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Published online before print January 23, 2008, doi:10.1212/01.wnl.0000295505.74234.d0)
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NEUROLOGY 2008;70:762-770
© 2008 American Academy of Neurology

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

C. La Morgia, MD, A. Achilli, PhD, L. Iommarini, PhD, P. Barboni, MD, M. Pala, BSc, A. Olivieri, BSc, C. Zanna, PhD, S. Vidoni, PhD, C. Tonon, MD, R. Lodi, MD, R. Vetrugno, MD, PhD, B. Mostacci, MD, R. Liguori, MD, R. Carroccia, BSc, P. Montagna, MD, M. Rugolo, PhD, A. Torroni, PhD and V. Carelli, MD, PhD

From Dipartimento di Scienze Neurologiche (C.L.M., L.I., R.V., B.M., R. Liguori, R.C., P.M., V.C.), Dipartimento di Biologia Evoluzionistica Sperimentale (C.Z., S.V., M.R.), and Dipartimento di Medicina Clinica e Biotecnologia Applicata (C.T., R. Lodi), Università di Bologna; Dipartimento di Genetica e Microbiologia (A.A., M.P., A.O., A.T.), Università di Pavia; and Centro di Oftalmologia Salus (P.B.), Bologna, Italy.

Address correspondence and reprint requests to Dr. Valerio Carelli, Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy valerio.carelli{at}unibo.it

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.

Abbreviations: ERG = electroretinogram; LHON = Leber hereditary optic neuropathy; MELAS = mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome; MERRF = myoclonic epilepsy and ragged-red fibers; MRS = magnetic resonance spectroscopy; mtDNA = mitochondrial DNA; OCT = optical coherence tomography; RFLP = restriction fragment length polymorphism; RNFL = retinal nerve fiber layer; SEPs = somatosensory evoked potentials; VEPs = visual evoked potentials.

Supplemental data at www.neurology.org

e-Pub ahead of print on January 23, 2008, at www.neurology.org.

Supported by the Fondazione Gino Galletti (V.C.), the Italian Ministry of Health (Ricerca finalizzata 2004) (V.C.), the Telethon-Italy (grant #GGP06233 to V.C. and A.G.), the Italian Ministry of the University (Progetti Ricerca Interesse Nazionale 2005) (A.T.), Compagnia di San Paolo (A.T.), and Fondazione Cariplo (A.T.).

Disclosure: The authors report no conflicts of interest.

Received May 3, 2007. Accepted in final form September 25, 2007.






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