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November 2001

The Other Human Genome

Author Affiliations

From the Center for Congenital Disorders, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY (Dr A. L. Shanske), and the Department of Neurology, Columbia College of Physicians and Surgeons, New York, NY (Drs S. Shanske and DiMauro).

Arch Pediatr Adolesc Med. 2001;155(11):1210-1216. doi:10.1001/archpedi.155.11.1210

In the past 13 years, a new chapter of human genetics, "mitochondrial genetics", has opened up and is becoming increasingly important in differential diagnosis. Although the clinical manifestations of disorders related to mitochondrial DNA (mtDNA) are extremely variable, recent advances in genetic testing aid in the identification of patients. Muscle morphology can give important clues for diagnosis, but histological features alone cannot define a specific disorder. Biochemical analysis may reveal a single enzyme defect, or when multiple activities are affected, suggest an mtDNA mutation. However, definitive diagnosis often requires DNA analysis and documentation of a specific mtDNA abnormality. Disorders associated with mtDNA mutations are associated with a wide variety of syndromes, and owing to the properties and characteristics of mtDNA, these are often transmitted by maternal inheritance. Although therapy for mitochondrial diseases is limited, identification of the molecular defect is important for genetic counseling.

In addition to the nuclear genome, human cells also carry another, much smaller set of genetic information—mitochondrial DNA (mtDNA). Because of their ancestral origins as free-living bacterialike organisms, mitochondria have their own DNA. This small, circular, double-stranded 16.5-kilobase (kb) molecule is miniscule compared with the 3 million kilobases of nuclear DNA. During the past 30 years, human mtDNA has been extensively investigated, and as a result, it is one of the best-characterized portions of the human genome. Its complete sequence has been determined, and its genetic content and mode of expression have been clarified. Somewhat counterintuitively, this small mtDNA has proven to be a seemingly inexhaustible site for deleterious mutations that have been associated with a wide variety of syndromes.

In few fields of medicine has recent progress been as fast and exciting as in the area of mtDNA defects. In the past 13 years, a new chapter of human genetics, "mitochondrial genetics," has opened up and is becoming increasingly important in differential diagnosis and genetic counseling. Although the clinical manifestations of mtDNA-related disorders are extremely variable, recent advances in genetic testing aid in the identification of patients. What makes these diseases uniquely interesting from a genetic point of view is that mtDNA has several distinctive features and is transmitted maternally.

In this article, we will summarize the features of mtDNA and its transmission that are essential for understanding mtDNA-related disorders. We will then briefly review the morphological and biochemical testing that can contribute to the diagnosis of mitochondrial disorders, and go on to discuss the types of mtDNA mutations described to date.


Mitochondria are intracellular organelles that perform several vital metabolic functions, the most important being generation of adenosine triphosphate (ATP) through oxidative phosphorylation. Mitochondria are distinct from other mammalian cellular organelles in that they contain their own genetic material, mtDNA and are capable of synthesizing a small but vital set of proteins. This dual genetic control makes mitochondrial diseases uniquely interesting from a genetic point of view, as they can be due to mutations in either nuclear DNA or mtDNA. Although mtDNA was discovered more than 30 years ago, its importance in human pathology has become apparent only during the last 13 years, when pathogenic mutations of mtDNA have been described in an increasing number.

Human mtDNA is a small, circular, double-stranded molecule 16.5 kb in length (Figure 1). It contains 37 genes, which specify 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and 13 polypeptides. All 13 polypeptides encoded by mtDNA are components of the respiratory chain or oxidative phosphorylation system and include 7 subunits of complex I (nicotinamide adenine dinucleotide [NADH]–coenzyme Q [NADH-CoQ] oxidoreductase), 1 subunit of complex III (CoQ–cytochrome c oxidoreductase), 3 subunits of complex IV (cytochrome c oxidase), and 2 subunits of complex V (ATP synthase). These 4 complexes also contain approximately 75 subunits encoded by nuclear DNA that are imported from the cytoplasm into the mitochondria.

Map of the human mitochondrial genome. The structural genes for the mitochondrial DNA–encoded subunits of nicotinamide adenine dinucleotide [NADH]–coenzyme Q oxidoreductase (ND), cytochrome c oxidase (COX), cytochrome b (Cyt b), and adenosine triphosphate synthase (A8 and A6), in addition to the 12S and 16S ribosomal RNAs (rRNA) and the amino acids specified by the 22 transfer RNAs are shown.

