Journal of Inherited Metabolic Disease最新文献

Our research aimed to model primary hyperoxaluria type 1 in vitro using a stem cell model and assess the potential of adenine base editors in correcting the most common pathogenic AGXT genetic variant, c.508G>A (Gly170Arg), which leads to oxalate accumulation due to alanine-glyoxylate aminotransferase mislocalization. Patient-derived fibroblasts were induced to pluripotent stem cells, genetically corrected with adenine base editing, and subsequently differentiated into hepatocyte-like cells in parallel with their non-corrected isogenic counterparts. Enzyme localization was assessed through immunocytochemistry and confocal microscopy. The key metabolites associated with the disease were analyzed using liquid chromatography-mass spectrometry to evaluate the metabolic phenotype. Finally, lipid nanoparticle formulations were designed and tested as an in vivo-applicable delivery method for base editors. All induced pluripotent stem cell lines successfully differentiated into hepatocyte-like cells and expressed essential hepatocyte markers, including ALB, HNF1A, and AGXT. Adenine base editor-mediated genetic correction of the pathogenic AGXT mutation restored enzyme localization into peroxisomes and diminished oxalate accumulation without significant off-target effects. Base editor mRNA and AGXT variant targeting single guide RNA encapsulated within lipid nanoparticles mediated gene correction in the hepatocyte-like cell model. Using an in vitro model of primary hyperoxaluria type 1, we showed that base editor-mediated genetic correction of the most common hyperoxaluria-causing variant corrects enzyme mislocalization from mitochondria to peroxisomes and improves metabolic function. These results propose gene correction as a potential therapeutic approach to hyperoxaluria.

X-linked adrenoleukodystrophy (ALD) is a genetic disorder with neurological and endocrine manifestations, including myelopathy and hypergonadotropic hypogonadism. Many patients experience sexual dysfunction but the underlying cause has not been clarified. The aim of this study was to assess the prevalence of sexual dysfunction and its relationship with biochemical hypergonadotropic hypogonadism (i.e., low testosterone and high luteinizing hormone [LH] levels) and/or myelopathy. Male ALD patients from “the Dutch ALD cohort” at the Amsterdam University Medical Centers were questioned regarding sexual functioning, and underwent neurological examination to assess myelopathy. Testosterone, LH, and follicle-stimulating hormone (FSH) concentrations were analyzed from fasting blood samples. The prevalence of biochemical hypogonadism in the cohort was 4/36 patients (11%), of whom 3 were diagnosed prior to the initiation of this study. Eighteen out of 33 patients (55%), of whom clinical data were collected, experienced sexual dysfunction. Of these patients, 10 (55%) were biochemically eugonadal, 7 (39%) had biochemical subclinical hypogonadism, and 1 had biochemical hypogonadism. Neurological function differed significantly between patients with and without sexual dysfunction, with more severe myelopathy in patients with sexual dysfunction (Expanded Disability Status Scale: 4.8 [IQR 3–6] vs. 0.0 [IQR 0–2]; p < 0.001). In conclusion, we showed that half of all adult male ALD patients experienced sexual dysfunction and the majority of these patients had normal testosterone levels. Neurological impairment appears to play a more important role in these complaints than previously appreciated. We recommend discussing sexual dysfunction regularly, in order to start early and adequate treatment.

P. S. Kishnani, C. Rehder, K. Ozono, et al., “Revisiting the Genetics of Hypophosphatasia,” Journal of Inherited Metabolic Disease 48, no. 6 (2025): e70083, https://doi.org/10.1002/jimd.70083.

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North Sea-Progressive Myoclonus Epilepsy (NS-PME) is a progressive neurological disorder, initially only associated with the homozygous GOSR2 founder mutation (c.430G>T; p.Gly144Trp). Clinical symptoms include untreatable early-onset ataxia, cortical myoclonus and epilepsy. Recently, the spectrum of GOSR2 mutations and associated phenotypic variability has expanded. To improve care and to facilitate genotype–phenotype predictions for NS-PME patients, we systematically reviewed all reported GOSR2 mutations, clinical phenotypes, and pathophysiological findings. A narrative review literature search was conducted in PubMed, EMBASE, and Web of Science (1985—August 2024) using the keywords “GOSR2”, “GS27 protein”, “Bos1”, and “Membrin”. Only studies in English and specifically studies on GOSR2 function, pathogenic variants, clinical manifestations, and potential therapies were included. A total of 42 patients with 11 different GOSR2 mutations were identified. Three main phenotypes were observed: progressive myoclonus ataxia/epilepsy (PMA/PME), congenital muscular dystrophy, and hearing loss. Orthopedic abnormalities were frequently reported. Intercurrent infections or fever often led to a worsening of symptoms. Glycosylation defects were reported in several compound heterozygous GOSR2 variants. Molecularly, GOSR2 mutations result in (partial) loss of function of the GOSR2/SNARE complex, with mutation severity and the involvement of specific isoforms contributing to phenotypic variability. GOSR2 mutations lead to progressive neurological disorders, primarily characterized by myoclonus ataxia/epilepsy, muscular dystrophy, and hearing loss. The genotypic background of NS-PME has expanded with pathogenic biallelic GOSR2 variants beyond the original homozygous founder mutation. Understanding the clinical spectrum and molecular mechanisms of GOSR2-related diseases may facilitate more targeted treatment strategies as well as better-informed phenotype predictions.

