Journal of Inherited Metabolic Disease最新文献

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.

Imaging literature on propionic acidemia (PA) is predominantly concerned with deep gray matter changes. In order to investigate the spectrum and patterns of MRI changes, 45 MRI scans of 13 patients (0.31–33.2 years) were systematically analyzed. Deep and cortical gray matter changes were associated with acute metabolic decompensation. Striatum was affected in 10/13; T2-hyperintensity was often mild, normalizing and becoming T2-hypointense in one patient each without movement disorder. Pallidum was T2-hyperintense in the 3 infants imaged for acute decompensation, with restricted diffusion in 2/3 and normalizing in 2/2 with follow-up. Dentate and thalamus were T2-hyperintense in 7/13 and 2/13, respectively, without resolution. Cerebellar watershed injury (4/13) and cortico-subcortical involvement with transiently restricted diffusion, T2/FLAIR-hyperintensity, and/or swelling (3/13) were more common with seizures during decompensation. A pattern of predominantly subcortical leukoencephalopathy was observed in 7/9 patients aged 9 years and above. Small foci of restricted diffusion, T2/FLAIR-hyperintensity, and variable T1-hypointensity evolved into bilateral, sometimes extensive changes with restricted and facilitated diffusion, decreasing in 3/6 with follow-up MRI at 14.7–19.5 years. Volume deficit was common, including a thin brainstem in 9/13. Predominantly subcortical white matter changes are a characteristic finding in older children with PA, might reflect microvacuolation, and may improve. Transient pallidal changes in infants with acute decompensation might represent myelin splitting during active myelination of white matter-rich pallidum. Cortico-subcortical changes and cerebellar watershed injury during acute metabolic decompensation were more likely with seizures; like the more common striatal involvement they occurred without age-predilection.

Manganese (Mn) overload is a characteristic of multiple disease entities, from acquired manganism upon environmental or occupational overexposure, to end-stage liver disease and certain genetic disorders. The latter include hypermanganesaemia with dystonia 1 and 2 caused by pathogenic variants in the genes encoding the Mn transporters SLC30A10 and SLC39A14. Excess Mn accumulates in the brain, particularly in the globus pallidus, leading to progressive dystonia–parkinsonism. Furthermore, Mn dyshomeostasis is a characteristic feature of common neurodegenerative disorders such as Parkinson's disease, whether as a cause or consequence needs to be determined, suggesting that Mn as an environmental toxicant may play a role in its aetiology. Therefore, there is a need for therapeutics that effectively chelate Mn and remove excess Mn from the brain. This review discusses the Mn chelators currently used in clinical practice, their advantages and disadvantages as well as their adverse effects. Na₂CaEDTA is the primary chelating agent used to re-establish Mn homeostasis; however, its burdensome treatment regimen, need for intravenous administration, and lack of metal specificity make it a poor drug for clinical application. The development of novel, Mn-specific chelating agents is therefore a clinical priority. An ideal chelator would be orally bioavailable, soluble in both lipids and water to reach the sites of metal storage, chemically inert, and non-toxic whilst retaining chelating abilities at physiological pH. We discuss current progress in identifying novel Mn ligands that have been primarily developed as magnetic resonance imaging contrast agents.

Nitrogen scavengers play a critical role in treating acute and chronic hyperammonemia, especially in urea cycle disorders (UCDs), where impaired ammonia detoxification leads to toxic nitrogen accumulation. These agents complement low-protein diets and urea cycle intermediates. Sodium benzoate and sodium phenylacetate are the main scavengers, conjugating with glycine and glutamine to form hippurate and phenylacetylglutamine, which are excreted in urine. This therapeutic approach, introduced in the 1980s, was based on early findings linking benzoate to reduced urea excretion. Nitrogen scavengers are also used in secondary hyperammonemia from organic acidemias and fatty acid oxidation disorders, though they may become increasingly ineffective in progressing liver failure due to their reliance on hepatocyte function. To improve tolerability, phenylbutyrate was developed as an oral alternative to phenylacetate and is available in sodium-bound and prodrug forms, but issues with taste and side effects persist. While effective, current treatments target nitrogenous waste products rather than ammonia directly, offering an avenue of future drug development for UCDs. This review discusses the chemical properties, clinical use, and limitations of nitrogen scavengers, hereby focusing on phenylacetate and related substances, and highlights the need for improved therapies, including approaches that directly target ammonia removal. For the benefit of readers already experienced in nitrogen scavengers for UCDs, we also include considerations concerning the use of these drugs in animal experiments and a viewpoint on ornithine phenylacetate as a related substance.

X-linked adrenoleukodystrophy (X-ALD) is caused by ABCD1 pathogenic variants, leading to accumulation of very long-chain fatty acids (VLCFAs). Phenotypes include cerebral ALD (CALD) and adrenomyeloneuropathy (AMN). We assessed if quantitative MRI (qMRI) parameters from an automated tool (BrainQuant) could differentiate CALD from non-CALD and reflects myelopathy severity. Adult males from a prospective study (2015–2024) underwent annual neurological exams and brain MRI. Exclusion criteria were: fewer than two MRIs, non-ALD lesions, or prior transplantation. BrainQuant processed diffusion tensor imaging (DTI) to yield global metrics: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Patients were stratified by Loes score (0 vs. > 0) and expanded disability status scale (EDSS ≤ 2 vs. > 2). Longitudinal changes were modeled. Correlations with EDSS, severity score for progressive myelopathy (SSPROM), and 6-min walk test (6-MWT) were analyzed. The cohort included 62 patients (median age 36.5); 15 had CALD. Global DTI metrics did not differ significantly between CALD and non-CALD. A trend for higher radial diffusivity (RD) in the splenium (p = 0.037) was seen, but results were not significant after Bonferroni correction for multiple comparisons (p = 0.748). Patients with EDSS > 2 showed significantly worse global DTI values (p < 0.05), correlating with clinical scores (r = 0.40–0.69). Longitudinally, RD-global increased significantly (p < 0.001) at similar rates across EDSS groups. BrainQuant qMRI did not distinguish CALD and non-CALD but effectively tracked myelopathy. Radial diffusivity (RD)-global is a promising biomarker for monitoring X-ALD progression.

Propionic aciduria (PA-uria) and methylmalonic aciduria (MMA-uria) are caused by defects in propionate catabolism. While chronic kidney disease (CKD) is a well-established complication in MMA-uria, renal involvement in PA-uria has only come into focus more recently, and the underlying mechanisms remain poorly understood. We investigated human renal epithelial cells from patients with PA-uria, MMA-uria, and healthy controls under metabolic stress, induced by methylmalonic acid, methylcitric acid, high-protein, or isoleucine/valine-enriched media. Proteomic profiling revealed significant enrichment of extracellular matrix (ECM)-related pathways in PA-uria cells. Both PA-uria and MMA-uria cells exhibited increased deposition of fibronectin and collagen fibers, which were further amplified under metabolic stress conditions. Transforming growth factor beta (TGF-β) signaling was identified as a key pro-fibrotic pathway. Pharmacological inhibition of the TGF-β receptor signaling normalized fibronectin and collagen deposition in both PA-uria and MMA-uria cells. Treatment with losartan, an angiotensin II type 1 receptor blocker known to modulate TGF-β signaling, also reversed the enhanced ECM deposition. This is the first study to mechanistically link ECM remodeling and TGF-β signaling to CKD pathogenesis in both PA-uria and MMA-uria. Our findings highlight fibrotic remodeling as a shared pathogenic feature and suggest that losartan, a widely available and well-tolerated drug, could be repurposed to mitigate renal fibrosis in these disorders.