Maternally inherited diabetes and deafness

Maternally inherited diabetes and deafness (MIDD) is a form of diabetes that is often accompanied by hearing loss, especially of high tones. The diabetes in MIDD is characterized by high blood sugar (glucose) levels, known as hyperglycemia. This results from a shortage of the hormone insulin, which regulates the amount of glucose in the blood. In MIDD, the diabetes and hearing loss usually develop in mid-adulthood, although the age that they occur varies from childhood to late adulthood. Typically, hearing loss occurs before diabetes.

Some people with MIDD develop an eye disorder called macular retinal dystrophy, which is characterized by colored patches in the light-sensitive tissue that lines the back of the eye (the retina). This disorder does not usually cause vision problems in people with MIDD. Individuals with MIDD also may experience muscle cramps or weakness, particularly during exercise; heart problems; kidney disease; and constipation. Individuals with MIDD are often shorter than their peers.

About 1 percent of people with diabetes have MIDD. The condition is most common in the Japanese population and has been found in populations worldwide.

Mutations in the MT-TL1, MT-TK, or MT-TE gene cause MIDD. These genes are found in mitochondrial DNA, which is part of cellular structures called mitochondria. Although most DNA is packaged in chromosomes within the cell nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA).

The MT-TL1, MT-TK, and MT-TE genes provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks (amino acids) into functioning proteins. The MT-TL1 gene provides instructions for making a specific form of tRNA that is designated as tRNA^Leu(UUR). During protein assembly, this molecule attaches to the amino acid leucine (Leu) and inserts it into the appropriate locations in the growing protein. Similarly, the protein produced from the MT-TK gene, called tRNA^Lys, attaches to the amino acid lysine (Lys) and inserts it into proteins being assembled. Also, the protein produced from the MT-TE gene, called tRNA^Glu, attaches to the amino acid glutamic acid (Glu) and adds it to growing proteins.

These tRNA molecules are present only in mitochondria, and they help assemble proteins that are involved in producing energy for cells. In certain cells in the pancreas called beta cells, mitochondria also play a role in controlling the amount of glucose in the bloodstream. In response to high glucose levels, mitochondria help trigger the release of insulin, which stimulates cells to take up glucose from the blood.

Mutations in the MT-TL1, MT-TK, or MT-TE gene reduce the ability of tRNA to add amino acids to growing proteins, which slows protein production in mitochondria and impairs their functioning. Researchers believe that the disruption of mitochondrial function lessens the ability of mitochondria to help trigger insulin release. In people with this condition, diabetes results when the beta cells do not produce enough insulin to regulate blood glucose effectively. Researchers have not determined how the mutations lead to hearing loss or the other features of MIDD.

Genetic Testing Information

• Genetic Testing Registry: Diabetes-deafness syndrome maternally transmitted

Genetic and Rare Diseases Information Center

• Maternally-inherited diabetes and deafness

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• DIABETES AND DEAFNESS, MATERNALLY INHERITED; MIDD

Scientific Articles on PubMed

• PubMed

• Kameoka K, Isotani H, Tanaka K, Kitaoka H, Ohsawa N. Impaired insulin secretion in Japanese diabetic subjects with an A-to-G mutation at nucleotide 8296 of the mitochondrial DNA in tRNA(Lys). Diabetes Care. 1998 Nov;21(11):2034-5. doi: 10.2337/diacare.21.11.2034. No abstract available. Citation on PubMed
• Maassen JA, Jahangir Tafrechi RS, Janssen GM, Raap AK, Lemkes HH, 't Hart LM. New insights in the molecular pathogenesis of the maternally inherited diabetes and deafness syndrome. Endocrinol Metab Clin North Am. 2006 Jun;35(2):385-96, x-xi. doi: 10.1016/j.ecl.2006.02.014. Citation on PubMed
• Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med. 2008 Apr;25(4):383-99. doi: 10.1111/j.1464-5491.2008.02359.x. Epub 2008 Feb 18. Citation on PubMed
• Supale S, Li N, Brun T, Maechler P. Mitochondrial dysfunction in pancreatic beta cells. Trends Endocrinol Metab. 2012 Sep;23(9):477-87. doi: 10.1016/j.tem.2012.06.002. Epub 2012 Jul 4. Citation on PubMed
• van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, van de Kamp JJ, Maassen JA. 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. doi: 10.1038/ng0892-368. Citation on PubMed
• Vialettes BH, Paquis-Flucklinger V, Pelissier JF, Bendahan D, Narbonne H, Silvestre-Aillaud P, Montfort MF, Righini-Chossegros M, Pouget J, Cozzone PJ, Desnuelle C. 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. doi: 10.2337/diacare.20.11.1731. Citation on PubMed