Bringing CNS Members Together to Make Children’s Lives Better


Mechanism-Based Therapies for Genetic Diseases

By E. Steve Roach, MD | CNS President

E. Steve Roach, MD | CNS President
E. Steve Roach, MD
CNS President

Disease is from of old and nothing about it has changed. It is we who change as we learn to recognize what was formerly imperceptible. – Jean Martin Charcot 

Information about genetic neurological diseases has accumulated rapidly in recent years, leading to an increasingly sophisticated understanding of the molecular mechanisms that underpin many of these conditions. The promise of innovative disease-specific therapies that capitalize on these discoveries, however, has been slow to develop. At this year’s Presidential Symposium we will highlight recent progress toward developing targeted therapies for tuberous sclerosis complex, Rett syndrome, fragile X syndrome, Down syndrome, and autism. 

Dietary manipulation and vitamin supplementation have been used for many years to treat a handful of genetic diseases. Individuals with Refsum disease, for example, benefit from a diet low in phytanic acid, and dietary therapy has also been used for children with phenylketonuria and other genetic disorders. Pharmacologic vitamin doses also benefit children with pyridoxine dependency, homocystinuria, abetalipoproteinemia, biotinidase deficiency, and other disorders. 
Most such treatments were based on a relatively limited understanding of the disease. Babies with pyridoxine-dependent seizures were treated with supplemental vitamin B6 for a half century before the disorder was traced to an ALDH7A1 mutation that leads to accumulation of ?-piperideine-6-carboxylate -a-aminoadipic semialdehyde and inactivation of pyridoxal 5?-phosphate. 

Therapy that exploits discoveries about the molecular biology of genetic neurological diseases has finally begun to materialize. Restriction of dietary fat intake coupled with the administration of a mixture of glyceryl trioleate and glyceryl trierucate (Lorenzo oil) rapidly improves the plasma long chain fatty acid levels of individuals with X-linked adrenoleukodystrophy. More importantly, the diet also improves the neurological outcome of these individuals, provided that treatment is begun prior to the onset of either neurological symptoms or the appearance of brain lesions on magnetic resonance imaging.  Several neurological genetic diseases can be confirmed by cerebrospinal fluid neurotransmitter metabolite analysis, and an understanding of the altered metabolic pathways has in several instances lead to effective therapy.  Enzyme replacement benefits people with Fabry and Pompe diseases and may be feasible for other conditions.  Individuals with Fabry disease, for example, experience a reduction of symptoms and undergo dose-dependent reduction of glycosphingolipid globotriaosylceramide after infusions of recombinant alpha galactosidase A. 

Mechanism-based therapy is already a reality for tuberous sclerosis complex. A mutation of either TSC1 or TSC2 results in dysfunction of the tuberin-hamartin complex and impairment of the mammalian target of rapamycin (mTOR). Rapamycin has been utilized for years for organ transplant patients, but knowing of mTOR dysfunction in TSC lead to the successful use of rapamycin in individuals with TSC-related subependymal giant cell tumors and renal angiomyolipomas. Another mTOR inhibitor, everolimus, was recently approved by the FDA for use in these same TSC-related tumors. Even more exciting is the possibility that mTOR inhibitors improve other manifestations of tuberous sclerosis complex. Double blind clinical trials of mTOR inhibitors are difficult to perform because facial angiofibromas often dramatically improve after initiating an mTOR inhibitor. Some families also report far fewer epileptic seizures and improved cognition and behavior after starting these agents. If these observations are confirmed, then mTOR inhibitors will provide a specific disease-altering therapy rather than merely a treatment for its complications.

More complete understanding of the neurobiology of other conditions allows the creation of animal models in which we can develop testable hypotheses about pathogenesis and rational therapeutic targets. Recent advances also provide hope for mechanism-based therapy of fragile X syndrome, Down syndrome, and Rett syndrome. These disorders are associated with a high prevalence of autism, and targeting known genetic causes of autism could in turn lead to innovative treatment for autism due to other causes. 

This symposium should demonstrate that understanding the molecular mechanisms of genetic neurological diseases may lead to mechanism-based therapies. Clinical trials of such treatments are an increasingly realistic option for a growing number of genetic diseases. With the recently funded NeuroNext program designed to facilitate the rapid clinical application of basic scientific discoveries and with the growing number of disease-specific research consortiums, child neurologists are poised to lead the efforts to improve the lives of these children. What an exciting time to be a child neurologist!