Abstract
Dietary interventions are now being used as an adjunct therapy in the treatment of rare diseases. One such method is the high-fat, moderate-protein, and very low-carbohydrate diet which produces ketosis and therefore called the ketogenic diet. Some of the more common conditions that are treated with this method are pharmacoresistant epilepsy, infantile spasms, glycogen storage diseases, and other forms of rare metabolic disturbances. With this review, we look at different uses of the ketogenic diet in treating rare diseases and the recommendations based on current evidence.
1. Introduction
There are many obstacles when treating rare diseases as they may often depict only the tip of the iceberg, which represents some varied genetic and phenotypic characteristics. Certain dietary modifications such as the ketogenic diet and the modified Atkins diet (MAD) have been tried in a plethora of rare diseases ranging from epilepsy, infantile spasms, and glycogen storage diseases to other forms of rare metabolic disturbances [1–3]. In monogenic rare diseases, a continuum of therapeutic strategies can be employed, and medical nutrition therapy is one such option. With the expansion of our understanding of the affected metabolic pathways, we can now tailor these therapies on a personalized basis [4]. A ketogenic diet is one that is typically high in fat, with moderate protein and a very low-carbohydrate levels, or it can also be high in protein and lower in fat and carbohydrate levels, with the end result of producing ketosis. This produces a form of starvation and forces the body to deviate from its traditional fuel source glucose to primarily use fats [5]. The key to a ketogenic diet is limited carbohydrate intake to a total daily amount of 10 to 50 grams or 5% to 10% of total caloric intake which causes fat to be converted to various ketone bodies for cellular metabolism (e.g., acetoacetate, beta-hydroxybutyrate, and acetone) [6, 7]. Certain ketogenic dietary protocols use medium-chain triglycerides (MCT) to help boost ketone production as they are more rapidly broken down into ketones and energy [8]. This form of dietary modifications was documented since 1925 to treat drug-resistant epilepsy [9, 10]. However, a prolonged ketogenic diet is not endured well as there are several drawbacks such as retardation of growth in children and gastrointestinal side effects [11]. The aim of this review is to look at the different uses of a ketogenic diet in treating rare diseases and to make recommendations based on current evidence.
2. Pharmacoresistant Epilepsy, Infantile Spasms, and Tuberous Sclerosis
It is estimated that 30% of epilepsy patients are pharmacoresistant. In this group of patients, a ketogenic diet (KD) has offered some promising results [12]. In experimental cell culture models such as in rat hippocampal neuronal cells, the 3 ketone bodies, namely, acetone, acetoacetic acid, and β-hydroxybutyric acid, inhibit the opening of the acid-sensing ion channels through undermining their currents and, as a result, inhibit their function [11]. From the literature review done in MEDLINE, Google Scholar, and Cochrane library, six randomized control trials [13–18] have assessed the efficacy and safety of different KD regimes in patients with intractable childhood epilepsy. All 6 studies showed beneficial effects, especially in reducing the baseline seizure frequency. Findings from these studies are summarized in Table 1. The adverse side effects of KD included digestive problems such as diarrhea, constipation, vomiting, and issues related to lipid metabolism such as hyperlipidemia, hypercalciuria, and weight loss. The studies conducted thus far had the limitation of small sample size in the pediatric age group [19]. There were 5 randomized control trials [20–24] which were conducted to compare the efficacy between different KD regimes. These studies have compared different KD regimes by taking into account the efficacy and adverse effects. Findings from these studies are summarized in Table 2. A majority of these studies (n = 4) have not shown significant differences in efficacy; however, different regimes had different side effect profiles.
Infantile spasms (IS) are a form of epilepsies that occur in infancy and have a characteristic EEG pattern (hypsarrhythmia) accompanied sometimes with intellectual disability and neurodevelopmental regression [1]. Ketogenic diet has been tried with success; however, it has been looked at with reluctance by pediatricians owing to the age of patients and unknown side effects. In a larger study where 104 infants were started on KD after treatment failure with corticosteroids and vigabatrin, it was reported that 64% saw an improvement in spasms 6 months after starting treatment and 77% saw improvements following 1-2 years, and adverse effects were reported only in 33%. However, in 6%, there was diminished linear growth. They also observed that the older the onset of IS and fewer the anticonvulsant use, the greater the likelihood of improvement of spasms on a KD [25].
