La sindrome di Zellweger: un lavoro di squadra

A 1-month female infant with hypotonia, feeding difficulties, facial dysmorphic signs, hepatomegaly and seizures was admitted to the neonatal intensive care unit. Brain magnetic resonance revealed regions of cortical dysplasia, diffuse polymicrogyria (prominent in the frontal and perisylvian cortex), reduction of white matter volume, delayed myelination and germinolytic cysts. The result of the plasma dosage of very long chain fatty acids was very high. Genetic testing revealed a homozygous pathogenetic mutation of the HSD17B4 gene. Thus, clinical features together with biochemical and genetic findings led to the diagnosis of Zellweger spectrum disorder (ZSD). ZSD is included in peroxisome biogenesis disorders. Before the biochemical and molecular bases had been fully determined, ZSD was defined by a continuum of three phenotypes: Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. To identify a continuum of severity of the disease, the terms “severe,” “intermediate” and “milder” ZSD are now preferred. The individuals with ZSD mainly come to clinical attention in the newborn period or in childhood. Occasionally, the subtlety of symptoms delays diagnosis until adulthood. There is not specific therapy, in the severe ZSD prognosis is poor and survival is usually not beyond the first year of life.

The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a multi-organ syndrome with significant morbidity and mortality for which there is no current drug therapy. Mild PBD-ZSS patients can exhibit a more progressive disease course and could benefit from the identification of drugs to improve the quality of life and extend the lifespan of affected individuals. Our study used a high-throughput screen of FDA-approved compounds to identify compounds that improve peroxisome function and biogenesis in human fibroblast cells carrying the mild PBD-ZSS variant, PEX1G843D. Our screen identified the nitrogen oxide donor, S-nitrosoglutathione (GSNO), as a potential therapeutic for this mild form of PBD-ZSS. Further biochemical characterization showed that GSNO enhances both peroxisome number and function in PEX1G843D mutant fibroblasts and leads to increased survival and longer lifespan in an in vivo humanized Drosophila model carrying the PEX1G843D mutation. GSNO is therefore a strong candidate to be translated to clinical trials as a potential therapeutic for mild PBD-ZSS.

Overwhelming sepsis in a neonate affected by Zellweger syndrome due to a compound heterozygosis in PEX 6 gene: a case report

Background Peroxisome biogenesis disorders (PBDs) are a group of metabolic diseases caused by dysfunction of peroxisomes. Different forms of PBDs are described; the most severe one is the Zellweger syndrome (ZS). We report on an unusual presentation of Zellweger syndrome manifesting in a newborn with severe and fulminant sepsis, causing death during the neonatal period. Case presentation A term male Caucasian neonate presented at birth with hypotonia and poor feeding associated with dysmorphic craniofacial features and skeletal abnormalities. Blood tests showed progressive leukopenia; ultrasounds revealed cerebral and renal abnormalities. He died on the fourth day of life because of an irreversible Gram-negative sepsis. Post-mortem tests on blood and urine samples showed biochemical alterations suggestive of ZS confirmed by genetic test. Conclusions ZS is an early and severe forms of PBDs. Peroxisomes are known to be involved in lipid metabolism, but recent studies suggest their fundamental role in modulating immune response and inflammation. In case of clinical suspicion of ZS it is important to focus the attention on the prevention and management of infections that can rapidly progress to death.