BY CHRISTINE SHEELER; SEEMA ELAHI, MD
A 46-year-old man presented to the ED with multiple complaints, including fatigue and dizziness for one day. His primary care physician had diagnosed him with diabetes the previous day, and had prescribed him an oral hypoglycemic as well as insulin. Neither, however, was started at the time of presentation. The patient had a medical history significant for HIV, with his most recent CD4 count above 500, and bilateral sensorineural hearing loss, which had progressively worsened since its initial onset in his 20s. His physical exam was unremarkable except for decreased hearing bilaterally.
A laboratory workup was ordered, including CBC with differential, CMP, blood glucose, β-hydroxybutyrate, and an ECG. Laboratory results were remarkable for a blood glucose level of 593 mg/dl, β-hydroxybutyrate of 7.52 mmol/L, CO2 of 15 mmol/L, and an anion gap of 20, indicating that the patient was suffering from diabetic ketoacidosis. Laboratory results were also significant for a GFR of 33.3 ml/min and creatinine of 2.15 mg/dl, indicating kidney failure. All other results were within normal limits, and his ECG showed no abnormalities.
A thorough family history was taken, and was significant for both diabetes and deafness throughout the patient's maternal side and absent on the paternal side. (Figure.) The patient's brother and mother were deaf and had diabetes, and both were diagnosed before they were 45. His mother's siblings are all affected by at least one pathology. His maternal aunt and uncle were deceased due to stroke and kidney failure, respectively. His maternal grandmother was also affected by diabetes and deafness. His cousins born to maternal uncles were not affected.
The patient was immediately treated with insulin, and was admitted for further investigation and treatment. Due to the patient's strong family history of diabetes, hypoacusis, and pattern of inheritance, a working diagnosis of maternally inherited diabetes and deafness (MIDD) was explored. At the time of admission, the patient was being counseled on genetic testing for confirmation.
An Unrecognized Genetic Disease
MIDD is a distinct subtype of diabetes, caused by a single point mutation in mitochondrial DNA. The mutation most associated with MIDD involves the mtRNALeu(UUR) gene and consists of a 3243A>G transition. (Diabetes 1994;43:746.) It is believed to be part of a spectrum where patients most affected present with MELAS. (Arch Soc Esp Oftalmol 2009;84:360.) As a result of the involvement of mitochondrial DNA, MIDD is inherited by children of all the affected women, while the affected men pose no risk of passing on the mutated genes. (Diabetologia 1996;39:375.)
The syndrome consists of diabetes and sensorineural hearing loss, and may include other organ system manifestations, including ophthalmologic, cardiac, renal, muscular, and neurological pathologies. The organs that are most metabolically active are most commonly involved; they are most affected by deficiencies in mitochondrial-based respiratory oxidation, leading to inefficient cellular energy production. (Diabet Med 2008;25:383.) It is believed that MIDD is responsible for approximately one percent of all diabetic diagnoses. It is, however, often misdiagnosed as Type 1 or 2 diabetes or as Alport syndrome when only deafness and renal symptoms are present. (Diabet Med 2008;25:383.)
The diabetes of MIDD appears to be due to lack of insulin secretion rather than insulin insensitivity. (Ann Intern Med 2001;134[9 Part 1]:721.) The onset of diabetes is usually gradual, with age of onset occurring at 37± 11 years, although up to 20 percent of patients will present acutely and up to eight percent will experience ketoacidosis. (Diabet Med 2008;25:383.)
More than 75 percent of patients will experience sensorineural hypoacusis attributed to the cochlea rather than the cranial nerve. This hearing loss most often presents before the diabetes manifests itself, and is often the only clinical manifestation of the mutation. (Ann Intern Med 2001;134[9_Part_1]:721.)
Associated diseases include end-stage renal failure, myocardiopathies with early heart failure and stroke, muscular abnormalities including biopsies indicating ragged red fibers, characteristic macular retinal dystrophy, and psychiatric disorders such as depression and schizophrenia. (Diabet Med 2008;25:385.)