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Neurometabolic Disorders - Treatment Update

Neurometabolic Disorders - Treatment Update



This symposium will provide an update of the current optimal standards of care in the longterm management and treatment approaches for different groups of neurometabolic disorders including mitochondrial disorders, fatty acid oxidation defects, the neuronal ceroid lipofuscinoses and the lysosomal storage disorders (highlighting the mucopolysaccharidoses). It will also highlight current promising clinical trials for potential international research collaborations and existing research networks.


1. To acquire current optimal standards of care in the longterm management and treatment of mitochondrial disorders, fatty acid oxidation defects, the neuronal ceroid lipofuscinoses and selected lysosomal storage disorders.
2. To promote international research collaborations in evaluating treatment efficacy through entry into current prospective multi-centre clinical trials.
3. To acquire knowledge of existing clinical task force and research networks for future initiatives and collaborations.


1) Treatment update in fatty acid oxidation disorders (Ingrid Tein, Canada)
2) Treatment update in neuronal ceroid lipofuscinoses (Rose-Mary Boustany, Lebanon)
3) Treatment update in mitochondrial disorders (Salvatore DiMauro, USA)
4) Treatment update in lysosomal storage disorders (Linda DeMeirleir, Belgium)

1) Treatment update in fatty acid oxidation disorders (Ingrid Tein, Canada)
Ingrid Tein MD
Director, Neurometabolic Clinic and Research Laboratory, Division of Neurology
Associate Professor of Pediatrics, Laboratory Medicine and Pathobiology
Senior Associate Scientist, Genetics and Genome Biology Program
The Research Institute The Hospital for Sick Children
University of Toronto, Toronto, Ont.

Defects in FAO are important because they are potentially rapidly fatal and a source of major morbidity encompassing a spectrum of clinical disorders including recurrent myoglobinuria, progressive lipid storage myopathy, neuropathy, pigmentary retinopathy, progressive cardiomyopathy, recurrent hypoglycemic hypoketotic encephalopathy or Reye-like syndrome, seizures, and cognitive delays. As all are autosomal recessive, there is a frequent family history of SIDS in siblings. Early recognition and prompt institution of therapy and preventative measures, and in certain cases specific therapy, may be life-saving, significantly decreasing long-term morbidity, particularly with respect to CNS sequelae.

There are at least 21 recognized enzyme defects. Mechanistically, tissue dysfunction arises from insufficient ATP production, deficient hepatic ketogenesis and lipid storage. Increased short- or medium-chain fatty acids and their dicarboxylic metabolites may also lead to secondary impairment of gluconeogenesis, ß-oxidation, and the citric acid cycle leading to further decreases in cellular ATP production. Excessive long-chain fatty acids and long-chain acylcarnitines may have arrhythmogenic and membranotoxic effects.

General treatment approaches include strict avoidance of precipitating factors such as prolonged fasting (age-specific guidelines), prolonged aerobic exercise (>30 min), stress, and cold exposure (shivering thermogenesis). In the event of progressive lethargy, obtundation or vomiting, the child should be taken immediately to the emergency for intravenous glucose (8-10 mg/kg/min). In general, it is advisable to institute a high-carbohydrate, low-fat diet with frequent feedings throughout the day, commensurate with the nutritional needs of the child given their age. Augmentation of the diet with essential fatty acids reduces the risk of EFA deficiency; flaxseed, canola, walnut or safflower oils can be used for this purpose.

In HMG-CoA lyase deficiency, a high-carbohydrate, low-fat, low-protein diet with leucine restriction should be implemented. To delay the onset of fasting overnight in children who have early morning hypoglycemia, nightly uncooked corn starch will prolong the postabsorptive state and delay fasting. Specific measures include the following.