Map of the human mitochondrial genome. The structural genes for the mitochondrial DNA–encoded subunits of nicotinamide adenine dinucleotide [NADH]–coenzyme Q oxidoreductase (ND), cytochrome c oxidase (COX), cytochrome b (Cyt b), and adenosine triphosphate synthase (A8 and A6), in addition to the 12S and 16S ribosomal RNAs (rRNA) and the amino acids specified by the 22 transfer RNAs are shown.

There are several distinctive features of mtDNA that are relevant to the understanding of mtDNA-related diseases.

Maternal Inheritance

At fertilization, all mitochondria are contributed by the oocyte; thus, mtDNA is inherited only from the mother. Therefore, most mtDNA point mutations are maternally inherited: a woman carrying an mtDNA point mutation will transmit it to all of her children, males as well as females, but only the daughters will transmit it to their progeny.

Heteroplasmy and Threshold Effect

In contrast to nuclear genes, each consisting of 1 maternal and 1 paternal allele, there are hundreds or thousands of copies of mtDNA in every cell. Thus, when there is a deleterious mutation, both normal and mutated mtDNAs may coexist within a patient's tissues, a condition known as heteroplasmy. The situation in healthy individuals, in whom all mtDNAs are identical, is called homoplasmy. Nondeleterious mutations of mtDNA (neutral polymorphisms) are homoplasmic, whereas pathogenic mutations are usually, but not always, heteroplasmic. A critical number of mutated mtDNAs must be present before tissue dysfunction and clinical signs become apparent (the so-called threshold effect). Tissues with high requirements for oxidative energy metabolism, such as muscle, heart, eye, and brain, have relatively low thresholds and are particularly vulnerable to mtDNA mutations. Relatively low levels of mutated mtDNAs can affect the respiratory capacity of these tissues, and high levels can be devastating. It is therefore not surprising that most mtDNA disorders are encephalomyopathies, affecting primarily brain and muscle.

Mitotic Segregation

At cell division, the proportion of mutant mtDNAs in daughter cells can shift—a phenomenon termed mitotic segregation. If and when the pathogenic threshold for a particular tissue is exceeded, the phenotype can change. Thus, in a patient who is heteroplasmic for a pathogenic mutation, the clinical phenotype can change during the course of time. The features of mtDNA are summarized in Table 1.

Table 1. 
Features of Mitochondrial DNA*
Features of Mitochondrial DNA*

A modification of the Gomori trichrome histochemical stain allows for the detection of abnormal deposits of mitochondria, which appear as reddish blotches. These so-called ragged-red fibers (RRF) have become the signature of mitochondrial myopathies. However, while the presence of RRF in muscle biopsy specimens is a strong indication of a mitochondrial disorder, it is important to keep in mind that RRF are not a prerequisite for the diagnosis of mitochondrial disease.


Mutations in mtDNA often result in variable biochemical abnormalities, but in some patients with documented mtDNA mutations, results of biochemical studies are normal. Since the 13 proteins encoded by mtDNA are components of 4 respiratory chain complexes, and only a portion of the mitochondrial genome is mutated (heteroplasmy), the biochemical consequences of mtDNA mutations in tRNA genes (see the "Genetic" subsection) are usually partial deficiencies in multiple respiratory chain enzyme complexes. The observation of combined defects of several complexes (except for complex II, which is entirely encoded by nuclear DNA) should immediately suggest the possibility of an mtDNA defect. In contrast, mutations in protein-coding genes often result in a single specific enzyme defect. So respiratory chain enzyme analysis can give clues as to whether and where in mtDNA to look for mutations, but the definitive diagnosis of diseases due to mtDNA mutations relies on DNA analysis.


Since the initial descriptions of mtDNA deletions and point mutations in 1988,1,2 there has been a virtual explosion of information linking mtDNA mutations to human diseases. Although this situation may seem somewhat paradoxical considering that only 13 subunits of respiratory chain complexes are encoded by mtDNA, while the approximate 75 remaining subunits are encoded by nuclear genes, this is probably explained by the small size of mtDNA and the relative ease with which it can be studied. Several different types of defects affecting mtDNA have been described (Table 2).

