Developing a systematic approach to the diagnosis and classification of mitochondrial disease

Abstract

The accurate diagnosis and classification of mitochondrial diseases are essential first steps in understanding the natural history and true health care burden imposed by these protean and devastating disorders. Epidemiologic studies place the incidence of genetic forms of mitochondrial disease between 1 in 2000 and 1 in 5000 live births. Symptoms may not appear for years after birth, even when inherited. Once they occur, however, the course is often relentlessly progressive. Diagnosis requires a combination of clinical and laboratory studies that are applied systematically. DNA analysis and respiratory chain studies remain the mainstays of diagnosis, but several other disciplines may contribute to achieving diagnostic confidence when a single study is suggestive but inconclusive. A comprehensive classification system for mitochondrial diseases has not yet been developed. The current International Classification of Diseases, 10th Revision (ICD-10) includes just 10 codes for mitochondrial disorders. Supplementary data of 347 proposed ICD-10 codes is included to assist with the development of a more comprehensive system for the diagnosis and classification of mitochondrial disease.

Introduction

This chapter deals with the diagnosis and classification of mitochondrial diseases defined in their strictest sense, as primary disorders of oxidative phosphorylation. Excellent reviews of the basic biology (Shoffner, 2001), animal models (Wallace, 2002) and clinical presentations (Kerr, 1997, Nissenkorn et al., 2000, Devivo et al., 2003) of mitochondrial disease have appeared in recent years. Mitochondrial medicine is one of the fastest growing areas of biology, and newest fields in medicine, but it has suffered from growing pains in recent years. This has resulted in part from an embarrassment of riches. A dizzying array of signs and symptoms and ages of onset may arise from a single mitochondrial defect. Almost any organ can be affected, and any disease produced by mitochondrial dysfunction. For example, a point mutation such as A3243G in mitochondrial DNA may lead to deafness and diabetes (Maassen et al., 1996), isolated diabetes (Ng et al., 2000), peripheral neuropathy (Fang, 1996), congestive heart failure (Nan et al., 2002), mitochondrial encephalomyopathy and stroke-like episodes (MELAS) (Pavlakis et al., 1984, de Vries et al., 1994), short stature and seizures (Sue et al., 1999), schizophrenia (Mizukami et al., 1992), kidney disease (Kurogouchi et al., 1998), or chronic progressive external ophthalmoplegia (CPEO) (Morgan et al., 1995). Indeed, only about 40% of patients found to have the A3243G mutation have the full MELAS phenotype (Deschauer et al., 2001). Many genes in the genetic background of families and individuals, along with dietary, medical, and unknown environmental factors may influence the expression of mitochondrial disease. These factors have relegated genotype-phenotype correlations to rules of thumb at best, and to seriously flawed paradigms leading to clinical overconfidence and diagnostic errors at worst. A broad knowledge of the epidemiology of mitochondrial disease is needed to guide investigators in their studies of pathogenesis, and ultimately to develop effective treatments. Good epidemiologic studies are absolutely dependent on accurate diagnosis and classification. The latest strategies and efforts toward comprehensive mitochondrial disease diagnosis and classification are reviewed.