Cell Type-Selective Loss of Peroxisomal β-Oxidation Impairs Bipolar Cell but Not Photoreceptor Survival in the Retina

Retinal degeneration is a common feature in peroxisomal disorders leading to blindness. Peroxisomes are present in the different cell types of the retina; however, their precise contribution to retinal integrity is still unclear. We previously showed that mice lacking the central peroxisomal β-oxidation enzyme, multifunctional protein 2 (MFP2), develop an early onset retinal decay including photoreceptor cell death. To decipher the function of peroxisomal β-oxidation in photoreceptors, we generated cell type selective Mfp2 knockout mice, using the Crx promotor targeting photoreceptors and bipolar cells. Surprisingly, Crx-Mfp2−/− mice maintained photoreceptor length and number until the age of 1 year. A negative electroretinogram was indicative of preserved photoreceptor phototransduction, but impaired downstream bipolar cell signaling from the age of 6 months. The photoreceptor ribbon synapse was affected, containing free-floating ribbons and vesicles with altered size and density. The bipolar cell interneurons sprouted into the ONL and died. Whereas docosahexaenoic acid levels were normal in the neural retina, levels of lipids containing very long chain polyunsaturated fatty acids were highly increased. Crx-Pex5−/− mice, in which all peroxisomal functions are inactivated in photoreceptors and bipolar cells, developed the same phenotype as Crx-Mfp2−/− mice. In conclusion, the early photoreceptor death in global Mfp2−/− mice is not driven cell autonomously. However, peroxisomal β-oxidation is essential for the integrity of photoreceptor ribbon synapses and of bipolar cells.

Peroxisomes in intracellular cholesterol transport: from basic physiology to brain pathology

Peroxisomes are actively involved in the metabolism of various lipids including fatty acids, ether phospholipids, bile acids as well as the processing of reactive oxygen and nitrogen species. Recent studies show that peroxisomes can regulate cholesterol homeostasis by mediating cholesterol transport from the lysosomes to the endoplasmic reticulum and towards primary cilium as well. Disruptions of peroxisome biogenesis or functions lead to peroxisomal disorders that usually involve neurological deficits. Peroxisomal dysfunction is also linked to several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In many peroxisomal disorders and neurodegenerative diseases, aberrant cholesterol accumulation is frequently encountered yet largely neglected. This review discusses the current understanding of the mechanisms by which peroxisomes facilitate cholesterol trafficking within the cell and the pathological conditions related to impaired cholesterol transport by peroxisomes, with the hope to inspire future development of the treatments for peroxisomal disorders and neurodegenerative diseases.

Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency

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.

Advanced Diagnostic System and Introduction of Newborn Screening of Adrenoleukodystrophy and Peroxisomal Disorders in Japan

We established a diagnostic system for adrenoleukodystrophy (ALD) and peroxisomal disorders (PD) over 35 years ago in Japan, and have diagnosed 237 families with ALD and more than 100 cases of PD other than ALD using biochemical and molecular analyses. In particular, since the only treatment for the cerebral form of ALD is hematopoietic stem cell transplantation at an early stage of onset, we have developed a protocol for the rapid diagnosis of ALD that can provide the measurements of the levels of very-long-chain fatty acids in the serum and genetic analysis within a few days. In addition, to improve the prognosis of patients with ALD, we are working on the detection of pre-symptomatic patients by familial analysis from the proband, and the introduction of newborn screening. In this review, we introduce the diagnostic and newborn screening approaches for ALD and PD in Japan.

Clinico-Metabolic Profile of Neurometabolic Disorders of Children in a Tertiary Care Hospital of Bangladesh

