neurodevelopmental outcomes.

Post‐Treatment Movement Disorder in a Child with Late‐onset Cobalamin Deficiency

“…Indeed, in our patient, there was evidence of a subtle movement disorder present before treatment, with an intermittent right‐sided hand tremor witnessed in previous video EEG recordings. This is in keeping with previous reports of patients with this pathogenic genetic mutation 10 …”

“…It has been hypothesized that the sudden availability of cobalamin after prolonged deficiency leads to intense stimulation of cobalamin metabolic pathways and temporary imbalance of substrates 2 . It has been reported both as a new phenomenon after treatment, and an exacerbation of a pre‐existing mild movement disorder present 2,4,8,10 . Indeed, in our patient, there was evidence of a subtle movement disorder present before treatment, with an intermittent right‐sided hand tremor witnessed in previous video EEG recordings.…”

“…EEG recordings do not demonstrate an epileptic origin. Movement disorders including tremors and dyskinesias, as well as both generalized and focal seizures, have been described clinically in children with the pathogenic c.394C > T (p.Arg132Ter) variant, which was found in our patient 10 …”

Screening for Methylmalonic and Propionic Acidemia: Clinical Outcomes and Follow-Up Recommendations

“…The phenotype for disorders of cobalamin metabolism is variable but includes global developmental delay, encephalopathy, neurologic symptoms, and cytopenia [ 3 ]. It has been well documented that newborn screening for methylmalonic acidemia and PA improves outcomes, and more recent studies also show improved outcomes for cblC deficiency [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].…”

Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

“…It is well tolerated and normally does not cause side effects, yet, one case of epileptic seizures and two of cerebral edema in the association of highly increased Met were reported ( Devlin et al., 2004 ; Enns et al., 1999 ; Yaghmai et al., 2002 ). Supplementation with oral folic or folinic acid is commonly used in cblC disease ( Ahrens-Nicklas et al., 2017 ; Bourque et al., 2021 ; Carrillo-Carrasco et al., 2012 ). It is thought to bypass the folate trap owing to decreased MS activity.…”