Maternally Inherited Diabetes and Deafness is Phenotypically and Genotypically Heterogeneous

Letters to the Editor on every patient with any one of the 39 signs and symptoms as listed by Dr. George et al. As part of their proforma, they mention "a high clinical suspicion" of GCA, but it is not stated what constitutes a "high clinical suspicion." Our algorithm allows for a simple stratification (very low, moderate, and high clinical suspicion) based on 7 signs and symptoms (in addition to accounting for comorbid conditions that can mimic GCA) to improve on the possibility of obtaining a positive TAB. Ultimately, however, to confirm or refute the diagnosis of GCA requires a TAB. Mays A. El-Dairi, MD Department of Ophthalmology Duke Eye Center and Duke University Medical Center Durham, North Carolina Thomas J. Cummings, MD Alan D. Proia, MD, PhD Departments of Ophthalmology and Pathology Duke Eye Center and Duke University Medical Center Durham, North Carolina The authors report no conflicts of interest. M. Tariq Bhatti, MD Departments of Ophthalmology and Neurology Duke Eye Center and Duke University Medical Center Durham, North Carolina Maternally Inherited Diabetes and Deafness is Phenotypically and Genotypically Heterogeneous REFERENCE 1. El-Dairi MA, Chang L, Proia AD, Cummings TJ, Stinnett SS, Bhatti MT. Diagnostic algorithm for patients with suspected giant cell arteritis. J Neuroophthalmol. 2015;35:246-253. TABLE 1. Phenotypic manifestations of MIDD Organs Affected W ith interest we read the article by Cardenas-Robledo et al (1) regarding 2 patients with maternally inherited diabetes and deafness (MIDD) who presented with multisystem involvement, including vestibular impairment. We have the following comments and concerns. As the authors point out in their introduction, numerous organ systems are affected in patients with MIDD. These are summarized in Table 1. Regarding the reported patients by Cardenas-Robledo et al, did the authors search for subclinical involvement of the gastrointestinal tract and kidneys? With regard to Patient 2, one would expect a sensory problem with regard to the bilateral thalamic lesions. Did the patient report any sensory problems or were any detected on recording of somatosensoryevoked potentials? Did Patient 2 undergo magnetic resonance spectroscopy to search for the nature of the thalamic lesions? Interestingly, Patient 2 developed rhabdomyolysis on administration of statins suggesting that statin myopathy develops particularly in patients with a mitochondrial disorder with myopathy. Which statin over what timeframe was given? What was the dosage? Were additional triggers, such as infection, ruled out as a cause of rhabdomyolysis? Both patients were reported to have cerebral atrophy. What were the clinical manifestations of cerebral atrophy? Did patients undergo neuropsychological testing to see if there was cognitive impairment or not? There are also patients with MIDD who progressed over time and developed phenotypic features of mitochondrial encephalopathy lactacidosis and stroke-like episodes (MELAS) (21). Did either patient develop 344 Central nervous system Supratentorial atrophy Cerebellar atrophy Cerebellar ataxia Basal ganglia calcification Leukoencephalopathy Nystagmus Elevated CSF protein Elevated CSF lactate Neuropsychological deficits Depression Peripheral nervous system Myopathy Rhabdomyolysis Ptosis Polyneuropathy Ears Hypoacusis, anacusis Vestibular system Impaired vestibularocular reflex Eyes Pigmentary retinopathy Macular degeneration Optic atrophy Central retinal vein occlusion Retinal/choroidal atrophy CardenasRobledo et al Literature Reference 1 1 2 1 1 1 1 1 (2) (3) (4) (5) 1 1 1 1 2 2 2 2 1 1 (1) (1) (1) (3) (3) 2 1 (2) 1 1 2 1 1 2 1 2 (6) (1) (7) (1) 1 1 (8) 1 2 (1) 1 1 1 1 1 1 2 1 (9) (10) (1) (11) 1 1 (12) Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 343-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor (Continued ) Organs Affected Endocrine system Diabetes Hypoaldosteronism Short stature Cardiac Arterial hypertension Cardiomyopathy Heart failure Gastrointestinal Pancreatitis Intestinal pseudoobstruction Constipation Diarrhea Kidneys Renal failure Glomerulosclerosis CardenasRobledo et al 2. Literature Reference 3. 