T. Muramatsu

Association of aldehyde dehydrogenase with inheritance of NIDDM

SummaryTo investigate the influence of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) genotype on the clinical features of diabetes, 212 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) (154 males and 58 females aged 17–83 years; mean age 58.2 years) were investigated. Genotyping of ALDH2 was performed by the polymerase chain reaction — restriction fragment length polymorphism (PCR-RFLP) method. The pattern of inheritance of diabetes and various clinical parameters was compared between active and inactive ALDH2 groups. Of the 212 subjects, 120 had active ALDH2 and 92 had inactive ALDH2. The percentage of patients with a diabetic mother was higher in the inactive ALDH2 group (32.6%) than in the active ALDH2 group (19.2%) (p<0.05). The prevalence of proliferative retinopathy was lower in the inactive ALDH2 group than in the active ALDH2 group (p<0.05). However, other clinical parameters showed no difference. We conclude that maternal inheritance of diabetes was common in the inactive ALDH2 group. The finding is suggestive of a relationship between alcohol intolerance and inheritance of diabetes. We speculate that the interaction between mitochondrial DNA and ALDH2 inactivity causes an increase of mitochondrial DNA mutations or deletions, thereby inducing the maternal inheritance of diabetes. The relationship of the ALDH2 genotype with proliferative retinopathy is interesting, because it resembles that of chlorpropamide alcohol flushing with severe diabetic retinopathy. The interaction of aldehyde dehydrogenase isoenzymes might have an aetiological role, since aldehyde dehydrogenase 1 plays an important part in oxidation of retinal to retinoic acid. However, the number of affected patients with proliferative retinopathy was small, hence, our result should be considered as a preliminary finding.

Acute metabolic cataract as a first manifestation of diabetes mellitus in a 12-year-old girl.

To the Editor: We report a case of juvenile cataract and Type 2 diabetes in a 26-year-old female (154 cm, 51 kg). A sibling of her mother had impaired glucose tolerance. Polydipsia and leg paresthesia were apparent in this patient with cataract since the age of 10, and she was diagnosed with diabetes at the age of 12. On her first visit, her intelligence and physical examination results were normal, except for bilateral cataracts (an unusual manifestation in a 12-year-old girl). Ptosis, ophthalmoplegia and hearing loss were not observed. Her fasting plasma glucose concentration was 25.3 mmol/l, and her HbA1c was 20.1%. Other laboratory examination data were normal. She began intensive insulin treatment and 4 months later her HbA1c rapidly decreased to 5.9%, and the leg paresthesia disappeared. She underwent successful bilateral cataract extraction with intraocular lens implantation. Four years later, she stopped insulin therapy and has been under excellent control (HbA1c 6.0%) with oral hypoglycaemic agents, and she has been free of symptoms. Neuroimaging findings at the globus pallidus are a sign of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) or mitochondrial diabetes. In this patient, high intensity areas in the bilateral globus pallidus were noted on T1-weighted magnetic resonance imaging at the age of 18 (Fig. 1). However, she was not recognised as showing signs of mitochondrial disease, because the results of detecting mitochondrial DNA (mtDNA) mutation at position 3243 were negative in the laboratories, where the cut-off degree of heteroplasmy ranged from 0.2 to 1%. Informed consent was obtained and the study was approved by the local ethics committee of Saiseikai Central Hospital. Other important data, as to whether other family members had considerable mitochondrial DNA mutation, were not available. A new technology using real-time PCR with a TaqMan Probe was introduced in Diabetologia [1], which can quantify as little as 0.001% of the 3243 mtDNA mutation in blood cells.

Aldehyde dehydrogenase 2 genotype in type 1 diabetes mellitus

a Saiseikai Central Hospital, 1-4-17 Mita, Minato-ku, Tokyo, Japan b Kitazato University, Kanagawa, Japan c Department of Internal Medicine, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Miyagi, Japan d Department of Neuropsychiatry, Keio University, Tokyo, Japan e Fujigaoka Hospital, Showa University, Kanagawa, Japan f Department of Biochemistry and Cell Biology, Institute of Gerontology, Nippon Medical School, Kanagawa, Japan g National Institute of Alcoholism, Kurihama National Hospital, Kanagawa, Japan

No association of ALDH2 genotype in MELAS.

Dear Sir Mitochondrial DNA encodes only for a limited number of mitochondrial proteins whereas the majority of the proteins which constitute the mitochondrion are of nuclear origin. Therefore, alterations in both mitochondrial and nuclear DNA have the potential to affect mitochondrial function [1]. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and mitochondrial diabetes mellitus associated with 3243 tRNALeu(UUR) mutation (MDM3243) are both related to the same 3243 mutation [2]. The mechanism for the different association of the same mutation with the two diseases has not been clarified. We previously reported the importance of inactive aldehyde dehydrogenase 2 (ALDH2) genotype, a nuclear DNA mutation, for inheritance of non-insulin-dependent diabetes mellitus (NIDDM) and its high prevalence in patients with MDM-3243 [3, 4]. This time, we investigated the genotype further in MELAS associated with the 3243 tRNALeu(UUR) mutation (MELAS-3243). We recruited 34 MELAS subjects from four different institutes (National Institute of Neuroscience, Tohoku University, Saiseikai Central Hospital, and Showa University [16 male, 18 female, age from 4 to 50 years, mean ± SD: 23.4 ± 13.4 years, onset of MELAS from 3 to 44 years, 18.2 ± 12.2 years]). They were unrelated. They had hallmarks of MELAS, such as stroke, epilepsy, headache or convulsion. The 3243 mtDNA mutations and ALDH2 genotype were determined in peripheral leukocytes and/or in muscle. The details for the mitochondrial DNA and ALDH2 genotype examination have been described elsewhere [4–6]. The non-diabetic control group for ALDH2 genotype consisted of 461 Japanese who were the same as we previously reported elsewhere. We found 11 (33%) patients with MELAS-3243 had the inactive ALDH2 genotype (Table 1). The frequency of the ALDH2 genotype in MELAS-3243 and normal control subjects were not different. This suggests that the inactive ALDH2 genotype is not associated with MELAS-3243 in contrast to the association of ALDH2 with MDM-3243 as we previously reported [4]. Odawara et al. [7] postulated that, because many MELAS families with 3243 mutation have diabetes and families with diabetes rarely complicate MELAS, factors other than the 3243 mutation are required to account for the phenotypes of MELAS. However, in general, MELAS-3243 patients have an high amount of 3243 mutation in tissues, while MDM-3243 patients show a very low percentage of the mutation even in tissues such as muscles [6]. Since the genetic contribution to pathogenesis in mitochondrial disease is supposed to be greater in those carrying large amounts of deleterious mutation MELAS-3243 may have a greater genetic contribution of 3243 mutation to the initiation of the disease than MDM3243. In contrast, in MDM-3243, other factors like easy acetadehyde accumulation due to inactive ALDH2 genotype or other unknown environmental factors may make a contribution in altering mitochondrial function [3, 4]. Thus, our results suggest the different association of ALDH2 genotype with MELAS-3243 and MDM-3243. This difference may give an hint as to the different aetiologies between the two diseases.