ライソゾーム病

Fabry disease (FD) is the most common lysosomal storage disorder in which a severe, classical phenotype as well as a milder, non-classical phenotype can be distinguished. In this study we investigated the impact of the introduction of broader DNA sequencing techniques and subsequently the addition of the GLA-gene to NGS or WES based panels on the type of FD patient that is diagnosed by analyzing changes in the composition of the Dutch Fabry cohort over time. The current study confirms that Fabry disease is a genetically heterogeneous disorder with 64 different GLA variants established in a cohort of 319 patients. The introduction of broader DNA sequencing techniques, applied to a broader range of individuals with less specific symptoms, results in the identification of a higher proportion of individuals with less deleterious GLA variants and consequently a milder clinical phenotype. For the majority of individuals identified using the broader sequencing techniques cardiomyopathy is the presenting and only symptom of the disorder, in contrast to the multisystem classical Fabry disease phenotype. This phenotypic shift should be taken into account when comparing current to historical clinical and treatment effect data and requires tailored genetic counseling and clinical follow-up to prevent both over- and undertreatment.

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA) enzyme. This deficiency induces progressive glycogen accumulation, leading to weakness of the respiratory muscle, including the diaphragm. As established enzyme replacement therapy is available for Pompe disease, earlier detection of potential Late-Onset Pompe Disease (LOPD) and subsequent intervention would have a significant clinical impact. PURPOSE: Our hypothesis was that sleep problems, including sleep-disordered breathing (SDB) and clinical symptoms, may indicate an early stage of LOPD, since decreased respiratory muscle activity often presents initially during sleep. The primary aim of the PSSAP-J study was to demonstrate a higher prevalence of LOPD in a sleep-laboratory-based population. Secondary aims included identifying predictive factors for LOPD from diagnostic polysomnography (PSG) findings and clinical symptoms. METHODS: This prospective multicenter observational cohort study enrolled consecutive patients presenting to sleep laboratories for overnight PSG due to suspected SDB. All patients underwent a Dried Blood Spot (DBS) screening for GAA activity. Genetic analysis of the GAA gene was performed for confirmatory testing when indicated. RESULT: A total of 724 participants were analyzed, although the COVID-19 pandemic prevented reaching the target sample size (n = 1,500). No definitive LOPD cases were confirmed among those who completed the confirmatory testing (prevalence 0%; 95% confidence interval [CI], 0.00%-0.51%). However, seven screen-positive patients declined confirmatory testing and were classified as indeterminate cases. Consequently, we could not definitively establish a higher prevalence or identify predictive factors for LOPD in this population. CONCLUSION: Although the primary study aims could not be confirmed due to the sample size shortfall and the presence of indeterminate cases, our findings highlight the importance for sleep physicians to maintain a high index of suspicion for underlying myopathies, such as LOPD, in clinical practice. CLINICAL TRIAL REGISTRATION: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Loss-of-function mutations in the endoplasmic reticulum membrane protein CLN8 cause Batten disease, a neurodegenerative lysosomal storage disorder. CLN8 acts with the lysosomal enzyme CLN5 to produce bis(monoacylglycero)phosphate (BMP), a signature lysosomal phospholipid with unique S,S stereochemistry. However, the role of CLN8 in this pathway has remained unclear. Here we establish that CLN8 is a glycerophosphoglycerol acyltransferase that catalyses the stereospecific acylation of S,S-glycerophosphoglycerol to generate S,S-lysophosphatidylglycerol, the CLN5 substrate in BMP synthesis. Cryo-electron microscopy structures define the CLN8 active site and support a ping-pong acyl transfer mechanism. Batten disease mutations impair CLN8 enzymatic activity and abolish BMP production in mice. Exogenous S,S-lysophosphatidylglycerol, but not the R,S stereoisomer, restores BMP synthesis in CLN8-deficient cells and mice and improves neurological phenotypes in cln8 mutant zebrafish. These findings define the function of CLN8, explain the biochemical basis of CLN8 Batten disease and establish BMP precursor supplementation as a proof-of-concept therapeutic strategy.

According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol, resulting in the formation of lysophosphatidylglycerol. The acyltransferase reaction is catalysed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived lysophosphatidylglycerol is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis but not into phosphatidylglycerol or cardiolipin. CLN8-knockout cells and mice cannot utilize glycerophosphoglycerol for BMP synthesis, resulting in BMP deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders.

Congenital metabolic disorders often lead to irreversible organ damage beginning during fetal life or shortly after birth. Advances in prenatal diagnostics have enabled earlier identification of these conditions, creating opportunities for prenatal therapeutic intervention. Preclinical studies have demonstrated that prenatal cell therapies can result in donor cell engraftment, enzyme production, and partial correction of metabolic defects in several disease models. The fetal environment may support immune tolerance and enhance treatment effectiveness. Limited clinical experience suggests that these approaches are feasible and may be beneficial in selected conditions, including lysosomal storage diseases and infantile-onset Pompe disease. In utero gene therapy has also shown long-term metabolic correction in animal models. However, important challenges remain, including limited engraftment, immune responses, vector safety, ethical concerns, and regulatory barriers. Prenatal cellular and gene-based therapies are promising but remain experimental. Current evidence is strongest for biological rationale and preclinical proof of concept; clinical benefit has not yet been established for most disorders. Further clinical studies are needed to determine their safety, efficacy, and future role in the treatment of congenital metabolic disorders. This article reviews the current status of prenatal fetal cellular and gene‑based therapeutic approaches for inborn errors of metabolism.