Dataset Information

CblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period.

ABSTRACT: This study describes a cblE type of homocystinuria associated with haemolytic-uremic syndrome (HUS) features. We report on a male infant aged 43 days presenting with failure to thrive, hypotonia, pancytopaenia, HUS symptoms (microangiopathic haemolytic anaemia and thrombocytopaenia with signs of renal involvement) and fatal evolution. An underlying cobalamin disorder was diagnosed after a bone marrow examination revealed megaloblastic changes associated with hyperhomocysteinaemia. An urinary organic acid analysis revealed normal methylmalonic acid excretion. The cblE diagnosis was confirmed with a complementation analysis using skin fibroblasts and genetic studies of the MTRR gene. The patient treatment included parenteral hydroxocobalamin, carnitine, betaine and folinic acid, but there was no response. After the autopsy, the histopathological examination of the kidneys showed marked myointimal proliferation and narrowing of the vascular lumen. The central nervous system showed signs of haemorrhage that affected the putamen and the thalamus; diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis were also observed. Microangiopathy was observed with an increase in vessel wall thickness, a reduction of the arterial inner diameter and capillary oedema. The signs of necrosis and haemorrhage were detected in the cerebellum, the cerebellar peduncles, the tegmentum and the bulbar olives.In conclusion, cblE should be considered when diagnosing patients presenting with HUS signs and symptoms during the newborn period. Despite early diagnosis, however, the specific treatment measures were not effective in this patient.

SUBMITTER: Palanca D

PROVIDER: S-EPMC3565672 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period.

Palanca Daniel D Garcia-Cazorla Angels A Ortiz Jessica J Jou Cristina C Cusí Victoria V Suñol Mariona M Toll Teresa T Perez Belén B Ormazabal Aida A Fowler Brian B Artuch Rafael R

JIMD reports 20120721

This study describes a cblE type of homocystinuria associated with haemolytic-uremic syndrome (HUS) features. We report on a male infant aged 43 days presenting with failure to thrive, hypotonia, pancytopaenia, HUS symptoms (microangiopathic haemolytic anaemia and thrombocytopaenia with signs of renal involvement) and fatal evolution. An underlying cobalamin disorder was diagnosed after a bone marrow examination revealed megaloblastic changes associated with hyperhomocysteinaemia. An urinary org ...[more]

PMID: 23430521

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Project description:The aim of this study was to perform a quantitative microbial risk assessment (QMRA) of Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) linked to the consumption of Kosher beef produced in Argentina and consumed in Israel in children under 14 years. A probabilistic risk assessment model was developed to characterize STEC prevalence and contamination levels in the beef supply chain (cattle primary production, cattle transport, processing and storage in the abattoir, for export and at retail, and home preparation and consumption). The model was implemented in Microsoft Excel 2016 with the @Risk add-on package. Results of 302 surveys with data collected in Israel were as follows: 92.3% of people consumed beef, mostly at home, and 98.2% preferred levels of cooking that ensured STEC removal from the surface of beef cuts. The preferred degree of ground beef doneness was "well-done" (48.2%). Cooking preference ranged from red to "medium-well done" (51.8%). Median HUS probability from Argentinean beef cut and ground beef consumption in children under 14 years old was <10-15 and 8.57x10-10, respectively. The expected average annual number of HUS cases and deaths due to beef cut and ground beef consumption was zero. Risk of infection and HUS probability correlated with salting effect on E. coli count, processing raw beef before vegetables, ways of storage and refrigeration temperature at home, joint consumption of salad and beef cuts, degree of beef doneness and cutting board washing with detergent after each use with beef and vegetables. The STEC-HUS risk in Israel from consumption of bovine beef produced in Argentina was negligible. The current QMRA results were similar to those of previous beef cut consumption QMRA in Argentina and lower than any of the QMRA performed worldwide in other STEC-HUS linked to ground beef consumption. This study confirms the importance of QMRA to estimate and manage the risk of STEC-HUS from beef consumption. The impact variables identified in the sensitivity analysis allowed us to optimize resources and time management, to focus on accurate actions and to avoid taking measures that would not have an impact on the risk of STEC-HUS.

Project description:IntroductionComprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains challenging owing to the complexity of functional studies with mutant proteins. This study was designed: 1) To identify a tool for rapid functional determination of complement gene variants; 2) To uncover inherited complement dysregulation in aHUS patients who do not carry identified gene variants.MethodsTo address the above goals, we employed an ex-vivo assay of serum-induced C5b-9 formation on ADP-activated endothelial cells in 223 subjects from 60 aHUS pedigrees (66 patients and 157 unaffected relatives).ResultsSera taken from all aHUS patients in remission induced more C5b-9 deposition than control sera, independently from the presence of complement gene abnormalities. To avoid the possible confounding effects of chronic complement dysregulation related to aHUS status, and considering the incomplete penetrance for all aHUS-associated genes, we used serum from unaffected relatives. In control studies, 92.7% of unaffected relatives with known pathogenic variants exhibited positive serum-induced C5b-9 formation test, documenting a high sensitivity of the assay to identify functional variants. The test was also specific, indeed it was negative in all non-carrier relatives and in relatives with variants non-segregating with aHUS. All but one variants in aHUS-associated genes predicted in-silico as likely pathogenic or of uncertain significance (VUS) or likely benign resulted as pathogenic in the C5b-9 assay. At variance, variants in putative candidate genes did not exhibit a functional effect, with the exception of a CFHR5 variant. The C5b-9 assay in relatives was helpful in defining the relative functional effect of rare variants in 6 pedigrees in which the proband carried more than one genetic abnormality. Finally, for 12 patients without identified rare variants, the C5b-9 test in parents unmasked a genetic liability inherited from an unaffected parent.DiscussionIn conclusion, the serum-induced C5b-9 formation test in unaffected relatives of aHUS patients may be a tool for rapid functional evaluation of rare complement gene variants. When combined with exome sequencing the assay might be of help in variant selection, to identify new aHUS-associated genetic factors.

Dataset Information

CblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period.

Publications

cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period.

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