Management of Inborn Errors of Metabolism

By: dr. Klara Yuliarti, Sp.A(K)

After reading the article “What is a rare disease?”, surely your next question will be, is there any treatment for inborn errors of metabolism (IEM) ? The answer is Yes! A number of IEM is treatable, however, most are palliative in nature. A child may have a normal growth and development when diagnosed early, undergo the available treatment as early as possible and is compliant towards the therapy given.
The history of IEM started of when Dr. Horst Bickel found the disease phenylketonuria (PKU) in the year 1953. A child with PKU is unable to metabolize the amino acid, phenylalanine. Therefore, the deposition of phenylalanine may cause an irreversible severe mental retardation. Dr. Horst Bickel has an idea to make a special milk formula that does not contain phenylalanine. A child with PKU who can be diagnosed through newborn screening and treated with this specialized formula since birth can have a normal growth and development. Since this revolutionary event, there were interests in finding out other therapies for IEM.
Based on the therapeutic perspective, IEM is divided into 3 groups, i.e. (1) disorders that result in intoxication, (2) disorders that involve energy metabolism, and (3) disorders that involve complex molecules.
The first group of disorders involves the deposition of the toxins due to a faulty metabolism. This deposition causes acute or progressive intoxication. An example of an IEM from this group that has been diagnosed in Indonesia is phenylketonuria, 6-pyruvayl tetrahydropterin synthase deficiency (PTPS), maple syrup urine disease (MSUD), isovaleric aciduria, homocystinuria, tyrosine hydroxylase deficiency and Wilson disease. Nutritional therapy is the backbone of the management for these disorders.
Patients need a special milk formula that does not contain the molecule that can’t be metabolized. This formula is also known as special medical purpose formula (SMPF) that can only be accessed through a doctor’s prescription and it’s use should be under the supervision of a competent metabolic specialist. A few sxamples of SMPF are PKU Anamix® which is a phenylalanine free formula for phenylketonuria, MSUD Anamix® is a leucine, isoleucine and valine free formula for MSUD, and LMD® is a leucine free formula for isovaleric academia. If the diet is started as soon as possible, i.e. right after birth, the child will have a normal growth and development.
Management of IEM may also include medication, such as in PTPS, which is caused due to a disturbance in the synthesis of tetrahydrobiopterin (BH4). Tetrahydrobiopterin is a cofactor to the enzyme phenylalanine hydroxylase, therefore the medication is a synthetic form of BH4, dopamine and typtophan.
In the second group of IEM, there is a defect in production or in energy utilization in the liver, cardiac muscle, skeletal muscle, brain or other tissues. An effective therapy for this type of IEM has still not been established.
The third group of IEM involves a disturbance in the cell organelles and includes diseases which is caused by a disturbance in the synthesis or catabolism of complex molecules. The signs and symptoms are permanent, progressive and is not related to food intake. The examples of a few diseases that has been diagnosed in Indonesia are Mucopolysaccharidosis (MPS), Gaucher disease, Niemann Pick disease, and Fabry disease. The management of this group of diseases is enzyme replacement therapy. Enzyme replacement therapy is a procedure where patients are administered enzymes via an intravenous route or an oral route to replace the lack of enzymes in these patients due to a genetic mutation.
The first enzyme replacement therapy for metabolic disease in Indonesia was conducted in Cipto Mangunkusumo Hospital on January 2015 for a patient with MPS type IVA. Up to May 2017, there have already been 3 patients (1 patient with MPS type IVA, 1 patient with MPS type II, and 1 patient with Gaucher disease) undergoing enzyme replacement therapy at Cipto Mangunkusumo Hospital. The patient with MPS type IVA has managed to buy the enzyme from their private funds, however, the other 2 patients have managed to receive the enzymes through a donation program known as ICAP. Besides these 3 patients, there are 2 additional patients whose donation request have been agreed upon and are currently waiting for the medications. All 3 patients who have received enzyme replacement therapy have had a significant improvement in their quality of life, which can be seen through a reduction in snoring and upper respiratory tract obstruction, improvement in walking an writing skills. Objectively, the improvement of quality of life can be evaluated through the 6 minute walking step, 3-minute stair climbing test as well as through a particular questionnaire.
At the moment, research about the management of metabolic disease is significantly increasing and there are new medications that have been produced. The management that has been discussed above are palliative in nature, which means it does not cure but can reduce symptoms and should is a long-life therapy. A definitive treatment that is currently being developed is the gene therapy.
After reading this article, patients and families of patients with metabolic disease can still be optimistic because there are a number of metabolic diseases that can be treated. The earlier the treatment is given, the better the hope for success.

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