Case of the Month
Episodic weakness and Charcot–marie–tooth disease due to a mitochondrial MT-ATP6 mutation
Francis B. Panosyan MD, PhD,
Rabi Tawil MD,
David N. Herrmann MBBCh,
Corresponding Author
Francis B. Panosyan MD, PhD
Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, New York, 14642 USA
Correspondence to: F.B. Panosyan; e-mail: [email protected]Search for more papers by this authorRabi Tawil MD
Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, New York, 14642 USA
Search for more papers by this authorDavid N. Herrmann MBBCh
Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, New York, 14642 USA
Search for more papers by this authorFrancis B. Panosyan MD, PhD,
Rabi Tawil MD,
David N. Herrmann MBBCh,
Corresponding Author
Francis B. Panosyan MD, PhD
Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, New York, 14642 USA
Correspondence to: F.B. Panosyan; e-mail: [email protected]Search for more papers by this authorRabi Tawil MD
Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, New York, 14642 USA
Search for more papers by this authorDavid N. Herrmann MBBCh
Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, New York, 14642 USA
Search for more papers by this authorABSTRACT
Introduction
Episodic muscle weakness is the hallmark of a heterogeneous group of disorders known as periodic paralysis. A majority are due to single nucleotide mutations causing membrane depolarization.
Methods
We report 2 family members with chronic, slowly progressive, distal axonal neuropathy, or Charcot–Marie–Tooth disease type 2 (CMT2) and episodic weakness resembling periodic paralysis.
Results
Next generation sequencing (NGS) identified a mitochondrial MT-ATP6 mutation m.9185T>C (p.Leu220Pro) in both patients, consistent with a previous report of an association with this phenotype. The episodic weakness has been responsive to acetazolamide therapy for a few decades. By contrast, the underlying axonal neuropathy is quite progressive despite treatment with acetazolamide.
Conclusions
Mitochondrial DNA mutations should be considered in patients with a history of episodic weakness and axonal inherited neuropathy (CMT2). The episodic weakness is responsive to acetazolamide therapy, and electrophysiological testing for periodic paralysis with a long exercise protocol is negative in these cases. Muscle Nerve 55: 922–927, 2017
REFERENCES
- 1 Childs AM, Hutchin T, Pysden K, Highet L, Bamford J, Livingston J, et al. Variable phenotype including Leigh syndrome with a 9185T>C mutation in the MTATP6 gene. Neuropediatrics 2007; 38: 313–316.
- 2 Castagna AE, Addis J, McInnes RR, Clarke JTR, Ashby P, Blaser S, et al. Late onset Leigh syndrome and ataxia due to a T to C mutation at bp 9,185 of mitochondrial DNA. Am J Med Genet A 2007; 143A: 808–816.
- 3 Pfeffer G, Blakely EL, Alston CL, Hassani A, Boggild M, Horvath R, et al. Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations. J Neurol Neurosurg Psychiatry 2012; 83: 883–886.
- 4 Brum M, Semedo C, Guerreiro R, Pinto Marques J. Motor neuron syndrome as a new phenotypic manifestation of mutation 9185T>C in gene MTATP6. Case Rep Neurol Med 2014; 2014: 701761–701761.
- 5 Pitceathly RDS, Murphy SM, Cottenie E, Chalasani A, Sweeney MG, Woodward C, et al. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology 2012; 79: 1145–1154.
- 6 Aure K, Dubourg O, Jardel C, Clarysse L, Sternberg D, Fournier E, et al. Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations. Neurology 2013; 81: 1810–1818.
- 7 Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain 2006; 129: 8–17.
- 8 Cannon SC. Pathomechanisms in channelopathies of skeletal muscle and brain. Ann Rev Neurosci 2006; 29: 387–415.
- 9 Sansone V, Meola G, Links TP, Panzeri M, Rose MR. Treatment for periodic paralysis. Cochrane Database Syst Rev 2008;Jan 23(1): CD005045.
- 10 Sansone VA, Burge J, McDermott MP, Smith PC, Herr B, Tawil R, et al. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology 2016; 86: 1408–1416.
- 11 Saporta ASD, Sottile SL, Miller LJ, Feely SME, Siskind CE, Shy ME. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 2011; 69: 22–33.
- 12 Murphy SM, Laura M, Fawcett K, Pandraud A, Liu Y-T, Davidson GL, et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012; 83: 706–710.
- 13 Braathen GJ. Genetic epidemiology of Charcot-Marie-Tooth disease. Acta Neurol Scand Suppl 2012;( 193): iv–22.
- 14 Rudnik-Schoneborn S, Tolle D, Senderek J, Eggermann K, Elbracht M, Kornak U, et al. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet 2016; 89: 34–43.
- 15 Miller TM, da Silva MRD, Miller HA, Kwiecinski H, Mendell JR, Tawil R, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology 2004; 63: 1647–1655.
- 16 Tengan CH, Antunes AC, Gabbai AA, Manzano GM. The exercise test as a monitor of disease status in hypokalaemic periodic paralysis. J Neurol Neurosurg Psychiatry 2004; 75: 497–499.
