Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy

Abstract

BackgroundThe cblC defect is a rare inborn error of intracellular cobalamin metabolism. Biochemical hallmarks are elevated homocysteine and low methionine in plasma accompanied by methylmalonic aciduria. Due to the heterogeneous clinical picture, patients with the late-onset form of the disease (onset >12 months) come to the attention of diverse medical specialists, e.g. paediatricians, neurologists, nephrologists, psychiatrists or haematologists. The report reviews the published clinical data and adds three new cases to raise awareness for this severe but often treatable disease.MethodsThe Pubmed and the Cochrane databases were searched for clinical reports on cblC patients and three unreported cases are presented to illustrate the clinical spectrum.ResultsReports on 58 cases (30 females, 22 males, 6 = no information) and the three new cases underlined the clinical heterogeneity of the disease. Time between first symptoms and diagnosis ranged from three months to more than 20 years. Haemolytic uraemic syndrome and pulmonary hypertension were main presenting symptoms in preschool children. In older children/adolescents, psychiatric symptoms, cognitive impairment, ataxia and myelopathy were frequently observed while thromboembolic events and glomerulopathies were almost exclusively seen in adults. Brain atrophy, white matter lesions and myelopathy were frequently encountered. The majority of patients showed marked biochemical and clinical response to treatment with parenteral hydroxocobalamin combined with oral betaine, folate, carnitine and rarely methionine. The course was less favourable in late treated or untreated patients.ConclusionsThe late-onset cblC defect is a rare disease and unfortunately, diagnosis is often delayed. Raising awareness for this disorder can significantly improve patients’ outcome and perspective by timely initiation of targeted treatment. Newborn screening (NBS) for the cblC defect might be of benefit especially for late-onset patients since treatment seems efficient when initiated before irreversible organ damage. In general, inborn errors of metabolisms should be considered in unexplained medical cases at any age, especially in patients with multisystemic disease. More specifically, total homocysteine in plasma and methylmalonic acid in urine/plasma should be measured in unexplained neurologic, psychiatric, renal, haematologic and thromboembolic disease.

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

“…The overall disease load did not increase as significantly over time as in the very low activity group and mortality was less; this finding corresponds with the observations in the late-onset cblC defect (Huemer et al 2014b).…”

An international consensus approach to the management of atypical hemolytic uremic syndrome in children

“…2). Cases presenting with aHUS that are rescued by hydroxocobalamin treatment appear to be at least as frequent in late-onset cblC defect as in neonatal forms [29][30][31][32][33][34] (Table 1).…”

“…Biological assays to confirm the clinical diagnosis of aHUS In children, clinical presentation and baseline laboratory results usually allow the diagnosis of Streptococcus pneumoniae, STEC and cobalamin C (cblC) defect-HUS or of TTP with a good degree of certainty to inform adequate treatment initiation (Table 1) [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Figure 2 outlines confirmatory investigations for each of the common differential diagnoses [35][36][37][38][39][40][41][42][43][44][45][46][47].…”

“…Eighty-six percent of women who have the first episode of HUS during pregnancy (mostly in the post-partum) have a complement mutation. Therefore, pregnancy-HUS is classified as alternative complement pathway dysregulation-aHUS [19] Post Congenital TTP [21][22][23] Acquired TTP [21,22,24,25] STEC-HUS [26][27][28] CblC defect-HUS [29][30][31][32][33][34] aHUS [3] Age, years Eculizumab is prescribed in some countries for patients with brain/cardiac/multivisceral involvement. Further studies are required to establish the benefit of complement blockade treatment in STEC-HUS adults [1,3].…”

Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinese children

“…[7] Among patients with cbl-C disorder, HUS has been reported in white children. [8][9][10] In addition, recent studies [11,12] have reported that approximately 10% of patients with cbl-C disorder develop HUS and the occurrence of HUS is at least as frequent in late forms of cbl-C defect as in neonatal forms. [11] In the present report, we presented with clinical characteristics of 3 Chinese children with HUS secondary to cbl-C disorder.…”