Our translational research focuses on the diagnosis, treatment, and understanding of copper metabolism disorders, a recently expanded collection of human diseases that impact varied components of the central and peripheral nervous systems. Acquired as well as inherited forms of abnormal copper homeostasis are implicated in neurologic dysfunction. Menkes disease (MD), a prototypical genetic syndrome of defective copper transport, is characterized by low brain copper, infantile neurodegeneration, and premature death. MD is caused by mutations in an X-linked copper transporter gene, ATP7A. The occipital horn syndrome (OHS) is a milder allelic variant associated with leaky ATP7A splice junction mutations, in which autonomic dysfunction predominates. Recently, we identified several families with motor neuron disease resembling Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, that are caused by several novel missense mutations in the carboxyl half of ATP7A. These are mild loss-of- function defects that appear to affect intracellular trafficking of ATP7A. Thus, the phenotypic spectrum of ATP7A mutations has expanded;discovery of these new allelic variants indicates a previously unappreciated role for the ATP7A in motor neuron maintenance and function. Current treatment for MD is limited to subcutaneous copper injections and is effective in patients with mutant alleles that do not completely abrogate ATP7A function, and who are identified near birth (N Engl J Med 2008;358:605-614). For patients with complete loss-of-function mutations, however, copper delivered peripherally does not cross the blood-brain barrier efficiently, and alternative treatment approaches are needed. In our recent exploration of treatment alternatives, we rescued a mouse model of severe Menkes disease using combination brain-directed therapies: recombinant adeno-associated virus serotype 5 (AAV5) vector expressing a reduced size human ATP7A, plus copper. Neither treatment alone was effective, but combination therapy dramatically shifted the Kaplan-Meier survival curve, with 5 of 16 (31%) combination-treated mutants surviving beyond 110 days of age (p<0.0002). Combination-treated mo-br mice weighed more than untreated mo-br mice (5.2 g vs. 4.2 g at 9 days of age, p<0.02) and less than wild type controls (11.9 g vs. 15.1 grams at 27 days of age, p<0.01). The combination-treated survivors appear healthy, active, and fertile. The mechanisms underlying this pronounced synergistic effect help to illuminate the normal processes of copper transport in brain, and the role of ATP7A in neuronal and neuroglial cells. In addition, this advance may hold future clinical implications for Menkes disease patients with severe ATP7A mutations, as well as for patients with ATP7A-related motor neuron disease. The synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS) is highly effective in reversing neurogenic orthostatic hypotension and correcting neurochemical abnormalities in patients with autosomal recessive congenital absence of dopamine-beta-hydroxylase (DBH). L-DOPS is metabolized by the enzyme DOPA decarboxylase to produce norepinephrine, thus bypassing the DBH enzymatic defect. Individuals occipital horn syndrome (OHS), have partial deficiency of DBH, which is copper-dependent, and show distinctive neurochemical abnormalities and often symptoms of dysautonomia, such as syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction. As in patients with congenital absence of DBH, these problems in autonomic nervous system function seem potentially responsive to restoration of normal neurochemical levels. We hypothesize that L-DOPS treatment in OHS patients with dysautonomia will correct or improve blood neurochemical levels, and produce concurrent symptomatic improvement. A recently IRB-approved pilot study will test this hypothesis in six patients with dysautonomic symptoms, by providing L-DOPS treatment (5mg/kg/d po qd) and assessing the neurochemical response (in-hospital plasma catechol levels) and the longer-term effect on symptoms (out-of-hospital autonomic symptom questionnaire completed weekly by subject and/or parent), during an eight-week period while receiving the study drug.
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