- 17 Cleland JC, Tawil R. Post-exercise increment in compound muscle action potential amplitude in hyperkalemic periodic paralysis. Clin Neurophysiol 2014; 125: 2134–2135.
- 18 Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta Bioenerg 2004; 1659: 115–120.
- 19 Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008; 63: 35–39.
- 20 Houstek J, Pickova A, Vojtiskova A, Mracek T, Pecina P, Jesina P. Mitochondrial diseases and genetic defects of ATP synthase. Bioch Biophys Acta Bioenerg 2006; 1757: 1400–1405.
- 21 Cain BD, Simoni RD. Impaired proton conductivity resulting from mutations in the a-subunit of F1F0 ATPase in Escherichia-coli. J Biol Chem 1986; 261: 43–50.
- 22 Carrozzo R, Tessa A, Vazquez-Memije ME, Piemonte F, Patrono C, Malandrini A, et al. The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome. Neurology 2001; 56: 687–690.
- 23 Kucharczyk R, Zick M, Bietenhader M, Rak M, Couplan E, Blondel M, et al. Mitochondrial ATP synthase disorders: molecular mechanisms and the quest for curative therapeutic approaches. Biochim Biophy Acta Mol Cell Res 2009; 1793: 186–199.
- 24 Wittig I, Schaegger H. Structural organization of mitochondrial ATP synthase. Biochim Biophys Acta Bioenerg 2008; 1777: 592–598.
- 25 Wittig I, Meyer B, Heide H, Steger M, Bleier L, Wumaier Z, et al. Assembly and oligomerization of human ATP synthase lacking mitochondrial subunits a and A6L. Biochim Biophys Acta Bioenerg 2010; 1797: 1004–1011.
- 26 Strauss M, Hofhaus G, Schroeder RR, Kuehlbrandt W. Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J 2008; 27: 1154–1160.
- 27 Lopez-Gallardo E, Solano A, Herrero-Martin MD, Martinez-Romero I, Castano-Perez MD, Andreu AL, et al. NARP syndrome in a patient harbouring an insertion in the MT-ATP6 gene that results in a truncated protein. J Med Genet 2009; 46: 64–67.
- 28 Burrage LC, Tang S, Wang J, Donti TR, Walkiewicz M, Luchak JM, et al. Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) plus associated with a novel de novo mutation (m.8969G>A) in the mitochondrial encoded ATP6 gene. Mol Genet Metabol 2014; 113: 207–212.
- 29 Duno M, Wibrand F, Baggesen K, Rosenberg T, Kjaer N, Frederiksen AL. A novel mitochondrial mutation m.8989G>C associated with neuropathy, ataxia, retinitis pigmentosa—the NARP syndrome. Gene 2013; 515: 372–375.
- 30 Holt IJ, Harding AE, Petty RKH, Morganhughes JA. A new mitochondrial disease associated with mitochondrial-DNA heteroplasmy. Am J Hum Genet 1990; 46: 428–433.
- 31 Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JTR, Wherret J, Smith C, et al. Heteroplasmic mtDNA mutation (T-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 1992; 50: 852–858.
- 32 Takahashi S, Makita Y, Oki J, Miyamoto A, Yanagawa J, Naito E, et al. De novo mtDNA nt 8993 (T→G) mutation resulting in Leigh syndrome. Am J Hum Genet 1998; 62: 717–719.
- 33 De Vries DD, van Engelen BGM, Gabreels FJM, Ruitenbeek W, van Oost BA. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol 1993; 34: 410–412.
- 34 Rantamaki MT, Soini HK, Finnila SM, Majamaa K, Udd B. Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T→C mutation. Ann Neurol 2005; 58: 337–340.
- 35 Craig K, Elliott HR, Keers SM, Lambert C, Pyle A, Graves TD, et al. Episodic ataxia and hemiplegia caused by the 8993T→C mitochondrial DNA mutation. J Med Genet 2007; 44: 797–799.
- 36 Lamminen T, Majander A, Juvonen V, Wikstrom M, Aula P, Nikoskelainen E, et al. A mitochondrial mutation at nt-9101 in the ATP synthase-6 gene associated with deficient oxidative-phosphorylation in a family with Leber hereditary optic neuroretinopathy. Am J Hum Genet 1995; 56: 1238–1240.
- 37 Thyagarajan D, Shanske S, Vazquezmemije M, Devivo D, Dimauro S. A novel mitochondrial ATPase 6-point mutation in familial bilateral striatal necrosis. Ann Neurol 1995; 38: 468–472.
- 38 Campos Y, Martin MA, Rubio JC, Solana LG, Garcia-Benayas C, Terradas JL, et al. Leigh syndrome associated with the T9176C mutation in the ATPase 6 gene of mitochondrial DNA. Neurology 1997; 49: 595–597.
- 39 Dionisi-Vici C, Seneca S, Zeviani M, Fariello G, Rimoldi M, Bertini E, et al. Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene. J Inher Metab Dis 1998; 21: 2–8.
Citing Literature
