Decoding Genetic Metabolic Disorders

Dr Anup Rawool, Associate Director, Medical Genetics and Head, Scientific and Medical Affairs, MedGenome talks about the roadmap from detection to treatment of genetic disorders

In recognition of Rare Disease Day, it’s crucial to highlight the significance of decoding rare genetic metabolic disorders like Inborn Errors of Metabolism (IEM). These conditions, though individually rare, collectively affect a substantial portion of the population, imposing significant challenges on affected individuals and their families.

Metabolism is the chemical reaction in the body’s cells that breaks down food into energy and uses it for movement, growth, development and reproduction. Genetic defects can cause different types of medical conditions that can interfere with the body’s metabolism. These genetic defects are commonly inherited from both parents or could be denovo in occurrence, meaning manifesting in the patient for the first time. These conditions are known as Inborn errors of metabolism (IEM).

The disorders collectively affect 1 per cent to 3 per cent of the world population. One in 1000 infants is known to inherit a metabolic disorder, which therefore creates a health burden in society. One In India, the prevalence of Inborn errors of metabolism (IEM) is one in 2,497 newborns. Worldwide, the incidence of IEM is more than 1/1000. 

Symptoms of IEM can emerge suddenly or progress gradually, triggered by various factors. Despite diverse clinical presentations, all IEMs invariably have underlying molecular genetic aetiology which, if inherited could be genetically transmitted from one generation to the next through various modes of inheritance patterns viz., autosomal recessive or X-linked recessive patterns. The main categories of IEM include aminoacidopathies (defects in protein synthesis pathways which result in a range of biochemical disorders and clinical presentations), organic acidemias (a class of inborn errors of metabolism characterized by accumulation of abnormal organic acid metabolites and increased excretion of organic acids in urine), fatty acid oxidation defects, urea cycle defects etc. Early diagnosis of these diverse genetic metabolic disorders is crucial for timely intervention to mitigate or prevent the complications.

Why do you need to test for Genetic Metabolic Disorders?

Timely identification of metabolic disorders is crucial for more effective and cost-efficient disease management. For instance, in individuals with specific urea cycle disorders, supplementing their diets with arginine becomes imperative due to inadequate natural production. Similarly, those with phenylketonuria (PKU) benefit from a specialised diet restricting foods rich in phenylalanine, while also avoiding high-protein content foods. Early diagnosis enables targeted interventions, ensuring a more tailored and economical approach to precisely managing these conditions.

When do you need to get tested for Genetic Metabolic Disorders?

Genetic metabolic disorders often lack distinct clinical appearances, and their manifestations are intricate and diverse with lots of conditions having a phenotype overlap. Common symptoms include weight loss, failure to thrive, lethargy, poor appetite, abdominal pain, vomiting, jaundice, seizures, developmental delay, coma, and the presence of abnormal odours in urine, breath, sweat, or saliva. The complexity and variability of these symptoms underscore the importance of a comprehensive and specialised approach towards diagnosis and management, as early detection becomes paramount in addressing the implications of a broad spectrum of clinical presentations associated

with these disorders in individuals presenting with the symptoms of metabolic disorders.

What are the test methodologies?

  • Next-generation Sequencing (NGS) – Using DNA extracted from blood, the protein-coding regions of all the genes are captured and sequenced simultaneously by NGS technology. The sequenced data that is generated is aligned to the reference genome assembly and analysed for sequence variants (abnormalities).
  • Multiplex Ligation-Dependent Probe Amplification (MLPA) – Targeted Deletion and duplication analysis of genomic DNA is carried out by MLPA. This method allows for the amplification of multiple targets with only a single primer-probe set.
  • Fragment Analysis PCR for Repeat Expansion Analysis – These rely on the detection of changes in the length of a specific DNA sequence to indicate the presence of repeat expansions. Biochemical markers, analysed through blood and urine tests, contribute valuable insights into metabolic imbalances. Elevated levels of specific substances will indicate the presence of a metabolic disorder, further facilitating while cutting short the diagnostic journey.

Medical Geneticists are pivotal in molecular genetic diagnosis, genotype-phenotype correlation, and analysis in sync with the paediatrician/neonatologist, streamlining patient management. While genetic counsellors provide essential information about the nature of the disorder, inheritance patterns, and available treatment options, empowering and equipping families with the right information.

Early diagnosis will help in the timely initiation of appropriate interventions, often involving dietary modifications and supportive therapies. The overarching goal is to manage symptoms effectively, prevent potential complications, and enhance the overall quality of life for individuals with genetic metabolic disorders. The information obtained could also be utilised for risk estimation of recurrence in subsequent pregnancy and planning prenatal diagnosis or IVF with Pre-implantation genetic diagnosis (PGD) where appropriate. This proactive approach emphasises the importance of early detection in shaping successful treatment strategies.

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