Maternally inherited diabetes and deafness (MIDD) is a syndromic mitochondrial disorder (MID) characterized by type 2 diabetes and hearing impairment.1 In up to 85% of cases, MIDD is due to the mitochondrial (mt)DNA mutation m.3243A>G,2 but other mtDNA mutations may also cause MIDD.3 Though MIDD was originally described to affect only the pancreas and ears,4 during the following years it turned out that it is a mitochondrial multiorgan disorder syndrome (MIMODS) rather than restricted to two organs [Table 1].5–24 In addition to the central nervous system (CNS) and the endocrine organs, MIDD may manifest with affection of the peripheral nerves, ears, vestibular system, eyes, heart, gastrointestinal tract, and kidneys. Here, we describe a patient with MIDD who presented with infertility in addition to other previously described features of MIDD [Table 1].

Case Report

Our patient, a 44-year-old Caucasian male (height 185 cm, weight 88 kg) was referred for a first tonic-clonic seizure during general anesthesia for surgery of a right-sided inguinal hernia. Despite this event, anesthesia and surgery were continued without further complications. His history was noteworthy for deafness since birth, requiring hearing devices since aged five. Additionally, his history was positive for otitis media at age nine months, dysarthria since early childhood (attributed to deafness), diabetes since age 41 years, mild creatine kinase (CK) elevation, emphysema, nicotine abuse, and hyperlipidemia. Infertility in the patient was diagnosed by history, clinical exam, hormone testing, and semen analysis. His family history was positive for diabetes and impaired hearing in his mother. His maternal grandmother was wheel-chair bound because of muscle weakness. More detailed information about other family members was not available since he was an adopted child.

Clinical neurologic examination at age 44 years revealed bilateral hypoacusis and mild left-sided ataxia. Blood chemical investigations showed a glycated hemoglobin (HbA1c)of 12.4% (n < 6.0%) and hyperlipidemia. Ultrasound of the abdomen was non-informative. Colonoscopy was normal. The patient was assumed to have multisystem MIDD. The patient did not consent to a muscle biopsy or genetic workup to confirm the diagnosis.

Discussion

Our patient with putative MIDD is interesting for two reasons. First, he presented with a phenotypic feature, hypogonadism, which has not been reported previously [Table 1]. Hypogonadism in the form of infertility was attributed to MIDD since urologists excluded other causes and since MIDs, except MIDD, have been previously reported to be associated with hypogonadism.25 Hypogonadism has been found in mitochondrial encephalopathy, lactic acidosis, stroke-like episodes, chronic progressive external ophthalmoplegia, mitochondrial neuro gastro-intestinal encephalopathy, Kearns-Sayre syndrome, and several non-specific MIDs. Urologists diagnosed his infertility but did not offer any effective treatment. An argument against diabetes as the cause of infertility is that diabetes did not occur earlier than aged 41 years, but infertility was diagnosed earlier. Since cerebral imaging was normal and his history was negative for birth trauma, traumatic brain injury, meningitis, or juvenile febrile seizures, they were attributed to the suspected underlying MID. A further argument for attributing seizures to the suspected MIDD is that epilepsy has been reported as a CNS manifestation of a MID.26

Second, for years the patient was not regarded as having a MID as his family history was incomplete because of difficulties taking it and since nobody regarded the clinical presentation of the patient as indicative of a MID and since it is not well-known that MIDD is not only characterized by diabetes and deafness but in fact a multisystem disease as most of the MIDs. MIDs potentially affect all body tissues and turn into a MIMODS during the disease course. The multisystem nature of MIDD is well documented. Organs described to be affected by MIDD include the CNS, peripheral nervous system, eyes, ears, vestibular system, skeletal muscle, endocrine system, heart, and intestines [Table 1].2 The patient did not complain about sleep disorder, which has been reported as a manifestation of diabetes.27 Since MIDD may manifest with myopathy, including rhabdomyolysis, muscle biopsy may show features of a MID and biochemical investigations of the muscle homogenate may show decreased activity of some or all complexes of the respiratory chain.

Conclusions

This case shows that MIDD is indeed a multisystem MID, that the phenotypic spectrum of MIDD is broader than previously reported, and that hypogonadism may be an additional manifestation of the MIDD.

