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Inborn Errors of Metabolism

INBORN ERRORS OF METABOLISM

Inborn errors of metabolism (IEMs) represent a large class of rare genetic disorders and affects about 3.5 -5.9% of the worldwide population[1]. The first IEM conditions were described in 1908 by Sir Archibald Garrod where he described albinism, alkaptonuria, cystinuria and pentosuria to illustrate the concept of IEM[2]. Since then, many more IEMs have been described, currently estimated as >600 and the successes of diet and vitamins therapies lead onto developing more complex treatments like enzyme replacement therapy, oral enzyme substitution therapy and gene therapies. Phenylketonuria (PKU) is an example of one of the first disorders in this group that was successfully treated by dietary measures.[3]


Inborn errors of metabolism (IEM) are rare genetic disorders which result in the body not being able to properly metabolise nutrients derived from food to maintain health and normal growth. These disorders are usually caused by genetic defects leading to abnormal enzymes, co-factors and disruption of the complex communication systems which maintains our healthy bodies.


Nutrients that are not broken down can build up in the body and this can lead to a variety of symptoms or the lack of nutrients can cause failing metabolism leading to specific disorders. IEM`s are affecting many body systems but sadly more than 50% start in childhood and affects the brain but with early diagnose many of them now have therapies to change the disease progression.


IEM are typically categorised into main types but as more groups are discovered the classification keeps being updated. A significant number of these disorders can be improved by changes to diet or using appropriate vitamins and supplements whilst being supervised by an expert.


Here are some of the main categories[4]:

  1. DISORDERS OF NITROGEN-CONTAINING COMPOUNDS
  2. DISORDERS OF VITAMINS, COFACTORS AND MINERALS
  3. DISORDERS OF CARBOHYDRATES
  4. MITOCHONDRIAL DISORDERS OF ENERGY METABOLISM
  5. DISORDERS OF LIPIDS
  6. DISORDERS OF TETRAPYRROLES
  7. STORAGE DISORDERS
  8. DISORDERS OF PEROXISOMES AND OXALATE
  9. CONGENITAL DISORDERS OF GLYCOSYLATION

To give you a sense of this one example is used below.


Disorders of Nitrogen containing compounds will include amino acid (protein) metabolism.


Many of the disorders in groups affecting nitrogen, carbohydrates and lipids primarily managed with either lifelong dietary intervention alone or a combination of diet, vitamins, supplements, and drug therapy.


Newborn screening programs help to identify infants with IEM shortly after birth. Many, but not all IEM are tested for in newborn screening; this will vary in each country.


An example of a disorder of amino acid (protein) metabolism is Phenylketonuria (PKU). PKU is one of the more common disorders although it is still rare, it occurs in approximately 1 in every 23 930 newborns worldwide.[5]


The ‘building blocks’ of protein are called amino acids. In PKU, due to the lack of an enzyme known as phenylalanine hydroxylase, the body cannot properly deal with one of the amino acids known as phenylalanine (Phe) and Phe can then build up to toxic levels in the blood. This means that people with PKU need to severely restrict the amount of natural protein they eat.


A key element in the dietary management of PKU is the use of a phenylalanine-free protein substitutes. These provide all the amino acids needed in combination with small, measured amounts of dietary protein, protein substitutes will ensure that an individual with PKU has an adequate intake of protein for normal growth and development. The primary role of a protein substitute is to provide the protein (minus Phe) that cannot be consumed by eating protein-containing foods. Modern protein substitutes may contain vitamins, minerals and omega fats which are limited within a restricted low protein diet.


Protein substitutes developed for PKU have improved dramatically over the years. Compliance to the strict diet can be difficult; therefore, protein substitutes are specifically designed to complement modern living. This is achieved through a combination of easily transported ‘single use’ formats, available in a range of flavours that do not require mixing, weighing or measuring.


In combination, all of the above attributes help make taking the protein substitute easier, therefore encouraging good compliance. New research in this condition is looking at different ways to provide the missing enzyme to patients and improve their quality of life.


Anyone affected by IEM wanting more information about the disorder, management, and outcomes, should seek medical advice from their clinician / dietitian.

References

  1. Nguengang Wakap, S., et al., Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet, 2020. 28(2): p. 165-173.
  2. Scriver, C.R., Garrod's Croonian Lectures (1908) and the charter ‘Inborn Errors of Metabolism’: Albinism, alkaptonuria, cystinuria, and pentosuria at age 100 in 2008. Journal of Inherited Metabolic Disease, 2008. 31(5): p. 580.
  3. Green, A., The First Treatment for PKU: The Pioneers-Birmingham 1951. Int J Neonatal Screen, 2021. 7(1).
  4. Ferreira, C.R., et al., An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis, 2021. 44(1): p. 164-177.
  5. Hillert, A., et al., The Genetic Landscape and Epidemiology of Phenylketonuria. American journal of human genetics, 2020. 107(2): p. 234-250.


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