Cobalamin C Defect Presenting With Isolated Pulmonary Hypertension

Iodice, Francesca; Chiara, Luca Di; Boenzi, Sara; Aiello, Chiara; Monti, Lidia; Cogo, Paola; Dionisi‐Vici, Carlo

doi:10.1542/peds.2012-1945

Cited by 35 publications

(24 citation statements)

References 17 publications

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“…At present there is only anecdotal data suggesting that earlier diagnosis of affected subjects through expanded newborn screening improves overall outcome but not neurological and ocular symptoms (Weisfeld-Adams et al 2013; C. Dionisi-Vici personal observation). The report of a family showing a non-neurological phenotype with fatal isolated pulmonary hypertension at the age of 2 years in one sibling and with haemolytic uremic syndrome at the age of 3 years in the eldest one (Iodice et al 2013), highlights the possibility that if expanded newborn screening would have been performed, these two brothers might have experienced a different clinical outcome. Early intervention preceding the appearance of severe signs related to micro-angiopathy might well be expected to also avoid the occurrence of hydrocephalus, one of the more severe abnormalities occurring in the cblC defect.…”

Section: Discussionmentioning

confidence: 97%

Clinical presentation and outcome in a series of 88 patients with the cblC defect

Fischer

Huemer

Baumgartner

et al. 2014

J of Inher Metab Disea

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No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with "overall impression" as judged by treating physicians. Physician's impression of patient's well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.

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Section: Discussionmentioning

confidence: 97%

Clinical presentation and outcome in a series of 88 patients with the cblC defect

Fischer

Huemer

Baumgartner

et al. 2014

J of Inher Metab Disea

Self Cite

140

159

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“…Histological findings of the kidneys include widening of the mesangium, swelling of endothelial cells with detachment from the basement membrane, and granular deposits in the subendothelial space (Van Hove et al 2002; Russo et al 1992; Brunelli et al 2002; McCully 1969). Isolated pulmonary hypertension has been observed (Iodice et al 2013; Gündüz et al 2014) in cblC patients. Early onset combined pulmonary hypertension and renal thrombotic microangiopathy with a fatal course in several untreated cases has been reported (Kömhoff et al 2013), this picture is also seen in rare cases of late onset cblC patients (Grangé et al 2015).…”

Section: Which Parameters Allow Valid and Timely Laboratory Diagnosis?mentioning

confidence: 99%

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Huemer

Diodato

Schwahn

et al. 2016

J of Inher Metab Disea

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242

368

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BackgroundRemethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.ObjectiveTo summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.Data sourcesReview, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.Key recommendationsWe strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9991-4) contains supplementary material, which is available to authorised users.

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“…In 11 of the 16 nonsurvivors, a cardiopulmonary problem was noted, with pulmonary arterial hypertension diagnosed in seven. The concept of cardiorenal syndrome with pulmonary hypertension and TMA in MMACHC deficiency is supported by hemolytic anemia in an infant with cblC defect who died from cor pulmonale [49] and by increased creatinine and LDH levels in another infant who died from pulmonary hypertension and MMACHC [50]. The increased risk for pulmonary hypertension should thus prompt a thorough evaluation of MMACHC patients by a pediatric cardiologist with expertise in pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity

et al. 2016

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Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B12) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and variable extracentral nervous system involvement (failure to thrive, cardiovascular, renal, ocular) manifesting predominantly early in life, sometimes during gestation. To enhance awareness and understanding of renal disease associated with cblC defect, we studied biochemical, genetic, clinical, and histopathological data from 36 patients. Consistent clinical chemistry features of renal disease were intravascular hemolysis, hematuria, and proteinuria in all patients, with nephrotic-range proteinuria observed in three. Renal function ranged from normal to renal failure, with eight patients requiring (intermittent) dialysis. Two thirds were diagnosed with atypical (diarrhea-negative) hemolytic uremic syndrome (HUS). Renal histopathology analyses of biopsy samples from 16 patients revealed glomerular lesions typical of thrombotic microangiopathy (TMA). Treatment with hydroxycobalamin improved renal function in the majority, including three in whom dialysis could be withdrawn. Neurological sequelae were observed in 44 % and cardiopulmonary involvement in 39 % of patients, with half of the latter group demonstrating pulmonary hypertension. Mortality reached 100 % in untreated patients and 79 and 56 % in those with cardiopulmonary or neurological involvement, respectively. In all patients presenting with unclear intravascular hemolysis, hematuria, and proteinuria, cblC defect should be ruled out by determination of blood/plasma homocysteine levels and/or genetic testing, irrespective of actual renal function and neurological status, to ensure timely diagnosis and treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00467-016-3399-0) contains supplementary material, which is available to authorized users.

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Cobalamin C Defect Presenting With Isolated Pulmonary Hypertension

Cited by 35 publications

References 17 publications

Clinical presentation and outcome in a series of 88 patients with the cblC defect

Clinical presentation and outcome in a series of 88 patients with the cblC defect

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity

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