Cobalamin C deficiency

Gunduz M, Unal O, Taskin BD, Karalok ZS. 2017. Cobalamin C Deficiency: Case Report

of Two Different Clinical Presentations. J Neurol Exp Neurosci 2(2): 40-44.

Abstract

Cobalamin C deficiency (CblC) is the most frequent inborn error of cobalamin (Cbl) metabolism, which has a wide clinical spectrum. Cbl C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. Here we presented two distinct clinical forms of patients with CblC. First patient with early onset form was presented with failure to thrive, mild hypotonia, megaloblastic anemia and leukopenia at 2.5 months old. Second patient was presented with mental status changes, loss of speech, inability to walk and megaloblastic anemia at 12 years old. Laboratory analysis showed hyperhomocysteinemia, low plasma methionine levels and high urinary methylmalonic acid in both patients. Molecular analysis supported the diagnosis of CblC and treatment resulted in improvement of biochemical abnormalities, and neurologic findings in both patients.

A 2.5-months-old boy was hospitalized failure to thrive, mild hypotonia, megaloblastic anemia and leukopenia to evaluate the etiology of.

Laboratory investigations revealed; Hb: 7.6 g/dL, N: 10.5- 14 g/dL; MCV: 100.1 fl, N: 81.4–91.9 fl; WBC: 3500/mm3 N: 5000-15000/mm3 ; absolute granulocyte count: 500/mm3 (N: 1000-8500/mm3 ), liver enzymes, renal functions and electrolytes were within normal limits. Vitamin B12: 1033 pg/ mL (N: 145-914 pg/mL). Reticulocyte was 4.97% (0.6-2.6%), and elevated. Cranial Magnetic Resonance Imaging (MRI) showed hyperintensity on T1 weighted images confluence of sinuses and left lateral sinus. Magnetic resonance venography demonstrated thrombosis of left lateral sinus. Coagulation parameters were normal. Homocysteine level was found highly elevated (78 μmol/L N: 3.3-8.3). Methionine level was at lower normal limits (14 μmol/L N: 10-53). Urine organic acid analysis showed 22 folds elevated MMA. Developmental delay, megaloblastic anemia, hyperhomocysteinemia, cerebral venous sinus thrombosis, and elevated urine methlymalonic acid excretion were suggested cobalamin metabolism defect.  Molecular analysis revealed compound heterozygote NM_015506.2 (MMACHC): c.142A>G (p.I48V) / c.394C>T (p.R132*) mutation (MIM 611935) and CblC defect was confirmed.

Hydroxocobalamin injections were commenced daily for 7 days followed by three times weekly injections (1 mg/day, i.m.). Oral folic acid (5 mg/day) and oral betaine (100 mg/kg/day) were started for hyperhomocysteinemia, and cerebral venous sinus thrombosis was treated with enoxaparin sodium. He is now two years old, he can walk with support, and has a few words…

Previously healthy 12-year-old boy presented to the emergency department with a 1-week history of mental status changes, loss of speech and inability to walk…

During hospitalization, he developed focal seizures needing treatment with levetiracetam. Electroencephalogram (EEG) showed diffuse low-amplitude slow waves…

Complete blood count showed macrocytic anemia (Hb: 8.7 g/ dl, N: 10.5–14 g/dl; MCV: 99.6 fl, N: 81.4–91.9 fl). Vitamin B12 level (1020 pg/mL; reference range >200 pg/mL) was normal. Total folate (>23.2 ng/mL, N: 3.1-19.9 ng/mL) was increased, possibly secondary to a methylfolate trap from a dysfunctional cobalamin pathway. Electromyography (EMG) revealed a mild lower limb predominant demyelinating polyneuropathy.

Three weeks after admission, he developed right femoral vein thrombosis, which was treated with anticoagulant therapy. Screening for A1298C MTHFR mutation was heterozygous positive. Metabolic investigation revealed high plasma homocysteine (80 μmol/L; N: 0-13 μmol/L), high urinary MMA (225 μmol/mmol creatinine; normally not detectable) and low plasma methionine levels (7.9 μmol/L; N: 10-53 μmol/L). These findings suggested the cobalamin defects. Molecular diagnosis by gene MMACHC (MIM 611935) sequencing analysis was performed, and revealed homozygous NM_015506.2 (MMACHC): c.394C>T (p.R132*) mutation.

Hydroxocobalamin injections were commenced daily for 7 days followed by three times weekly injections (1 mg/ day, i.m.). In addition, oral folic acid (5 mg/day) and betaine (150 mg/kg/day) were started. Four months later after treatment, he progressively recovered his ability to walk with support. Plasma homocysteine and urine MMA levels decreased and, clinically his speech and walking improved.

His initial cranial MRI (before treatment) showed cortical atrophy and bilateral focal hyperintensities in the white matter at the level of centrum semiovale. T2 and Fluid-attenuated inversion recovery (FLAIR) hyperintensities were observed of posterior parietal periventricular white matter.  Second MRI, performed 3 months later after treatment, revealed slightly reduction of hyperintensities in the white matter.