Martina Messina

Neuronal ceroid lipofuscinosis type 1 (CLN1) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the PPT1 gene, leading to lipofuscin accumulation, neurodegeneration, psychomotor regression, seizures, and vision loss, with early death in infancy. Currently, no curative treatment exists. Neuroinflammation plays a major role in CLN1 pathophysiology, making anti-inflammatory treatments a potential option. Fingolimod, an immune modulator approved for multiple sclerosis (MS), has shown efficacy in reducing neurodegeneration in CLN1 mouse models. Neurofilament light chain (NfL), a key axonal structural protein, is a biomarker of neuronal damage, with elevated levels indicating axonal injury in various neurologic diseases. We report on 2 pediatric patients with CLN1 treated with fingolimod to assess clinical response and its impact on NfL levels. This study involved 2 patients with CLN1 who were treated with fingolimod under a compassionate use program at Great Ormond Street Hospital. Inclusion criteria required a molecular diagnosis of CLN1. Patient 1 was monitored over a 36-month period, while patient 2 was followed for 15 months. Fingolimod was administered daily, with dosing adjusted based on age and weight. Lymphocyte counts and NfL levels were regularly measured throughout the study to assess treatment response. The primary outcome was the evaluation of the safety profile following the SOP for fingolimod administration at GOSH. Secondary outcomes included clinical assessments to monitor disease progression and lymphocyte count. As an exploratory outcome, we measured NfL levels, which serve as a biomarker of neuroinflammation and axonal injury. Two patients with CLN1 were treated with fingolimod under compassionate use. Patient 1 showed a >50% reduction in NfL levels after 14 months, approaching normal results after 2 years, while patient 2 had limited NfL data but generally lower levels, possibly due to later disease onset. No major safety concerns were observed. No clinical improvements were seen, although some stabilization was observed despite expected disease progression. The significant reduction in NfL levels observed suggests reduced neuroaxonal damage secondary to immune modulation. This finding highlights the potential role of immune modulation in addressing underlying inflammatory processes in CLN1, even if it does not fully halt disease progression.

Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3‐methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S )-4-(3- ¹⁸ F-fluoropropyl)- l -glutamate ([ ¹⁸ F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [ ¹⁸ F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.