Table 2. 
Mitochondrial DNA Defects and Associated Syndromes*
Mitochondrial DNA Defects and Associated Syndromes*
mtDNA Point Mutations

The first point mutation in mtDNA was described in 1988,2 and this was associated with Leber's hereditary optic neuropathy. Since then, more than 100 pathogenic mtDNA mutations have been documented,3,4 and new ones are still being described. Point mutations are characterized by single base changes, and these base substitutions can affect either a gene involved in protein synthesis (a tRNA or rRNA gene), or a protein-coding gene (one of the 13 genes encoding subunits of specific complexes of the respiratory chain).

Mutations Affecting Mitochondrial Protein Synthesis

Most point mutations described to date have been in tRNA genes. Since tRNAs are needed for translation of the mtDNA-encoded proteins, all of the 13 mtDNA-encoded proteins can be affected, thus explaining how these mutations affect multiple enzyme activities. Numerous clinical observations have suggested that these mutations are usually associated with multisystem disorders, lactic acidosis, and massive mitochondrial proliferation in muscle, resulting in RRF.

The clinical phenotypes associated with pathogenic mtDNA point mutations in tRNA genes vary widely and include devastating encephalomyopathy, myopathy, optic neuropathy, progressive external ophthalmoplegia (PEO), cardiomyopathy, diabetes and deafness, and isolated neurosensory hearing loss.3,4 Age at onset can be anywhere between infancy and the fifth decade of life (or even later), but many patients with mtDNA point mutations exhibit some symptoms in early childhood. Some of these mutations have been reported in only one or a few families, while others seem to be more common. The clinical features associated with 2 of the more common mtDNA point mutations in tRNA genes, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), and MERRF (myoclonus epilepsy and RRF) are presented in Table 3.

Table 3. 
Clinical Features of Mitochondrial Encephalomyopathies*
Clinical Features of Mitochondrial Encephalomyopathies*

It has become apparent during the past several years that the A-to-G transition at nucleotide position 3243 is the most frequently encountered mtDNA point mutation, and that it can cause a spectrum of clinical presentations. This was the third pathogenic mtDNA mutation to be reported5 and was originally described in patients with the MELAS syndrome.6 It was subsequently observed that maternal relatives carrying this mutation could be oligosymptomatic and have diabetes, short stature, migraine headaches, hearing loss, or other features either alone or in various combinations.7 In addition, this same mutation has been described in some patients with maternally inherited PEO8 as well as diabetes and deafness.9 Age at onset is variable; in one study of 23 patients, onset occurred between the ages of 1 and 53 years.7 Infantile occurrence, while infrequent, has also been reported.10

Pathogenic mutations in rRNA genes are rare. The most common one is in the 12S rRNA gene (A1555G) and has been reported in families with aminoglycoside-induced deafness or nonsyndromic hearing loss.11 Point mutations in tRNA and rRNA genes are transmitted maternally.

Mutations in Protein-Coding Genes

The most common mutations in protein-coding genes are associated with 2 disorders: Leber's hereditary optic neuropathy and NARP/MILS (neuropathy, ataxia, and retinitis pigmentosa/maternally inherited Leigh syndrome).

The first point mutation reported in mtDNA was a G-to-A transition at nucloetide position 11778 in patients with Leber's hereditary optic neuropathy, a disorder characterized by acute or subacute onset of bilateral vision loss in a young adult.2 The Leber hereditary optic neuropathy is associated with 3 primary mutations in genes encoding subunits of complex I of the respiratory chain: G3460A, G11778A, and T14484C.12 Mutations are usually homoplasmic, and muscle biopsies do not show RRF.

A T-to-G mutation at nt8993 in the mtDNA gene encoding adenosine triphosphatase (ATPase) 6 was initially described in patients with a maternally inherited multisystem disorder characterized by NARP.13 Subsequently, the case of a family was reported in which an adult male had the NARP syndrome and 3 children had MILS.14 This association has since been confirmed, and it is now established that, for this particular mutation, there is a good correlation between the percentage of mutant genomes (ie, degree of heteroplasmy) and the severity of the clinical phenotype (ie, patients with low levels of mutation are unaffected or have only mild symptoms, those with intermediate levels have NARP, and those with very high levels [>95%] of mutation are associated with MILS).15 Age at onset for MILS is infancy, and it is characterized by developmental delay with psychomotor regression, signs of brainstem dysfunction such as abnormal respiration and nystagmus, and lactic acidosis; and, in most cases, the course is rapidly progressive. The clinical features associated with these syndromes are presented in Table 3. A few additional point mutations in the ATPase 6 gene have now been reported in association with Leigh-like phenotypes, although clinical manifestations are milder than those in patients with the T8993G mutation.16,17

The mutations in the ATPase 6 gene are maternally inherited and are not associated with RRF in muscle.

