Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)

2014-08-27 03:17:11 | BioPortfolio


Can what you eat alter the progression of amyotrophic lateral sclerosis (ALS)? We propose that the answer may be yes. Mitochondrial dysfunction may play a pivotal role in the death of motor neurons in ALS. Ketones, generated from ketogenic diets, can overcome certain types of mitochondrial dysfunction and in doing so, help restore the motor neuron to better health and thereby slow or stop the disease progression. The primary aim of our study is to prove that ketogenic diets are safe and tolerable in patients with ALS so that larger studies to test this hypothesis can be safely performed.


The cause of amyotrophic lateral sclerosis is unknown. There is growing evidence implicating mitochondrial dysfunction as being an integral part of the process that ultimately results in the death of the motor neuron. Studies from the G93A transgenic mouse model of ALS show abnormal mitochondrial structure, intramitochondrial inclusions, possible mitochondrial sites of direct interaction with the mutant SOD1 molecule, and disruption of the energy generating function of the mitochondrion, particularly complex I, the NADH dehydrogenase complex. In vitro and preliminary evidence from G93A mice suggest that ketones, particularly D beta hydroxybutyrate (DßHB) are able to stimulate other components of the mitochondrial membrane complexes (2,3,4 and cytochrome c) when complex 1 is blocked, essentially bypassing the dysfunctional complex I and providing continued mitochondrial energy supply. DßHB is one of the main products formed during ketosis, the metabolic state resulting from an effective ketogenic diet. When G93A transgenic mice are maintained on a ketogenic diet, the ketotic animals live longer, have better motor performance, and have significantly larger diameter neurons remaining in the anterior horn region of the spinal cord compared to disease controls. Interestingly, G93 mice seemed to produce more ketones compared to control animals fed the same high fat, low carbohydrate diet, suggesting the possibility of an inherent defect in metabolizing fats and protein in the setting of hypoglycemia.

Ketogenic diets have been used for decades to treat intractable seizures. The mechanism conferring anticonvulsant activity is uncertain, but one possible mechanism may be related to hyperpolarization resulting from increased levels of ATP. Ketogenic diets have never been used in patients with ALS. Therefore the specific aims of our study are the following: 1. To determine if gastrostomy-fed ALS patients adhering to the 4:1 ketogenic diet (ratio of grams of fat to grams of protein plus carbohydrate) is safe and tolerable. We will determine safety and tolerance by measuring incidence and severity of adverse effects as well as careful monitoring of weight. 2. To evaluate changes in strength, fatigue and cognitive function while strictly adhering to the ketogenic diet. 3. To evaluate the changes in the percentage of body fat during the course of the study to determine the metabolic impact of the ketogenic diet. If safety and tolerability are established, further studies to determine efficacy of the ketogenic diet in patients with ALS will be planned.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment


Amyotrophic Lateral Sclerosis


KetoCal Diet


The Robert Packard Center for ALS Research at Johns Hopkins
United States




Weill Medical College of Cornell University

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:17:11-0400

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Medical and Biotech [MESH] Definitions

A glutamate antagonist (RECEPTORS, GLUTAMATE) used as an anticonvulsant (ANTICONVULSANTS) and to prolong the survival of patients with AMYOTROPHIC LATERAL SCLEROSIS.

A superoxide dismutase (SOD1) that requires copper and zinc ions for its activity to destroy SUPEROXIDE FREE RADICALS within the CYTOPLASM. Mutations in the SOD1 gene are associated with AMYOTROPHIC LATERAL SCLEROSIS-1.

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A widely-expressed protein of approximately 400 to 500 amino acids. Its N-terminal region (DENN domain) interacts with RAB GTP-BINDING PROTEINS and may regulate AUTOPHAGY, as well as PROTEIN TRANSPORT to ENDOSOMES. Expansion of the GGGGCC hexanucleotide repeat in the first intron of the C9orf72 gene is associated with FRONTOTEMPORAL DEMENTIA with AMYOTROPHIC LATERAL SCLEROSIS (FTDALS1).

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