Diabetes And Deafness, Maternally Inherited

A number sign (#) is used with this entry because of evidence that the disorder can be caused by mutation in several mitochondrial genes, including MTTL1 (590050), MTTE (590025), and MTTK (590060).

The most common mutation is a 3243A-G transition in the MTTL1 gene (590050.0001).

Description

Maternally inherited diabetes-deafness syndrome (MIDD) is a mitochondrial disorder characterized by onset of sensorineural hearing loss and diabetes in adulthood. Some patients may have additional features observed in mitochondrial disorders, including pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, renal problems, and neuropsychiatric symptoms (Ballinger et al., 1992; Reardon et al., 1992; Guillausseau et al., 2001).

The association of diabetes and deafness is observed with Wolfram syndrome (see 222300), Rogers syndrome (249270), and Herrmann syndrome (172500), but all 3 of these disorders have other clinical manifestations.

Clinical Features

Kressmann (1976) reported a large family in which diabetes and deafness were transmitted over 4 generations, with a total of 13 affected individuals. The clinical history was the same for all affected patients: the first manifestation was deafness, beginning at 20 to 30 years of age, with a rapid and severe increase in bilateral sensory hearing loss. Diabetes mellitus developed later in the third decade, and insulin was required either immediately or at a later date. At that time, persons from the fourth generation who were less than 20 years of age presented no deafness or diabetes. No pedigree member had ptosis, ophthalmoplegia, or muscle weakness. Reexamination of members of the family by Negrier et al. (1998) demonstrated no ragged-red fibers on skeletal muscle biopsy specimens and very limited lipid storage on electron microscopy.

Ballinger et al. (1992) described a family in which a mother, all of her 6 children by 2 husbands, and a granddaughter of 1 daughter had diabetes and deafness. The onset of diabetes was between ages 20 and 30 years except for 1 male in whom diabetes was first diagnosed at about age 43 years. The characteristics of the deafness were not specified. (Wallace (1992) indicated that the hearing loss was neurosensory and relatively late in onset; however, deafness generally preceded diabetes.) No member of the pedigree had ptosis, ophthalmoplegia or muscle weakness, features of other mitochondrial deletion syndromes. Infarcts occurred in the first generation and in 1 member of the second generation. In 1 of the patients, administration of Zidovudine (400-500 mg/d), a known inhibitor of mitochondrial replication, was associated with pancytopenia.

Van den Ouweland et al. (1992) observed maternally transmitted type II diabetes mellitus and deafness in 3 generations of a Dutch family. All 9 children of a woman with noninsulin-dependent diabetes mellitus had NIDDM and deafness; 2 grandchildren through a female also had the combination. None of the diabetic subjects showed optic atrophy, mental retardation, photomyoclonus, epilepsy, or myopathy.

Reardon et al. (1992) described a family with MIDD. Diabetes was associated with deafness in 7 individuals in 3 generations, only some of whom were available for study. Reduction of circulating insulin levels was a presenting feature of a multisystem disorder without significant neurologic involvement in this kindred. The proband presented with diabetes in his mid-twenties and received insulin therapy. Progressive bilateral hearing impairment was noted in his late thirties. ECG showed left bundle branch block and an echocardiographic diagnosis of cardiomyopathy was made shortly before his death at age 43. A salt-and-pepper retinopathy was noted in some affected members of the family.

Schulz et al. (1993) reported the case of a 47-year-old deaf man who was admitted for his first acute manifestation of hyperglycemia. Progressive bilateral sensorineural hearing loss had started in his early twenties. He had a 2-year history of dizziness, unsteady gait, and epilepsy. He also had pigmentary retinal degeneration with normal visual acuity but concentric narrowing of visual fields, external ophthalmoplegia, impaired vestibular function, and dysarthria.

Velho et al. (1996) reported 5 French pedigrees with the common 3243A-G mutation associated with variable clinical features, ranging from normal glucose tolerance to insulin-requiring diabetes. They described the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in 7 mutation-positive individuals who had a range of glucose tolerance from normal to impaired to NIDDM. All subjects, including those with normal glucose tolerance, demonstrated abnormal insulin secretion on at least 1 test. The data suggested to Velho et al. (1996) that a defect of glucose-regulated insulin secretion is an early and possible primary abnormality in carriers of the mutation. They speculated that this defect may result from the progressive reduction of oxidative phosphorylation and may implicate the glucose-sensing mechanism of beta cells.

Guillausseau et al. (2001) ascertained 54 patients with type II diabetes mellitus and the 3243 mtDNA mutation through 16 departments of internal medicine and diabetes and metabolic diseases in France. On average, patients with maternally inherited diabetes and deafness were young at diabetes onset and presented with a normal or low body mass index. None was obese. Maternal family history of diabetes was found in 73% of probands. Diabetes was noninsulin-dependent at onset in 87% of patients; however, 46% of patients had noninsulin-dependent disease at onset but progressed to insulin therapy after a mean duration of approximately 10 years. Neurosensory hearing loss was present in almost all patients. In 86% of patients who had received an ophthalmologic examination, macular pattern dystrophy (a specific retinal lesion of MIDD) was found. Myopathy was present in 43%, cardiomyopathy in 15%, and neuropsychiatric symptoms in 18% (9 of 51). Although the prevalence of diabetic retinopathy was 8% among patients who had received an ophthalmologic examination, a lower than expected percentage after a mean 12-year duration of diabetes, the prevalence of kidney disease was 28%. This suggested that a specific renal involvement results from mitochondrial disease. Fischel-Ghodsian (2001) suggested that early treatment with nephroprotective agents, such as angiotensin-converting enzyme inhibitors, may be beneficial in heading off the renal disease.

