C. La Morgia

Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus

Objective: To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON). Methods: Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle (31P) and cerebral (1H) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed. Results: All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. 31P-MRS was abnormal in five of six patients and 1H-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/cyt b variants was supported by amino acid conservation analysis. Conclusions: Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants.

Loss of temporal retinal nerve fibers in Parkinson disease: a mitochondrial pattern?

Background and purpose:  Optic nerve involvement is frequent in mitochondrial disease, and retinal abnormalities are described in Parkinson’s disease (PD).

Cigarette toxicity triggers Leber’s hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways

Leber’s hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that modulate LHON penetrance must take into account also the exposure to environmental triggers such as tobacco smoke.

Busulfan neurotoxicity and EEG abnormalities: a case report

Abstract.A 21-year-old woman with acute lymphoblastic leukemia underwent bone marrow transplantation (BMT). The conditioning regimen consisted of an association of busulfan (BU) and cyclophosphamide (Cy). The day after starting BU, she suffered a generalized tonic-clonic seizure. Electroencephalography (EEG) performed the day after the seizure showed diffuse polyspikes and spike-and-wave discharges. EEG on the following days showed persistent abnormalities (slowing of background activity intermixed with diffuse slow waves and isolated delta and theta bursts). These abnormalities persisted for about 20 days with complete normalization one month after the seizure. We suggest that BU is implicated in these abnormalities and emphasize the importance of EEG recording before and after bone marrow transplantation to disclose BU neurotoxicity.

EHMTI-0271. Refractory chronic daily headache and idiopathic intracranial hypertension: preliminary results of a prospective study

Results Among the 23 consecutive patients enrolled, 19 (13 F, 6 M; mean age 47.9 ± 12.3; mean BMI 26.1± 4.8) completed the study, 4 female patients dropped out. None of the 19 patients had papilledema. We found a TSS in 11 of 19 cases (58%): bilateral in 3 patients and unilateral in 8 cases. All of 19 cases displayed OP lower than 250 mmH2O (range 102-245) and normal CSF composition. We found a OP greater than 200 mmH2O only in four patients (1M, 3 F) (17%): two of them achieved an improvement of headache intensity and frequency after 12-18 ml CSF withdrawal; one of them had bilateral TSS.