• adrenal insufficiency
• adrenoleukodystrophy
• case report
• developmental delay
• newborn screening
• optic atrophy

• financial

Peroxisomes share metabolic pathways with other organelles and peroxisomes are embedded into key cellular processes. However, the specific function of many peroxisomal proteins remains unclear and restricted knowledge of the peroxisomal protein interaction network limits a precise mapping of this network into the cellular metabolism. Inborn peroxisomal disorders are autosomal or X-linked recessive diseases that affect peroxisomal biogenesis (PBD) and/or peroxisomal metabolism. Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. To investigate the phenotypic complexity of PEX26 deficiency, we performed a combined organelle protein interaction screen and network medicine approach and 1) analyzed whether PEX26 establishes interactions with other peroxisomal proteins, 2) deciphered the PEX26 interaction network, 3) determined how PEX26 is involved in further processes of peroxisomal biogenesis and metabolism, and 4) showed how variant-specific disruption of protein-protein interactions (edgetic perturbations) may contribute to phenotypic variability in PEX26 deficient patients. The discovery of 14 novel protein-protein interactions for PEX26 revealed a hub position of PEX26 inside the peroxisomal interactome. Analysis of edgetic perturbations of PEX26 variants revealed a strong correlation between the number of affected protein-protein interactions and the molecular phenotype of matrix protein import. The role of PEX26 in peroxisomal biogenesis was expanded encompassing matrix protein import, division and proliferation, and membrane assembly. Moreover, the PEX26 interaction network intersects with cellular lipid metabolism at different steps. The results of this study expand the knowledge about the function of PEX26 and refine genotype-phenotype correlations, which may contribute to our understanding of the underlying disease mechanism of PEX26 deficiency.

• BRET
• PEX26
• edgetic perturbations
• network medicine
• peroxisome

X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation, is caused by defects in the ATP Binding Cassette Subfamily D Member 1 (ABCD1) gene. X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild, severe cerebral adrenoleuko-dystrophy to mild adrenomyeloneuropathy (AMN). Although most female heterozygotes present with AMN-like symptoms after 60 years of age, occasional cases of females with the cerebral form have been reported. Phenotypic variability has been described within the same kindreds and even among monozygotic twins. There is no association between the nature of ABCD1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.

• X-adrenoleukodystrophy
• Cerebral adrenoleukodystrophy
• Adrenomyelo-neuropathy
• Phenotypic variation
• Modifiers

• ABCD1
• X-linked adrenoleukodystrophy
• natural history
• peroxisomal diseases
• women

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters/genetics
• ATP-Binding Cassette Transporters/metabolism
• Adrenal Insufficiency/metabolism
• Adrenoleukodystrophy/diagnosis
• Adrenoleukodystrophy/drug therapy
• Adrenoleukodystrophy/genetics
• Adrenoleukodystrophy/metabolism
• Brain/diagnostic imaging
• Disease Progression
• Fatty Acids/metabolism
• Female
• Glucocorticoids/therapeutic use
• Hormone Replacement Therapy
• Humans
• Leukoencephalopathies/diagnostic imaging
• Leukoencephalopathies/metabolism
• Male
• Peripheral Nervous System Diseases/metabolism
• Spinal Cord Diseases/metabolism

• Adrenoleukodystrophy
• Cytochrome P450
• Dicarboxylic acids
• Modifier gene
• Omega-oxidation
• Peroxisomes

• Age-related disease
• Biogenesis disorder
• Epigenetics
• Intracellular signaling
• Mitochondria
• Peroxisome

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs.

• AMN
• X-ALD
• incidence
• mutations
• newborn screening
• prenatal diagnosis

Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients.

We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol).

Median age at diagnosis was 59 years (range: 28–77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis.

This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.