In the tuberous sclerosis complex (TSC), a condition frequently associated with epilepsy and infantile spasms; a KD has been tried with success. In a study spanning 5 years conducted at Johns Hopkins Hospital and Massachusetts General Hospital, 12 children between the ages of 8 and 18 years were started on a KD. Among them, 92% (n = 11) showed a significant (>50%) improvement in the initial 6 months itself [26]. In another study, 21 out of 31 patients showed a significant reduction in seizures (>50%) in the initial 3 months of initiating a KD [27]. Both studies have concluded that KD appeared to be effective as a therapeutic intervention in intractable pediatric epilepsy in TSC. However, its long-term efficacy needs further evaluation.
3. Inherited Metabolic Disorders
3.1. Glycogen Storage Diseases (III and V)
Glycogen storage disease type III (GSD III) is an autosomal recessive disease caused by the deficiency of the glycogen debranching enzyme, encoded by the AGL gene. It is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSD IIIa is the most common subtype present in about 85% of affected individuals; it manifests with liver and muscle involvement. GSD IIIb, with liver involvement only, comprises about 15% of all GSD III [28]. Currently, the treatment to limit glycogen storage is the diet. High-carbohydrate diet prevents fasting hypoglycaemia but increases glycogen storage and does not slow the progression of cardiac and muscular manifestation [29]. Several case reports and case series report beneficial effects on the muscle disease component of GSD IIIa with KD (study details are summarized in Table 3).
GSD V disease is caused by genetic defects of the muscle-specific isozyme of glycogen phosphorylase, which blocks ATP formation from glycogen in skeletal muscles [34]. Patients with this rare disease present with exercise intolerance due to blocked glycogen breakdown in skeletal muscles. Introducing alternative fuel substrates, such as ketone bodies (by providing a ketogenic diet), could potentially alleviate muscle symptoms. The summary of case reports relevant to the management of GSD V with KD is given in Table 3.
4. Mitochondrial Disorders
4.1. Pyruvate Dehydrogenase Complex Deficiency
The pyruvate dehydrogenase complex (PDHc) is a member of a family of multienzyme complexes that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the decarboxylation of various 2-oxoacid substrates to their corresponding acyl-CoA derivatives, NADH, and CO2 [37]. PDHc deficiency is a metabolic disorder commonly associated with lactic acidosis and progressive neurological and neuromuscular degeneration [38]. In 1976, Falk et al. showed that KD would be beneficial in PDHc deficiency [39, 40]. Since then, several case reports report the efficacy of the KD in the management of this disease (Table 4).
4.2. Mitochondrial DNA Depletion Syndromes (MDS)
Mitochondrial DNA depletion syndromes are characterized by a severe, tissue-specific decrease in the mitochondrial DNA (mtDNA) copy number with resulting organ failure. Polymerase gamma (POLG) is one of the enzymes catalyzing mtDNA replication. MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral, or neurogastrointestinal.
5. Conclusion
The KD is an efficacious therapy for pharmacoresistant epilepsy in children, and it should be considered strongly after failure of traditional treatment. It has several gastrointestinal side effects which can be modified with different ketogenic diet regimes. Before prescribing such dietary modifications, it is vital that parents or the caregivers in younger children are able to comprehend and carry out such a nutritional plan intelligently.
The main indications to start with a KD in GSD III patients were cardiomyopathy, skeletal myopathy, or a combination of both, and the KD had good beneficial outcomes according to the existing case reports. Treatment of KD in mitochondrial diseases also showed promising results in improvement of the clinical picture, but for these diseases, evidence is limited as these diseases are rare, and available evidence is in the form of case reports or case series. Furthermore, carefully designed systematic studies are warranted in patients with rare metabolic diseases to address issues of dietary compliance and the effect of both standard and ketogenic diets on short- and long-term outcomes.
Data Availability
There are no additional data other than which are mentioned in the article already.
Conflicts of Interest
The authors declare that they have no conflicts of interest.