Victoria Nesbitt,1 Robert D S Pitceathly,2 Doug M Turnbull,1 Robert W Taylor,1 Mary G Sweeney,3 Ese E Mudanohwo,3 Shamima Rahman,2 Michael G Hanna,2 Robert McFarland1

ABSTRACT

Background Population-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with several clinical syndromes including mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS), maternally inherited deafness and diabetes (MIDD) and progressive external ophthalmoplegia (PEO). Many patients affected by this mutation exhibit a clinical phenotype that does not fall within accepted criteria for the currently recognised classical mitochondrial syndromes. Methods We have defined the phenotypic spectrum associated with the m.3243A>G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK. Results 10% of patients exhibited a classical MELAS phenotype, 30% had MIDD, 6% MELAS/MIDD, 2% MELAS/chronic PEO (CPEO) and 5% MIDD/CPEO overlap syndromes. 6% had PEO and other features of mitochondrial disease not consistent with another recognised syndrome. Isolated sensorineural hearing loss occurred in 3%. 28% of patients demonstrated a panoply of clinical features, which were not consistent with any of the classical syndromes associated with the m.3243A>G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic. Conclusion Following this study we propose guidelines for screening and for the management of confirmed cases.

Katie Nahay Robinson, PA-C1, Sari Terrazas2, Samantha Giordano-Mooga, PhD2, Neena A. Xavier, MD, FACE1

Abstract:

Objective: Maternally Inherited Diabetes and Deafness (MIDD) is a rare diabetic syndrome mainly caused by a point mutation in the mitochondrial DNA (mtDNA), mt3243 A>G. The objective of this paper is to review the genetic inheritance, the clinical manifestations and the treatment of patients with MIDD. Methods: The current review used a literature search of scientific papers on this rare syndrome. Results: MtDNA is primarily inherited through the maternal oocyte, therefore the genetic abnormalities in MIDD are associated with maternal inheritance. Mitochondria contain circular mtDNA which codes for various mitochondrial genes. The mtDNA can be heteroplasmic, containing more than one type of mtDNA sequence; if one of the mtDNAs contains the mt3243A>G mutation, a patient may develop MIDD. Patients can inherit different amounts of mutated mtDNA and normal mtDNA that effect the severity of the clinical manifestations of MIDD. The most common clinical manifestations include diabetes mellitus (DM), deafness, ophthalmic disease, cardiac disease, renal disease, gastrointestinal disease, short stature, and myopathies. In order to effectively treat patients with MIDD it is important to recognize the underlying pathophysiology of this specific form of diabetes and the pathophysiology associated with the organ-specific complications present in this disease. Conclusion: The heteroplasmic inheritance of mutated mtDNA play an important role in the clinical manifestations of various mitochondrial diseases, specifically MIDD. This review will alert endocrinologists of the signs and symptoms of MIDD patients and important clinical considerations when managing this disease.

Patrick Francis Chinnery and Gavin Hudson* Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK

Introduction:

In the last 10 years the field ofmitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aimof this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders.

Sources of data:

In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNAvariation.

Areas of agreement:

The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases.

Areas of controversy:

The exact mechanisms which govern the inheritance of mtDNA are hotly debated.

Growing points:

Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease.

Keywords: mitochondria/genetics/mitochondrial DNA/mitochondrial disease/ mtDNA

Aye Naing a, Manohar Kenchaiah a, Binu Krishnan a, Farheen Mir b, Amanda Charnley a, Catherine Egan c, Gul Bano d,⁎

Abstract

Article history: Received 25 November 2013 Received in revised form 4 March 2014 Accepted 5 March 2014 Available online xxxx Keywords: Mitochondrial disease Retinal dystrophy Deafness Mitochondrial DNA Familial diabetes A to G substitution at position 3243 Mutation 3243 in mitochondrial diabetes Coenzyme Q10 Maternally inherited diabetes with deafness is rare diabetes caused by a mitochondrial DNA defect. 85% of cases are associated with m.3243A N G mutation. It is important to diagnose this form of diabetes because of the unique management issues and associated comorbidities. A very strong family history of diabetes, deafness and presence of retinal dystrophy should prompt an investigation for MIDD. Microvascular complications out of keeping with duration of diabetes are another clue to the diagnosis. Retinal and renal manifestations of mitochondrial disease may be confused for diabetic complications. Glutamic acid decarboxylase (GAD) autoantibody negativity in a nonobese diabetic is another clue. Cardiac conduction defects and GDM may also raise suspicion as to the diagnosis. Recognizing this etiology of DM should promote family screening, genetic counseling, screening of associated comorbidities, avoidance of metformin, and cautious use of statins. We report a 77 years old lady with MIDD who was being followed up as insulin requiring type 2 diabetes. We then identified 5 more patients with MIDD in the same clinic. They all had A3243 mutation with characteristic clinical presentation. The pharmacological approaches discussed in the paper are unlikely to work in these patients as they were diagnosed late.