Cobalamin c deficiency associated with antifactor h antibody-associated hemolytic uremic syndrome in a young adult

Philipponnet, Carole; Desenclos, Jean‐Claude; Braïlova, Marina; Aniort, Julien; Kemeny, Jean Louis; Deville, C.; Frémeaux‐Bacchi, Véronique; Souweine, Bertrand; Heng, Anne Elisabeth

doi:10.1186/s12882-020-01748-2

Cited by 8 publications

(5 citation statements)

References 15 publications

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“…A limitation of our retrospective analysis of the published adult onset CblC cases is that oftentimes the accuracy of the reported symptoms and the disease onset depended on the expertise of the authors. An emblematic example is the case report from Philipponnet and colleagues where the focus was the renal phenotype, while it was only mentioned that the patient had a “neurological impairment”, whose characteristics are unknown [ 31 ]. We believe that further knowledge and insight on the disorder is going to pave the way for more accurate recognition and description of all the associated symptoms and better care for the patients.…”

Section: Discussionmentioning

confidence: 99%

Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists

Kalantari

Brezzi

Bracciamà

et al. 2022

Orphanet J Rare Dis

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Background Methylmalonic aciduria and homocystinuria, CblC type (OMIM #277400) is the most common disorder of cobalamin intracellular metabolism, an autosomal recessive disease, whose biochemical hallmarks are hyperhomocysteinemia, methylmalonic aciduria and low plasma methionine. Despite being a well-recognized disease for pediatricians, there is scarce awareness of its adult presentation. A thorough analysis and discussion of cobalamin C defect presentation in adult patients has never been extensively performed. This article reviews the published data and adds a new case of the latest onset of symptoms ever described for the disease. Results We present the emblematic case of a 45-year-old male, describing the diagnostic odyssey he ventured through to get to the appropriate treatment and molecular diagnosis. Furthermore, available clinical, biochemical and molecular data from 22 reports on cases and case series were collected, resulting in 45 adult-onset CblC cases, including our own. We describe the onset of the disease in adulthood, encompassing neurological, psychiatric, renal, ophthalmic and thromboembolic symptoms. In all cases treatment with intramuscular hydroxycobalamin was effective in reversing symptoms. From a molecular point of view adult patients are usually compound heterozygous carriers of a truncating and a non-truncating variant in the MMACHC gene. Conclusion Adult onset CblC disease is a rare disorder whose diagnosis can be delayed due to poor awareness regarding its presenting insidious symptoms and biochemical hallmarks. To avoid misdiagnosis, we suggest that adult onset CblC deficiency is acknowledged as a separate entity from pediatric late onset cases, and that the disease is considered in the differential diagnosis in adult patients with atypical hemolytic uremic syndromes and/or slow unexplained decline in renal function and/or idiopathic neuropathies, spinal cord degenerations, ataxias and/or recurrent thrombosis and/or visual field defects, maculopathy and optic disc atrophy. Plasma homocysteine measurement should be the first line for differential diagnosis when the disease is suspected. To further aid diagnosis, it is important that genes belonging to the intracellular cobalamin pathway are included within gene panels routinely tested for atypical hemolytic uremic syndrome and chronic kidney disorders.

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Section: Discussionmentioning

confidence: 99%

Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists

Kalantari

Brezzi

Bracciamà

et al. 2022

Orphanet J Rare Dis

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“…More than eighty variants have been reported in the MMACHC gene in patients with Cbl C deficiency since 2006 [16]. c.271dupA (p.Arg91LysfsTer14) is the most frequent variant [17].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, WES cannot detect intronic or large structural variants [24]. Furthermore, one case report showed concurrence of Cbl C deficiency and anti-factor H antibody-related aHUS [16]. Unfortunately, we could not evaluate intronic complement gene variants or anti-factor H antibodies.…”

Section: Discussionmentioning

confidence: 99%

Concurrent Cobalamin C and Plasminogen Deficiencies in a Patient with Chronic Thrombotic Microangiopathy

