Mitochondrial (mt)DNA point mutations may produce severe clinical manifestations. Multiple organs may be vulnerable but none more than the nervous system. We are engaged in a long-term multi-faceted mutation. We hypothesize that maternally-inherited mtDNA point mutations cause chronic progressive encephalopathies and mental retardation. To date, we have studied 17 families with the 32143 mutation, 2 families with the 8344 mutation, and 1 family each with the 3271, 8993 and the 5537i mutation (Santorelli et al 1997). In the aggregate, 90 research subjects have been admitted to the Irving Center for Clinical Research-60 from families with the 3243 mutation, 15 from families with the 8344 mutation, 3 from families with the 8993 mutation, 8 with the 5377i mutation, and 4 with the 3271 mutation. These 90 subprojects represent probands (22), paternal controls (16) and asymptomatic/oligosymptomatic maternal relatives (52). We plan to follow this patient cohort for the next five years, and to admit additional patients with the 3243 and the 8344 mutation. Restricting entry to these two relative common mutations will allow us to address specific questions regarding pathophysiology, treatment, and prognosis in a more genotypically homogeneous population. Each family undergoes a comprehensive clinical and genetic-metabolic staging of their medical condition (Specific Aim #1), and responds to a questionnaire that is designed to evaluate the natural history of mtDNA-associated encephalomyopathies (Specific Aim #2). Functional MRI (BOLD effect) and MRSI studies (brain lactate concentrations) will be registered to assess the ability of a brain region to sustain mental work (Specific Aim #3). These patients will be selected according to their ability to participate in these standardized procedures. Selected patients with the """"""""MELAS"""""""" 3243 point mutation and elevated brain lactate will receive dichloroacetate or placebo in a randomized, blinded, 2-treatment controlled clinical trial (Specific Aim #4). This trial will incorporate a 3- period crossover study design and will focus on patients with the 3243 mutation-known to be associated with high brain lactate levels and a more devastating, truncated clinical course (Sano et al 1998; Kaufmann et al 1999).
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