Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria
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.
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ABSTRACT: Background: Atypical hemolytic uremic syndrome (aHUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Neonatal cases are extremely uncommon. Plasma therapy is the first choice therapy in patients with aHUS based on the belief of an underlying complement dysregulation. Alternatively, eculizumab, which targets complement 5, is used to block complement activation. Case-diagnosis/treatment: Sudden onset macroscopic hematuria, hypertension, and bruises over the entire body were noted in a 5 day-old newborn. Investigations revealed hemolytic anemia, thrombocytopenia, renal impairment, and a low serum C3, leading to the diagnosis of aHUS. Fresh frozen plasma (FFP) infusions and peritoneal dialysis for acute kidney injury were initiated. This approach yielded full renal and hematological remission. The patient was discharged with FFP infusions, but subsequently developed three life-threatening disease recurrences at 1, 3, and 6 months of age. The last relapse presented with uncontrolled hypertension and impaired renal function while the patient was receiving FFP infusions. After the first dose of eculizumab, his renal and hematological parameters returned to normal and his blood pressure normalized. Genetic screening of the CFH gene revealed a novel homozygous p. Tyr1177Cys mutation. Conclusion: Eculizumab can be considered as an alternative to plasma therapy in the treatment of specific patients with aHUS, even in infants.Pediatric Nephrology 09/2012; 28(1). DOI:10.1007/s00467-012-2296-4 · 2.86 Impact Factor
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ABSTRACT: Abstract The causes of cobalamin (B12, Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B12 deficiency in a cblC-disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level.Clinical Chemistry and Laboratory Medicine 12/2012; 51(3):1-12. DOI:10.1515/cclm-2012-0568 · 2.71 Impact Factor
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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.01/2013; 1(2). DOI:10.1517/21678707.2013.750579