| Diabetes and deafness (DAD) | |
|---|---|
| Other names | Diabetes mellitus and deafness, maternally inherited, (MIDD); Diabetes-deafness syndrome, maternally transmitted; Ballinger-Wallace syndrome; Noninsulin-dependent diabetes mellitus with deafness; Diabetes mellitus, type II, with deafness |
 | |
| This condition is inherited via a mitochondrial inheritance manner | |
| Symptoms | Noninsulin-dependent diabetes, deafness, may also have systemic symptoms including eye, muscle, brain, kidney, heart, and gastrointestinal abnormalities, rarely endocrine abnormalities and osteoporosis |
| Causes | Mutation in eitherMT-TL1,MT-TE, orMT-TK |
| Differential diagnosis | Mitochondrial disease |
Diabetes and deafness (DAD) ormaternally inherited diabetes and deafness (MIDD) ormitochondrial diabetes is a subtype ofdiabetes which is caused from a mutation inmitochondrial DNA, which consists of a circular genome. It is associated with the genesMT-TL1,MT-TE, andMT-TK.[1] Thepoint mutation at position 3243A>G, in gene MT-TL1 encoding tRNA leucine 1, is most common.[1][2][3] Because mitochondrial DNA is contributed to the embryo by theoocyte and not byspermatozoa, thisdisease is inherited from maternal family members only.[2] As indicated by the name, MIDD is characterized by diabetes andsensorineural hearing loss.[2] Some individuals also experience more systemic symptoms including eye, muscle, brain, kidney, heart, and gastrointestinal abnormalities, similar to othermitochondrial diseases.[4][5][6]
As suggested by the name, patients with MIDD are subject tosensorineural hearing loss.[2] This begins with a reduction in theperception offrequencies above approximately 5kHz which progressively declines, over the years, to severe hearing loss at allfrequencies.[2] The diabetes that accompanies the hearing loss can be similar toType 1 diabetes orType 2 diabetes; however, Type 1-like diabetes is the more common form of the two. MIDD has also been associated with a number of other issues includingkidney dysfunction,gastrointestinal problems, andcardiomyopathy.[4]
In the eye, MIDD is characterized by progressive atrophy of theretinal pigment epithelium. Initially, thefovea is spared. Thus, patients often have good visual acuity. However, over time the areas of atrophy expand with eventual loss of central vision.[7]
Table 1: Metabolically active organs that can be affected by the mitochondrial point mutation and the associated complication:[1][2][5][6]
| Organ affected | Associated complication |
|---|---|
| Ear (cochlea) | Sensorineural hearing loss |
| Brain (Hypothalamus) | Short stature |
| Brain (general) | Strokes, seizures,atrophy ofcerebellum orcerebrum,ataxia,central nervous system disease, encephalatrophy,basal ganglia calcification, migraine,cerebral infarction,dysarthria |
| Eye | Macular pattern dystrophy,macular degeneration, proliferatedretinopathy,external ophthalmoplegia,ptosis |
| Heart | Congestive heart failure,ventricular hypertrophy,arrhythmia |
| Kidney | Focal segmental glomerulosclerosis,nephropathy |
| Intestine | Malabsorption or constipation |
| Muscle | Mitochondrial myopathy,peripheral neuropathy |
| Testes | Hypogonadism |
| Adrenal glands | Hypoaldosteronism |
| Bones | Osteoporosis |
MIDD represents 1% of people who havediabetes. Over 85% of people that carry the mutation inmitochondrial DNA at position 3243 present symptoms of diabetes. The average age at which people who have MIDD are typically diagnosed is 37 years old but has been seen to range anywhere between 11 years to 68 years old. Of these people with diabetes carrying themitochondrial DNA mutation at position 3243, 75% experiencesensorineural hearing loss.[2] In these cases, hearing loss normally appears before the onset of diabetes and is marked by a decrease in perception of high tone frequencies.[4] The associated hearing loss with diabetes is typically more common and more quickly declining in men than in women.[8]
