Biochemical and molecular studies of mitochondrial function in diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.
OBJECTIVE
To determine if diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) combined with a cerebellar syndrome is associated with a systemic disorder of respiratory chain function as found in similar genetic syndromes.


METHODS
A muscle biopsy was taken from a patient with DIDMOAD, and a mitochondrial fraction was prepared. Respiratory chain function was assessed by analysis of intermediary metabolites, histochemical analysis of muscle biopsy, measurement of the activity of individual respiratory chain complexes, oxidative flux through the respiratory chain, and cytochrome concentration and compared with a population with normal respiratory chain function. Mitochondrial DNA from skeletal muscle, brain, and pancreas was examined for major rearrangements and specific point mutations. Brain tissue was examined neuropathologically for abnormalities, particularly those previously described in association with DIDMOAD.


RESULTS
No abnormality was found in mitochondrial oxidation, individual complex activity, or cytochrome concentration. Histochemical analysis and electron microscopy showed no abnormality known to be associated with mitochondrial dysfunction. A single-base substitution at position 12308 of the mitochondrial genome was found, but no major rearrangement of mitochondrial DNA was demonstrated. Neuropathological examination revealed severe demyelination and gliosis in the optic nerves and loss of Purkinje cells associated with gliosis in the white matter in the cerebellum.


CONCLUSIONS
We have found no evidence that DIDMOAD is associated with a systemic abnormality of respiratory chain function. The mitochondrial DNA single-base substitution noted is likely to be a polymorphism rather than a pathogenic point mutation. We have confirmed that DIDMOAD may be associated with a neurodegenerative disorder, but the cause of this remains undetermined.
Jackson
M J
MJ
Division of Clinical Neuroscience, University of Newcastle upon Tyne, U.K.
Bindoff
L A
LA
Weber
K
K
Wilson
J N
JN
Ince
P
P
Alberti
K G
KG
Turnbull
D M
DM
D000328:Adult; D001344:Autopsy; D001706:Biopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003573:Cytochrome b Group / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004272:DNA, Mitochondrial / Q000235:genetics / Q000302:isolation & purification; D003576:Electron Transport Complex IV / Q000378:metabolism; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D014929:Wolfram Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D003573:Cytochrome b Group; D003574:Cytochrome c Group; D004272:DNA, Mitochondrial; D004247:DNA; D003576:Electron Transport Complex IV