1 2 2 1 1 1 (13) (14) 1 2 2 1 1 1 (9) (15) (16) 2 2 1 1 (17) (18) 2 2 1 1 (19) (19) 2 2 1 1 (8) (20) 4. 5. 6. 7. 8. CSF, cerebrospinal fluid. typical features of MELAS syndrome, such as stroke-like episodes, seizures, vomiting, migraine-like headache, or cardiomyopathy during their disease course? It should be pointed out that the mtDNA mutation m.3243A.G is present in only 85% of the patients with MIDD (22). Other mutations causing MIDD include mtDNA mutations m.9267G.C (8), m.1555A.G (14), m.14530T.C (23), m.14709T.C (24), or m.3421G.A (25). Overall, these 2 interesting cases add much to the phenotypic spectrum of patients with MIDD. MIDD is a multisystem, syndromic mitochondrial disorder requiring the collaboration of various specialists to establish the correct diagnosis and provide optimal patient management. Josef Finsterer, MD, PhD Hospital Rudolfstiftung, Vienna, Austria Marlies Frank, MD First Medical Department, Hospital Rudolfstiftung, Vienna, Austria 9. 10. 11. 12. 13. 14. The authors report no conflicts of interest. REFERENCES 1. Cardenas-Robledo S, Saber Tehrani A, Blume G, Kattah JC. Visual, ocular motor, and cochleo-vestibular loss in patients with heteroplasmic, maternally-inherited diabetes mellitus and Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 343-352 15. deafness (MIDD), 3243 transfer RNA mutation. J Neuroophthalmol 2016;36:134-140. Kobayashi Z, Tsunemi T, Miake H, Tanaka S, Watabiki S, Morokuma Y. A mother and a child with maternally inherited diabetes and deafness (MIDD) showing atrophy of the cerebrum, cerebellum and brainstem on magnetic resonance imaging (MRI). Intern Med. 2005;44:328-331. Fromont I, Nicoli F, Valéro R, Felician O, Lebail B, Lefur Y, Mancini J, Paquis-Flucklinger V, Cozzone PJ, Vialettes B. Brain anomalies in maternally inherited diabetes and deafness syndrome. J Neurol. 2009;256:1696-1704. Imamura T, Konno S, Inoue M, Murata M, Nakazora H, Sugimoto H, Fujioka T. Convulsion and cerebellar ataxia associated with maternally inherited diabetes and deafness: a case report. Clin Case Rep. 2015;3:656-659. Lien LM, Lee HC, Wang KL, Chiu JC, Chiu HC, Wei YH. Involvement of nervous system in maternally inherited diabetes and deafness (MIDD) with the A3243G mutation of mitochondrial DNA. Acta Neurol Scand. 2001;103:159-165. Tanaka K, Takada Y, Matsunaka T, Yuyama S, Fujino S, Maguchi M, Yamashita S, Yuba I. Diabetes mellitus, deafness, muscle weakness and hypocalcemia in a patient with an A3243G mutation of the mitochondrial DNA. Intern Med. 2000;39:249-252. Ogun O, Sheldon C, Barton JJ. Pearls & oy-sters: maternally inherited diabetes and deafness presenting with ptosis and macular pattern dystrophy. Neurology. 2012;79:e54-56. Tabebi M, Mkaouar-Rebai E, Mnif M, Kallabi F, Ben Mahmoud A, Ben Saad W, Charfi N, Keskes-Ammar L, Kamoun H, Abid M, Fakhfakh F. A novel mutation MT-COIII m.9267G.C and MT-COI m.5913G.A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with severe nephropathy. Biochem Biophys Res Commun. 2015;459:353-360. Massin P, Dubois-Laforgue D, Meas T, Laloi-Michelin M, Gin H, Bauduceau B, Bellanné-Chantelot C, Bertin E, Blickle JF, Bouhanick B, Cahen-Varsaux J, Casanova S, Charpentier G, Chedin P, Dupuy O, Grimaldi A, Guerci B, Kaloustian E, LecleireCollet A, Lorenzini F, Murat A, Narbonne H, Olivier F, PaquisFlucklinger V, Virally M, Vincenot M, Vialettes B, Timsit J, Guillausseau PJ; GEDIAM (Mitochondrial Diabetes French Study Group). Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case-control study. Diabetologia. 2008;51:1664-1670. Daruich A, Matet A, Borruat FX. Macular dystrophy associated with the mitochondrial DNA A3243G mutation: pericentral pigment deposits or atrophy? Report of two cases and review of the literature. BMC Ophthalmol. 2014;14:77. Souied E, Mashhour B, Morel X, Cohen Y, Bonnefond JP, Munnich A, Chauvaud D, Renard G, Kaplan J. Retinal branch vein occlusion associated with macular dystrophy, maternally inherited diabetes, and deafness. Ophthalmic Genet. 1997;18:157-160. Bellmann C, Neveu MM, Scholl HP, Hogg CR, Rath PP, Jenkins S, Bird AC, Holder GE. Localized retinal electrophysiological and fundus autofluorescence imaging abnormalities in maternal inherited diabetes and deafness. Invest Ophthalmol Vis Sci. 2004;45:2355-2360. Mory PB, Santos MC, Kater CE, Moisés RS. Maternallyinherited diabetes with deafness (MIDD) and hyporeninemic hypoaldosteronism. Arq Bras Endocrinol Metabol. 2012;56:574-577. Mezghani N, Mnif M, Mkaouar-Rebai E, Kallel N, Charfi N, Abid M, Fakhfakh F. A maternally inherited diabetes and deafness patient with the 12S rRNA m.1555A.G and the ND1 m.3308T.C mutations associated with multiple mitochondrial deletions. Biochem Biophys Res Commun. 2013;431:670-674. Azevedo O, Vilarinho L, Almeida F, Ferreira F, Guardado J, Ferreira M, Lourenço A, Medeiros R, Almeida J. Cardiomyopathy and kidney disease in a patient with 345 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor 16. 17. 18. 19. 20. maternally inherited diabetes and deafness caused by the 3243A.G mutation of mitochondrial DNA. Cardiology. 2010;115:71-74. Mangiafico RA, Zeviani M, Bartoloni G, Fiore CE. Accelerated cardiomyopathy in maternally inherited diabetes and deafness. Int J Clin Pharmacol Res. 2004;24:15-21. Schleiffer T, 't Hart LM, Schürfeld C, Kraatz K, Riemann JF. Maternally inherited diabetes and deafness (MIDD): unusual occult exocrine pancreatic manifestation in an affected German family. Exp Clin Endocrinol Diabetes. 2000;108:81-85. Bergamin CS, Rolim LC, Dib SA, Moisés RS. Unusual occurrence of intestinal pseudo obstruction in a patient with maternally inherited diabetes and deafness (MIDD) and favorable outcome with coenzyme Q10. Arq Bras Endocrinol Metabol. 2008;52:1345-1349. Narbonne H, Paquis-Fluckinger V, Valero R, Heyries L, Pellissier JF, Vialettes B. Gastrointestinal tract symptoms in maternally inherited diabetes and deafness (MIDD). Diabetes Metab. 2004;30:61-66. Cao XY, Wei RB, Wang YD, Zhang XG, Tang L, Chen XM. Focal segmental glomerulosclerosis associated with maternally inherited diabetes and deafness: clinical pathological analysis. Indian J Pathol Microbiol. 2013;56:272-275. Maternally Inherited Diabetes and Deafness Is Phenotypically and Genotypically Heterogeneous: Response W e welcome the comments and table provided by Professors Josef Finsterer, MD, PhD and Marlies Frank, MD in relation to our recent JNO publication (1). They provide further evidence of the highly heteroplasmic nature of maternally inherited diabetes and deafness (MIDD) because of the A3243G mitochondrial RNA mutation. Table 1 from their letter outlines several reports of multiple organ compromise associated with MIDD. In addition, we are also able to answer some of their questions. Our 2 patients did not have ptosis, and there was no clinical evidence of gastrointestinal or renal involvement. Laboratory test results of renal, hepatic, and gastrointestinal functions also were normal. Patient 2 was diagnosed with MIDD in 1993, the same year that the clinical phenotype was first reported. She was not seen by the authors for 14 years. When evaluated in 2007, she had been on pravastatin, 40 mg daily for 3 years. Although she did not complain of muscle weakness or pain and had no clinical evidence of myopathy, her creatinine phosphokinase (CPK) was elevated (1,074 