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

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

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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 ((31)P) and cerebral ((1)H) 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. (31)P-MRS was abnormal in five of six patients and (1)H-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.

LanguageEnglish
Pages762-770
Number of pages9
JournalNeurology
Volume70
Issue number10
Early online date23 Jan 2008
DOIs
Publication statusPublished - 8 Apr 2008
Externally publishedYes

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Leber's Hereditary Optic Atrophy
Myoclonus
Mitochondrial DNA
Recurrence
Electroencephalography
Lactic Acid
Magnetic Resonance Spectroscopy
Muscles
Sequence Analysis
Comorbidity
Fibroblasts
Biopsy
Muscle Cramp
Migraine Disorders
Galactose
Energy Metabolism
Psychiatry
Reflex
Adenosine Triphosphate
Exercise

Cite this

Morgia, C. L., Achilli, A., Iommarini, L., Barboni, P., Pala, M., Olivieri, A., ... Carelli, V. (2008). Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. Neurology, 70(10), 762-770. https://doi.org/10.1212/01.wnl.0000295505.74234.d0
Morgia, C. L. ; Achilli, A. ; Iommarini, L. ; Barboni, P. ; Pala, M. ; Olivieri, A. ; Zanna, C. ; Vidoni, S. ; Tonon, C. ; Lodi, R. ; Vetrugno, R. ; Mostacci, B. ; Liguori, R. ; Carroccia, R. ; Montagna, P. ; Rugolo, M. ; Torroni, A. ; Carelli, V. / Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. In: Neurology. 2008 ; Vol. 70, No. 10. pp. 762-770.
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abstract = "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 ((31)P) and cerebral ((1)H) 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. (31)P-MRS was abnormal in five of six patients and (1)H-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.",
author = "Morgia, {C. L.} and A. Achilli and L. Iommarini and P. Barboni and M. Pala and A. Olivieri and C. Zanna and S. Vidoni and C. Tonon and R. Lodi and R. Vetrugno and B. Mostacci and R. Liguori and R. Carroccia and P. Montagna and M. Rugolo and A. Torroni and V. Carelli",
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Morgia, CL, Achilli, A, Iommarini, L, Barboni, P, Pala, M, Olivieri, A, Zanna, C, Vidoni, S, Tonon, C, Lodi, R, Vetrugno, R, Mostacci, B, Liguori, R, Carroccia, R, Montagna, P, Rugolo, M, Torroni, A & Carelli, V 2008, 'Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus.', Neurology, vol. 70, no. 10, pp. 762-770. https://doi.org/10.1212/01.wnl.0000295505.74234.d0

Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. / Morgia, C. L.; Achilli, A.; Iommarini, L.; Barboni, P.; Pala, M.; Olivieri, A.; Zanna, C.; Vidoni, S.; Tonon, C.; Lodi, R.; Vetrugno, R.; Mostacci, B.; Liguori, R.; Carroccia, R.; Montagna, P.; Rugolo, M.; Torroni, A.; Carelli, V.

In: Neurology, Vol. 70, No. 10, 08.04.2008, p. 762-770.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus.

AU - Morgia, C. L.

AU - Achilli, A.

AU - Iommarini, L.

AU - Barboni, P.

AU - Pala, M.

AU - Olivieri, A.

AU - Zanna, C.

AU - Vidoni, S.

AU - Tonon, C.

AU - Lodi, R.

AU - Vetrugno, R.

AU - Mostacci, B.

AU - Liguori, R.

AU - Carroccia, R.

AU - Montagna, P.

AU - Rugolo, M.

AU - Torroni, A.

AU - Carelli, V.

PY - 2008/4/8

Y1 - 2008/4/8

N2 - 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 ((31)P) and cerebral ((1)H) 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. (31)P-MRS was abnormal in five of six patients and (1)H-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.

AB - 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 ((31)P) and cerebral ((1)H) 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. (31)P-MRS was abnormal in five of six patients and (1)H-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.

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U2 - 10.1212/01.wnl.0000295505.74234.d0

DO - 10.1212/01.wnl.0000295505.74234.d0

M3 - Article

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SP - 762

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JO - Neurology

T2 - Neurology

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