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Diabetes and Deafness; Not All MODY Is MELAS

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Diabetes and Deafness; Not All MODY Is MELAS Diabetes Care In Press, published online May 31, 2007 Diabetes and deafness; is it sufficient to screen for the mitochondrial 3243A>G mutation alone? Received for publication 8 March 2007 and accepted in revised form 26 May 2007. Running title: Diagnostic strategies in diabetes and deafness. Roger G Whittaker MRCP1*, Andrew M Schaefer MRCP1, Robert McFarland MRCP1, Robert W Taylor MRCPath1, Mark Walker FRCP2, Douglass M Turnbull FRCP1. 1Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. 2Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. *Corresponding author; [email protected] Copyright American Diabetes Association, Inc., 2007 The m.3243A>G mitochondrial DNA mutation in either whole blood or mutation is well known to be urinary epithelial cells (8) . We associated with deafness and wanted to assess whether this is a diabetes, and patients presenting sensible investigation strategy in with these clinical features are patients presenting in this way. routinely screened for this mutation. Firstly, we wanted to assess how We wanted to assess whether this is many patients with other mutations a suitable screening strategy. We of the mitochondrial genome present retrospectively reviewed the clinical with the combination of diabetes and notes of 242 patients who had deafness, who would potentially be attended a specialist mitochondrial missed in this screening strategy. clinic in the preceding twenty five Secondly, we wanted to see whether year period. Out of the total of 29 other clinical features of patients with mitochondrial disease mitochondrial disease were present presenting with deafness and in these patients which might have diabetes, only 21 would have been provided additional clues as to the correctly diagnosed by screening for correct diagnosis (9). the m.3243A>G mutation in blood or urine. Of the remaining eight We retrospectively reviewed the patients, only six had other features clinical notes of 242 patients who suggestive of mitochondrial disease. had attended a specialist We recommend that all patients mitochondrial clinic in the preceding presenting to diabetes clinics with twenty five year period. All patients the combination of deafness and had proven mitochondrial disease on diabetes be screened for the the basis of muscle histochemistry or m.3243A>G mutation. In those mtDNA analysis. From this cohort patients in whom this test is negative we selected patients who were deaf we recommend referral to a at the time at which they presented specialist neuromuscular clinic for with diabetes. Diabetes was defined further investigation. according to WHO criteria (10). Deafness was defined clinically as Research design and methods hearing impairment not fully The association between maternally corrected with hearing aids. inherited diabetes and deafness Audiometry was not deemed (MIDD) and mitochondrial DNA necessary as this is unlikely to have (mtDNA) mutations is well been performed at the time of recognised (1,2). Several mutations presentation to a diabetes clinic. have been associated with this phenotype, including the Results m.3243A>G (3) and m.14709T>C (4) We found a total of 29 point mutations. So strong is the patients with mitochondrial disease association with the m.3243A>G who were deaf at the time of mutation (thought to account for up presentation with diabetes. 21 of to 1% of diabetes and 0.3% of these patients carried the deafness(5-7) ) that it has become m.3243A>G point mutation, the common practice in diabetes clinics deafness having preceded the for patients presenting with the diabetes by a mean of 6.0 years. In combination of diabetes and addition, there were two patients deafness to be screened for this with the m.12258C>A mutation, one patient with the m.8344A>G patients would not have been mutation, four with single, large- detected by this screening strategy, scale mtDNA deletions and one with underestimating the prevalence of multiple mtDNA deletions secondary diabetes and deafness due to to an unknown nuclear genetic mitochondrial DNA mutations. Six of defect. these patients had other clear signs of mitochondrial disease. It is likely The clinical features of these eight