P4 medicine for epilepsy and intellectual disability: nutritional therapy for inherited metabolic disease

Abstract

Early identification and treatment of inherited metabolic diseases (IMDs) are essential to prevent and minimize intellectual disability (ID) and epilepsy. The oldest form of treatment, nutritional modulation, has proved beneficial for many IMDs. These conditions represent a promising model for P4 medicine — predictive, preventive, personalized, and participatory — specifically through the interpretation of individual genetic, pathophysiological, and clinical characteristics. More than 1000 IMDs have been described, and for these different nutritional modulation strategies are applied, varying from substrate reduction, supplementation of vitamins for catalyzation of enzymatic reactions or supplementation of amino acids or other nutrients, to substitution for deficient or inactivated products. This review provides an overview of all IMDs presenting with epilepsy and/or ID amenable to nutritional modulation; these are 85 in number, belonging to 27 categories. Therapeutic strategies include protein-restricted diet, ketogenic diet, fat-restricted diet, lactose-restricted diet; supplementation of amino acids, carbohydrates, or others; and supplementation of vitamins or cofactors as well as a sick-day protocol. Nutritional therapies are generally safe, affordable, and accessible, but compliance is an issue. Three different types of response exist: (1) a positive effect on seizure control and/or psychomotor development; (2) efficacy in prevention of decompensation but ongoing damage occurs; and (3) insufficient insights or evidence to establish the treatment as effective. For the latter category, we describe pyridoxine-dependent epilepsy as a case vignette for P4 medicine, discuss the benefits and challenges of nutritional modulation in IMDs, and outline novel approaches and solutions.

2022 Overview of Metabolic Epilepsies

“…In some treatable metabolic epilepsies, more than one treatment strategy is applied. Relatively simple, inexpensive and (often) quite effective nutritional and vitamin/trace element substitution therapies [33] are effective in 59% and 32% of treatable metabolic epilepsies in this study. The majority of treatable metabolic epilepsies are related to the following three groups of IMDs: defects of intermediary metabolism of nutrients and energy, and cofactor/mineral metabolism defects.…”

“…In some treatable metabolic epilepsies, more than one treatment strategy is applied. Relatively simple, inexpensive and (often) quite effective nutritional and vitamin/trace element substitution therapies [ 33 ] are effective in 59% and 32% of treatable metabolic epilepsies in this study.…”

“…Potentially prognosis-altering specific treatments that are personalized and targeted to the disease pathophysiological mechanisms are becoming available for an increasing number of metabolic epilepsies. In many cases the treatment consists of relatively simple, inexpensive and (often) quite effective nutritional and vitamin/trace element substitution therapies [ 33 ] that comprised 59% and 32% of available specific treatments for metabolic epilepsies in this study. Unfortunately, this success has not been accompanied by similar success in the development of therapies for common epilepsies.…”

Multidisciplinary Care of Patients with Inherited Metabolic Diseases and Epilepsy: Current Perspectives

“… 8 Specific treatments include nutritional or vitamin/ cofactor supplementation therapies, relatively inexpensive and frequently highly effective treatment modalities. 47 Enzyme replacement and small molecule therapies, stem cell and solid organ transplantations, and cell or gene therapies may also provide opportunities of highly effective specific treatments. It is imperative for clinicians to have a sufficient index of suspicion for these diseases in order to identify and diagnose them in time, as early diagnosis and treatments may prevent major neurological sequelae and enable favorable outcomes.…”

Treatment of ARS deficiencies with specific amino acids

“…Based on the genetic diagnoses and in vitro functional studies, we developed personalized intervention and monitoring protocols for objective safety and outcome parameters (Table S1 ) as n = 1 studies with parents as partners in care [ 7 , 8 ].…”