Background: Neurometabolic disorders are inborn errors of metabolism with neurological manifestations. They are individually rare but as a group have a significant burden. They constitute 4.9% of genetic cause of moderate and severe mental retardation. Aims and objective: To explore clinical & metabolic profile of various forms of childhood Neurometabolic disorders. Methods: A hospital based retrospective study was conducted at Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University, and Dhaka from January 2016 to December 2020. Total 59 suspected children of Neurometabolic disorders (NMD), who admitted in hospital during the study period, were included. Among them 41 cases of NMD were diagnoses confirmed on the basis of clinical suspicion, biochemical test, and neuroimaging study and in few cases molecular genetics investigations. Results: Among 59 suspected cases, total 41 patients were diagnosed as Neurometabolic disorders. Most of the (63.2%) patients were within 0-3 years age. Male patients (70.73%) were outnumbered than female (29.26%). Male: Female ratio were 2.4:1. More than half of patients 25(60.90%) had parental consanguinity followed by Sib death 7 (17.07%), Prematurity 11 (26.82%). Common Neurometabolic disorders were aminoacidopathy 14 (34.14%) and lysosomal storage disorders 15 (36.58%) followed by mitochondrial disorders 5(12.19%), Urea cycle disorders 3(7.31%), CHO metabolism disorders 5(2.43%), Peroxisomal disorders 3(7.31%). Among aminoacidopathy, Organic acidamia 4(9.72%), MSUD 3(7.31%), PKU 2(4.86%), Gluteric Aciduria 3(7.31%), and Biotinidase deficiency disorder 1(2.43%) were common disorders. Among lysosomal storage disorders, mucopolysaccaridosis 4(9.72%) and metachromatic leukodystrophy 8(19.44%) were most common disorders. Common presentations were developmental delay 37(90.24%), developmental regression 21(51.21%), hypotonia 29(70.73) and seizures 26(63.41%). Neuroimaging changes found in about three fourth (80.49%) of cases. About 26.82% cases presented with white matter hyper intensity followed by basal ganglia hyper intensity (19.51%) and cerebral atrophy (14.63%). Abnormally high ammonia and lactate found in 6(14.63%) and 10(24.40%) cases respectively followed by Positive urinary ketones 8 (19.51%). Conclusions: Neurometabolic disorders are not uncommon. The commonest neurometabolic disorders were aminoaciduria and lysosomal storage disease in our study. Among aminoacid disorders, Organic acidamia, MSUD, Glutaric aciduria and in lysosomal storage disorders metachromatic leukodystrophy & Mucopolysaccharoidosis were common disorders. Neuroimaging changes were found in about three- forth cases in this study.

Metabolic Seizures

Metabolic diseases should always be considered when evaluating children presenting with seizures. This is because many metabolic disorders are potentially treatable and seizure control can be achieved when these diseases are appropriately treated. Seizures caused by underlying metabolic diseases (metabolic seizures) should be particularly considered in unexplained neonatal seizures, refractory seizures, seizures related to fasting or food intake, seizures associated with other systemic or neurologic features, parental consanguinity, and family history of epilepsy. Metabolic seizures can be caused by various amino acids metabolic disorders, disorders of energy metabolism, cofactor-related metabolic diseases, purine and pyrimidine metabolic diseases, congenital disorders of glycosylation, and lysosomal and peroxisomal disorders. Diagnosing metabolic seizures without delay is essential because the immediate initiation of appropriate therapy for many metabolic diseases can prevent or minimize complications.

Imaging in X-Linked Adrenoleukodystrophy

Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common peroxisomal disorders and is characterized by a defect in degradation of very long chain fatty acids (VLCFA), resulting in accumulation of VLCFA in plasma and tissues. The clinical spectrum of ALD is wide and includes adrenocortical insufficiency, a slowly progressive myelopathy in adulthood, and cerebral demyelination in a subset of male patients. Cerebral demyelination (cerebral ALD) can be treated with hematopoietic cell transplantation (HCT) but only in an early (pre- or early symptomatic) stage and therefore active MRI surveillance is recommended for male patients, both pediatric and adult. Although structural MRI of the brain can detect the presence and extent of cerebral lesions, it does not predict if and when cerebral demyelination will occur. There is a great need for imaging techniques that predict onset of cerebral ALD before lesions appear. Also, imaging markers for severity of myelopathy as surrogate outcome measure in clinical trials would facilitate drug development. New quantitative MRI techniques are promising in that respect. This review focuses on structural and quantitative imaging techniques—including magnetic resonance spectroscopy, diffusion tensor imaging, MR perfusion imaging, magnetization transfer (MT) imaging, neurite orientation dispersion and density imaging (NODDI), and myelin water fraction imaging—used in ALD and their role in clinical practice and research opportunities for the future.