Diabetes and deafness (DAD) or maternally inherited diabetes and deafness (MIDD) or mitochondrial diabetes is a subtype of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

which is caused from a

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...

at position 3243 in human

mitochondrial DNA Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...

, which consists of a circular genome. This affects the gene encoding tRNALeu.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, 25(4), 383-99. de Andrade PB, Rubi B, Frigerio F, van den Ouweland JM, Maassen JA, Maechler P. "Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function" ''Diabetologia''. 2006 Aug;49(8):1816-26. Because mitochondrial DNA is contributed to the embryo by the

oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...

and not by

spermatozoa A spermatozoon (; also spelled spermatozoön; ; ) is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote. (A zygote is a single cell, with a complete set of chromosomes, ...

, this

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

is inherited from maternal family members only. As indicated by the name, MIDD is characterized by diabetes and

sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...

Signs and symptoms

As suggested by the name, patients with MIDD are subject to

. This begins with a reduction in the

perception Perception () is the organization, identification, and interpretation of sensory information in order to represent and understand the presented information or environment. All perception involves signals that go through the nervous system ...

frequencies Frequency is the number of occurrences of a repeating event per unit of time. It is also occasionally referred to as ''temporal frequency'' for clarity, and is distinct from ''angular frequency''. Frequency is measured in hertz (Hz) which is eq ...

above approximately 5

kHz The hertz (symbol: Hz) is the unit of frequency in the International System of Units (SI), equivalent to one event (or cycle) per second. The hertz is an SI derived unit whose expression in terms of SI base units is s−1, meaning that on ...

which progressively declines, over the years, to severe hearing loss at all

. The diabetes that accompanies the hearing loss can be similar to

Type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

Type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

; however, Type 1-like diabetes is the more common form of the two. MIDD has also been associated with a number of other issues including

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

dysfunction,

gastrointestinal problem Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the gastrointestinal tract, namely the oesophagus, stomach, small intestine, large intestine and rectum, and the accessory organs of digestion, the liver ...

s, and

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

Genetics

Penetrance and age of onset

MIDD represents 1% of people who have

. Over 85% of people that carry the mutation in

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 the

mutation at position 3243, 75% experience

. In these cases, hearing loss normally appears before the onset of diabetes and is marked by a decrease in perception of high tone frequencies.Maassen JA, Hart LM, Van Essen E, Heine RJ, Nijpels G, Jahangir Tafrechi RS, Raap AK, Janssen GM, Lemkes HH. Mitochondrial diabetes: molecular mechanisms and clinical presentation." . ''Diabetes''. 2004 Feb;53(Suppl 1):S103-9. The associated hearing loss with diabetes is typically more common and more quickly declining in men than in women.Uimonen S, Moilanen JS, Sorri M, Hassinen IE, Majamaa K. Hearing impairment in patients with 3243A-->G mtDNA mutation: phenotype and rate of progression. ''Hum Genet''. 2001 Apr;108(4):284-9.

Effect of mutation on tRNALeu(UUR)

Mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

have their own

circular genome DNA supercoiling refers to the amount of twist in a particular DNA strand, which determines the amount of strain on it. A given strand may be "positively supercoiled" or "negatively supercoiled" (more or less tightly wound). The amount of a st ...

which contains 37

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, of which 22 code for

tRNAs Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino a ...

.Wittenhagen LM, Kelley SO. Dimerization of a pathogenic human mitochondrial tRNA. Nat Struct Biol. 2002 Aug;9(8):586-90 These

play an essential role in

protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...

by transporting

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

to the

ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...

. MIDD is caused by an A to G substitution in the

at position 3243, which encodes tRNALeu(UUR). This mutation is typically in

heteroplasmic Heteroplasmy is the presence of more than one type of organellar genome ( mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells ...

form. A mutation in this gene (A3243G) causes the

native conformation In biochemistry, the native state of a protein or nucleic acid is its properly folded and/or assembled form, which is operative and functional. The native state of a biomolecule may possess all four levels of biomolecular structure, with the ...

to be destabilized, as well as

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ( ...

ization in the tRNALeu(UUR). The

uridine Uridine (symbol U or Urd) is a glycosylated pyrimidine analog containing uracil attached to a ribose ring (or more specifically, a ribofuranose) via a β-N1-glycosidic bond. The analog is one of the five standard nucleosides which make up nuclei ...

at the

anticodon Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...

first position of the tRNALeu(UUR) is normally post- transcriptionally modified to ensure correct

codon The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...

recognition. Such modification is known as

taurine Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. It ...

modification, which is decreased as a result of the improper structure of the tRNALeu(UUR).4.Suzuki T, Suzuki T, Wada T, Saigo K, Watanabe K. Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases. EMBO J. 2002 Dec 2;21(23):6581-9. Incorrect tRNALeu(UUR) structure also results in decreased

aminoacylation Aminoacylation is the process of adding an aminoacyl group to a compound. See also *Acylation * tRNA aminoacylation *Transfer RNA-like structures Transfer RNA-like structures (tRNA-like structures) are RNA sequences, which have a similar tertiar ...

