The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment.

Zellweger spectrum disorder (ZSD) results from biallelic mutations in PEX genes required for peroxisome biogenesis. PEX1-G843D is a common hypomorphic allele in the patient population that is associated with milder disease. In prior work using a PEX1-G843D/null patient fibroblast line expressing a green fluorescent protein (GFP) reporter with a peroxisome-targeting signal (GFP-PTS1), we demonstrated that treatments with the chemical chaperone betaine and flavonoid acacetin diacetate recovered peroxisome functions. To identify more effective compounds for preclinical investigation, we evaluated 54 flavonoids using this cell-based phenotype assay. Diosmetin showed the most promising combination of potency and efficacy (EC50 2.5 µM). All active 5′,7′-dihydroxyflavones showed greater average efficacy than their corresponding flavonols, whereas the corresponding flavanones, isoflavones, and chalcones tested were inactive. Additional treatment with the proteostasis regulator bortezomib increased the percentage of importrescued cells over treatment with flavonoids alone. Cotreatments of diosmetin and betaine showed the most robust additive effects, as confirmed by three independent functional assays in primary PEX1-G843D patient cells, but neither agent was active alone or in combination in patient cells homozygous for the PEX1 c.2097_2098insT null allele. Moreover, diosmetin treatment increased PEX1, PEX6, and PEX5 protein levels in PEX1-G843D patient cells, but none of these proteins increased in PEX1 null cells. We propose that diosmetin acts as a pharmacological chaperone that improves the stability, conformation, and functions of PEX1/PEX6 exportomer complexes required for peroxisome assembly. We suggest that diosmetin, in clinical use for chronic venous disease, and related flavonoids warrant further preclinical investigation for the treatment of PEX1-G843Dassociated ZSD. K E Y W O R D SAAA ATPase, betaine, chaperone therapy, diosmetin, peroxisome biogenesis disorder, PEX1 J Cell Biochem. 2019;120:3243-3258.wileyonlinelibrary.com/journal/jcb

Mutations in the RASA1 gene are known to cause arteriovenous malformations (AVMs), with evidence of associated lymphatic malformations. We report for the first time, to the best of our knowledge, an infant with RASA1 mutation presenting with hydrops fetalis and chylothorax, but without an associated AVM. Previously, researchers studying rodents have found chylothorax associated with RASA1 mutations, and, in previous case reports, researchers have reported on infants with RASA1 mutations born with hydrops fetalis and AVMs. In this report, we describe the case of a “late preterm” female infant born with nonimmune hydrops fetalis and congenital chylothorax who was detected to have a RASA1 deletion on genetic workup. Although classically described phenotypes of RASA1 mutations present with venous malformations, no such malformations were found in this infant on extensive imaging. This combination is a novel and nonclassic presentation of RASA1 mutation. In cases of congenital chylothorax, especially with nonimmune hydrops fetalis, RASA1 mutations should be considered as part of the differential diagnosis and genetic testing should be included as part of a complete workup to allow for screening for associated vascular anomalies.

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Moisture-associated skin damage, especially incontinence-associated dermatitis, continues to present significant health challenges and requires multidisciplinary input to provide effective prevention and treatment. In the absence of mandatory reporting such damage is under- or wrongfully reported, resulting in a lack of accurate data on prevalence and costs of associated care. In March this year, a multidisciplinary team of experts met in the UK to seek to determine measures to improve patient skin care. They aimed to identify activities to increase awareness and education, collect data, and improve prevention and treatment regimes. This article describes that discussion and the conclusions made by the group, such as the key actions required to effect policy changes.