Публикации

X-linked adrenoleukodystrophy (ALD) is a progressive neurometabolic disorder caused by pathogenic variants in the ABCD1 gene, resulting in the systemic accumulation of very-long-chain fatty acids (VLCFAs). C26:0- lysophosphatidylcholine (LPC(26:0)) is the primary biochemical marker of ALD and the basis for newborn screening programs worldwide. LPC(26:0) arises from the accumulation of VLCFA-CoA species that are incorporated into phosphatidylcholine via the lysophospholipid acyltransferase LPLAT10, followed by phospholipase A2-mediated hydrolysis. Compared to conventional plasma VLCFA analysis, measurement of LPC(26:0) by liquid chromatography or flow injection tandem mass spectrometry in plasma or dried blood spots offers superior sensitivity and specificity, even in female patients, for whom VLCFA analysis yields false-negative results in 15–20% of cases. Beyond diagnosis, accumulating evidence indicates that LPC(26:0) and the broader landscape of VLCFA-containing lipids correlate with disease severity. Higher levels are associated with cerebral ALD, adrenal insufficiency, and severe spinal cord disease, and data from newborn screening cohorts suggest that neonatal LPC(26:0) levels may also stratify risk for early-onset disease manifestations. LPC(26:0) accumulates in CNS lipoproteins and exhibits direct neurotoxic and proinflammatory properties in experimental models. This implicates LPC(26:0) not only as a biomarker, but also as a potential mediator of ALD pathology. Furthermore, LPC(26:0) shows promise as a pharmacodynamic biomarker of biochemical correction across therapeutic strategies, from hematopoietic stem cell transplantation to emerging approaches including ELOVL1 inhibition. However, key questions remain regarding the cell type and tissue origin of circulating LPC(26:0), its precise contribution to neuroinflammation, and the threshold levels that reliably predict clinical outcomes in individual patients.

Adrenoleukodystrophy (ALD or X-ALD) is a rare devastating neurological disease caused by mutations in the ATP binding cassette D1 (ABCD1) gene, the product of which is involved in the transport of very long-chain fatty acids (VLCFAs) into peroxisomes for degradation by β-oxidation. Deficiency in ABCD1 results in VLCFAs accumulation in many tissues, including the brain and spinal cord. Elevated VLCFA levels, specifically C26:0, are consistent biochemical markers of ALD and are implicated in the ALD pathogenesis. ALD disease is manifested by multiple phenotypes: the most severe cerebral disease (cerebral ALD, cALD), adrenomyeloneuropathy (AMN) and adrenal insufficiency (Addison disease). VLCFA accumulation is a hallmark of all ALD phenotypes, and reduction/normalization of VLCFA levels is an attractive approach for the treatment of all ALD manifestations. VLCFAs synthesis involves enzymes from elongase of very long-chain fatty acids (ELOVL) enzyme family with ELOVL1 being a rate-limiting enzyme in C26:0 synthesis, making ELOVL1 an attractive target for medical intervention in ALD via Substrate Reduction Therapy (SRT). In this paper, we describe the in vitro assays established to support medicinal chemistry efforts to develop small-molecule ELOVL1 inhibitors for ALD. Notably, we developed novel, breakthrough in vitro methods to monitor enzymatic and cellular ELOVL1 activity, enabling high-throughput screening (HTS) of Sanofi library collections. We successfully identified CNS-active, small-molecule ELOVL1 inhibitors shown to be efficacious in the reduction of C26:0 VLCFA levels in cells and multiple tissues, including brain and spinal cord, in animal models.

X-linked adrenoleukodystrophy (X-ALD) is the mostcommonperoxisomaldisorder, caused by mutations in the ABCD1 gene. Early diagnosis is critical to manage adrenal insufficiency and cerebral forms of the disease. Since 2021, a pilot newborn screening (NBS) program for X-ALD has been launched in Lombardy, Italy. From September 2021 to June 2025, 138,116 newborns (≥37 weeks’ gestational age) were screened for elevated C26:0-lysophosphatidylcholine (C26:0-LPC) levels using a two-tier algorithm. Genetic testing was performed in non-negative cases. Males found to be ABCD1 variant carriers were enrolled in multidisciplinary follow-up, including neurological, endocrinological, and nutritional assessments. Eleven individuals (six males, five females) carried pathogenic or likely pathogenic ABCD1 variants. Three males were diagnosed with adrenal insufficiency and started hydrocortisone therapy between 1 and 2 years of age. Growth parameters were within normal range overall, but two children showed signs of stunting associatedi with poor dietary compliance. Additionally, three patients were diagnosed with Zellweger spectrum disorders (ZSDs). No patients affected with Aicardi-Goutières Syndrome were identified. Newborn screening for X-ALD in Italy is feasible and enables early detection andintervention. Biochemical markers and genetic analysis are reliable tools for identifying affected males and female carriers. Multidisciplinary management is essential to address medical and psychosocial challenges during follow-up.

