Recent advances in neurometabolic diseases: The genetic role in the modern era

Epilepsy Behav. 2023 Aug:145:109338. doi: 10.1016/j.yebeh.2023.109338. Epub 2023 Jul 13.


The global birth prevalence of all inborn errors of metabolism (IEMs) in children (49 studies, 1980-2017) is approximately 50.9/100,000 live births. Regional pooled birth prevalence showed higher rates in Eastern Mediterranean regions (75.7/100,000 live births) and highest in Saudi Arabia (169/100,000) with higher parental consanguinity rates of ∼60%. Case fatality rates globally are estimated to be 33% or higher. IEMs are a group of >600 heterogeneous disorders often presenting in newborns and infants with drug-resistant seizures and/or encephalopathy. Early diagnosis and treatments are key in the prevention of morbidity, early mortality, and high lifetime health care costs, such as the early recognition of the newborn with pyridoxine- or pyridoxal-L-phosphate-dependent seizures which do not respond to standard antiepileptic drugs. The earlier the recognition and intervention in the specific cofactor- or vitamin-responsive epilepsies, the better the outcome and prevention of intractable seizures and encephalopathy leading to irreversible neurologic injury. In recent years, the genetics of IEMs has been transformed by the emergence of new molecular genetic technologies. Depending upon the clinical phenotype, current genetic testing may include chromosomal microarray (deletion/duplication analysis), single target gene sequencing, gene panels (sequencing and deletion/duplication analysis), DNA methylation analysis, mitochondrial nuclear gene panel, and mtDNA sequencing and/or trio WES or WGS (which have reduced in costs). A meta-analysis, showed WES and epilepsy gene panels to be the most cost-effective genetic tests for unknown epilepsies versus chromosomal microarray. Most recently, rapid genomic sequencing (RGS) has been associated with a shorter time to diagnosis (3 days) and increased diagnostic yield when compared with standard-of-care testing, including gene panels and microarrays. A randomized controlled trial (RCT) of rapid(r) WGS or rWES in acutely ill infants with diseases of unknown etiology in pediatric ICUs in San Diego, California found RGS to be highly clinically useful for 77% of 201 infants. RGS changed clinical management in 28% of infants and outcomes in 15%. An Australian study of ultra-rapid (ur) exome sequencing (mean time to genomic test report of 3.3 days) in 108 critically ill infants and children with suspected monogenic conditions, had a molecular diagnostic yield of 51% with 20% requiring further genetic analysis. In 42/55 (76%), ur exome sequencing was felt to have influenced clinical management for targeted treatments, surveillance, or palliative care, however, the study was not designed or powered to measure differences in major clinical outcomes compared to standard care of critically ill patients. Further research is needed to understand this tool's clinical value and generalizability balanced against its high costs. A paradigm shift is evolving from pattern- and evidence-based medicine toward algorithm-based, precision medicine targeted to individual mutations. Meticulous clinical phenotyping and pedigree analysis, combined with advances in high-throughput metabolomics, proteomics, transcriptomics (RNAseq in clinically relevant tissues), and genomics, have expedited the identification of novel pathomechanisms and new therapeutic targets. Evaluation of these therapies in IEMs, many of which manifest with encephalopathy and epilepsy, will depend on international registries of well-characterized phenotypes in RCTs and measurement of clinically relevant endpoints. The earlier the recognition and diagnosis and intervention with targeted therapies, the better the overall outcome in terms of the impact on intellectual disability and the effective management of the associated epilepsy.

Keywords: Genetics; Inborn errors of metabolism; Neurometabolic diseases; Whole exome sequencing; Whole genome sequencing.

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Australia
  • Brain Diseases* / diagnosis
  • Brain Diseases* / genetics
  • Critical Illness
  • Epilepsy* / diagnosis
  • Epilepsy* / genetics
  • Genetic Testing
  • Humans
  • Randomized Controlled Trials as Topic
  • Seizures / genetics