Abstract
Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal Charcot- Marie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination.
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Amato AA, Barohn RJ (1996) Hereditary neuropathy with liability to pressure palsies: assocation with central nervous system demyelination. Muscle Nerve 19:770–773
Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacin M, Vidal H, Rivera F, Brand M, Zorzano A (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 278:17190–17197
Baloh RH, Schmidt RE, Pestronk A, Milbrandt J (2007) Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci 27:422–430
Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD (2002) N-acetylaspartate is an axon-specific marker of mature white matter in vivo: A biochemical and immunohistochemical study on the rat optic nerve. Ann Neurol 51:51–58
Brand A, Richter-Landsberg C, Leibfritz D (1993) Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 15:289–298
Brockmann K, Dechent P, Bönnemann C, Schreiber G, Frahm J, Hanefeld F (2007) Quantitative proton MRS of cerebral metabolites in Laminin α2 chain deficiency. Brain & Development 29:357–364
Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200
Cho HJ, Sung DH, Kim BJ, Ki CS (2007) Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2. Clin Genet 71:267–272
Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH, Kim WK, Seo BC, Kim SH, Son IH, Kim SM, Sunwoo IN, Choi BO (2006) Early onset severe and late-onset mild Charcot- Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 129:2103–2118
Dackovic J, Rakocevic-Stojanovic V, Pavlovic S, Zamurovic N, Dragasevic N, Romac S, Apostolski S (2001) Hereditary neuropathy with liability to pressure palsies associated with central nervous system myelin lesions. Eur J Neurol 8:689–692
Engelfried K, Vorgerd M, Hagedorn M, Haas G, Gilles J, Epplen JT, Meins M (2006) Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC Med Genet 7:53
Frahm J, Hanefeld F (1996) Localized proton magnetic resonance spectroscopy of cerebral metabolites. Neuropediatrics 27:64–69
Frahm J, Michaelis T, Merboldt KD, Bruhn H, Gyngell ML, Hänicke W (1990) Improvements in localized proton NMR spectroscopy of human brain. Water suppression, short echo times, and 1 mL resolution. J Magn Reson 90:464–473
Frith JA, McLeod JG, Nicholson GA, Yang F (1994) Peroneal muscular atrophy with pyramidal tract features (hereditary motor and sensory neuropathy type V): a clinical, neurophysiological, and pathological study of a large kindred. J Neurol Neurosurg Psychiatry 57:1343–1346
Griffin JL, Mann CJ, Scott J, Shoulders CC, Nicholson JK (2001) Choline containing metabolites during cell transfection: an insight into magnetic resonance spectroscopy detectable changes. FEBS Lett 509:263–266
Hales KG, Fuller MT (1997) Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90:121–129
Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD (2003) Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation. Arch Neurol 60:605–609
Harding AE, Thomas PK (1984) Peroneal muscular atrophy with pyramidal features. J Neurol Neurosurg Psychiatry 47:168–172
Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K (2005) Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 116:23–27
Lawson VH, Graham BV, Flanigan KM (2005) Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 65:197–204
Lee MJ, Nelson I, Houlden H, Sweeney MG, Hilton-Jones D, Blake J, Wood NW, Reilly MM (2002) Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry 73:304–306
Natt O, Bezkorovaynyy V, Michaelis T, Frahm J (2005) Use of phased array coils for a determination of absolute metabolite concentrations. Magn Reson Med 53:3–8
Panas M, Karadimas C, Avramopoulos D, Vassilopoulos D (1998) Central nervous system involvement in four patients with Charcot-Marie-Tooth disease with connexin 32 extracellular mutations. J Neurol Neurosurg Psychiatry 65:947–948
Paulson HL, Garbern JY, Hoban TF, Krajewski KM, Lewis RA, Fischbeck KH, Grossman RI, Lenkinski R, Kamholz JA, Shy ME (2002) Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease. Ann Neurol 52:429–434
Pich S, Bach D, Briones P, Liesa M, Camps M, Testar X, Palacin M, Zorzano A (2005) The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet 14:1405–1415
Provencher SW (1993) Estimation of metabolite concentration from localized in vivo proton NMR spectra. Magn Reson Med 30:672−679
Rieseberg S, Merboldt KD, Kuntzel M, Frahm J (2005) Diffusion tensor imaging using partial Fourier STEAM MRI with projection onto convex subsets reconstruction. Magn Reson Med 54:486–490
Saifi GM, Szigeti K, Snipes GJ, Garcia CA, Lupski JR (2003) Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies. J Investig Med 51:261–283
Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114:867–864
Urenjak J, Williams SR, Gadian DG, Noble M (1993) Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 13:981–989
Verhoeven K, Claeys KG, Zuchner S, Schroder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, Goemans N, Auer-Grumbach M, Robberecht W, Milic Rasic V, Nevo Y, Tournev I, Guergueltcheva V, Roelens F, Vieregge P, Vinci P, Moreno MT, Christen HJ, Shy ME, Lupski JR, Vance JM, De Jonghe P, Timmerman V (2006) MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 129:2093–2102
Vucic S, Kennerson M, Zhu D, Miedema E, Kok C, Nicholson GA (2003) CMT with pyramidal features. Charcot-Marie-Tooth. Neurology 60:696–699
Zhu D, Kennerson ML, Walizada G, Zuchner S, Vance JM, Nicholson GA (2005) Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology 65:496–497
Zuchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J, Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T, Timmerman V, Shy M, Vance JM (2006) Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 59:276–281
Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak- Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451
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Brockmann, K., Dreha-Kulaczewski, S., Dechent, P. et al. Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations. J Neurol 255, 1049–1058 (2008). https://doi.org/10.1007/s00415-008-0847-1
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DOI: https://doi.org/10.1007/s00415-008-0847-1