Journal of Inherited Metabolic Disease最新文献

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most prevalent mitochondrial fatty acid β-oxidation disorder. In this study, we assessed the variability of the lipid profile in MCADD by analysing plasma samples obtained from 25 children with metabolically controlled MCADD (following a normal diet with frequent feeding and under l-carnitine supplementation) and 21 paediatric control subjects (CT). Gas chromatography–mass spectrometry was employed for the analysis of esterified fatty acids, while high-resolution C18-liquid chromatography-mass spectrometry was used to analyse lipid species. We identified a total of 251 lipid species belonging to 15 distinct lipid classes. Principal component analysis revealed a clear distinction between the MCADD and CT groups. Univariate analysis demonstrated that 126 lipid species exhibited significant differences between the two groups. The lipid species that displayed the most pronounced variations included triacylglycerols and phosphatidylcholines containing saturated and monounsaturated fatty acids, specifically C14:0 and C16:0, which were found to be more abundant in MCADD. The observed changes in the plasma lipidome of children with non-decompensated MCADD suggest an underlying alteration in lipid metabolism. Therefore, longitudinal monitoring and further in-depth investigations are warranted to better understand whether such alterations are specific to MCADD children and their potential long-term impacts.

We report the case of a Syrian female refugee with late diagnosis of glutaric aciduria type 1 characterised by massive axial hypotonia and quadriplegia who only started adequate diet upon arrival in Switzerland at the age of 4 years, after a strenuous migration journey. Soon after arrival, she died from an unexpected severe upper cervical myelopathy, heralded by acute respiratory distress after a viral infection. This was likely due to repeated strains on her hypotonic neck and precipitated by an orthotopic os odontoideum who led to atlanto-axial subluxation. This case reminds us not to omit handling patients with insufficient postural control and hypotonia with great care to avoid progressive cervical myelopathy.

This study aimed to evaluate the effect of intrathecal (IT) recombinant human arylsulfatase A (rhASA) on magnetic resonance imaging (MRI)-assessed brain tissue changes in children with metachromatic leukodystrophy (MLD). In total, 510 MRI scans were collected from 12 intravenous (IV) rhASA-treated children with MLD, 24 IT rhASA-treated children with MLD, 32 children with untreated MLD, and 156 normally developing children. Linear mixed models were fitted to analyze the time courses of gray matter (GM) volume and fractional anisotropy (FA) in the posterior limb of the internal capsule. Time courses for demyelination load and FA in the centrum semiovale were visualized using locally estimated scatterplot smoothing regression curves. All assessed imaging parameters demonstrated structural evidence of neurological deterioration in children with MLD. GM volume was significantly lower at follow-up (median duration, 104 weeks) in IV rhASA-treated versus IT rhASA-treated children. GM volume decline over time was steeper in children receiving low-dose (10 or 30 mg) versus high-dose (100 mg) IT rhASA. Similar effects were observed for demyelination. FA in the posterior limb of the internal capsule showed a higher trend over time in IT rhASA-treated versus children with untreated MLD, but FA parameters were not different between children receiving the low doses versus those receiving the high dose. GM volume in IT rhASA-treated children showed a strong positive correlation with 88-item Gross Motor Function Measure score over time. In some children with MLD, IT administration of high-dose rhASA may delay neurological deterioration (assessed using MRI), offering potential therapeutic benefit.

Among genetic disorders of vesicular trafficking, there are three causing recurrent acute liver failure (RALF): NBAS, RINT1, and SCYL1-associated disease. These three disorders are characterized by liver crises triggered by febrile infections and account for a relevant proportion of RALF causes. While the frequency and severity of liver crises in NBAS and RINT1-associated disease decrease with age, patients with SCYL1 variants present with a progressive, cholestatic course. In all three diseases, there is a multisystemic, partially overlapping phenotype with variable expression, including liver, skeletal, and nervous systems, all organ systems with high secretory activity. There are no specific biomarkers for these diseases, and whole exome sequencing should be performed in patients with RALF of unknown etiology. NBAS, SCYL1, and RINT1 are involved in antegrade and retrograde vesicular trafficking. Pathomechanisms remain unclarified, but there is evidence of a decrease in concentration and stability of the protein primarily affected by the respective gene defect and its interaction partners, potentially causing impairment of vesicular transport. The impairment of protein secretion by compromised antegrade transport provides a possible explanation for different organ manifestations such as bone alteration due to lack of collagens or diabetes mellitus when insulin secretion is affected. Dysfunction of retrograde transport impairs membrane recycling and autophagy. The impairment of vesicular trafficking results in increased endoplasmic reticulum stress, which, in hepatocytes, can progress to hepatocytolysis. While there is no curative therapy, an early and consequent implementation of an emergency protocol seems crucial for optimal therapeutic management.

Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan-α-glucosaminide N-acetyltransferase (HGSNAT; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep–wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster, we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi-mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age-dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre-synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.

Since the description of ‘inborn errors of metabolism’ as a novel field of medicine by Archibald Garrod in 1908,¹ various breakthroughs in management and therapeutic milestones have been achieved: specific diets, newborn screening and enzyme replacement therapy to name a few (Figure 1). Genomic assays, including exome, genome and RNA sequencing, have led to the identification of a rapidly growing number of new inborn errors of metabolism and many new patients in recent years.

