Endocrine dysfunction in mitochondrial disease is commonplace, but predominantly restricted to disease of the endocrine pancreas resulting in diabetes mellitus. performed, and in many cases should be screened in both adults and children prior to nuclear genetic testing, a process which may require investigating numerous candidate genes. This once laborious process is being revolutionised by the next-generation sequencing revolution leading to the identification of many new mitochondrial disease genes over the last 2C3?years. 4.?Diabetes mellitus Diabetes mellitus is well recognised within mitochondrial phenotypes and is the most common endocrine manifestation of disease. This is mainly because of its association with the MIDD phenotype which is usually common in patients carrying the m.3243A?>?G mutation (van den Ouweland et al., 1992; Whittaker et al., 2007). Diabetes is also a common condition in its own right, estimated to affect 4.45% of the UK population. It is not surprising, therefore, that it is common for mitochondrial diabetes to be misdiagnosed, even in the presence of other features that may provide clues as to the underlying genetic disease. The importance of pattern recognition in diagnosis is usually discussed subsequently, but for the m.3243A?>?G mutation, the cardinal features are of maternal Rabbit polyclonal to ZNF215. inheritance and pre-senile sensorineural hearing loss. Prevalence of the m.3243A?>?G mutation in unselected diabetic populations varies between 0% and 2.8% from the larger studies (Vionnet et al., 1993; Katagiri et al., 1994; Otabe et al., 1994; tHart et al., 1994; Kishimoto et al., 1995; Odawara et al., 1995; Uchigata et al., 1996; Abad et PKI-402 al., 1997; Saker et al., 1997; Tsukuda et al., 1997; Holmes-Walker et al., 1998; Lehto et al., 1999; Matsuura et al., 1999; Malecki et al., 2001; Ohkubo et al., 2001; Suzuki et al., 2003; Maassen et al., 2004; Murphy et al., 2008). Deafness, neuromuscular disease, end stage renal disease, and a maternal family history all increase the likelihood of mitochondrial disease (tHart et al., 1994; Majamaa et al., 1997; Newkirk et al., 1997; Smith et al., 1999; Ng et al, 2000; Iwasaki et al., 2001; Klemm et al., 2001; Suzuki et al., 2003; Murphy et al., 2008). There are several other mtDNA mutations recognised to consistently express a phenotype which includes diabetes. These include the m.14709T?>?C mutation (Hanna et al., 1995; Vialettes et al., 1997; Choo-Kang et al., 2002) which has been reported to be homoplasmic in PKI-402 some patients (McFarland et al., 2004) and may cause up to 13% of mitochondrial diabetes in the North East of England (Whittaker et al., 2007). The m.8296A?>?G gene mutation was identified in 0.9% unrelated Japanese patients with diabetes, and 2.3% with diabetes and deafness (Kameoka PKI-402 et al., 1998). The m.14577T?>?C mutation, associated with isolated complex I deficiency, was found in 0.79% unrelated Japanese patients with diabetes (Tawata et al., 2000). Other mtDNA point mutations have been described but appear much rarer. The m.12258T?>?C gene mutation has been associated with diabetes (Lynn et al., 1998) but in other maternally-related kindreds, diabetes has been notably absent (Mansergh et al., 1999). The m.3271T?>?C mutation has been associated with the MIDD, MELAS and MERRF phenotypes (Goto et al., 1991; Suzuki et al., 1996; Tsukuda et al., 1997), whilst the m.3264T?>?C mutation was observed with MIDD, the proband having chronic progressive external ophthalmoplegia (CPEO) and cervical lipomata in addition (Suzuki et al., 1997). PKI-402 In a number of mtDNA mutations, diabetes is not considered part of the established phenotype, despite rare reports. This group includes the m.8344A?>?G mutation causing myoclonic epilepsy and ragged-red fibres (MERRF) (Austin et al., 1998; Whittaker et al., 2007), the m.8993T?>?C mutation which is associated with the maternally-inherited Leigh.