Multiomics tools for the diagnosis and treatment of rare neurological disease

Abstract

Conventional workup of rare neurological disease is frequently hampered by diagnostic delay or lack of diagnosis. While biomarkers have been established for many neurometabolic disorders, improved methods are required for diagnosis of previously unidentified or underreported causes of rare neurological disease. This would result in a higher diagnostic yield and increased patient numbers required for interventional studies. Recent studies using next-generation sequencing and metabolomics have led to identification of novel disease-causing genes and biomarkers. This combined approach can assist in overcoming challenges associated with analyzing and interpreting the large amount of data obtained from each technique. In particular, metabolomics can support the pathogenicity of sequence variants in genes encoding enzymes or transporters involved in metabolic pathways. Moreover, metabolomics can show the broader perturbation caused by inborn errors of metabolism and identify a metabolic fingerprint of metabolic disorders. As such, using "omics" has great potential to meet the current needs for improved diagnosis and elucidation of rare neurological disease.

Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing

“…The solvent utilized for the extraction of the biochemicals in a given sample will dictate the efficiency of the extraction of that molecule or family of molecules as well as influence which macromolecules are excluded by actions such as precipitation or phase partitioning. For example, chloroform‐based extractions are more efficient at extraction lipid‐containing or lipophilic compounds . Polar solvents will do the same for more polar and charged compounds .…”

“…For example, chloroform-based extractions are more efficient at extraction lipid-containing or lipophilic compounds. 7,16 Polar solvents will do the same for more polar and charged compounds. 1,3,16 Standardizing extractions and outlining protocols specifically are two mechanisms for consistently monitoring biochemical levels between laboratories.…”

“…Clinical metabolomics testing is also proving a useful complement to clinical genomic testing . It also has merit in screening for rare diseases not yet described or for which the few number of cases limits the ability to develop targeted diagnostic tests . Since no roadmap and few guideposts exist, the major goal of this review is to point out the key elements involved in developing, launching, and performing clinical metabolomics testing .…”

“…[2][3][4] It also has merit in screening for rare diseases not yet described or for which the few number of cases limits the ability to develop targeted diagnostic tests. 2,[5][6][7] Since no roadmap and few guideposts exist, the major goal of this review is to point out the key elements involved in developing, launching, and performing clinical metabolomics testing. The development of untargeted clinical metabolomics testing builds on the precedent established by untargeted clinical whole exome sequencing (WES) whose application has been used to classify genes not previously associated with epilepsy, 8 NDUFS8-related Complex I deficiency, 9 and for diagnostic evaluation of critically ill infants in pediatric and neonatal intensive care units.…”

“…Traditional diagnostic biomarker assays must identify disease with high specificity and high sensitivity to help streamline clinical care but recently 'omics tests have enabled the ability to screen and diagnose disease in an untargeted manner. 1,2,4,7 Of the 'omics technologies, genomics was the first to be accepted in the clinical space. [20][21][22][23][24][25][26][27][28][29][30] Metabolomics, a term introduced in 1998, 31 is a relatively newer technology that has been used increasingly over the past decade ( Figure 1) and may be utilized to screen for and to identify the cause of disease.…”