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Download Title: A novel MFN2 mutation causing Charcot-Marie
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Case report A novel MFN2 mutation causing Charcot-Marie-Tooth type 2A disease in a Chinese family CHING Chor Kwan1 (MSc, MBChB), LAU Kwok Kwong2 (FRCP, FHKAM (Medicine)), YU Kwok Wai1 (BSc), CHAN Yan Wo Albert1 (MD, FHKAM(Pathology)) and MAK Miu Chloe1 (PhD, FHKAM(Pathology)) 1 Department of Pathology, Princess Margaret Hospital, Hong Kong, China 2 Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China *Correspondence to: Dr MAK Miu Chloe, Department of Pathology, Princess Margaret Hospital, Hong Kong, China Tel: (852)29901882 Fax: (852)29901883 Email: [email protected] Keywords: Charcot-Marie-Tooth type 2A; MFN2; Hong Kong Chinese Word Count: 1680 (text) Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathies, comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progressive distal weakness, muscle atrophy, distal sensory loss and loss of deep tendon reflexes. Following electrophysiological criteria, CMT is divided into two main forms: the primarily demyelinating neuropathy CMT1 with severely decreased nerve conduction velocity (NCV) (<38 m/s), and CMT2, the primarily axonal form with normal or slightly reduced NCV (>38 m/s) but decreased amplitudes.1 CMT2A, an autosomal dominant disease caused by mitofusin 2 gene (MFN2) mutations, is the most common type of CMT2, accounting for up to 33% of familial CMT2 cases.2 We report a patient with clinical diagnosis of CMT2 caused by a novel MFN2 mutation. To our knowledge, this is the first case of genetically confirmed CMT2A in Chinese. CASE REPORT The patient is a 31-year-old Hong Kong Chinese woman who first presented with steppage gait at 9 years old. She developed progressive distal muscle weakness and atrophy in lower limbs and upper limbs. Neurological examination at the age of 31 years revealed atrophy of distal lower and upper limbs muscles, severe weakness of distal lower limbs, and mild paresis over proximal lower limbs and distal upper limbs. She had impaired sensation to pinprick up to the knees, and the sensation was nearly absent from ankles downward. There was no sensory disturbance in upper limbs. Her proprioception and vibration sensation was normal. Ankle jerks were absent, and deep tendon reflexes of the upper extremities were also diminished. Other clinical features, such as optic atrophy, hearing loss, or pyramidal signs, were not found. Laboratory tests, including vitamin B12 level, were all unremarkable. Visual evoked potentials which tested the intracerebral visual pathway were normal. Nerve conduction studies showed low compound muscle action potential and preserved motor NCV in median and ulnar nerves. Sural sensory nerve action potential was absent on left side and decreased on right side. The compound muscle action potential of peroneal and tibial nerves was not demonstrable. These findings were compatible with those of axonal sensorimotor peripheral neuropathy. In view of the typical clinical and electrophysiological features and the early age of onset, CMT2 was suspected in the patient. Molecular genetic studies were performed after obtaining informed consent of the patient. Genomic DNA was extracted from peripheral blood samples. The 19 coding exons and the flanking introns of the MFN2 gene were amplified by polymerase chain reaction. Direct sequence analysis of the MFN2 gene revealed a novel heterozygous missense mutation, MFN2 NM_014874.2:c.828G>C (p.Gln276His), in the patient (Figure 1). The novel mutation was not found in 300 chromosomes from healthy controls using real-time amplification refractory mutation system polymerase chain reaction (Figure 2). Primer sequences and protocols are available upon request. The amino acid substitution was predicted to affect protein function using the algorithm tool SIFT (Sorting Intolerant From Tolerant). The amino acid glutamine at position 276 is also conserved among different species. Hence, the mutation is conceivably disease causing. The patient initially did not recall any family history of neuropathy. Family screening was performed for her parents after obtaining informed consent. Her mother was surprisingly found to carry the same heterozygous mutation. She enjoyed good past health. She only described recent onset mild distal lower limb weakness, which was managed as osteoarthritis by a general practitioner. After the mutation detection in the mother, electrophysiological study was performed and was normal. On further inquiry, it was noted that the proband’s deceased maternal grandfather also had a history of limping gait but the age of onset was unclear. The proband’s five siblings were asymptomatic and were not available for medical consultation and genetic testing at the time of writing. Her two minor children were completely asymptomatic. Presymptomatic genetic