Recently, many mutations have been reported in the mtDNA cytochrome b gene18 and in genes encoding subunits of cytochrome c oxidase19,20 and NADH-dehydrogenase.21 Interestingly, some of these patients had only exercise intolerance.18 While exercise intolerance is a common symptom in patients with mitochondrial encephalomyopathies, it is often overshadowed by other symptoms and signs. Only recently have we come to appreciate the fact that exercise intolerance and myalgia, with or without myoglobinuria, can be the sole presentation in patients with mtDNA mutations. While patients with mutations in tRNA genes usually show maternal inheritance, almost all patients with mutations in protein-coding genes have been sporadic, with no evidence for maternal transmission. Additionally, in most cases, these mutations were present only in muscle and were not detectable in blood or fibroblasts. It is believed that these are somatic mutations, ie, spontaneous events that occurred during embryogenesis in muscle after germ layer differentiation and do not affect germ line cells.

Since family history does not provide any useful clues in these cases, one must rely on laboratory testing (in which the presence of lactic acidosis is a useful clue) or muscle biopsy findings. Morphological analysis often shows the presence of RRF, and biochemical analysis shows decreased activity for a specific complex of the respiratory chain: complex III in cases of cytochrome b mutations, complex IV or cytochrome c oxidase in patients with mutations in genes encoding cytochrome c oxidase subunits, or complex I in patients with mutations in genes encoding subunits of NADH-dehydrogenase.

It is important to emphasize that most mitochondrial disorders are a result of mutations in nuclear-encoded genes. For example, cytochrome c oxidase deficiency presenting as Leigh syndrome in infancy is known to be an autosomal recessive disorder. These disorders are not reviewed here. Our purpose is to point out that many mutations in mtDNA structural genes have been documented, and to describe the clinical presentation of these patients.


Point mutations in mtDNA can be readily screened for, usually one at a time, using a combination of polymerase chain reaction and restriction fragment length polymorphism analysis. These analyses can establish, with certainty, whether or not a particular point mutation is present. Of practical importance is the fact that many of these mutations are detectable in DNA isolated from blood; thus, a simple blood test can often establish the diagnosis. In some cases, however, this analysis needs to be performed in DNA isolated from muscle.


Large-scale deletions in mtDNA were first reported in 1988,1 and shortly thereafter, it was shown they are present in almost all patients with the Kearns-Sayre syndrome and in approximately 50% of patients with sporadic PEO and RRF.22 Although dozens of different deletions have been described, each patient harbors only a single type of deletion, and the number of deleted genomes varies in different patients and in different tissues from the same patient (heteroplasmy). Virtually all patients with deletions in mtDNA have been sporadic; mothers of affected individuals and children of affected women are clinically normal, and when tested, they do not show deletions on muscle biopsies. This suggests that deletions arise de novo early in embryogenesis or in the ovum.

Deletions in mtDNA are detected by Southern blot analysis, which shows, in addition to the normal 16.5-kb mtDNA, a population of smaller mtDNA. Deletions in mtDNA are best demonstrated by testing DNA isolated from muscle since most patients with PEO and some patients with Kearns-Sayre syndrome do not show deletions in DNA isolated from blood. Deletions in mtDNA are also detected in blood from infants with Pearson syndrome, which is characterized by refractory sideroblastic anemia, vacuolization of marrow precursors, and exocrine pancreas dysfunction. These patients usually die in infancy, but the few who survive go on to develop symptoms and signs of Kearns-Sayre syndrome.23

The clinical features associated with mtDNA deletions are presented in Table 3. In addition to single mtDNA deletions, some patients harbor more complex rearrangements in mtDNA, which may include duplicated species. A duplication in mtDNA has been associated with maternally inherited diabetes mellitus,24 so some mtDNA rearrangements may be maternally transmitted.