Disclosure

The authors declared no conflicts of interest.

references

1. 1. Li HZ, Li RY, Li M. A review of maternally inherited diabetes and deafness. Front Biosci (Landmark Ed) 2014 Jan;19:777-782.
2. 2. Naing A, Kenchaiah M, Krishnan B, Mir F, Charnley A, Egan C, et al. Maternally inherited diabetes and deafness (MIDD): diagnosis and management. J Diabetes Complications 2014 Jul-Aug;28(4):542-546.
3. 3. Finsterer J, Frank M. Maternally inherited diabetes and deafness is phenotypically and genotypically heterogeneous. J Neuroophthalmol 2016 Sep;36(3):346-347.
4. 4. van den Ouweland JM, Lemkes HH, Gerbitz KD, Maassen JA. Maternally inherited diabetes and deafness (MIDD): a distinct subtype of diabetes associated with a mitochondrial tRNA(Leu)(UUR) gene point mutation. Muscle Nerve Suppl 1995;3:S124-S130.
5. 5. 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 Apr;44(4):328-331.
6. 6. Fromont I, Nicoli F, Valéro R, Felician O, Lebail B, Lefur Y, et al. Brain anomalies in maternally inherited diabetes and deafness syndrome. J Neurol 2009 Oct;256(10):1696-1704.
7. 7. Imamura T, Konno S, Inoue M, Murata M, Nakazora H, Sugimoto H, et al. Convulsion and cerebellar ataxia associated with maternally inherited diabetes and deafness: a case report. Clin Case Rep 2015 Jul;3(7):656-659.
8. 8. 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 Mar;103(3):159-165.
9. 9. 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 deafness (MIDD), 3243 transfer rna mutation. J Neuroophthalmol 2016 Jun;36(2):134-140.
10. 10. 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(2):81-85.
11. 11. Tanaka K, Takada Y, Matsunaka T, Yuyama S, Fujino S, Maguchi M, et al. Diabetes mellitus, deafness, muscle weakness and hypocalcemia in a patient with an A3243G mutation of the mitochondrial DNA. Intern Med 2000 Mar;39(3):249-252.
12. 12. Ogun O, Sheldon C, Barton JJ. Pearls & oy-sters: maternally inherited diabetes and deafness presenting with ptosis and macular pattern dystrophy. Neurology 2012 Aug;79(6):e54-e56.
13. 13. Tabebi M, Mkaouar-Rebai E, Mnif M, Kallabi F, Ben Mahmoud A, Ben Saad W, et al. 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 Apr;459(3):353-360.
14. 14. Massin P, Dubois-Laforgue D, Meas T, Laloi-Michelin M, Gin H, Bauduceau B, et al; 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 Sep;51(9):1664-1670.
15. 15. 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 Jun;14:77.
16. 16. Souied E, Mashhour B, Morel X, Cohen Y, Bonnefond JP, Munnich A, et al. Retinal branch vein occlusion associated with macular dystrophy, maternally inherited diabetes, and deafness. Ophthalmic Genet 1997 Sep;18(3):157-160.
17. 17. Bellmann C, Neveu MM, Scholl HP, Hogg CR, Rath PP, Jenkins S, et al. Localized retinal electrophysiological and fundus autofluorescence imaging abnormalities in maternal inherited diabetes and deafness. Invest Ophthalmol Vis Sci 2004 Jul;45(7):2355-2360.
18. 18. Mory PB, Santos MC, Kater CE, Moisés RS. Maternally-inherited diabetes with deafness (MIDD) and hyporeninemic hypoaldosteronism. Arq Bras Endocrinol Metabol 2012 Nov;56(8):574-577.
19. 19. Mezghani N, Mnif M, Mkaouar-Rebai E, Kallel N, Charfi N, Abid M, et al. 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 Feb;431(4):670-674.
20. 20. Azevedo O, Vilarinho L, Almeida F, Ferreira F, Guardado J, Ferreira M, et al. Cardiomyopathy and kidney disease in a patient with maternally inherited diabetes and deafness caused by the 3243A>G mutation of mitochondrial DNA. Cardiology 2010;115(1):71-74.
21. 21. Mangiafico RA, Zeviani M, Bartoloni G, Fiore CE. Accelerated cardiomyopathy in maternally inherited diabetes and deafness. Int J Clin Pharmacol Res 2004;24(1):15-21.
22. 22. 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 Nov;52(8):1345-1349.
23. 23. 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 Feb;30(1):61-66.
24. 24. 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 Jul-Sep;56(3):272-275.
25. 25. Mukai M, Sugaya K, Matsubara S, Cai H, Yabe I, Sasaki H, et al. [Familial progressive external opthalmoplegia, parkinsonism and polyneuropathy associated with POLG1 mutation]. Rinsho Shinkeigaku 2014;54(5):417-422.
26. 26. Finsterer J. Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 2006 Oct;114(4):217-238.
27. 27. Al-Abri MA, Jaju D, Al-Sinani S, Al-Mamari A, Albarwani S, Al-Resadi K, et al. Habitual Sleep Deprivation is Associated with Type 2 Diabetes: A Case-Control Study. Oman Med J 2016 Nov;31(6):399-403.