U/L, normal: 30-135 U/L) but myoglobin was not present in the urine. Pravastin was discontinued, and we recommended avoiding future use of statins. Unfortunately, the patient changed residence over the years, with inadequate continuity of care; as a result, a new prescription for rosuvastatin, 20 mg daily, was prescribed sometime in 2012. One month later, she had severe rhabdomyolysis, which gradually improved. She did not contact us during this period of time, and we do not know the serum CPK level. Her muscle examination in 2013, approximately 1 year later, was normal, and the last 346 21. de Wit HM, Westeneng HJ, van Engelen BG, Mudde AH. MIDD or MELAS: that's not the question MIDD evolving into MELAS: a severe phenotype of the m.3243A.G mutation due to paternal co-inheritance of type 2 diabetes and a high heteroplasmy level. Neth J Med. 2012;70:460-462. 22. Naing A, Kenchaiah M, Krishnan B, Mir F, Charnley A, Egan C, Bano G. Maternally inherited diabetes and deafness (MIDD): diagnosis and management. J Diabetes Complications. 2014;28:542-546. 23. Bannwarth S, Abbassi M, Valéro R, Fragaki K, Dubois N, Vialettes B, Paquis-Flucklinger V. A novel unstable mutation in mitochondrial DNA responsible for maternally inherited diabetes and deafness. Diabetes Care. 2011;34:2591-2593. 24. Perucca-Lostanlen D, Taylor RW, Narbonne H, Mousson de Camaret B, Hayes CM, Saunieres A, Paquis-Flucklinger V, Turnbull DM, Vialettes B, Desnuelle C. Molecular and functional effects of the T14709C point mutation in the mitochondrial DNA of a patient with maternally inherited diabetes and deafness. Biochim Biophys Acta. 2002;1588:210-216. 25. Chen FL, Liu Y, Song XY, Hu HY, Xu HB, Zhang XM, Shi JH, Hu J, Shen Y, Lu B, Wang XC, Hu RM. A novel mitochondrial DNA missense mutation at G3421A in a family with maternally inherited diabetes and deafness. Mutat Res. 2006;602:26-33. CPK was only modestly elevated at 150 U/L (normal: 30- 135 U/L). Since then, her mild cholesterol elevation has been managed primarily with diet control. In relation to additional neurologic symptoms and findings, neither one of our patients has developed acute complications mimicking mitochondrial encephalopathy, lactic acidosis and stroke (MELAS) nor do they report disabling headaches. Both patients had a normal mini- mental status when last examined, and Patient 1 retired from work. Patient 2 has been successfully using a monaural cochlear implant for 22 years, learned how to communicate very efficiently during regular conversation, and raised a family. The question of central nervous system structure-function in this disorder is interesting; one would anticipate greater neurologic impairment considering the imaging findings. To answer this question, one must hypothesize that brain plasticity in response to overt mitochondrial-related structural, neuronal, or glial change has provided effective cognitive, sensory, and motor compensation. Moreover, our 2 patients did not have long-tract sensory signs, and the only sensory abnormality found was decreased pin prick in a stocking distribution in Patient 1. Evoked potentials were not performed. The white-matter signal changes and cerebral/cerebellar atrophy noted on magnetic resonance imaging (MRI) are likely due to gliosis and neuronal loss; they coincide with tissue calcification on computed tomography in Patient 2 and do not bear similarity to the larger MRI hemispheric lesions found in the classic MELAS phenotype. Cerebral MRI spectroscopy would have been of interest, but was not performed since the diagnosis has been made from the muscle biopsy. Finsterer and Frank also raise an important point in reference to the MIDD genotype; other mitochondrial mutations may be responsible; thus, the tissue analysis Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 343-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.