Type 3 Gaucher disease (GD3) is characterized by progressive neurological features in addition to the typical systemic manifestations. Enzyme replacement therapy (ERT), the main stay treatment for Gaucher disease (GD), is not efficacious for the neurological manifestations. Ambroxol, in combination with ERT has been suggested to have potential as a promising therapy for patients with GD3. The purpose of this study is to assess the effect of Ambroxol on glucosylsphingosine (Lyso-Gb1) levels, and on the neurological morbidity, in two Canadian patients with GD3.

Infantile Spasms syndrome is a catastrophic, epileptic encephalopathy of infancy that is often refractory to current antiepileptic therapies. The ketogenic diet has emerged as an alternative treatment for patients with medically intractable epilepsy, though the prospective validity and mechanism of action for Infantile Spasms remains largely unexplored. We investigated the ketogenic diet’s efficacy as well as its mechanism of action in a rodent model of intractable Infantile Spasms. The spasms were induced using the triple-hit paradigm and the animals were then artificially reared and put on either the ketogenic diet (4:1 fats: carbohydrate + protein) or a control-milk diet (CM; 1.7:1). 31Phosphorus magnetic resonance spectroscopy (MRS) and head-out plethysmography were examined in conjunction with continuous video-EEG behavioural recordings in lesioned animals and sham-operated controls. The ketogenic diet resulted in a peripheral ketosis observed both in the blood and urine. The ketogenic diet led to a robust reduction in the frequency of spasms observed, with approximately a 1.5-fold increase in the rate of survival. Intriguingly, the ketogenic diet resulted in an intracerebral acidosis as measured with 31Phosphorus magnetic resonance spectroscopy. In addition, the respiratory profile of the lesioned rats on the ketogenic diet was significantly altered with slower, deeper, and longer breathing, resulting in decreased levels of expired CO2. Sodium bicarbonate supplementation, acting as a pH buffer, partially reversed the ketogenic diet’s protective effects on spasm frequency. There were no differences in the mitochondrial respiratory profiles in the liver and brain frontal cortex measured between the groups, supporting the notion that the effects of the ketogenic diet on breathing are not entirely due to changes in intermediary metabolism. Together, our results indicate that the ketogenic diet produces its anticonvulsant effects through changes in respiration leading to intracerebral acidosis. These findings provide a novel understanding of the mechanisms underlying the anti-seizure effects of the ketogenic diet in Infantile Spasms. Further research is required to determine whether the effects of the ketogenic diet on breathing and intracerebral acid-base balance are seen in other pediatric models of epilepsy.

The infantile spasms (IS) syndrome is a catastrophic developmental epileptic encephalopathy syndrome characterized by an age-specific expression of epileptic spasms that are associated with extremely abnormal, oftentimes described as chaotic, interictal EEG pattern known as hypsarrhythmia. Patients with IS generally have poor neurodevelopmental outcomes, in large part because of the frequent epileptic spasms and interictal EEG abnormalities. Current first-line treatments such as adrenocorticotropic hormone or vigabatrin are often ineffective and are associated with major toxic side effects. There is therefore a need for better and safer treatments for patients with IS, especially for the intractable population. Hope is on the horizon as, over the past 10 years, there has been robust progress in the development of etiology-specific animal models of IS. These models have been used to identify potential new treatments for IS and are beginning to provide some important insights into the pathophysiological substrates for this disease. In this review, we will highlight strengths and weaknesses of the currently available animal models of IS in addition to new insights into the pathophysiology and treatment options derived from these models.