Regular Article
Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes

https://doi.org/10.1053/beem.2001.0149Get rights and content

Abstract

Inherited diabetes syndromes are individually rare but collectively make up a significant proportion of patients attending diabetes clinics, some of whom have multiple handicaps. This chapter focuses on syndromes in which major advances have been made in our understanding of the underlying molecular genetics. These conditions demonstrate novel genetic mechanisms such as maternal inheritance and genetic imprinting. They are also fascinating as they aid our understanding of insulin metabolism, both normal and abnormal. As the causative genes are identified, future issues will be the availability of genetic testing, their contribution to the genetic heterogeneity of the more common types of diabetes, and functional studies of the relevant proteins. It is probable that other subtypes of diabetes will be identified as the relevant metabolic pathways are characterized. This is an exciting time to be a diabetes physician as diabetology returns to being a diagnostic rather than a mainly management-based speciality.

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      Generally, tissues with high-energy requirements, such as the brain, heart, liver and skeletal muscle, are most affected by mitochondrial disease. Inherited syndromes involving diabetes are estimated to make up about 5% of children seen in diabetes clinics (1). Diabetes due to mitochondrial disease can result from point mutations (maternally inherited diabetes and deafness, mitochondrial encephalopathy lactic acidosis and strokelike episodes); deletions or rearrangements in mtDNA (such as Kearns Sayre syndrome (KSS) or other deletion syndromes); or nuclear mutations (Wolfram syndrome, thiamine-responsive megaloblastic anemia).

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      This protein is a large molecule that has been proposed to reside within the endoplasmic reticulum [11], although it is not clear whether this represents its only site of localisation. Inherited mutations in the molecule have been found in familial cases of Wolfram syndrome [2–7], but it has not proved possible to group these within specific functional domains, suggesting that even relatively minor alterations to the structure of the molecule may exert detrimental effects on cell function [2]. However, the mechanistic link between mutations in wolframin and specific cell dysfunction has not been established.

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