Faculty Bibliography

BACKGROUND:Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome can present management challenges. Refractory seizures and stroke-like episodes leading to disability are common. PATIENT/METHODS:We analyzed the clinical, electrophysiologic, and radiologic data of a 22-year-old woman with multiple episodes of generalized and focal status epilepticus and migratory cortical stroke-like lesions who underwent muscle biopsy for mitochondrial genome sequencing. RESULTS:Although initial mitochondrial genetic testing was negative, muscle biopsy demonstrated a mitochondrial DNA disease-causing mutation (m.3260A > G). New antiepileptic medications were added with each episode of focal status epilepticus with only temporary improvement, until a modified ketogenic diet and magnesium were introduced, leading to seizure freedom despite development of a new stroke-like lesion, and subsequent decrease in frequency of stroke-like episodes. We propose a metabolic model in which the ketogenic diet may lead to improvement of the function of respiratory chain complexes. CONCLUSIONS:The ketogenic diet may lead to improvement of mitochondrial dysfunction in MELAS, which in turn may promote better seizure control and less frequent stroke-like episodes.

The homeodomain transcription factor Pitx3 is critical for the survival of midbrain dopaminergic (mDA) neurons. Pitx3-deficient mice exhibit severe but selective developmental loss of mDA neurons, with accompanying locomotor deficits resembling those seen in Parkinson's disease (PD) models. Here, we identify specific mDA cell subpopulations that are consistently spared in adult Pitx3-hypomorphic (aphakia) mice, demonstrating that Pitx3 is not indiscriminately required by all mDA neurons for their survival. In aphakia mice, virtually all surviving mDA neurons in the substantia nigra (SN) and the majority of neurons in the adjacent ventral tegmental area (VTA) also express calbindin-D28k, a calcium-binding protein previously associated with resistance to injury in PD and in animal models. Cell-mapping studies in wild-type mice revealed that Pitx3 is primarily expressed in the ventral SN, a region particularly susceptible to MPTP and other dopaminergic neurotoxins. Furthermore, Pitx3-expressing SN cells are preferentially lost following MPTP treatment. Finally, SN mDA neurons in Pitx3 hemizygous mice show increased sensitivity when exposed to MPTP. Thus, SN mDA neurons are represented by at least two distinct subpopulations including MPTP-resistant Pitx3-autonomous, calbindin-positive neurons, and calbindin-negative Pitx-3-dependent cells that display elevated vulnerability to toxic injury, and probably correspond to the subpopulation that degenerates in PD. Impairment of Pitx3-dependent pathways therefore increases vulnerability of mDA neurons to toxic injury. Together, these data suggest a novel link between Pitx3 function and the selective pattern of mDA cell loss observed in PD.