Mitochondrial Mutation A3243G Research Articles

Mitochondrial Mutations as a Cause of Gastrointestinal Dysmotility in Older Patients

Purpose: Mitochondrial mutations affect several organ systems including the gastrointestinal tract. These mutations usually manifest before the 4th decade of life. The most common mitochondrial disorder affecting the gut is MNGIE (Mitochondrial Neuro GastroIntestinal Encephalomyopathy) associated with a thymidine phosphorylase gene mutation. Other mitochondrial diseases associated with GI disease include MIDD (maternally inherited diabetes and deafness) and MELAS (myoencephalopathy, lactic acidosis, stroke like episodes). In these diseases the commonest mutation is with a substitution of A with G at position 3243 in the mitochondrial DNA. We describe two older patients presenting with dysmotility that was associated with the mitochondrial mutation A3243G. Case 1: A 64 year old Caucasian male with history of deafness, diabetes and cardiac dysrhythmia presented with 3 month history of abdominal distention. Imaging studies revealed markedly distended colon with no evidence of mechanical obstruction. He was on TPN for nutritional support. Tests for secondary causes of intestinal dysmotility including connective tissue disorders, amyloidosis, spinal lesions and paraneoplastic dysmotility were negative. Colonic motility testing revealed megacolon with an absent contractile responses to a meal and to intravenous neostigmine. He underwent subtotal colectomy with primary anastomosis and is doing well at 9 months, off TPN and maintaining his weight with oral intake. Full thickness biopsies did not reveal any histological abnormalities Case 2: A 48 year old female with history of diabetes for 20 years, myoclonic epilepsy, lactic acidosis and chronic abdominal pain presented with gastroparesis and constipation. She had a history of a failed pancreatic transplant and brittle diabetes. Her family history was significant for a sister with hearing loss, diabetes, cardiomyopathy and short stature and mother with diabetes and stroke. She was unable to tolerate oral nutrition. She was treated with CoQ10, thiamine and an enterostomy tube was placed for nutritional support. Conclusion: Patients with mitochondrial diseases may have delayed onset of gastrointestinal symptoms. Therefore this needs to be considered and tested for regardless of age in all who present with gastrointestinal dysmotility, diabetes and other features of mitochondrial disease. The phenotypic presentation of mitochondrial disease varies, even with the same mutation. The first patient likely has MIDD while the second patient has MELAS. In carefully selected patients surgical treatment may be appropriate, though one needs to carefully balance the increased surgical risks of malignant hyperthermia and lactic acidemia in patients with MELAS.

Etiological investigation of diabetes in young adults presenting with apparent type 2 diabetes.

Young adults with newly diagnosed apparent type 2 diabetes present the clinician with a wide differential diagnosis of possible etiology, including autoimmune and genetic causes as well as young-onset type 2 diabetes (YT2D). The characteristics of these groups have been described, but it is not known in which subjects investigation for etiology may be beneficial. A total of 268 unselected U.K. Caucasian subjects diagnosed at ages 18-45 years and not treated with permanent insulin for < or =6 months were studied. All subjects underwent clinical assessment and screening for GAD antibodies (GADA) and tyrosine phosphatase IA-2 antibodies (IA-2A). Screening for a common mutation in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene and the common mitochondrial mutation was performed in the antibody-negative subjects. Subjects without insulin resistance were selected for sequencing of the HNF-1 alpha gene. A specific etiology was defined in 11.6% of the 268 subjects and in 24.7% of the lean subjects. Twenty-six subjects (9.7%) were positive for a beta-cell antibody, one subject had familial partial lipodystrophy and the lamin A/C mutation R482W, and two subjects had the mitochondrial mutation A3243G. Two of 15 selected subjects had HNF-1 alpha mutations, the novel missense mutation A501T, and the previously reported R583Q. This unselected series shows that there is considerable heterogeneity in apparent YT2D. beta-Cell autoantibodies should be performed in all those presenting at ages 18-45 years. Genetic investigations can be targeted to phenotypically defined subjects. The finding of a specific etiology will allow individualization of management and give patients valuable information about their condition.