Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria.

Department of Maternal and Pediatric Sciences, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via Commenda 9, 20122 Milan, Italy.
Pediatric Nephrology (Impact Factor: 2.88). 03/2012; 27(8):1401-5. DOI: 10.1007/s00467-012-2152-6
Source: PubMed

ABSTRACT BACKGROUND: Inborn errors of cobalamin (Cbl) absorption and metabolism form a large group of rare diseases that include Cbl-C disorder. Among the renal complications of Cbl-C disorder, atypical hemolytic uremic syndrome (HUS) is the least common and has been described only in a small number of cases. CASE-DIAGNOSIS/TREATMENT: Four patients were admitted to our clinic after 15-30 days of life with vomiting associated with poor sucking, failure to thrive, lethargy and hypotonia. Examinations showed thrombocytopenia and microangiopathic hemolytic anemia associated with renal damage. The neonates had high blood homocysteine levels, increased urinary levels of both homocystine and methylmalonic acid, increased propionylcarnitine (C3) levels and an increased C3/acetylcarnitine ratio. Homozygosity for c.271-272dupA (p.Arg91LysfsX14) of the MMACHC gene was detected in three patients, and heterozygosity for c.271-272dupA and c.666C > A(p.Tyr222X) in one patient, which confirmed the diagnosis of Cbl-C disorder. Treatment with parenteral hydroxycobalamin in combination with folic acid and betaine gradually normalized the metabolic test findings and hematological and renal parameters after about 1 week. CONCLUSIONS: Atypical HUS in neonates with Cbl-C disorder may be associated with mild to moderate renal involvement also in early-onset disease, and early adequate therapy can reverse renal damage.

  • Advances in Pediatrics 08/2014;
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    ABSTRACT: Introduction: This review focuses on the use of an orphan drug eculizumab (Soliris®; Alexion Pharmaceuticals Inc.), for the treatment of an extremely rare disease, atypical hemolytic uremic syndrome (aHUS). aHUS is associated with very high mortality and morbidity rates. Current therapies (plasma therapy, liver transplant) are imperfect and fraught with complications. The authors briefly describe the clinical features and diagnosis of aHUS. The pathogenesis is the result of mutations in genes encoding alternative complement regulators. This results in unregulated activity of the alternate complement pathway, endothelial injury, and thrombotic microangiopathy (TMA). Eculizumab is a humanized monoclonal antibody that inhibits the production of the terminal complement components C5a and the membrane attack complex (C5b-9) by binding to complement protein C5a. This blocks the proinflammatory and cytolytic effects of terminal complement activation. Areas covered: Eculizumab use is described in many case reports and in two prospective Phase II open-label clinical trials in adolescent and adult patients with aHUS. There is also a retrospective study in children, adolescents and adults with aHUS. There are few serious side-effects and no reports of tachphylaxis or drug resistance. Expert opinion: The results are very encouraging and more information is being obtained regarding the optimal timing of initiation, doses and maintenance protocols. Cost and availability may be important limitations to its widespread use. In summary, eculizumab therapy is now the standard of care in the prevention and treatment of episodes of aHUS. Prophylactic eculizumab should be used for renal transplant candidates with a genetically determined risk of post-transplantation aHUS recurrence.
    Expert Opinion on Orphan Drugs. 01/2013; 1(2).
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    ABSTRACT: There is a group of diseases that may manifest with thrombotic microangiopathy and present clinical overlap. Among these we emphasize the thrombotic thrombocytopenic purpura and Hemolytic Uremic Syndrome, and the latter can occur by the action of toxins, systemic diseases, overactivation of the alternative complement system pathway, which can occur due to changes in regulatory proteins (atypical HUS) and finally, idiopathic. You must carry out a series of tests to differentiate them. aHUS is a diagnosis of exclusion of other causes of MAT. The treatment of aHUS with plasma therapy, results in most cases with good shortterm response, especially hematological; however, it is a progressive and devastating disease and can lead to death and terminal chronic renal disease. Treatment with plasma displays great recurrence of long-term disease and renal insufficiency. Eculizumab, a monoclonal antibody anti-C5, has been associated with hematological remission, benefits on renal function and no need of plasma therapy.
    Orgão oficial de Sociedades Brasileira e Latino-Americana de Nefrologia 04/2014; 36(2):208-220.