Journal of Inherited Metabolic Disease最新文献

Decisions about expensive drugs for rare diseases (EDRDs) raise complex ethical challenges beyond the allocation of limited healthcare resources. This paper examines the ethical dimensions of EDRD decision-making, arguing that the framing of such decisions as simply ethical or unethical is inadequate. In complex healthcare systems characterized by diversity and inequality, no single normative theory provides an incontrovertible solution. EDRD decisions require both ethical justification (grounded in carefully interpreted and balanced values) and ethical legitimacy (achieved through fair processes that respect autonomy). Interest-based accounts of procedural justice are insufficient because they mischaracterize how people form identities and interests. Deliberative democratic approaches that engage multiple perspectives through reflective, inclusive processes are more promising, though they face challenges of complexity, time constraints, and resistance to transparency. Transparency is essential, and courageous leadership is needed to establish processes that accommodate diverse perspectives while addressing the practical realities of healthcare systems. Such leadership can help create ethically defensible EDRD decisions that balance patient needs with system sustainability.

Pathological ectopic calcification of soft tissues can arise from reduced or absent levels of inorganic pyrophosphate (PPi), a key inhibitor of calcium hydroxyapatite deposition in soft connective tissues. The role of PPi in regulating mineralization has been recognized for decades, thanks to the pivotal work of Herbert Fleisch and colleagues; and its clinical relevance has been underscored by the identification of hereditary metabolic disorders, collectively termed PPi deficiency syndromes. These are caused by pathogenic variants in the essential genes for maintaining PPi homeostasis: ATP-binding cassette subfamily C member 6 (ABCC6), ectonucleotide pyrophosphate phosphodiesterase 1 (ENPP1), progressive ankylosis protein (ANK), tissue-nonspecific alkaline phosphatase (ALPL), CD73, and CD39. In recent years, abnormalities in lipid metabolism have been reported in these monogenic conditions. However, a common understanding of these alterations has yet to be established. This review provides an overview of the pathophysiology of PPi deficiency syndromes—pseudoxanthoma elasticum, generalized arterial calcification of infancy, arterial calcification due to CD73 deficiency, ankylosis, and Hutchinson-Gilford progeria syndrome—highlighting the lipid metabolism alterations in cells, animal models, and patients. We explore the evidence for a potential role of PPi-regulating proteins in lipid metabolic pathways to demonstrate that lipid alterations are not coincidental but entail opportunities for future research and for potential therapeutic interventions.

D-bifunctional protein deficiency (DBP-D) is a rare autosomal recessive peroxisomal disorder caused by biallelic pathogenic HSD17B4 variants. Its clinical spectrum ranges from severe neonatal-onset encephalopathy to milder, juvenile-onset forms, but comprehensive data on long-term outcomes remain limited. We conducted a retrospective, multicentre review of 26 DBP-D patients managed at seven centres in the United Kingdom and Spain from 1982 to 2024. Clinical, biochemical, neuroimaging, neurophysiological, and genetic data were systematically collected. A literature review was performed to contextualize our findings. Most patients (92%) presented within the first 5 days of life with neonatal seizures and hypotonia. Mortality was high: 77% died before the age of 2 years and 20% between ages two and five. Notably, three patients survived beyond 5 years, including one with neonatal-onset now aged 19. Two others had infantile-juvenile presentations with hearing loss, ataxia, and cerebellar atrophy. While 68% of patients had elevated very long-chain fatty acids (VLCFAs), 32% had normal or mildly raised levels; all of these survived beyond 2 years. Pathogenic variants were distributed across all three HSD17B4 domains, with 14 novel alleles identified. Neuroimaging findings varied with severity: polymicrogyria and cysts predominated in neonatal-onset cases, while cerebellar atrophy was typical in later-onset survivors. This study expands the clinical and genetic landscape of DBP-D, demonstrating that survival into adulthood is possible and that normal or mildly elevated VLCFA levels are associated with milder phenotypes. Early molecular testing is essential in all suspected cases, even with normal VLCFAs, to guide diagnosis, prognosis, and long-term care.

Kidney disease in glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (G6Pase-α), is associated with acute kidney injury (AKI) and renal fibrosis. During AKI, autophagy is typically activated to eliminate protein aggregates and damaged organelles; however, sustained autophagy can contribute to maladaptive repair and fibrosis. Using a GSD-Ia mouse model, we demonstrate that renal G6Pase-α deficiency results in heightened autophagy activation, as indicated by increased expression of multiple autophagy-related components and enhanced autophagic flux. Notably, both positive regulators of autophagy, including sirtuin-1, forkhead box O3a, and AMP-activated protein kinase, as well as the key negative regulator, mammalian target of rapamycin (mTOR), were concurrently activated in the kidneys of GSD-Ia mice. Previous studies have shown that in response to AKI, renal levels of cyclin G1 (CG1) and cyclin-dependent kinase 5 (CDK5) increase, promoting maladaptive dedifferentiation, G2/M cell cycle arrest in proximal tubular epithelial cells, and the formation of a TOR-autophagy spatial coupling compartment. This sequence of events contributes to profibrotic factor production and accelerates the progression of kidney disease. In this study, we observed a significant elevation of renal CG1 and CDK5 in GSD-Ia mice with enhanced autophagy, suggesting a potential mechanistic link to the development of renal fibrosis in GSD-Ia. A deeper understanding of these pathways may facilitate the development of targeted therapies for GSD-Ia nephropathy.

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by loss-of-function variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene encoding for the acid sphingomyelinase (ASM). Aberrantly high levels of sphingosylphosphorylcholine (SPC), the deacylated form of sphingomyelin which is the primary accumulated lipid, are key biomarkers in ASMD. The identification of small molecules targeting SPC is an attractive approach for treating ASMD. We screened 1813 Food and Drug Administration-approved compounds to identify promising candidates that reduce SPC for treating ASMD, using a liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) assay. Eight compounds, floxuridine, dexamethasone, indacaterol maleate, triethylenethiophosphoramide, cytarabine, doramectin, cepharanthine (CEP), and tetrandrine (TE), were identified to abate the accumulation of SPC in ASMD cells. CEP and TE were selected for further pharmacological studies because of their ability to confer the greatest reduction effect on SPC. Finally, a reduction of SPC storage was verified in ASMD lymphoblasts, SMPD1-KO cells and SMPD1^Y496H fibroblasts by CEP treatment. Additionally, CEP could improve mitochondrial morphology and function, and stimulated lysosome biogenesis by promoting TFEB nuclear translocation in ASMD cells. These results suggest that CEP could potentially be developed as a promising candidate for treating ASMD.

d-glyceric aciduria is a very rare inborn error of serine and fructose metabolism which is caused by d-glycerate kinase (GLYCTK) deficiency. So far, 18 individuals with this tentative diagnosis have been reported. Patients present with a wide range of clinical phenotypes, but asymptomatic cases have also been described. Given the highly variable clinical outcomes it has been suggested that d-glycerate kinase deficiency may be a mere biochemical variant rather than a disease. Previously, it was proposed and widely distributed in public databases, that two GLYCTK isoforms, which result from alternative splicing, are ubiquitously expressed in human tissues. It was further stated that the two isoforms are differentially localized in the cytosol and in mitochondria. Here, we show that human GLYCTK exclusively localizes to mitochondria. We propose that mitochondrial GLYCTK represents the functional enzyme and that the second transcript variant is nonfunctional under physiological conditions.