Clinical Manifestations due to a Point Mutation of the Mitochondrial tRNAleu(UUR) Ge Five Families with Diabetes Mellitus.

Abstract

It has been shown that an adenine (A) to guanine (G) transition at position 3243 of the mitochondrial transfer RNA(tRNA)leu(UUR) gene is associated with a subgroup of diabetes mellitus. Therefore, we screened for this transition in 86 patients with non-insulin-dependent diabetes mellitus (NIDDM)in which two or three generations were affected with diabetes, in 14 patients with insulin-dependent diabetes mellitus, and in 9 families with diabetes mellitus and/or associated disorders suggesting mitochondrial gene abnormalities. Wefailed to identify the mutation in 100 diabetic patients, 86 NIDDMand 14 insulin-dependent diabetes mellitus (IDDM). Out of the latter 9 families, we identified an A to G transition in 14 individuals in 5 families. Diabetes mellitus was shown to be maternally inherited in one family. In 9 of 14 patients with the mutation, insulin was required to treat diabetes mellitus, indicating impaired insulin secretion. A hyperglycemic clamp test performed in one subject revealed significant impairment of insulin secretion, whereas euglycemic clamp test showed normal insulin sensitivity in this patient. The heteroplasmy of the mutant mitochondrial DNA(mtDNA)in leukocytes does not appear to correlate with the severity of diabetes in terms of the insulin therapy required. Bodymass index of the affected individuals was less than 23.3. In one family, in addition to diabetes mellitus and hearing loss, hypoparathyroidism was associated with the mutation, suggesting that hypoparathyroidism is caused by the impaired processing and/or secretion of proparathyroid hormone due to the mutation. In addition, the affected subjects presented with proteinuria at the time of diagnosis of diabetes mellitus which appeared not to be related with diabetic nephropathy. (Internal Medicine 37: 265-272, 1998)

Respiratory chain deficiency presenting as congenital nephrotic syndrome

“…Delayed-onset steroid-unresponsive NS with focal segmental glomerulosclerosis, mostly ascribed to the 3243 MELAS mutation, has been reported in children and adults, in association with muscle weakness, neurological disturbance, deafness, pigmentary retinopathy, and/or diabetes mellitus [9,10,11,12,13,14,15]. Proteinuria was the first symptom of the disease in 12 patients aged 10-32 years [16,17,18,19,20,21]. There have been rare reports of NS linked to RC disorders in the absence of the MELAS mutation; one was associated with quinone deficiency [9,14,15].…”

“…Delayed-onset NS has occasionally been the first manifestation of the disease and the 3243 MELAS mitochondrial (mt) DNA mutation has been detected in most cases [1,16,17,18,19,20,21]. To date, however, respiratory chain (RC) deficiency has never been described as a cause for congenital NS, although secondary mitochondrial dysfunction has been documented in NS of Finnish type.…”

Mitochondrial DNA A3243G mutation in patients with early‐ or late‐onset type 2 diabetes mellitus in Hong Kong Chinese

“…The clinical features were variable amongst subjects carrying mitochondrial mutations. Although defective pancreatic β‐cell function has been demonstrated in diabetic patients carrying this mutation (Kadowaki et al ., 1994; Velho et al ., 1996; Shigemoto et al ., 1998), the mutation carriers in this study showed variable fasting plasma C‐peptide levels (0.23–0.83 nmol/l). Only one subject required insulin treatment (Table 2).…”

Diabetes Mellitus, Deafness, Muscle Weakness and Hypocalcemia in a Patient with an A3243G Mutation of the Mitochondrial DNA.

“…The parathyroid gland may also be vulnerable to mutations in mtDNA because its function requires a high energy supply. In fact, idiopathic hypoparathyroidism has been described in another mitochondrial encephalomyopathy, Kearns-Sayre syndrome (14)(15)(16)(17), as well as in diabetic patients with an A3243G mutation of mtDNA (18,19 may also be necessary to examine mutations in the mtDNAof individuals with idiopathic hypoparathyroidism, especially those with a family history of the disease and/or with diabetes mellitus or impaired hearing.…”