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Zellweger syndrome with severe malnutrition, immunocompromised state and opportunistic infections.

ABSTRACT: Peroxisome biogenesis disorders are related to a spectrum of genetic diseases that range from severe Zellweger syndrome to milder infantile Refsum disease. Zellweger syndrome is characterised by dysmorphic features, severe hypotonia, seizures, failure to thrive, liver dysfunction and skeletal defects. Increased levels of very long chain fatty acids are the biochemical hallmark and the most common mutations found in the PEX1 gene. We report an unusual presentation of Zellweger syndrome in a 2-month-old female infant with severe malnutrition, opportunistic infections, lymphopaenia and a small thymic shadow on chest radiography. With this clinical picture, an initial hypothesis of primary immunodeficiency was considered. It was later confirmed to not be the case. On follow-up, global developmental delay, bilateral optic nerve atrophy and moderate bilateral sensorineural deafness grade II were documented. There were no further infectious complications and we concluded malnutrition was the cause of the infant's immunocompromised state.

SUBMITTER: Cardoso P

PROVIDER: S-EPMC4840729 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Zellweger syndrome with severe malnutrition, immunocompromised state and opportunistic infections.

Cardoso Patrícia P Amaral Maria Emanuel ME Lemos Sónia S Garcia Paula P

BMJ case reports 20160418

Peroxisome biogenesis disorders are related to a spectrum of genetic diseases that range from severe Zellweger syndrome to milder infantile Refsum disease. Zellweger syndrome is characterised by dysmorphic features, severe hypotonia, seizures, failure to thrive, liver dysfunction and skeletal defects. Increased levels of very long chain fatty acids are the biochemical hallmark and the most common mutations found in the PEX1 gene. We report an unusual presentation of Zellweger syndrome in a 2-mon ...[more]

PMID: 27090541

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Project description:BackgroundImmunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. The transfer of pathogen-specific Cytotoxic T-Lymphocytes has shown a minimal toxicity profile and effectiveness in treating Cytomegalovirus, Adenovirus, Epstein - Barr virus, BK Virus and Aspergillus infections, but this therapy have the main limitations of regulatory issues, high cost, and absence of public cell banks. However, CD45RA- cells containing pathogen-specific memory T-cells involve a less complex manufacturing and regulatory process and are cheaper, feasible, safe, and potentially effective.MethodsWe present preliminary data from six immunocompromised patients: four who had severe infectious diseases and two who had EBV lymphoproliferative disease. All of them underwent multiple safe familial CD45RA- T-cell infusions as adoptive passive cell therapy, containing Cytomegalovirus, Epstein - Barr virus, BK virus, and Aspergillus-specific memory T-cells. We also present the method for selecting the best donors for CD45RA- cells in each case and the procedure to isolate and store these cells.ResultsThe infusions were safe, there was no case of graft-versus host disease, and they showed a clear clinical benefit. The patients treated for BK virus nephritis, Cytomegalovirus encephalitis, Cytomegalovirus reactivation, and disseminated invasive aspergillosis experienced pathogen clearance, complete resolution of symptoms in 4-6 weeks and a lymphocyte increase in 3 of 4 cases after 3-4 months. Donor T cell transient microchimerism was detected in one patient. The two patients treated for EBV lymphoproliferative disease underwent chemotherapy and several infusions of CD45RA- memory T-cells containing EBV cytotoxic lymphocytes. Donor T-cell microchimerism was observed in both patients. The viremia cleared in one of the patients, and in the other, despite the viremia not clearing, hepatic lymphoproliferative disease remained stable and was ultimately cured with EBV-specific Cytotoxic T-Lymphocytes.ConclusionThe use of familial CD45RA- T-cells containing specific Cytotoxic T-lymphocytes is a feasible, safe and potential effective approach for treating severe pathogen infections in immunocompromised patients through a third party donor. Furthermore, this approach might be of universal use with fewer institutional and regulatory barriers.

Project description:BackgroundGoals of treating childhood severe acute malnutrition (SAM), in addition to anthropometric recovery and preventing short-term mortality, include reducing the risks of subsequent serious infections. How quickly and how much the risk of serious illness changes during rehabilitation are unknown but could inform improving the design and scope of interventions.ObjectiveThe aim of this study was to investigate changes in the risk of life-threatening events (LTEs) in relation to anthropometric recovery from SAM.DesignThis was a secondary analysis of a clinical trial including 1778 HIV-uninfected Kenyan children aged 2-59 mo with complicated SAM, enrolled after the inpatient stabilization phase of treatment, and followed for 12 mo. The main outcome was LTEs, defined as infections requiring rehospitalization or causing death. We examined anthropometric variables measured at months 1, 3, and 6 after enrollment in relation to LTEs occurring during the 6 mo after each of these time points.ResultsOver 12 mo, there were 823 LTEs (257 fatal), predominantly severe pneumonia and diarrhea. At months 1, 3, and 6, 557 (34%), 764 (49%), and 842 (56%) children had a weight-for-height or -length z score (WHZ) ≥-2, respectively, which, compared with a WHZ <-3, was associated with lower risks of subsequent LTEs [adjusted HRs (95% CIs): 0.50 (0.40, 0.64), 0.30 (0.23, 0.39), and 0.23 (0.16, 0.32), respectively]. However, children with a WHZ ≥-2 at 1, 3, and 6 mo still had 39 (95% CI: 32, 47), 26 (95% CI: 22, 32), and 15 (95% CI: 12, 20) LTEs/100 child-years of observation during the following 6 mo. WHZ at study enrollment predicted subsequent WHZ but not the risk of LTEs. Changes in height-for-age z score did not predict LTEs.ConclusionsAnthropometric response was associated with a rapid and substantial reduction in risk of LTEs. However, reduction in susceptibility lagged behind anthropometric improvement. Disease events, together with anthropometric assessment, may provide a clearer picture of the effectiveness of interventions. Robust protocols for detecting and treating poor anthropometric recovery and addressing broader vulnerabilities that complicated SAM indicates may save lives. This trial was registered at www.clinicaltrials.gov as NCT00934492.

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Zellweger syndrome with severe malnutrition, immunocompromised state and opportunistic infections.

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Zellweger syndrome with severe malnutrition, immunocompromised state and opportunistic infections.

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