Molecular genetics and metabolism最新文献

Metachromatic leukodystrophy (MLD) is a progressive demyelinating disorder resulting from the toxic accumulation of sulfatides. The stereotyped neurodegeneration of MLD is well understood, and cases are categorized into subtypes by age at neurologic onset: late infantile (LI), juvenile (J), and adult. The systemic burden of disease, such as gallbladder involvement, however, is less well characterized. It is important to understand the longitudinal trajectory of gallbladder complications in MLD and its relationship with neurologic progression as this has the potential to identify cases of active disease before neurologic onset. Additionally, as newborn screening is established in MLD, it will inform clinical care during the presymptomatic period. To address this knowledge gap, we leveraged a retrospective natural history study of MLD and published cases in the medical literature. Medical records from subjects consented to a natural history study were used to collect information of disease course, including gallbladder abnormality. Neurologic function was retrospectively assessed using the gross motor function classification scale (GMFC-MLD). Additionally, a comprehensive review identified published cases of MLD with subject-level information around gallbladder disease. Data was summarized using descriptive statistics, Fisher's exact test for significance, and survival analysis with log rank test. The natural history cohort includes 40 subjects with gallbladder reports (imaging or pathology). The first gallbladder evaluation occurred after neurologic onset in 35/40 cases. Gallbladder abnormalities were noted in 36 subjects, often within the initial evaluation (97.2 %). There was no difference in the time to first gallbladder abnormality (log rank: p = 0.4170) and risk of polyps or higher (log rank: p = 0.6414) between the LI- and non-LI subtypes. The level of gallbladder involvement does not correlate with GMFC-MLD score (Fisher's exact: p = 0.321). A review of the literature identified 87 additional cases of MLD with mention of gallbladder status across 40 published studies. Gallbladder involvement was noted in 74 cases and occurred at similar rates across subtypes (X² = 4.68, p = 0.7925). Overall, the study showed a high prevalence of gallbladder complications in MLD. Gallbladder abnormalities were commonly found at first evaluation, even in pre- or early symptomatic disease. Since gallbladder disease has the potential to progress to malignancy, this supports the integration of regular gallbladder monitoring as clinical care and its potential as a predictive biomarker supporting disease onset.

The 3-methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of inborn errors of metabolism defined biochemically by detectable elevation of 3-methylglutaconic acid (3-MGA) in the urine. In type 1 (or primary) 3-MGA-uria, distal defects in the leucine catabolism pathway directly cause this elevation. Secondary 3-MGA-uria syndromes, however, are unrelated to leucine metabolism-specific defects but share a common biochemical phenotype of elevated 3-MGA. It is currently thought that this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA. In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method. Here, we retrospectively evaluated a cohort of nine patients with confirmed 3-MGA-uria syndromes. It was observed that UOA analysis obtained from three separate patients did not identify detectable 3-MGA levels. This inherent limitation highlights the need for a more sensitive clinical modality. Untargeted metabolomics profiling is a rapidly emerging technology that is being used to detect and characterize biochemical abnormalities in many inborn errors of metabolism. Untargeted metabolomics profiling performed on plasma samples in this cohort identified significant elevations of 3-MGA in all nine individuals. This high degree of clinical sensitivity demonstrates the promising potential for untargeted metabolomics analysis as both an effective biochemical screening tool for 3-MGA-uria syndromes and a functional method to assist with validation of genomic variants of uncertain significance in these disorders.

Background: Impaired oxidation of branched chain amino acids may give rise to volatile organic compounds (VOCs). We hypothesized that VOCs will be present in exhaled breath of participants with propionic acidemia (PA), and their relative abundance would correlate with clinical and biochemical characteristics of the disease.

Methods: We enrolled 5 affected participants from a natural history study of PA (ClinicalTrials.gov ID NCT02890342) plus five age- and sex-matched unaffected controls. We collected exhaled breath using a non-invasive breath sampling platform paired with thermal desorption-gas chromatography-mass spectrometry. Clinical and biochemical parameters were correlated with the relative abundance of VOCs.

Results: Unbiased screening identified several candidate VOC biomarkers of PA. One candidate putatively identified as 3-pentanone was the most abundant (45-fold higher in cases vs. controls, p-value <0.05). 3-Pentanone abundance positively correlated with plasma propionylcarnitine (p = 0.01), plasma 2-methylcitrate (p < 0.05), 3-OH-propionate (p < 0.01), full scale IQ (p < 0.01), and showed a statistical trend with height z-scores (p = 0.08). It inversely correlated with the whole-body in vivo oxidation of 1-¹³C-propionate (p < 0.05). In a participant who received an orthotopic liver transplant, 3-pentanone levels were lower and segregated with "mild" PA.

Conclusion: Non-invasive breath sampling is a promising method to identify and quantitate VOCs that correlate with the clinical and biochemical parameters of PA. Our proof-of-principle findings may have wide implications for the diagnosis and severity stratification of inborn errors of metabolism affecting oxidation of amino acids which might be monitored in a similar fashion.

Synopsis: A proof-of-principle study putatively identifies 3-pentanone in exhaled breath as a correlate of the clinical and biochemical outcomes in propionic acidemia.