Journal of Inherited Metabolic Disease最新文献

GM1 gangliosidosis is a rare, progressively neurodegenerative lysosomal storage disorder characterized by profound central nervous system involvement and substantial clinical heterogeneity. The development of reliable biomarkers is essential for tracking disease progression, stratifying patients, and advancing clinical trial readiness. Primary substrate markers, including cerebrospinal fluid (CSF) GM1 ganglioside and related lysosphingolipids, provide direct biochemical indices of lysosomal dysfunction. Emerging glycan signatures may further reflect disruptions in glycosylation pathways and responses to therapeutic intervention. Neurofilament light chain (NfL), a sensitive indicator of axonal injury, is consistently elevated in GM1 and shows promise as a fluid biomarker, although it does not convey regional specificity. Neuroimaging offers complementary insight into the structural and metabolic consequences of disease. Characteristic findings include diffuse white matter abnormalities, thalamic and basal ganglia signal changes, cortical and cerebellar atrophy, and ventriculomegaly. Quantitative MRI and magnetic resonance spectroscopy (MRS) reveal longitudinal declines in tissue volume and neuronal integrity that parallel functional deterioration. Diffusion-based methods, including differential tractography, highlight progressive loss of white matter microstructure relative to age-matched controls. However, severe anatomical distortion in GM1 limits the applicability of standard neuroimaging atlases, necessitating manual or semi-automated segmentation approaches. Together, fluid biomarkers (gangliosides, lysosphingolipids, glycans, NfL) and advanced neuroimaging metrics (volumetry, MRS, diffusion imaging) establish a multimodal framework for evaluating disease burden and therapeutic response. Standardized methodologies, harmonized natural history datasets, and genotype-stratified analyses will be critical for validating these biomarkers across GM1 subtypes. Strengthening this biomarker ecosystem will enable sensitive and clinically meaningful endpoints to support future therapeutic development in GM1 gangliosidosis.

Mitochondrial trifunctional protein (TFP) deficiency is an inherited disorder of long-chain fatty acid β-oxidation (FAO). TFP is a heteromeric enzyme composed of two α and two β-subunits. Despite early detection and dietary treatment, TFP deficiency patients often develop hypoglycemia, rhabdomyolysis, cardiomyopathy, and peripheral neuropathy. Degenerative retinopathy and milder peripheral neuropathy occur in patients with an isolated deficiency of the αTFP subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity. Triheptanoin treatment improves most complications, but not peripheral neuropathy and retinopathy. Notably, TFP also carries a fourth enzymatic function involved in cardiolipin remodeling, which we previously found to be impaired in TFP/LCHAD deficiency. We therefore tested whether elamipretide, a synthetic cardiolipin-binding peptide, could improve mitochondrial function and cardiolipin levels in βTFP-deficient mice and patient-derived fibroblasts. Mice were treated with elamipretide delivered by osmotic minipump and challenged with treadmill exercise or cold stress after fasting. βTFP-deficient mice treated with elamipretide showed improved exercise endurance, but cold tolerance was not altered. Liver mitochondria from male βTFP-deficient mice demonstrated improved FAO-ETC enzyme activities. However, cardiolipin content and composition were unchanged. In patient fibroblasts, elamipretide produced a possible genotype-dependent increase in mitochondrial bioenergetics and a reduction in ROS. These results support a mechanism in which elamipretide stabilizes between FAO enzymes and ETC complexes, thereby improving mitochondrial function independently of changes in cardiolipin levels. Elamipretide thus emerges as a potential therapeutic agent for TFP/LCHAD deficiency, warranting further preclinical studies.

