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

Beck, Bodo B.; Spronsen, Francjan van; Diepstra, Arjan; Berger, Rudolphus; Kömhoff, Martin

doi:10.1007/s00467-016-3399-0

Cited by 89 publications

(77 citation statements)

References 53 publications

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“…As case 2, patients with early disease onset and needs of dialysis had worse prognosis [8]. Despite prompt treatment, a significant proportion of patients with homozygous mutation c.271dupA died in first year of their life [9].…”

Section: Discussionmentioning

confidence: 99%

Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency

Topaloğlu

İnözü

Gülhan

et al. 2019

Nephron

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The most common disorder of vitamin B12 metabolism is methylmalonic aciduria and homocystinuria type cobalamin C (cblC), which accounts for most of the cases is referred to as cblC deficiency. Cobalamin deficiency is one of the causes of early-onset hemolytic uremic syndrome (HUS). Here, we present the cases of 2 infants with cobalamin deficiency who presented with early-onset HUS. The first patient was a 5-month-old female who was admitted to the hospital with seizure, pallor, and yellow-colored diarrheal stools. Initial laboratory examination showed direct Coombs test-negative hemolytic anemia. Later, she developed acute kidney injury and thrombocytopenia. Bone marrow aspiration showed megaloblastic features, and urinary examination showed elevated levels of methylmalonic acid (MMA), methyl citrate, and 3-hydroxypropionic acid. Methionine-restricted diet, parenteral hydroxocobalamine, folinic acid, carnitine, and betaine were initiated. Hemolytic activity was controlled with this treatment. Genetic screening showed homozygous mutation on the <i>MMACHC</i>gene (p.R161*[c.481C>T]). The second patient was a 3-month-old male infant who was admitted to the hospital with malaise and diarrhea. Laboratory examination showed direct Coombs test-negative hemolytic anemia with leukopenia. Later he developed acute kidney injury and thrombocytopenia. Bone marrow aspiration revealed megaloblastic changes. Urine organic acid test showed increased levels of MMA. Parenteral hydroxocobalamine, folinic acid, carnitine, and betaine were initiated. He died due to respiratory failure and cardiac arrest. Direct sequencing of <i>MMACHC</i> identified homozygous mutation, c.271dup A. CblC deficiency is an important cause of early-onset HUS and prompt diagnosis will provide specific treatment modalities.

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Section: Discussionmentioning

confidence: 99%

Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency

Topaloğlu

İnözü

Gülhan

et al. 2019

Nephron

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“…TMA can manifest in methylmalonic aciduria and homocystinuria, cobalamin C type, which is the most common inherited form of functional cobalamin (vitamin B12) deficiency (50). It is caused by recessive (homozygous or compound heterozygous) mutations in the MMACHC gene, can present in adulthood as well as childhood, and the phenotype may comprise developmental, ophthalmologic, neurologic, cardiac, and kidney manifestations, although severity varies.…”

Section: Cobalamin C Deficiencymentioning

confidence: 99%

“…It is caused by recessive (homozygous or compound heterozygous) mutations in the MMACHC gene, can present in adulthood as well as childhood, and the phenotype may comprise developmental, ophthalmologic, neurologic, cardiac, and kidney manifestations, although severity varies. The pathophysiologic mechanisms that cause endothelial damage and subsequent TMA have not yet been determined (50). Mortality is high if untreated or if there is cardiopulmonary involvement, but metabolic therapy (hydroxocobalamin and betaine) is very effective (50).…”

Section: Cobalamin C Deficiencymentioning

confidence: 99%

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Thrombotic Microangiopathy and the Kidney

Brocklebank

Wood

Kavanagh

2017

CJASN

288

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Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive management and, in some cases, effective specific treatment can result in good outcomes. This review considers the classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, and outlines a pragmatic approach to diagnosis and management.

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“…F o r t r e a t m e n t o f C b l C d i s e a s e , p a r e n t e r a l hydroxocobalamin (1 mg/daily or alternate day) combined with oral folinic acid (5-15 mg/day) and betaine (150-250 mg/kg/day) are recommended [11,14,15]. Prognosis is variable, but high mortality rates are reported [16,17]. Timely treatment can improve outcome with better growth, hematological improvement and preservation of renal function [11].…”

Section: Discussionmentioning

confidence: 99%

A child presenting with severe hypertension and circulatory failure—a diagnostic conundrum: Answers

2017

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Answers Question 1The differential diagnostic options we considered:-Thrombotic microangiopathy (TMA) [atypical hemolytic uremic syndrome (HUS), cobalamin deficiencyassociated HUS, non-Shiga toxin-infectious HUS, ADAMTS13 deficiency] -Systemic lupus erythematosus -Polyarteritis nodosa -Neuroblastoma/pheochromocytoma -Tumor lysis syndrome secondary to leukemia -Sepsis with acute kidney injury (AKI) -Acute disseminated encephalomyelitis -Hyperthyroidism (adenoma, auto immune) -Other causes of glomerulonephritis, e.g. C3 glomerulonephritis/post-infectious glomerulonephritis. Question 2Complement levels of component 3 (C3; 0.7 g/L, reference level 0.9-1.8 g/L) were low, while C4 levels were at the lower limit (0.1 g/L, reference 0.1-0.4 g/L) of the normal range. Plasma renin levels were strongly elevated (1609 pg/mL, reference <35.7 pg/mL) with concomitant high aldosterone levels (>132 ng/dL, reference 3.7-43.2 dL). Cortisol levels were elevated (31.8 μg/dL, reference 2.69-10.4 μg/dL). Thyroid hormones were low [thyroid stimulating hormone 0.64 mU/L, reference 0.7-6.0; free thyroxine (FT4) 0.6 ng/ dL, reference 1.0-1.8 ng/dL]. Autoimmune testing was negative for anti-nuclear antibodies, anti-cytoplasmatic antibodies and anti-double-stranded DNA antibodies. Repeated blood and urine cultures and intensive work-up for viral infections (including Epstein-Barr virus, cytomegalovirus, varicella, herpes simplex virus) was negative. A nasal swab was positive for adenovirus and corona virus.Repeated abdominal ultrasound scans were negative for neuroblastoma and feochromocytoma, but neuron-specific enolase (a tumor marker for neuroblastoma) was moderately elevated (46.5 μg/L, reference 0-12.5 μg/L). Tests for catecholamines in urine were negative. Metabolic screening demonstrated sky high homocysteine levels (131.5 μmol/L, reference 3.3-8.3 μmol/L) with normal methionine levels (20 μmol/L, reference 11-76 μmol/L) while the remaining plasma amino acid profile was normal. Elevated plasma levels of vitamin B12 (1420 ng/L, reference 197-866 μmol/L), vitamin B6 (292 nmol/L, reference 26-102 nmol/L) and folate (14.4 μg/L, reference 2.0-9.1 μg/L) were noted, and the diagnosis of cobalamin deficiency-associated HUS was strongly This refers to the article that can be found at http://dx.

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

Cited by 89 publications

References 53 publications

Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency

Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency

Thrombotic Microangiopathy and the Kidney

A child presenting with severe hypertension and circulatory failure—a diagnostic conundrum: Answers

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