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

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.