Nizubaglustat is a novel selective inhibitor of glucosylceramide synthase (GCS) and the non-lysosomal glucocerebrosidase (NLGase, GbA2) with brain penetrant properties. It is currently in clinical development as an oral treatment for rare lysosomal storage diseases with neurological involvement. One such disease group called GM2 gangliosidosis, to date, has no approved therapeutic treatment. To test the potential efficacy of nizubaglustat in a mouse model of GM2 gangliosidoses, we treated Sandhoff disease (SD) mice carrying a homozygous null mutation in the Hexb gene, as well as healthy heterozygous controls, to understand exposure versus effect under disease conditions. Oral doses of nizubaglustat from 0.2 to 6 mg/kg/day showed linear pharmacokinetics with plasma and brain concentrations sufficient to drive pharmacodynamic changes in markers of target engagement and efficacy. In the brain, an approximately 10-fold increase in GlcCer C16:0 and C18:0 was observed, which is consistent with NLGase inhibition. A statistically significant increase in survival (22%) was noted in SD mice treated at doses as low as 0.2 mg/kg/day compared to controls. Behavioral analyses, which included rotarod and open field tests, were also significantly improved. To understand the added potential mechanism of the improved survival, a subset of neuroinflammatory markers was also examined in specific brain regions. Gene expression studies showed an anti-inflammatory pattern with downregulation of Itgax, Trem2, Cxcl10 genes as an example. Brain immunohistochemistry for GFAP was decreased compared to vehicle treated control animals. These results provide proof-of-concept that nizubaglustat can be a promising therapeutic drug to treat patients with GM2 gangliosidoses.

Glutaric aciduria type 1 (GA1) is a neurometabolic disorder characterized by striatal injury in infancy and extrastriatal central nervous system abnormalities, the latter depending on the biochemical subtype. Whether the peripheral nervous system (PNS) is also affected has not been systematically studied. Therefore, we conducted a cross-sectional study of 21 GA1 patients (15 high excretor [HE], 6 low excretor [LE]), identified either by newborn screening (NBS, n = 11) or targeted metabolic diagnostics (TMD, n = 10). All underwent clinical evaluation, cerebral MRI, neurophysiology, and MR-neurography (MRN) of the sciatic nerve with magnetization transfer imaging and diffusion tensor imaging (DTI). Nerve magnetization transfer ratio (MTR) was analyzed across subgroups and against 21 age-matched controls, while fractional anisotropy (FA) was assessed within the patient cohort. MRN revealed frequent abnormalities in GA1, particularly among HE patients, who showed lower MTR and FA values, indicating neuropathic changes. These alterations correlated with age, extrastriatal MRI abnormalities, and subependymal nodules, but not with striatal lesions or movement disorder. Clinical neuropathic symptoms were rare (4/15 HE patients) yet consistently associated with abnormal MRN. In HE patients exclusively, neurophysiology demonstrated reduced compound motor action potentials, slowed nerve conduction, and prolonged tibial somatosensory evoked potential latencies. Within the HE subgroup, NBS-identified patients showed higher MTR values than those identified by targeted metabolic diagnostics, suggesting less severe nerve involvement. These results expand the GA1 phenotype by demonstrating frequent, predominantly subclinical PNS involvement in HE patients, linked to chronic metabolic toxicity. They underscore the need for further research into long-term complications and therapeutic strategies for HE individuals.

Nonketotic hyperglycinemia is a severe neonatal epileptic encephalopathy caused by deficient glycine cleavage enzyme activity, for which currently no effective treatment exists. Incomplete understanding of brain biochemistry represents a major knowledge gap to develop new treatments. We examined the biochemistry in blood, liver, cortex, hippocampus, and cerebellum of a mouse model homozygous for the Gldc variant p.Ala394Val. Glycine was increased in all compartments and caused increased brain neurotoxic metabolites guanidinoacetate and methylglyoxal, and also N-acetylglycine and cystathionine. The glycine extruding transporter Slc6a20 was increased. There was reduced one-carbon folate charging with secondarily reduced methionine in the cortex, and reduced alternative one-carbon donors L-serine and formate. Serine deficiency was associated with reduced amounts of sphingosine, sphingomyelin, and ceramide species important for myelination, but not phosphatidylserines. There was a region-specific deficiency of D-serine in the cortex and hippocampus. This difference, also present in humans, was strain- and age-related, most evident in young J129X1/SvJ mice, reflecting symptomatology. There was no evidence of oxidative stress or a bioenergetic defect. The biochemistry of the nonketotic hyperglycinemia mouse model can be traced to three components: increased glycine, reduced folate one-carbon charging, and decreased L- and D-serine. These changes will need to be addressed in new therapeutic approaches.