Gene therapy centred around gene addition and editing therapy has emerged in parallel with the technological progress in engineering nucleic acids, nucleases and viruses. Seminal early milestones have raised a huge hope for inherited metabolic diseases (IMDs) with little or no therapeutic benefit under standard of care.^{2, 3} Complex biotechnologies such as gene addition mediated by adeno-associated viral vectors (AAV) and integrating vectors that rely upon lentiviral and CRISPR-Cas9 mediated gene-editing platforms are now the basis of approved drug products for monogenic diseases.^4-6 Application of gene therapy has been studied in many rare IMDs. Proof-of-concept data using varied technologies, nucleic acids, and delivery platforms to achieve gene replacement, integration and editing, especially in the liver and the central nervous system, have served to enable a wide range of exciting new therapies for genetic and metabolic disorders. Whilst first-in-man clinical trials expand, the challenges for this rapidly evolving field include the development of safer and more efficient vectors, more accessible technologies, and the development of new regulatory paradigms to expedite approvals. Today, a one-size-fits-all strategy remains elusive for most disorders given that even within a rare IEM patient population, phenotypic heterogeneity, variable disease progression and uncertainties surrounding the natural history can further complicate the risk–benefit balance for clinical trials.

This themed issue of Journal of Inherited Metabolic Disease reviews state-of-the-art of gene therapy technologies applied to various inborn metabolic diseases. It provides updates on clinical successes, limitations and future directions whilst considering specificities for liver and fetal applications. The special issue starts with two reviews concerning liver-directed gene therapy. Baruteau et al. present an overview of the progress, challenges and perspectives for the main liver IMDs from a clinical perspective.⁷ Chuecos and Lagor introduce AAV, which represent currently the leading liver-targeting gene therapy technology, with a particular focus on AAV physiology, AAV transduction including sex differences and an updated review of AAV clinical trials for liver IMDs and their contribution to the field of gene therapy.⁸ Pontoizeau et al. provide an additional pro

Inborn errors of neurotransmitter (NT) metabolism are a group of rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap with other disorders has led to delayed diagnosis and treatment, and some conditions are refractory to oral pharmacotherapies. Gene therapies have been developed and translated to clinics for paediatric inborn errors of metabolism, with 38 interventional clinical trials ongoing to date. Furthermore, efforts in restoring dopamine synthesis and neurotransmission through viral gene therapy have been developed for Parkinson's disease. Along with the recent European Medicines Agency (EMA) and Medicines and Healthcare Products Regulatory Agency (MHRA) approval of an AAV2 gene supplementation therapy for AADC deficiency, promising efficacy and safety profiles can be achieved in this group of diseases. In this review, we present preclinical and clinical advances to address NT-related diseases, and summarise potential challenges that require careful considerations for NT gene therapy studies.

Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.

Cerebral folate transport deficiency, caused by a genetic defect in folate receptor α, is a devastating neurometabolic disorder that, if untreated, leads to epileptic encephalopathy, psychomotor decline and hypomyelination. Currently, there are limited data on effective dosage and duration of treatment, though early diagnosis and therapy with folinic acid appears critical. The aim of this long-term study was to identify new therapeutic approaches and novel biomarkers for assessing efficacy, focusing on myelin-sensitive MRI. Clinical, biochemical, structural and quantitative MRI parameters of seven patients with genetically confirmed folate receptor α deficiency were acquired over 13 years. Multimodal MRI approaches comprised MR-spectroscopy (MRS), magnetization transfer (MTI) and diffusion tensor imaging (DTI) sequences. Patients started oral treatment immediately following diagnosis or in an interval of up to 2.5 years. Escalation to intravenous and intrathecal administration was performed in the absence of effects. Five patients improved, one with a presymptomatic start of therapy remained symptom-free, and one with inconsistent treatment deteriorated. While CSF 5-methyltetrahydrofolate and MRS parameters normalized immediately after therapy initiation, myelin-sensitive MTI and DTI measures correlated with gradual clinical improvement and ongoing myelination under therapy. Early initiation of treatment at sufficient doses, considering early intrathecal applications, is critical for favorable outcome. The majority of patients showed clinical improvements that correlated best with MTI parameters, allowing individualized monitoring of myelination recovery. Presymptomatic therapy seems to ensure normal development and warrants newborn screening. Furthermore, the quantitative parameters of myelin-sensitive MRI for therapy assessments can now be used for hypomyelination disorders in general.

Proteostatic regulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis, is crucial for maintaining proper brain neurotransmitter homeostasis. Variants of the TH gene are associated with tyrosine hydroxylase deficiency (THD), a rare disorder with a wide phenotypic spectrum and variable response to treatment, which affects protein stability and may lead to accelerated degradation, loss of TH function and catecholamine deficiency. In this study, we investigated the effects of the TH cofactor tetrahydrobiopterin (BH₄) on the stability of TH in isolated protein and in DAn- differentiated from iPSCs from a human healthy subject, as well as from THD patients with the R233H variant in homozygosity (THDA) and R328W and T399M variants in heterozygosity (THDB). We report an increase in TH and dopamine levels, and an increase in the number of TH+ cells in control and THDA cells. To translate this in vitro effect, we treated with BH₄ a knock-in THD mouse model with Th variant corresponding to R233H in patients. Importantly, treatment with BH₄ significantly improved motor function in these mice, as demonstrated by increased latency on the rotarod test and improved horizontal activity (catalepsy). In conclusion, our study demonstrates the stabilizing effects of BH₄ on TH protein levels and function in THD neurons and mice, rescuing disease phenotypes and improving motor outcomes. These findings highlight the therapeutic potential of BH₄ as a treatment option for THDA patients with specific variants and provide insights into the modulation of TH stability and its implications for THD management.