analysis was not recommended by us for her children after genetic counseling because of their young age and the lack of curative therapy for CMT2A. DISCUSSION CMT is one of the most common inherited neuromuscular disorders, with a prevalence of about 1 in 2500.3 Today, at least 36 loci and 28 genes have been linked to CMT.3 The demyelinating CMT1 is the most common form, and among this group, about 70% of the cases are due to CMT1A caused by duplication of the PMP22 gene; the X-linked CMTX associated with GJB1/Cx32 mutations with either demyelinating or axonal phenotype accounts for about 12% of all CMT cases.3 The axonal CMT2 is very genetically heterogeneous, and there are more than 10 subtypes. CMT2A associated with MFN2 mutations accounts for about one-third of CMT2 cases.3 In addition to the classical demyelinating and axonal CMT, there are also autosomal dominant intermediate CMT (DI-CMT) with NCV overlapped those of CMT1 and CMT2 (NCV 25 – 45 m/s). Two genes and one additional locus have been identified for this group. To further complicate the picture, mutations in a few genes can cause both demyelinating and axonal neuropathies with NCV ranged from severely reduced to normal levels. For example, mutations in the MPZ, NEFL, and GDAP1 genes, which are related to CMT1B, CMT1F, and CMT4A respectively, can also give rise to an axonal phenotype with normal or slightly decreased NCV. Besides, NCV of X-linked CMT affected females caused by GJB1/Cx32 mutations are often within the CMT2 range. What’s more, the distinction between CMT and either distal hereditary motor neuropathies or hereditary sensory and autonomic neuropathies may not be always straight forward when either motor or sensory loss predominates. Initially CMT2A was reported to be related to KIF1B gene mutation in a single Japanese family.4 However, no further KIF1B mutations were found in other CMT2A patients. Investigation of other genes in this locus finally identified MFN2 as the primary gene mutated in CMT2A.5 Mitofusin 2 encoded by MFN2 is a large mitochondrial outer membrane GTPase, with a large N-terminal and a smaller C-terminal domain exposed in the cytoplasm. This protein plays an important role in mediating mitochondrial fusion. It has been postulated that defects in mitochondrial fusion, oxidative phosphorylation and mitochondrial transport could be implicated in the pathology of CMT2A.6 Peripheral nerves are particularly involved because the energy demands are high and the long axons would be mostly affected by the mitochondrial transport defect.6 In addition to the classical motor and sensory peripheral neuropathy, extra clinical features, including tremor, scoliosis, optic atrophy, sensorineural hearing loss, pyramidal signs, cognitive impairment, parkinsonism and stroke, have also been described in MFN2 mutations.2,7,8 The age of onset of CMT2A is variable, ranging from 1 to 45 years in one study with 29 probands.2 The clinical features were markedly different for the early onset group (<10 years) and the late onset group (≥10 years), with a more severe phenotype and more progressive disease course in the former.2,9 We have identified a novel missense mutation, MFN2 NM_014874.2:c.828G>C (p.Gln276His). This novel mutation is located in the region linking the GTPase domain and the first coiled-coil region of mitofusin 2. A known mutation with different amino acid substitution at the same codon [MFN2 NM_014874.2:c.827A>G (p.Gln276Arg)] has been reported to be associated with CMT2 and optic atrophy,2,10 though visual impairment is not observed in our patient. A significant proportion of MFN2 mutations have been shown to be de novo (up to 34%), implying that this gene may be prone to spontaneous mutations.2,8,9,11 Phenotypic heterogeneity with intrafamilial variability and incomplete penetrance has also been reported for MFN2 mutations.7,12 In our case, the patient’s mother who carried the same heterozygous mutation only developed mild symptoms recently at her fifties with normal electrophysiological study, suggesting noteworthy intrafamilial variability in this family. The patient’s deceased maternal grandfather might also be affected by CMT2A in view of his unexplained limping gait. MFN2 mutations have been described in different ethnic groups, although population data is still limited. In an American study, MFN2 mutations were detected in 23% of 13 unrelated probands with CMT2.12 MFN2 mutation was found to be the cause of CMT2 in just one out of 18 families in the Netherlands (5.6%).13 In a study of Japanese population, seven of 81 unrelated patients with axonal or unclassified CMT carried MFN2 mutations (8.6%).14 Higher frequencies were revealed in two Korean studies of CMT2, with MFN2 mutations detected in 24.2% of 62 families and 33.3% of 12 families respectively.9,15 The different diagnostic yields in these studies could also be attributed by the variable selection criteria