that these patients would have been patients who did not carry the referred for a neurological opinion m.3243A>G mutation are and the correct diagnosis made. summarised in the table. The patient However, one patient with the with m.8344A>G also had ptosis, m.12258C>A mutation and one with dysarthria and cerebellar ataxia at a single deletion had either no other the time of presentation with features or only non-specific features diabetes. One patient with the (ie fatigue) which are unlikely to m.12258C>A mutation had no other have alerted the assessing physician clinical features, whereas the other to the possibility of an alternative had only mild constipation, fatigue diagnosis. and a mild dysarthria. Three of the patients with single mtDNA deletions Conclusions had clear evidence of mitochondrial We recommend that all disease with ptosis, marked external patients presenting to diabetes ophthalmoplegia and clear clinics with the combination of dysarthria. However the fourth had deafness and diabetes be screened only a history of mild fatigue in for the m.3243A>G mutation. addition to deafness and diabetes. Screening of urine is preferred as The patient with multiple mtDNA this has a greater sensitivity than deletions also had ptosis and either buccal mucosa or blood (8- ophthalmoplegia. 11), is non-invasive and widely Out of the total of 29 patients available. However, in those patients with mitochondrial disease in whom this test is negative we presenting with deafness and recommend referral to a specialist diabetes, 21 would have been neuromuscular clinic for further correctly diagnosed with investigation, to ensure that patients mitochondrial disease by screening harbouring other mtDNA mutations for the m.3243A>G mutation in blood are correctly diagnosed. or urine. The remaining eight References 1. van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, et al: Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992 Aug;1(5):368- 71. 2. Walker M, Taylor RW, Turnbull DM. Mitochondrial diabetes: Diabet Med. 2005 Sep;22 Suppl 4:18-20. 3. Maassen JA, LM TH, Van Essen E, Heine RJ, Nijpels G, Jahangir Tafrechi RS, et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes. 2004 Feb;53 Suppl 1:S103-9. 4. Vialettes BH, Paquis-Flucklinger V, Pelissier JF, Bendahan D, Narbonne H, Silvestre-Aillaud P, et al. Phenotypic expression of diabetes secondary to a T14709C mutation of mitochondrial DNA. Comparison with MIDD syndrome (A3243G mutation): a case report. Diabetes Care. 1997 Nov;20(11):1731-7. 5. Suzuki S. Diabetes mellitus with mitochondrial gene mutations in Japan. Ann N Y Acad Sci. 2004 Apr;1011:185-92. 6. Newkirk JE, Taylor RW, Howell N, Bindoff LA, Chinnery PF, Alberti KG, et al. Maternally inherited diabetes and deafness: prevalence in a hospital diabetic population. Diabet Med. 1997 Jun;14(6):457-60. 7. Usami S, Abe S, Akita J, Namba A, Shinkawa H, Ishii M, et al. Prevalence of mitochondrial gene mutations among hearing impaired patients. Journal of medical genetics. 2000 Jan;37(1):38-40. 8. McDonnell MT, Schaefer AM, Blakely EL, McFarland R, Chinnery PF, Turnbull DM, et al. Noninvasive diagnosis of the 3243A > G mitochondrial DNA mutation using urinary epithelial cells. Eur J Hum Genet. 2004 Sep;12(9):778-81. 9. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nature reviews. 2005 May;6(5):389-402. 10. Ballinger SW, Shoffner JM, Hedaya EV, Trounce I, Polak MA, Koontz DA, et al. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet. 1992 Apr;1(1):11-5. 11. Shanske S, Pancrudo J, Kaufmann P, Engelstad K, Jhung S, Lu J, et al. Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet A. 2004 Oct 1;130(2):134-7. Table 1 Mitochondrial DNA Percentage Years that Clinical features at genotype heteroplasmy deafness time of presentation in muscle preceded with diabetes diabetes m.8344A>G 90 13 ptosis/ dysarthria/ ataxia m.12258C>A 85 0 none m.12258C>A 68 16 mild constipation/ dysarthria/ fatigue Single mtDNA n/d 9 ptosis/ CPEO deletion /dysarthria/ ataxia Single mtDNA 50 12 ptosis/ CPEO/ deletion dysarthria/ ataxia Single mtDNA n/d 15 ptosis/ dysarthria/ mild deletion ataxia Single mtDNA 10 4 fatigue deletion Multiple mtDNA n/a 3 ptosis/ CPEO/ deletions dysarthria/ ataxia CPEO = chronic progressive external ophthalmoplegia n/a not applicable n/d not determined .
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