Milestones in treatments for inborn errors of metabolism: Reflections on Where chemistry and medicine meet

Abstract

From Sir Archibald Garrod's initial description of the tetrad of albinism, alkaptonuria, cystinuria, and pentosuria to today, the field of medicine dedicated to inborn errors of metabolism has evolved from disease identification and mechanistic discovery to the development of therapies designed to subvert biochemical defects. In this review, we highlight major milestones in the treatment and diagnosis of inborn errors of metabolism, starting with dietary therapy for phenylketonuria in the 1950s and 1960s, and ending with current approaches in genetic manipulation.

Incidence and genetic variants of inborn errors of metabolism identified through newborn screening: A 7‐year study in eastern coastal areas of China

“…With the rise of molecular testing for inherited metabolic diseases, the detection of genetic variants of these diseases could conduce to a more rapid diagnosis of IEM. Massively parallel sequencing can simultaneously sequence millions of DNA molecules in parallel and has gradually become the dominant technology in clinical genetic diagnosis (Vernon & Manoli, 2021 ; Yohe & Thyagarajan, 2017 ). Gene variants in common IEM can be quickly and accurately detected through massively parallel sequencing.…”

Probiotic Combination CBLEB Alleviates Streptococcus pneumoniae Infection Through Immune Regulation in Immunocompromised Rats

“… 46 Second, CBLEB alleviates the downregulation of some important life activity-related pathways, including phenylalanine metabolism, pantothenate and CoA biosynthesis, renin-angiotensin system, nonhomologous end-joining, ErbB signalling, TCR signalling, phosphatidylinositol signalling, cell adhesion molecules, and cytokine-cytokine receptor interaction. Defects in the phenylalanine metabolism pathway are the cause of three well-known disorders: phenylketonuria, albinism, and alkaptonuria; 47 coenzyme A (CoA) is an essential cofactor for cell growth and involved in many metabolic reactions, such as phospholipid synthesis, fatty acid synthesis and degradation, and TCA cycle function; 48 the renin-angiotensin system is involved in the regulation of smooth muscle of the blood vessels and bowel, the absorption and secretion of glucose, amino acids, fluids and electrolytes, the permeability of the gut mucosa, and gut inflammation; 49 non-homologous end-joining is the predominant DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks throughout the cell cycle, and defects in its function may result in severe combined immunodeficiency; 50 disruption of the ErbB signalling network, an essential component for mucosal protection and/or the adaptive response to external injury in the gut, will result in major defects in gut epithelial development and in the reparative response to gut injury; 51 TCR activation promotes a number of signalling cascades that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation; various phosphoinositides are involved in many signalling pathways, such as the PI3K-Akt pathway that mediates cell proliferation, survival, and metabolism; 52 and cell adhesion molecules play a critical role in many biological processes, such as haemostasis, the immune response, inflammation, embryogenesis, and neuronal tissue development. 53 Therefore, the regulation of these pathways in the intestine is an important part of the mechanism by which CBLEB combats SP infection.…”

Natural history of propionic acidemia in the Amish population

“…Early diagnosis and treatment of inborn errors of metabolism has been shown to have beneficial outcomes for patients [ 20 ]. Treatment for PA in the form of an intact protein restricted diet with supplemental metabolic formulas decreases exposure to propiogenic precursors, decreasing episodes of metabolic decompensation and other negative outcomes [ 2 ].…”