Neurodegenerative disorders are a group of diseases characterized by progressive degeneration of the nervous system, leading to a gradual loss of previously acquired motor, sensory and/or cognitive functions. Leukodystrophies are amongst the most frequent childhood-onset neurodegenerative diseases and primarily affect the white matter of the brain, often resulting in neuro-motor disability. Notably, gastrointestinal (GI) symptoms and complications, such as gastroesophageal reflux disease (GERD) and dysphagia, significantly impact patients’ quality of life, highlighting the need for comprehensive management strategies. Gut dysbiosis, characterized by microbial imbalance, has been implicated in various GI disorders and neurodegenerative diseases. This narrative review explores the intricate relationship between GI symptoms, Gut Microbiota (GM), and neurodegeneration. Emerging evidence underscores the profound influence of GM on neurological functions via the microbiota gut-brain axis. Animal models have demonstrated alterations in GM composition associated with neuroinflammation and neurodegeneration. Our single-centre experience reveals a high prevalence of GI symptoms in leukodystrophy population, emphasizing the importance of gastroenterological assessment and nutritional intervention in affected children. The bidirectional relationship between GI disorders and neurodegeneration suggests a potential role of gut dysbiosis in disease progression. Prospective studies investigating the GM in leukodystrophies are essential to understand the role of gut-brain axis dysfunction in disease progression and identify novel therapeutic targets. In conclusion, elucidating the interplay between GI disorders, GM, and neurodegeneration holds promise for precision treatments aimed at improving patient outcomes and quality of life.

Adrenomyeloneuropathy is an X-linked recessive disorder characterized by myelopathy, peripheral neuropathy, and cerebral demyelination, which develop in association with the accumulation of very-long-chain fatty acids. The administration of oleic and erucic acids inhibits the synthesis of very-long-chain fatty acids. Recently such dietary treatment has been widely publicized as a possible cure for this disease.

Background and purpose: Nervonic acid plays a vital role in maintaining normal brain and neuronal function. Nervonic acid has gained increasing attention because of its potential neuroprotective and anti-inflammatory properties. Nonetheless, the beneficial effects of nervonic acid are yet to be fully investigated. Adrenomyeloneuropathy (AMN), a type of X-linked adrenoleukodystrophy (ALD), is a progressive inherited metabolic disease characterised by accumulation of saturated very long-chain fatty acids (VLCFAs) in plasma and tissues, leading to increasing oxidative stress, mitochondrial dysfunction, neuroinflammation, cognitive dysfunction and disability. We previously found that nervonic acid can biochemically reverse the accumulation of saturated VLCFAs and increase cellular ATP production in ALD. Here, we investigated nervonic acid as a potential therapy for ALD by assessing its impact on mitochondrial function. Experimental approach: We assessed the effect of nervonic acid on cellular bioenergetics and oxidative stress in AMN patient-derived fibroblasts. We employed Seahorse real-time cell metabolic analysis and imaging of cells treated with increasing concentrations of nervonic acid. Normal dermal fibroblasts served as the healthy control. Key results: AMN cells demonstrate significantly impaired basal respiration, ATP production, maximal respiration and spare respiratory capacity compared to healthy fibroblasts. These mitochondrial respiration parameters significantly improved on treatment with nervonic acid in a concentration-dependent manner. Nervonic acid treatment also significantly reduced mitochondria-derived and total cellular reactive oxygen species, indicating mitigation of total oxidative stress. Conclusion and implications: Our findings indicate a new mechanism of action for nervonic acid in ALD and other mitochondrial dysfunction-associated diseases. This can also indirectly prevent downstream inflammation, thus altering disease progression.

Adrenoleukodystrophy (ALD) is an X-linked inherited peroxisomal disorder due to mutations in the ALD protein and characterized by accumulation of very long-chain fatty acids (VLCFA), specifically hexacosanoic acid (C26:0). This can trigger other pathological processes such as mitochondrial dysfunction, oxidative stress, and inflammation, which if involves the brain tissues can result in a lethal form of the disease called childhood cerebral ALD. With the recent addition of ALD to the Recommended Uniform Screening Panel, there is an increase in the number of individuals who are identified with ALD. However, currently, there is no approved treatment for pre-symptomatic individuals that can arrest or delay symptom development. Here, we report our observations investigating nervonic acid, a monounsaturated fatty acid as a potential therapy for ALD. Using ALD patient-derived fibroblasts, we examined whether nervonic acid can reverse VLCFA accumulation similar to erucic acid, the active ingredient in Lorenzo's oil, a dietary intervention believed to alter disease course. We have shown that nervonic acid can reverse total lipid C26:0 accumulation in a concentration-dependent manner in ALD cell lines. Further, we show that nervonic acid can protect ALD fibroblasts from oxidative insults, presumably by increasing intracellular ATP production. Thus, nervonic acid can be a potential therapeutic for individuals with ALD, which can alter cellular biochemistry and improve its function.

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology and potential drug–target interactions, specifically at the site of action, would improve drug repurposing and facilitate drug development. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early-stage clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.