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A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.

Amino acids are organic molecules that serve as basic substrates for protein synthesis and have additional key roles in a diverse array of cellular functions, including cell signaling, gene expression, energy production and molecular biosynthesis. Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism. Individually, these disorders are rare, but collectively, they represent an important group of potentially treatable disorders. In this Clinical Puzzle, we discuss the pathophysiology, clinical features and management of three disorders that showcase the diverse clinical presentations of disorders of amino acid metabolism: phenylketonuria, lysinuric protein intolerance and homocystinuria due to cystathionine β-synthase (CBS) deficiency. Understanding the biochemical perturbations caused by defects in amino acid metabolism will contribute to ongoing development of diagnostic and management strategies aimed at improving the morbidity and mortality associated with this diverse group of disorders., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are related disorders of mitochondrial propionate metabolism, caused by defects in methylmalonyl-CoA mutase (MUT) and propionyl-CoA carboxylase (PCC), respectively. These biochemical defects lead to a complex cascade of downstream metabolic abnormalities, and identification of these abnormal pathways has important implications for understanding disease pathophysiology. Using a multi-omics approach in cellular models of MMA and PA, we identified serine and thiol metabolism as important areas of metabolic dysregulation., Methods: We performed global proteomic analysis of fibroblasts and untargeted metabolomics analysis of plasma from individuals with MMA to identify novel pathways of dysfunction. We probed these novel pathways in CRISPR-edited, MUT and PCCA null HEK293 cell lines via targeted metabolomics, gene expression analysis, and flux metabolomics tracing utilization of 13 C-glucose., Results: Proteomic analysis of fibroblasts identified upregulation of multiple proteins involved in serine synthesis and thiol metabolism including: phosphoserine amino transferase (PSAT1), cystathionine beta synthase (CBS), and mercaptopyruvate sulfurtransferase (MPST). Metabolomics analysis of plasma revealed significantly increased levels of cystathionine and glutathione, central metabolites in thiol metabolism. CRISPR-edited MUT and PCCA HEK293 cells recapitulate primary defects of MMA and PA and have upregulation of transcripts associated with serine and thiol metabolism including PSAT1. 13 C-glucose flux metabolomics in MUT and PCCA null HEK293 cells identified increases in serine de novo biosynthesis, serine transport, and abnormal downstream TCA cycle utilization., Conclusion: We identified abnormal serine metabolism as a novel area of cellular dysfunction in MMA and PA, thus introducing a potential new target for therapeutic investigation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.

Patients with primary serine biosynthetic defects manifest with intellectual disability, microcephaly, ichthyosis, seizures and peripheral neuropathy. The underlying pathogenesis of peripheral neuropathy in these patients has not been elucidated, but could be related to a decrease in the availability of certain classical sphingolipids, or to an increase in atypical sphingolipids. Here, we show that patients with primary serine deficiency have a statistically significant elevation in specific atypical sphingolipids, namely deoxydihydroceramides of 18-22 carbons in acyl length. We also show that patients with aberrant plasma serine and alanine levels secondary to mitochondrial disorders also display peripheral neuropathy along with similar elevations of atypical sphingolipids. We hypothesize that the etiology of peripheral neuropathy in patients with primary mitochondrial disorders is related to this elevation of deoxysphingolipids, in turn caused by increased availability of alanine and decreased availability of serine. These findings could have important therapeutic implications for the management of these patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although individual cases of inherited metabolic disorders are rare, overall they account for a substantial number of disorders affecting the central nervous system. Organic acidemias and aminoacidopathies include a variety of inborn errors of metabolism that are caused by defects in the intermediary metabolic pathways of carbohydrates, amino acids, and fatty acid oxidation. These defects can lead to the abnormal accumulation of organic acids and amino acids in multiple organs, including the brain. Early diagnosis is mandatory to initiate therapy and prevent permanent long-term neurologic impairments or death. Neuroimaging findings can be nonspecific, and metabolism- and genetics-based laboratory investigations are needed to confirm the diagnosis. However, neuroimaging has a key role in guiding the diagnostic workup. The findings at conventional and advanced magnetic resonance imaging may suggest the correct diagnosis, help narrow the differential diagnosis, and consequently facilitate early initiation of targeted metabolism- and genetics-based laboratory investigations and treatment. Neuroimaging may be especially helpful for distinguishing organic acidemias and aminoacidopathies from other more common diseases with similar manifestations, such as hypoxic-ischemic injury and neonatal sepsis. Therefore, it is important that radiologists, neuroradiologists, pediatric neuroradiologists, and clinicians are familiar with the neuroimaging findings of organic acidemias and aminoacidopathies. © RSNA, 2018.

End stage kidney disease is a well-known complication of methylmalonic acidemia (MMA), and can be treated by dialysis, kidney transplant, or combined kidney-liver transplant. While liver and/or kidney transplantation in MMA may reduce the risk of metabolic crisis and end-organ disease, it does not fully prevent disease-related complications. We performed detailed metabolite and kinetic analyses in a 28-year-old patient with mut (0) MMA who underwent hemodialysis for 6 months prior to receiving a combined liver/kidney transplant. A single hemodialysis session led to a 54 % reduction in plasma methylmalonic acid and yielded a plasma clearance of 103 ml/min and VD0.48 L/kg, which approximates the total body free water space. This was followed by rapid reaccumulation of methylmalonic acid over 24 h to the predialysis concentration in the plasma. Following combined liver/kidney transplantation, the plasma methylmalonic acid was reduced to 3 % of pre-dialysis levels (6,965 ± 1,638 (SD) μmol/L and 234 ± 100 (SD) μmol/L) but remained >850× higher than the upper limit of normal (0.27 ± 0.08 (SD) μmol/L). Despite substantial post-operative metabolic improvement, the patient developed significant neurologic complications including acute worsening of vision in the setting of pre-existing bilateral optic neuropathy, generalized seizures, and a transient, focal leukoencephalopathy. Plasma methylmalonic acid was stable throughout the post-operative course. The biochemical parameters exhibited by this patient further define the whole body metabolism of methylmalonic acid in the setting of dialysis and subsequent combined liver/kidney transplant.