The essential indication for carnitine therapy is the OCTN2 defect, characterized by carnitine-responsive cardiomyopathy, myopathy, recurrent coma and very low plasma and tissue concentrations of carnitine (<5% of normal) in which life-long high-dose oral L-carnitine is life-saving and reverses the pathology. In the intramitochondrial ß-oxidation defects with secondary carnitine deficiency, the results of carnitine therapy have been variable. Further, carnitine administration may have deleterious arrhythmogenic and membranotoxic effects in long-chain FAO disorders which should be avoided.

Certain cases of multiple acyl-CoA dehydrogenase deficiency (GAII) respond to riboflavin supplementation. Medium-chain triglyceride oil as a nutritional source may be useful in long-chain FAO disorders. Oral prednisone led to dramatic reversal of limb-girdle myopathy and marked reduction in episodic myoglobinuria in a boy with myoneuropathic LCHAD deficiency. Docosahexaenoic acid leads to marked clinical and electrophysiological recovery of the progressive peripheral sensorimotor axonopathy in myoneuropathic LCHAD deficiency and improvement of the visual dysfunction arising from the pigmentary retinopathy.

Triheptanoin (anaplerotic odd-chain triglyceride) may be useful in long-chain defects. PPAR agonists (e.g. bezafibrate) increase palmitate oxidation in mild CPT II and VLCAD deficient fibroblasts and is undergoing clinical trials. Vulnerability to oxidative stress has been demonstrated in SCAD and TFP/LCHAD deficient fibroblasts with rescue by antioxidants and PPAR agonists. Thermolability and protein misfolding have been implicated in SCAD deficiency, underlining the critical importance of early aggressive treatment of fever and infection and raise the question of future chaperone therapy.

Early detection and interventional therapy of FAO disorders through serum acylcarnitine newborn screening programs has had a significant impact on morbidity and mortality.

2) Treatment update in neuronal ceroid lipofuscinoses (Rose-Mary Boustany, Lebanon)

Rose-Mary Boustany, MD
Professor of Pediatrics and Adolescent Medicine
Professor of Biochemistry
Director, Neurogenetics Program and AUBMC Special Kids Clinic
Division Chief, Pediatric Neurology
American University of Beirut Medical Center
Adjunct Professor of Pediatricsic
Duke University Medical Center

The NCLs are neurodegenerative disorders with neurocognitive decline/seizures/blindness and early death. Cell-biological features include dysregulated lipid trafficking/apoptosis/autophagy and prolonged inflammation, endoplasmic reticulum/cytosol calcium imbalance and cellular stress. These provide novel targets for therapy.

Irreversible neuronal death/brain tissue loss/scarring are under way before diagnosis, and there are problems of drug delivery. Intracerebral/intrathecal strategies have succeeded in animal models, but are invasive.  In disorders even caused by mutations in soluble enzymes TPP-1/PPT-1, storage is secondary to altered membrane turnover, apoptosis and autophagy.

ERT/stem-cell therapies successful in animal models are now under development for patients with NCL. CLN3 disease caused by a membrane protein defect is not amenable to protein/gene/stem-cell therapies. Hypothesis-driven therapeutic approaches include antiapoptotic agents (flupirtine maleate), anti-inflammatory strategies (mycophenolate mofetil), and potential use of GalCer to correct lipid raft stoichiometry. Of therapies for CLN3 disease, only mycophenolate mofetil is in trials.

Apoptosis/inflammation are implicated in CLN3/CLN5/CLN6/CLN8 diseases and are feasible therapies for NCLs. Therapeutic suggestions include use of agents that upregulate TPP-1 in CLN2 mouse brain. Approaches for disease due to premature stop-codons is inhibition of nonsense-mediated decay of mRNA tran¬scripts.  Strategies to modify the course of NCLs are imperfect. Screening of at-risk popu¬lations/newborns/prenatal and pre-implantation diagnosis remain the best remedies to lessen the NCL burden on society.

In a perfect world universal screening, accurate/ accessible/affordable bioinformatic analysis of personalized genomic testing on a global scale would exist leading to a universe ‘freer’ of genetic diseases.  For now, we aim for timely diagnosis, and implementation of emerging therapies.