of cases for genetic testing. CMT is suspected when there are typical clinical phenotype, characteristic nerve conduction studies findings and positive family history, after excluding common causes of polyneuropathy like diabetes mellitus, vitamin B12 deficiency and monoclonal gammopathies. Genetic testing is of paramount importance for confirming diagnosis, classification and also genetic counseling. The selection of genetic test should be guided by the clinical phenotype, inheritance pattern, electrophysiological studies and occasionally sural nerve biopsy if available. Since CMT2A is the most common type of CMT2, genetic testing for patients suspected of autosomal dominant hereditary axonal neuropathy should begin with MFN2. A suggested decision algorithm for selecting genetic tests in evaluation of suspected hereditary neuropathies has been published recently.3 For those with axonal neuropathy and autosomal dominant inheritance pattern, MFN2 mutations should be screened first, followed by MPZ mutations which can give rise to both CMT1 and CMT2.3 Given that a significant proportion of mutations are de novo, genetic testing should also be considered for apparently sporadic cases if suspicion of axonal CMT is high. For these patients, it has been suggested to start with MFN2 and also GJB1/Cx32, which is the causative gene of CMTX1 with both demyelinating and axonal phenotypes, and MPZ gene analysis as the second tier testing.3 In conclusion, we have identified a novel mutation, MFN2 NM_014874.2:c.828G>C (p.Gln276His), in a family with CMT2 phenotype. Intrafamilial variability was observed in this family. This is the first report of MFN2 mutation in Chinese. Clinical information, inheritance pattern, nerve conduction studies and molecular analysis are indispensable for diagnosis of different types of CMT. De novo MFN2 mutations are not uncommon, and considerable phenotypic heterogeneity within a family could be present, thus screening of the gene for apparently sporadic cases with typical clinical phenotype should still be warranted. REFERENCES 1. Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980;103:259–280. PMID: 7397478 2. Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 2006;129:2093–2102. PMID: 16714318 3. England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, et al. Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009;72:185–192. PMID: 19056666 4. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, et al. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bβ. Cell 2001;105:587–597. PMID: 11389829 5. Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004;36:449–451. PMID: 15064763 6. Cartoni R, Martinou JC. Role of mitofusin 2 mutations in the physiopathology of Charcot-Marie-Tooth disease type 2A. Exp Neurol 2009;218:268–273. PMID: 19427854 7. Del Bo R, Moggio M, Rango M, Bonato S, D’Angelo MG, Ghezzi S, et al. Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction. Neurology 2008;71:1959–1966. PMID: 18946002 8. Ajroud-Driss S, Fecto F, Ajroud K, Yang Y, Donkervoort S, Siddique N, et al. A novel de novo MFN2 mutation causing CMT2A with upper motor neuron signs. Neurogenetics 2009;10:359–361. PMID: 19350291 9. Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, et al. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 2006;129:2103–2118. PMID: 16835246 10. Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 2006;59:276–281. PMID: 16437557 11. Neusch C, Senderek J, Eggermann T, Elolff E, Bähr M, Schneider-Gold C. Mitofusion 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A). Eur J Neurol 2007;14:575–577. PMID: 17437620 12. Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005;65:197–204. PMID: 16043786 13. Bienfait HME, Baas F, Koelman JHTM, de Haan RJ, van Engelen BGM, Gabreëls-Festen AAWM, et al. Phenotype of Charcot-Marie-Tooth disease type 2. Neurology 2007;68:1658–1667. PMID: 17502546 14. Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, et al. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 2005;116:23–27. PMID: 15549395 15. Cho HJ, Sung DH, Kim BJ, Ki CS. Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2. Clin Genet 2007;71:267–272. PMID: 17309650 Figure 1. DNA sequencing electrophoretogram of the MFN2 gene shows the mutation MFN2 NM_014874.2:c.828G>C (p.Gln276His) (arrow) of the index patient in the sense direction. Figure 2. Screening of the novel mutation MFN2 NM_014874.2:c.828G>C (p.Gln276His) in healthy controls using real-time amplification refractory mutation system polymerase chain reaction. Amplification plots of the index patient, the normal controls and water blank using primers specific for the mutant (A) and the wild type (B). Reaction with cycle threshold <30 is considered to be positive. The index patient sample was positive with both mutant specific and wild type specific primers; whereas the healthy controls samples were positive with the wild type specific primers only (arrows).