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Letters to the Editor

Maternally Inherited Diabetes and Deafness Is Phenotypically and Genotypically Heterogeneous: Response

Kattah, Jorge C. MD; Cardenas, Simon R. MD

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Journal of Neuro-Ophthalmology: September 2016 - Volume 36 - Issue 3 - p 344-346
doi: 10.1097/WNO.0000000000000386
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We welcome the comments and table provided by Professors Josef Finsterer, MD, PhD and Marlies Frank, MD in relation to our recent JNO publication (1). They provide further evidence of the highly heteroplasmic nature of maternally inherited diabetes and deafness (MIDD) because of the A3243G mitochondrial RNA mutation. Table 1 from their letter outlines several reports of multiple organ compromise associated with MIDD. In addition, we are also able to answer some of their questions.

Our 2 patients did not have ptosis, and there was no clinical evidence of gastrointestinal or renal involvement. Laboratory test results of renal, hepatic, and gastrointestinal functions also were normal. Patient 2 was diagnosed with MIDD in 1993, the same year that the clinical phenotype was first reported. She was not seen by the authors for 14 years. When evaluated in 2007, she had been on pravastatin, 40 mg daily for 3 years. Although she did not complain of muscle weakness or pain and had no clinical evidence of myopathy, her creatinine phosphokinase (CPK) was elevated (1,074 U/L, normal: 30–135 U/L) but myoglobin was not present in the urine. Pravastin was discontinued, and we recommended avoiding future use of statins. Unfortunately, the patient changed residence over the years, with inadequate continuity of care; as a result, a new prescription for rosuvastatin, 20 mg daily, was prescribed sometime in 2012. One month later, she had severe rhabdomyolysis, which gradually improved. She did not contact us during this period of time, and we do not know the serum CPK level. Her muscle examination in 2013, approximately 1 year later, was normal, and the last CPK was only modestly elevated at 150 U/L (normal: 30–135 U/L). Since then, her mild cholesterol elevation has been managed primarily with diet control.

In relation to additional neurologic symptoms and findings, neither one of our patients has developed acute complications mimicking mitochondrial encephalopathy, lactic acidosis and stroke (MELAS) nor do they report disabling headaches. Both patients had a normal mini–mental status when last examined, and Patient 1 retired from work. Patient 2 has been successfully using a monaural cochlear implant for 22 years, learned how to communicate very efficiently during regular conversation, and raised a family. The question of central nervous system structure–function in this disorder is interesting; one would anticipate greater neurologic impairment considering the imaging findings. To answer this question, one must hypothesize that brain plasticity in response to overt mitochondrial-related structural, neuronal, or glial change has provided effective cognitive, sensory, and motor compensation. Moreover, our 2 patients did not have long-tract sensory signs, and the only sensory abnormality found was decreased pin prick in a stocking distribution in Patient 1. Evoked potentials were not performed.

The white-matter signal changes and cerebral/cerebellar atrophy noted on magnetic resonance imaging (MRI) are likely due to gliosis and neuronal loss; they coincide with tissue calcification on computed tomography in Patient 2 and do not bear similarity to the larger MRI hemispheric lesions found in the classic MELAS phenotype. Cerebral MRI spectroscopy would have been of interest, but was not performed since the diagnosis has been made from the muscle biopsy.

Finsterer and Frank also raise an important point in reference to the MIDD genotype; other mitochondrial mutations may be responsible; thus, the tissue analysis should be comprehensive if the transfer RNA A/G 3243 mutation is not found.

Finally, we agree with the need to proactively test patients with MIDD for subclinical organ failure. Patients with MIDD are eligible for care at muscular dystrophy clinics, where there may be a monetary supplement to their private insurance. Although there is no cure for this disorder at the present time, preventive care may impact substantially on the quality of life.


1. Cardenas SR, Saber Tehrani AS, Blume G, Kattah JC. Visual, ocular motor and cochleo-vestibular loss in patients with heteroplasmic maternally-inherited diabetes mellitus and deafness (MIDD), 3243 Transfer RNA Mutation. J Neuroophthalmol. 2016. in press.
Copyright © 2016 by North American Neuro-Ophthalmology Society