Ogun et al. (2012) reported a 54-year-old woman with the 3243A-G MTTL1 mutation in heteroplasmic state (40% in skeletal muscle) who had ptosis since her early teens, with worsening in her forties. She had hearing loss since her early twenties. Although visual acuity was normal, funduscopy showed macular dystrophy with a perimacular ring of retinal atrophy in both eyes, characteristic of MIDD. She did not have cardiac disease or diabetes, but her mother and brother both had deafness, and her brother had diabetes.

Inheritance

The transmission pattern in the family with MIDD reported by Ballinger et al. (1992) was consistent with mitochondrial inheritance, only through the female line.

The implication of mitochondrial mutations in diabetes mellitus is suggested by the fact that patients with noninsulin-dependent diabetes mellitus are more likely to have affected mothers than affected fathers (Alcolado and Alcolado, 1991).

Pathogenesis

Ballinger et al. (1994) restudied their original family and demonstrated that the mtDNA deletion was associated with the cotransmission of a related mtDNA duplication. The levels of 3 mtDNA forms, normal, deleted, and duplicated, varied between family members and between tissues within family members. The duplicated and deleted molecules shared the same breakpoint junction, np4398/14822. The duplicated molecule was thought to have a 6.1-kb insertion which duplicated the heavy-strand origin, O(H), but not the light-strand origin, O(L). It appeared that the deleted molecules accumulated in postmitotic tissues with age, presumably causing a progressive decline in tissue OXPHOS. When the mitochondrial ATP production of the pancreatic beta cells falls below the level necessary for glucose 'sensing,' diabetes mellitus ensues.

Molecular Genetics

In affected members of a family with maternally inherited diabetes and deafness, Ballinger et al. (1992) found a 10.4-kb mtDNA deletion (nucleotides 4398-14822), which was unique in being inherited through 3 generations at high levels and by the fact that the deletion lacked O(L), the origin of the light chain for mtDNA replication. The maternal inheritance of the deletion and, hence, its clear replication was strongly at variance with biochemical studies which suggested that O(L) is essential for mammalian mtDNA replication. Mitochondrial protein synthesis was inhibited in these patients. The deleterious effects of OXPHOS inhibition on pancreatic islet cell function was suggested by the finding that, in rats, streptozotocin, which impairs mtDNA replication, transcription, and OXPHOS function, results in diabetes.

Negrier et al. (1998) reported a partial tandem triplication of 9.2 kb mtDNA in 1 member of a family presenting maternally inherited diabetes and deafness associated with a tandem duplication of 4.6 kb. The family had previously been reported by Kressmann (1976).

Mutation in the MTTL1 Gene

In 3 generations of a Dutch family with MIDD, van den Ouweland et al. (1992) demonstrated cosegregation of a single point mutation in the MTTL1 gene (3243A-G; 590050.0001). The 3243-bp mtDNA mutation has most commonly been observed in patients with MELAS syndrome (540000). The reason for the differences in phenotype was not clear. In their family, van den Ouweland et al. (1992) found a second mtDNA mutation in tRNA(lys) at the conserved nucleotide position 8334. This homoplasmic mutation was absent in 75 controls. Since it was present in 1 unaffected member of the family, a sister of the grandmother, it did not associate with the disease but might contribute to the phenotype in combination with the tRNA(leu-UUR) mutation. The same Dutch group ('t Hart et al., 1996) examined whether the levels of heteroplasmy of the 3243 mutation changed with aging. They compared DNA samples from peripheral blood collected recently and those collected 1.5 to 6 years ago, from 18 individuals carrying the mutation. They found that 17 of these 18 individuals showed a decrease on aging (p = 0.001). Data indicated a continuous selection against hematopoietic cells carrying high levels of the 3243 mutation. Thus 't Hart et al. (1996) concluded that the levels of heteroplasmy may decline below the detection level if DNA from peripheral blood is analyzed from elderly individuals. They found DNA from oral mucosa cells to be a good alternative as heteroplasmy levels for the 3243 mutation were on the average 1.5-fold higher than in DNA from peripheral blood.

Reardon et al. (1992) identified the 3243A-G mutation in the MTTL1 gene in a family with MIDD. The mutation was found in all 3 diabetic patients and in postmortem tissues from the proband. It was also found in 7 offspring of female patients, but not in the 2 children of the male proband.

To determine if the percentage level of a pathogenic mtDNA molecule is caused by a purely random process, Chinnery et al. (1999) studied the tissue distribution of the 3243A-G point mutation in 5 members of a family with maternally inherited diabetes and deafness. These individuals showed a nonrandom tissue distribution of the mutation, with highest levels in the skeletal muscle, followed by hair follicles and buccal mucosa, and with the lowest level in blood. The probability of observing any strict hierarchy in a family was calculated to be very small, leading the authors to suggest that the distribution of the 3243A-G mutation is not solely determined by random processes. Since the level of mutated mtDNA in hair follicles was most similar to the level in muscle, the authors suggested that hair follicles may be the best tissue for noninvasive quantitation of the 3243A-G mutation.

Sue et al. (1993) and Schulz et al. (1993) identified the 3243A-G mutation in affected individuals.

Velho et al. (1996) detected the mt3243 mutation in 25 of 50 tested members of 5 white French pedigrees.

Mutation in the MTTE Gene

Vialettes et al. (1997) identified a 14709T-C mutation in the MTTE gene (590025.0001) in a proband with adult-onset IDDM and severe myopathy. The patient was also found to have a subclinical hearing impairment of high frequencies, suggesting maternally inherited diabetes and deafness.

Mutation in the MTTK Gene

Kameoka et al. (1998) identified an 8396A-G mutation in the MTTK gene (590060.0005) in patients with maternally inherited diabetes and deafness.