It is known that mtDNA requires several factors encoded by nuclear DNA for its replication, transcription, and translation, but the interactions between the nuclear and mitochondrial genomes are still poorly understood. Thus, it is not surprising that some defects of mtDNA result from mutations in nuclear DNA. Several disorders have been associated with multiple mtDNA deletions, and in these patients, Southern blot tests of DNA isolated from muscle show multiple bands representing species of mtDNA molecules harboring deletions of different sizes. The first family to be described with multiple mtDNA deletions had PEO that was transmitted as an autosomal dominant trait,25 and many cases of additional families with autosomal dominant PEO have now been reported.3 Two families with autosomal recessive PEO and multiple mtDNA deletions also had severe hypertrophic cardiomyopathy.26 A distinctive autosomal recessive multisystem disorder, mitochondrial-neuro-gastrointestinal encephalopathy, is often, but not always, associated with multiple mtDNA deletions.27 Because of the mendelian mode of inheritance, these disorders have been classified as defects of intergenomic signaling, ie, mutations in nuclear genes that either facilitate an intrinsic propensity of mtDNA to undergo rearrangements or impair recognition and elimination of spontaneously occurring rearrangements.

Another defect of intergenomic signaling is mtDNA depletion syndrome, a disorder of infancy or childhood in which the amount of mtDNA is severely reduced in muscle or liver.28 At the molecular level, this disorder is diagnosed by demonstrating a reduced ratio of mitochondrial to nuclear DNA on Southern blot tests, but a definitive diagnosis requires clinical, morphological, and biochemical correlations.29(pp97-108)


Treatment of patients with mitochondrial diseases is woefully inadequate and is often limited to anecdotal cases or to trials that insufficiently allowed for definite conclusions.29(pp173-198),30 One therapeutic approach has been aimed at the removal of noxious metabolites, in particular lactic acid. Dichloroacetate, an experimental agent, lowers serum lactate levels by its direct action on the pyruvate dehydrogenase complex, and preliminary data are encouraging.31 Another approach is supplementation of respiratory chain components. The frequent reports of subjective or objective beneficial results and the virtual lack of deleterious adverse effects have encouraged the use of CoQ10, often in conjunction with L-carnitine. The administration of vitamins, especially thiamin and riboflavin (cofactors of mitochondrial enzymes), is also a common practice for patients with mitochondrial diseases.


Patients suspected of having a mitochondrial encephalomyopathy need to be evaluated at several levels, and relevant studies are presented in Table 4. The diagnostic process starts with a careful clinical assessment and family history. For example, the involvement of extraocular muscles or the presence of maternal inheritance suggests the possibility of an mtDNA mutation. Laboratory tests (such as elevated blood lactate values) and neuroradiological findings offer clues as to mitochondrial etiology. While molecular studies in DNA isolated from blood can sometimes provide a diagnosis, a muscle biopsy is often required. The importance of muscle histology and histochemistry cannot be overestimated. While the presence of RRF confirms mitochondrial dysfunction, the absence of RRF does not rule out mitochondrial disease. Biochemical studies in muscle may provide a definitive diagnosis (eg, a deficiency of a specific enzyme) or provide clues pointing to the possibility of an mtDNA defect (eg, partial deficiencies of multiple enzyme activities). Molecular genetic studies of DNA isolated from muscle are often necessary for the detection of point mutations as well as mtDNA deletions.

Table 4. 
Evaluation of Patients With Suspected Mitochondrial Encephalomyopathy
Evaluation of Patients With Suspected Mitochondrial Encephalomyopathy

In summary, histological features can be important for diagnosis and classification, but morphological features are neither specific nor sensitive enough to define mitochondrial disorders. Single enzyme defects can be determined by biochemical analysis in the affected tissue(s), and these are usually the result of either nuclear DNA defects or mutations in mtDNA protein-coding genes. Mutations in mtDNA can be diagnosed by DNA analysis, often in DNA isolated from blood. Because of the properties and characteristics of mtDNA, these disorders have variable clinical presentations and are usually transmitted by maternal inheritance. Therapy for mitochondrial diseases is limited; however, the rationale for the use of certain compounds, such as carnitine, CoQ10, and many vitamins is sufficient justification of their use in individual patients.

Accepted for publication August 9, 2001.

Some of the work described here was supported by grants PO1HD32062 and NS11766 from the National Institutes of Health (Bethesda, Md) and by a grant from the Muscular Dystrophy Association (Tucson, Ariz).

Corresponding author and reprints: Alan L. Shanske, MD, Center for Congenital Disorders, Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467 (e-mail: ashanske@montefiore.org).

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