Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls

Vaisbich, María Helena; Braga, Andressa; Gabrielle, M.; Bueno, Clarissa; Piazzon, Flávia Balbo; Kok, Fernando

doi:10.1007/s00467-017-3615-6

Cited by 19 publications

(11 citation statements)

References 12 publications

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“…This case holds important pathophysiological implications, as it strongly supports the role of plasma disturbances in TMA, as opposed to the hypothesis of a primitive involvement of cblC deficiency in vascular endothelial injury at the cellular level. HUS have also been described in cblG 26 and cblE disease, 27 characterized by hyperhomocysteinemia without MMA, whereas only tubulo-interstitial injuries have been reported during MMA without hyperhomocysteinemia. 28 These 2 points remove the potential role of urine or plasma methylmalonic acid.…”

Section: Discussionmentioning

confidence: 99%

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

Lemoine

François

Grangé

et al. 2018

Kidney International Reports

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IntroductionCobalamin C (cblC) deficiency is the most common inborn error of vitamin B12 metabolism. Renal failure attributed to thrombotic microangiopathy (TMA) has occasionally been described in the late-onset presentation of cblC deficiency, but kidney lesions associated with cblC deficiency remain poorly defined. This study aims to describe the characteristics of kidney disease in cblC deficiency, and to provide a comparative histological analysis with cblC-independent renal TMA.MethodsWe performed a multicenter retrospective study including 7 patients with cblC deficiency and 16 matched controls with cblC-independent TMA. The patients included were aged 6 to 26 years at the time of the first manifestations. All patients presented with acute renal failure, proteinuria, and hemolysis; 5 patients required dialysis.ResultsThe histological study revealed arteriolar and glomerular TMA in all patients. After comparison with the cblC-independent TMA control group, a vacuolated aspect of the glomerular basement membrane and the intensity of glomerular capillary wall IgM deposits were more present in cblC deficiency patients than in controls. Six patients were treated with hydroxycobalamin. All of them improved, with disappearance of hemolysis, and 3 of the 4 patients requiring renal replacement therapy were weaned off dialysis.ConclusionThis study provides a precise description of kidney pathology in cblC deficiency. Due to major therapeutic implications, we suggest that patients with renal TMA be screened for cblC deficiency regardless of age, particularly when the kidney biopsy provides evidence of long-lasting TMA, including a vacuolated aspect of the glomerular basement membrane and glomerular capillary wall IgM deposition.

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Section: Discussionmentioning

confidence: 99%

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

Lemoine

François

Grangé

et al. 2018

Kidney International Reports

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“…Occasional therapeutic failure has been observed with eculizumab. Some patients may require higher doses, whereas others are unresponsive because of TMA due to STEC‐HUS, cobalamin C defect, methionine synthase deficiency, or DGKE or INF2 mutations. Drug resistance has been reported in Japanese patients with PNH resulting from a polymorphism in complement C5 that impairs eculizumab binding …”

Section: Evidence For Treatment Of Ahusmentioning

confidence: 99%

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

et al. 2018

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Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4–8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin‐associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC‐HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC‐HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement‐related mutation in a significant proportion of aHUS cases. The presence of other TMA‐associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.

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“…Occasional therapeutic failure has been observed with eculizumab. Some patients may require higher doses, while others are unresponsive because of TMA due to STEC‐HUS, cobalamin C defect, methionine synthase deficiency, or DGKE or INF2 mutations. Drug resistance has been reported in Japanese patients with paroxysmal nocturnal haemoglobinuria resulting from a polymorphism in complement C5 that impairs eculizumab binding …”

Section: Evidence For Treatment Of Ahusmentioning

confidence: 99%

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

Fox

Cohney

Kausman

et al. 2018

Internal Medicine Journal

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Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto-antibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.

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Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls

Abstract: Methionine synthase deficiency is very rare and characterized by megaloblastic anemia and neurological symptoms. We report the second case of MSD associated to TMA previously diagnosed as aHUS in which the patient had a poor response to eculizumab.

Cited by 19 publications

References 12 publications

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

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