Dirim,

Safak,

Balci

et al. 2023

Nephron

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Background: Although most patients with atypical hemolytic uremic syndrome (aHUS) have variants in genes participating in alternative complement pathways, rare variants in non-complement pathway-related genes, including DGKE, INF2, MMACHC, PLG, and THBD, have also been described. Case Presentation: We report an 18-year-old male patient with renal biopsy-proven chronic thrombotic microangiopathy that raised suspicion of aHUS. Whole-exome sequencing revealed a novel pathogenic homozygous MMACHC c.484G>T (p.Gly162Trp) variant. Subsequently, clinical and laboratory findings confirmed cobalamin C (Cbl C) deficiency. Also, homozygous missense c.1112C>T PLG (p.Thr371Ile) variant was detected (it had been reported as a variant of unknown significance). However, the low serum plasminogen (PLG) activity proved the pathogenicity of c.1112C>T. Hence, the patient was diagnosed with concurrent Cbl C and PLG deficiencies. Segregation analysis revealed that the mother and father had the same heterozygous PLG and MMACHC variants. PLG variants have generally been described in aHUS patients concomitant with complement gene variants in the literature; therefore, the association between aHUS and PLG variants is controversial. The possible contribution of PLG deficiency to thrombotic microangiopathy was also discussed in this case. Conclusion: Non-complement-mediated aHUS is an exceptional disorder. A limited number of genes are involved in this entity. To our knowledge, this is the first aHUS patient diagnosed with both Cbl C and PLG deficiencies in the literature.

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“…Nevertheless, symptoms of cblC defect may initially occur at an older age, while potential misdiagnosis as atypical HUS may result in unnecessarily prolonged treatment with complement blockage factor, delayed diagnosis and subsequent severe complications, such as pulmonary hypertension and relapse of AKI [ 12 , 13 ]. Interestingly, cblC defect has also been identified in a few patients with alternative complement pathway disorders, including an infant with low complement factor H (CFH) activity [ 14 ], a child with CFH mutation [ 15 ], a child with encoding membrane cofactor protein (CD46) mutation [ 16 ] and a young adult with CFH antibody-mediated HUS [ 17 ]. Therefore, it seems prudent to perform the widely available and low-cost homocysteine assay as part of the HUS diagnostic workup, regardless of age-onset, and even in cases with defined genetic or acquired alternative complement pathway dysregulation.…”

Section: Discussionmentioning

confidence: 99%

Hemolytic Uremic Syndrome Due to Methylmalonic Acidemia and Homocystinuria in an Infant: A Case Report and Literature Review

et al. 2021

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Methylmalonic acidemia and homocystinuria cobalamin C (cblC) type is the most common inborn error of the intracellular cobalamin metabolism, associated with multisystem involvement and high mortality rates, especially in the early-onset form of the disease. Hemolytic uremic syndrome (HUS) is a rare manifestation and needs to be distinguished from other causes of renal thrombotic microangiopathy. We describe a case of a 3-month-old infant, with failure to thrive, hypotonia and pallor, who developed HUS in the setting of cblC deficit, along with dilated cardiomyopathy, and presented delayed response to optic stimulation in visual evoked potentials, as well as enlarged bilateral subarachnoid spaces and delayed myelination in brain magnetic resonance imaging. Renal damage was reversed, while neurodevelopmental profile and eye contact improved after supplementation with parenteral hydroxycobalamin, oral folic acid, betaine and levocarnitine. Homozygous mutation of c.271dupA in the MMACHC gene was ultimately detected. In this report, we highlight the diagnostic challenges as well as the significance of early recognition and multidisciplinary management of this unusual condition. A brief review of published case reports of early-onset cblC deficit and related HUS is depicted, pointing out the initial clinical presentation, signs of renal damage and outcome, MMACHC gene type of mutations and accompanying extra-renal manifestations.

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Cobalamin c deficiency associated with antifactor h antibody-associated hemolytic uremic syndrome in a young adult

Cited by 8 publications

References 15 publications

Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists

Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists

Concurrent Cobalamin C and Plasminogen Deficiencies in a Patient with Chronic Thrombotic Microangiopathy

Hemolytic Uremic Syndrome Due to Methylmalonic Acidemia and Homocystinuria in an Infant: A Case Report and Literature Review

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