Maternally transmitted syndrome with diabetes mellitus (DM), sensorineural deafness, and ophthalmic abnormalities.
Maternally Inherited Diabetes Mellitus-Deafness (MIDD) Syndrome; Noninsulin-Dependent Diabetes Mellitus with Deafness.
The substitution of adenine for guanine at position 3243 (3243A→G mutation; see below) has been found in up to almost 3% of patients with diabetes mellitus (DM) and approximately 60% of diabetic patients suffering from hearing loss. The frequency of the mutation in the hearing impaired population is about 0.3%. The calculated prevalence of the 3243A→G mtDNA mutation in the general adult population is approximately 16 in 100,000. DM affects 5% of the population in the Western world and consists of a genetically heterogeneous group of disorders with glucose intolerance being the common clinical feature. More than 60 different hereditary DM syndromes have been described. Maternally inherited DM and deafness represent a unique syndrome within this group.
This mitochondrial form of DM and deafness is inherited in a heterogeneous pattern. The syndrome has been associated with a 10.4-kb mitochondrial DNA (mtDNA) deletion and a heteroplasmic mutation of 3243A→G, altering the mitochondrial transfer RNA (tRNA) for leucine. The deletion is unique because it is maternally transmitted, removes the light strand origin of mtDNA replication, inhibits mitochondrial protein synthesis, and is not associated with the hallmarks of other mtDNA deletion syndromes (ptosis, ophthalmoplegia, or muscle weakness).
The mtDNA deletion causes a defect in the mitochondrial oxidative phosphorylation, which impairs pancreatic islet cell function. Once the mitochondrial adenosine triphosphate (ATP) production of the islet cells falls below the level required for appropriate glucose “sensing,” DM ensues. However, the exact mechanism of protein synthesis inhibition is unclear.
Based on the clinical features consistent with the disorder (ie, abnormal glucose tolerance test, audiometry testing, and ophthalmic findings). Family history demonstrates maternal inheritance. However, confirmation of the diagnosis requires the identification of the mutation in the mitochondrial genome.
This syndrome is characterized by DM in usually nonobese patients with onset typically between 20 and 40 years of age. Initially, DM is most often noninsulin dependent, but after an average of approximately 10 years it becomes insulin dependent. Sensorineural hearing loss is progressive (onset often between 15 and 50 years of age), bilateral, mainly affects the high frequencies, and is commonly severe. Occasionally impaired vestibular function (unsteady gait, dizziness) has been reported. The ear structures affected the most are the vascular striate and ciliate cells. More than 80% of MIDD patients develop bilateral macular pattern retinal dystrophy with the most common phenotype being bilateral perifoveal patchy atrophy that over time tends to coalesce to a perimacular, circumferential ring of retinal atrophy. The retinal pigment epithelium can appear granular with pale deposits and pigment clumping. ...