The current standard of care for patients with classic galactosemia (CG) involves lifelong dietary restriction of high galactose foods, including most dairy products. Here, we present the results of a pilot study testing whether pretreatment with GY007, a strain of baker's yeast selected to metabolize galactose despite the presence of other sugars, would be sufficient to prevent the metabolic impact of dietary galactose exposure in a GALT-null rat model of CG. Specifically, we dosed cohorts of adolescent GALT-null rats with either (a) placebo alone, (b) placebo followed by galactose, or (c) GY007 yeast followed by galactose. All rats were treated 3 times daily for 8 consecutive days, for a combined daily dose of almost 27 mg galactose per rat. Wild-type rats dosed with placebo served as controls. All rats also had ad libitum access to water and chow that contained about 0.15% calories from galactose. Rats grew at the expected pace for the duration of the study regardless of treatment group. To test the metabolic efficacy of the GY007 pretreatment, we followed galactose, galactitol, and gal-1P longitudinally in blood, and at euthanasia in brain and liver. In both liver and red blood cells, most metabolites remained near placebo levels despite the galactose exposure, limiting our ability to test the efficacy of GY007 pretreatment in those tissues. However, in both plasma and brain, metabolites showed a significant elevation following galactose exposure, and this rise was prevented by pretreatment with GY007. These results demonstrate the potential of GY007 yeast to prevent the metabolic consequences of transient low-level dietary galactose exposure in GALT deficiency.

Tyrosine hydroxylase (TH) catalyses the rate-limiting step in dopamine biosynthesis. Autosomal recessive tyrosine hydroxylase deficiency (THD) leads to clinical phenotypes reflecting the deficiency of dopamine, norepinephrine, or epinephrine in the central nervous system (CNS), presenting along a continuous spectrum from mild to severe forms of the disease. The diagnosis is suggested by the detection of low CSF homovanillic acid (HVA) and confirmed by identifying biallelic pathogenic variants in the TH gene. L-dopa/decarboxylase inhibitor (DCI) supplementation is often the first-line treatment, and most patients have a good therapeutic response. However, initiation of therapy can be challenging in patients with severe disease forms who develop L-dopa/DCI-induced dyskinesia. Therefore, alternative treatment options, such as monoamine oxidase (MAO) inhibitors, must be evaluated to optimize motor symptom control. Clinical experience suggests that early diagnosis and treatment initiation may improve the outcome. Additionally, a multidisciplinary treatment approach should be utilized to monitor neurocognitive development and other comorbidities that may occur in THD. In this consensus guideline, representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) and patient advocates evaluated all the evidence available in the literature on the diagnosis and management of THD and developed recommendations using the SIGN and GRADE methodologies. Based on the limited evidence, practical recommendations have been developed to support clinical diagnosis, laboratory testing, neuroimaging, medical treatment, and non-medical interventions. Research topics for further development were identified. This guideline aims to improve the care of patients with THD worldwide and raise general awareness of this rare disease.

Movement disorders are common in inherited metabolic diseases (IMDs) and significantly impact quality of life. Unfortunately, they are often underrecognised by metabolic physicians. This study investigated whether a new screening tool improves recognition of movement disorders in IMD patients by non-neurologists. Internists and paediatricians specialized in IMDs assessed videos of 44 IMD patients who perform four specific neurological tests, to evaluate the presence and phenotype of a movement disorder. Initially, baseline assessments were performed without the tool. Eight months later, the same videos were assessed using an instructional video demonstrating the four neurological tests, and a screening tool including these tests with 14 yes/no questions regarding observed abnormalities. One hundred and forty-nine assessments were conducted by 15 metabolic internists and paediatricians. At baseline, 70% (105/149) of assessments correctly determined the presence of a movement disorder. Sensitivity of the tool was 68%. In the second measurement, when the outcome of the tool was considered decisive (with at least one positive answer indicating a movement disorder), 79% (117/149) of assessments were correct. Sensitivity of the tool increased to 87% (Chi-square = 15.75, p < 0.001). All severe and moderately severe movement disorders were recognized in the second measurement. The tool and instructional video did not enhance recognition of specific movement disorder phenotypes. However, the tool did improve the accuracy of treatment indications (chi-square = 4.000, p < 0.05). The correct use of the screening tool significantly increased the sensitivity and thereby the recognition of movement disorders in IMD patients, though referral to a neurologist remains necessary for phenotype identification.