Mitochondria have their owncircular genome which contains 37genes, of which 22 code fortRNAs.[9] ThesetRNAs play an essential role inprotein synthesis by transportingamino acids to theribosome.[2] MIDD is caused by an A to G substitution in themitochondrial DNA at position 3243, which encodes tRNALeu(UUR).[2] This mutation is typically inheteroplasmic form. A mutation in this gene (A3243G) causes thenative conformation to be destabilized, as well asdimerization in the tRNALeu(UUR). Theuridine at theanticodon first position of the tRNALeu(UUR) is normally post- transcriptionally modified to ensure correctcodon recognition. Such modification is known astaurine modification, which is decreased as a result of the improper structure of the tRNALeu(UUR).[10] Incorrect tRNALeu(UUR) structure also results in decreasedaminoacylation.[9] The mutation has also been shown to result in decreased function of thetRNA and thusprotein synthesis.[11]
The A3243G mutation inmitochondrial DNA can be present in any tissue, however, it is more commonly present intissues with lowerreplication rates such asmuscle.[4] The presence of this mutation can lead to decreasedoxygen consumption as a result of reduced function of therespiratory chain and a decrease inoxidative phosphorylation.[12] In some people, this reduction in function of therespiratory chain is suggested to be caused by unbalanced amounts ofproteins that are encoded bymitochondrial DNA, due to the presence of the A3243G mutation.[4] However, in other people, the same amount ofmitochondrial proteins are generated, but their stability is compromised due to the improper incorporation ofamino acids at the UURcodons of themitochondrialmRNAs. This is a result of the mutated tRNALeu(UUR) with its decreased function inprotein synthesis.[12]A decrease in function of the respiratory chain as a result of amitochondrial DNA mutation could result in a decrease ofATP production. This decrease inATP could have detrimental effects on other processes in the body. One such process isinsulin secretion by pancreaticBeta-cells.[4] In pancreaticBeta-cells, precise levels ofATP/ADP regulate the opening and closing of the KATP channel, which controls the secretion ofinsulin. When mutations in themitochondria disrupt theATP/ADP ratio, this channel cannot function properly and this can result in a person being deficient ininsulin.[4] Since the age of onset is later in a person's life, it has been suggested that age plays a role in contributing, along with the reducedATP/ADP ratio, to the slow deterioration of the function ofB-cells.[4]
Hearing loss, as caused by the 3243mitochondrial DNA mutation, is seen in the form of progressivecochlear dysfunction. Although the mechanism by which the mutation in the tRNALeu(UUR) causes this dysfunction of thecochlea is still under investigation, it has been hypothesized that it involves the ion pumps required for soundtransduction.[13] As the mutation in the tRNALeu(UUR) leads to unbalanced amounts or unstablerespiratory chainenzymes,respiration andoxidative phosphorylation are reduced, leading to lower levels ofATP.[4][12] Naturally, the most metabolically active organs in a person will be affected by thisATP deficiency. Included in these metabolically active organs is thecochlearstria vascularis.[2] Thestria vascularis and thehair cells, both essential to sound transduction, make use ofion pumps to regulate the concentration of ions including K+, Na+, and Ca2+ usingATP. Without sufficient levels ofATP, these concentration gradients are not maintained and this can lead to cell death in both thestria vascularis and thehair cells, causing hearing loss.[13]
Renal impairment is common is MIDD, either as a complication of diabetes or as a distinct renal disease includingFSGS. In some cases, MIDD-related renal impairment may progress to end-stage kidney disease. There is an association between peripheral leucocyte heteroplasmy and the age of renal replacement therapy.[14]
Physical exams, blood tests, family history, biopsy,DNA testing.[6] Mutations in mitochondrial genesMT-TE,MT-TL1, andMT-TK have been associated with MIDD.[1] The most common mutation is the 3243A>G transition in the mitochondrial tRNA-leucine 1 gene (MT-TL1).[1]
Initially, the person is treated by dietary changes and hypoglycaemic agents. This does not last long before the person has to be started on insulin (within 2 years of diagnosis).[15]