. The mutation has also been shown to result in decreased function of the

tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...

and thus

.Flierl A, Reichmann H, Seibel P. Pathophysiology of the MELAS 3243 transition mutation. J Biol Chem. 1997 Oct 24;272(43):27189-96

Metabolic characteristics of diabetes in MIDD

The A3243G mutation in

can be present in any tissue, however, it is more commonly present in tissues with lower replication rates such as

muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

. The presence of this mutation can lead to decreased

oxygen consumption Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as well as ...

as a result of reduced function of the

respiratory chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

and a decrease in

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

.Janssen GM, Maassen JA, van Den Ouweland JM. The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate. J Biol Chem.1999 Oct 15;274(42):29744-8. In some people, this reduction in function of the

is suggested to be caused by unbalanced amounts of

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that are encoded by

, due to the presence of the A3243G mutation. However, in other people, the same amount of

mitochondrial proteins A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...

are generated, but their stability is compromised due to the improper incorporation of

at the UUR

codons The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...

of the

mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

mRNAs In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...

. This is a result of the mutated tRNALeu(UUR) with its decreased function in

. A decrease in function of the respiratory chain as a result of a

mutation could result in a decrease of ATP production. This decrease in ATP could have detrimental effects on other processes in the body. One such process is

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

secretion by pancreatic

Beta-cells Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimi ...

. In pancreatic

, precise levels of ATP/ ADP regulate the opening and closing of the KATP channel, which controls the secretion of

. When mutations in the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

disrupt the ATP/ ADP ratio, this channel cannot function properly and this can result in a person being deficient in

. 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 reduced ATP/ ADP ratio, to the slow deterioration of the function of

B-cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

Metabolic characteristics of deafness in MIDD

Hearing loss Hearing loss is a partial or total inability to Hearing, hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to Language ...

, as caused by the 3243

mutation, is seen in the form of progressive

cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus. A core component of the cochlea is the Organ of Corti, the sensory org ...

r dysfunction. Although the mechanism by which the mutation in the tRNALeu(UUR) causes this dysfunction of the

is still under investigation, it has been hypothesized that it involves the ion pumps required for sound transduction.Yamasoba T, Oka Y, Tsukuda K, Nakamura M, Kaga K. Auditory findings in patients with maternally inherited diabetes and deafness harboring a point mutation in the mitochondrial transfer RNA(Leu) (UUR) gene. ''Laryngoscope''. 1996 Jan;106:49-53 As the mutation in the tRNALeu(UUR) leads to unbalanced amounts or unstable

enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

respiration Respiration may refer to: Biology * Cellular respiration, the process in which nutrients are converted into useful energy in a cell ** Anaerobic respiration, cellular respiration without oxygen ** Maintenance respiration, the amount of cellula ...

and

are reduced, leading to lower levels of ATP. Naturally, the most metabolically active organs in a person will be affected by this ATP deficiency. Included in these metabolically active organs is the

stria vascularis The stria vascularis of the cochlear duct is a capillary loop in the upper portion of the spiral ligament (the outer wall of the cochlear duct). It produces endolymph for the scala media in the cochlea. Structure The stria vascularis is part of ...

. The

and the

hair cells Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment. ...

, both essential to sound transduction, make use of

ion pumps An ion pump (also referred to as a sputter ion pump) is a type of vacuum pump which operates by sputtering a metal getter. Under ideal conditions, ion pumps are capable of reaching pressures as low as 10−11 mbar. An ion pump first ionizes ga ...

to regulate the concentration of ions including K+, Na+, and Ca2+ using ATP. Without sufficient levels of ATP, these concentration gradients are not maintained and this can lead to cell death in both the

and the

, causing hearing loss. In the eye, MIDD is characterized by progressive atrophy of the

retinal pigment epithelium The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to the underlying choroid and overlying retinal visual ce ...

. Initially, the

fovea Fovea () (Latin for "pit"; plural foveae ) is a term in anatomy. It refers to a pit or depression in a structure. Human anatomy *Fovea centralis of the retina * Fovea buccalis or Dimple * Fovea of the femoral head * Trochlear fovea of the fr ...

is spared. Thus, patients often have good visual acuity. However, over time the areas of atrophy expand with eventual loss of central vision. Table 1: Metabolically active organs that can be affected by the 3243A>G mitochondrial point mutation and the associated complication:

Diagnosis

Treatment

Initial

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).

References

External links

{{Mitochondrial diseases Diabetes Deafness Mitochondrial diseases