INBORN ERRORS OF METABOLISM: UNDERSTANDING GENETIC DISORDERS

“𝓔𝓪𝓻𝓵𝔂 𝓭𝓮𝓽𝓮𝓬𝓽𝓲𝓸𝓷 𝓽𝓻𝓪𝓷𝓼𝓯𝓸𝓻𝓶𝓼 𝓲𝓷𝓫𝓸𝓻𝓷 𝓮𝓻𝓻𝓸𝓻𝓼 𝓸𝓯 𝓶𝓮𝓽𝓪𝓫𝓸𝓵𝓲𝓼𝓶 𝓯𝓻𝓸𝓶 𝓭𝓮𝓿𝓪𝓼𝓽𝓪𝓽𝓲𝓷𝓰 𝓭𝓲𝓼𝓮𝓪𝓼𝓮𝓼 𝓲𝓷𝓽𝓸 𝓶𝓪𝓷𝓪𝓰𝓮𝓪𝓫𝓵𝓮 𝓬𝓸𝓷𝓭𝓲𝓽𝓲𝓸𝓷𝓼.” - Professor Bridget Wilcken

🧬 Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders caused by defects in enzymes or transporters essential for normal metabolic pathways. These defects lead to toxic metabolite accumulation or deficiency of critical compounds, resulting in significant morbidity and mortality if untreated. Advances in biochemical genetics and newborn screening have dramatically improved outcomes.

          🔹 Major Classes of IEM are commonly classified by the affected pathway:

• Amino acid disorders (e.g., phenylketonuria, maple syrup urine disease),

• Carbohydrate metabolism disorders (e.g., galactosemia),

• Lipid metabolism disorders (e.g., Gaucher disease, Tay-Sachs disease),

• Organic acidemias causing metabolic acidosis and organ dysfunction,

• Complex disorders, including mitochondrial diseases and metal metabolism disorders such as Wilson disease.

          🔹 The hallmark of IEM is enzyme deficiency, disrupting normal metabolic flux. This results in either toxic substrate accumulation or failure to synthesize essential metabolites. Neurological injury, metabolic crises, and progressive organ damage are common consequences, particularly in untreated infancy.

           🔹 IEM often present with:

• Developmental delay, seizures, or encephalopathy,

• Acute metabolic decompensation (vomiting, hypoglycemia, lethargy),

• Failure to thrive,

• Characteristic odors (e.g., MSUD), and

• Liver, kidney, or neurological dysfunction

          ➡️ Early diagnosis through newborn screening using tandem mass spectrometry, complemented by biochemical and genetic testing, is critical. Management is disorder-specific and includes:

a) Targeted dietary modification,

b) Metabolite or cofactor supplementation,

c) Pharmacologic therapy (e.g., chelation in Wilson disease),

d) Liver transplantation in select conditions, and

e) Emerging gene-based therapies which addresses root genetic defects.

⚠️ In an Oystershell, IEM exemplify how precision medicine, early screening, and translational genetics can convert once-fatal disorders into manageable conditions. Continued research, clinician awareness, and equitable access to newborn screening remain essential to improving global outcomes.

Abubakar Abubakar ✍🏻

• Saudubray JM, et al. Lancet. 2022;399:1830-1844.

• Wilcken B, et al. N Engl J Med. 2003;348:2304-2312.

• Burton BK. N Engl J Med. 2015;372:2243-2252.

• Blau N, et al. Nat Rev Dis Primers. 2015;1:15040.

• Ferreira CR, et al. Genet Med. 2019;21:918-929.

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