Clinicogenetic characterization of cerebrotendinous xanthomatosis in Brazil.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants.

Differential expression of brummer and levels of TAG in different developmental stages Aedes aegypti (Diptera: Culicidae), including fasted adults.

Lipid storage in the form of triacylglycerol (TAG) is essential for insect life, as it enables flight, development, and reproduction. The activity of the lipase brummer (bmm) has been shown to be essential to insects' homeostasis. The objective of this study was to evaluate how bmm expression occurs in Aedes aegypti larvae and adults, and to observe TAG levels during fasting in adult females. The bmm sequence was identified in A. aegypti and exhibited a patatin-like phospholipase domain reinforced by the presence of a catalytic dyad with serine and aspartate residues, revealing a high degree of similarity with other organisms. Bmm expression was differentiated in the larvae and adult fat body (FB) following TAG reserve dynamics. Bmm was expressed three times in larval stages L3, L4, and pupae compared with L1 and L2, which could indicate its role in the maturation of these insects. In the postemergence (PE) and post-blood meal (PBM) FB of adult insects, bmm expression varied over several days. PE adults showed a pronounced bmm increase from the third day onward compared with those not subjected to fasting. This was accompanied by a decrease in TAG from the third day onward, suggesting the participation of bmm. Six hours after blood feeding, TAG levels increased in mosquitos reared in the absence of sucrose, suggesting lipid accumulation to guarantee reproduction. Bmm responded positively to fasting, followed by TAG mobilization in adult FB. During the previtellogenic period, bmm levels responded to low TAG levels, unlike the PBM period.

Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report.

BACKGROUND: Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia. CASE PRESENTATION: We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described. CONCLUSIONS: Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

Cerebrotendinous Xanthomatosis: A practice review of pathophysiology, diagnosis, and treatment.

Cerebrotendinous Xanthomatosis represents a rare and underdiagnosed inherited neurometabolic disorder due to homozygous or compound heterozygous variants involving the CYP27A1 gene. This bile acid metabolism disorder represents a key potentially treatable neurogenetic condition due to the wide spectrum of neurological presentations in which it most commonly occurs. Cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, parkinsonism, cognitive decline, intellectual disability, and neuropsychiatric disturbances represent some of the most common neurological signs observed in this condition. Despite representing key features to increase diagnostic index suspicion, multisystemic involvement does not represent an obligatory feature and can also be under evaluated during diagnostic work-up. Chenodeoxycholic acid represents a well-known successful therapy for this inherited metabolic disease, however its unavailability in several contexts, high costs and common use in patients at late stages of disease course limit more favorable neurological outcomes for most individuals. This review article aims to discuss and highlight the most recent and updated knowledge regarding clinical, pathophysiological, neuroimaging, genetic and therapeutic aspects related to Cerebrotendinous Xanthomatosis.

Lipids in Insect Oocytes: From the Storage Pathways to Their Multiple Functions.

In insect physiology, the mechanisms involved in the buildup and regulation of yolk proteins in developing oocytes have been thoroughly researched during the last three decades. Comparatively, the study of lipid metabolism in oocytes had received less attention. The importance of this issue lies in the fact that lipids make up to 40% of the dry weight of an insect egg, being the most important supply of energy for the developing embryo. Since the oocyte has a very limited capacity to synthesize lipids de novo, most of the lipids in the mature eggs arise from the circulation. The main lipid carriers in the insect circulatory system are the lipoproteins lipophorin and vitellogenin. In some species, the endocytosis of lipophorin and vitellogenin may account for about 10% of the lipids present in mature eggs. Thus, most of the lipids are transferred by a lipophorin-mediated pathway, in which the lipoprotein unloads its lipid cargo at the surface of oocytes without internalization. This chapter recapitulates the current status on lipid storage and its utilization in insect oocytes and discusses the participation of key factors including lipoproteins, transfer proteins, lipolytic enzymes, and dynamic organelles such as lipid droplets. The new findings in the field of lipophorin receptors are presented in the context of lipid accumulation during egg maturation, and the roles of lipids beyond energy source are summarized from the perspective of oogenesis and embryogenesis. Finally, prospective and fruitful areas of future research are suggested.