Dr. Anju Aggarwal*
Senior Lecturer, University College of Medical Sciences, New Delhi. Email:*
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is the essential final common pathway for aerobic metabolism, and tissues and organs that are highly dependent upon aerobic metabolism are preferentially involved in mitochondrial disorders. The first mitochondrial disorder was described in 1962, since then mitochondrial disorders have emerged as major clinical entities.
How mutations in mitochondrial genome cause disease
Each human cell contains thousands of copies of mtDNA. Mitochondrial DNA in any individual is inherited from the mother, sperms have no mitochondria. At birth these are usually all identical (homoplasmy). By contrast, individuals with mitochondrial disorders resulting from mtDNA mutations may harbor a mixture of mutant and wild-type mtDNA within each cell (heteroplasmy). The proportion of mutant mtDNA must exceed a critical threshold level before a cell expresses a biochemical abnormality of the mitochondrial respiratory chain (the threshold effect). The percentage level of mutant mtDNA may vary among individuals within the same individual. This is one explanation for the varied clinical phenotype seen in individuals with pathogenic mtDNA disorders.
Clinical manifestations
Mitochondrial disorders may affect a single organ or multiple organ systems. They usually present with prominent neurological and myopathic features. Mitochondrial disorders may present at any age. Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system findings are often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity.
Most common presentation in children is failure to thrive, ptosis and seizures. Many individuals display a cluster of clinical features that fall into a discrete clinical syndrome Common diagnosis were KSS, MELAS and encephalomyopathy. Some common syndromes are:
  1. MELAS: (Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). Presentation is stroke like episodes, seizures and/or dementia ragged red fibers and/or lactic acidosis. Patients may have associated cardiomyopathy, deafness, pigmentary retinopathy or cerebellar ataxia.

    They usually present with prominent neurological and myopathic features

  2. Leigh syndrome: Presentation is as subacute relapsing encephalopathy in infancy. Cerebellar and brain stem signs are common. MRI reveals basal ganglia lucencies. Maternal history of Leigh's syndrome or neurological disease may be seen.
  3. NARP : Neurological weakness with ataxia and retinitis pigmentosa. Presents as late childhood or adult onset peripheral neuropathy, ataxia and pigmentary retinopathy. MRI reveals basal ganglia lucencies and ERG is abnormal.
  4. Kearns-Sayre syndrome (KSS) Presents as progressive external ophthalmoplegia, pigmentary retinopathy, raised serum proteins and cerebellar ataxia. Associated features include bilateral deafness, myopathy, dysphagia, diabetes mellitus and hypoparathyroidism.

Other presentation may be as chronic external ophthalmoplegia, Pearson's syndrome, etc. Many individuals do not fall into one specific disease category. The situation is made all the more complex by the poor relationship between genotype and phenotype. This is the clinical classification.
Genetic classification is as follows
  1. Mitochondrial Disorders Caused by Nuclear DNA defects e.g. Leigh's. See Table 1.
  2. Mitochondrial Disorders Caused by mtDNA Defects e.g. MELAS, MERRF. See Table 2.

The genetic approach to classification has certain drawbacks. It is currently not possible to identify the genetic mutation in a significant number of affected individuals, particularly children. In addition, the same genetic mutations may cause a range of very different clinical syndromes (e.g., the A3243G point mutation may cause CPEO, diabetes mellitus and deafness, or a severe encephalopathy with recurrent strokes and epilepsy).

Table 1. Genetic Classification of Mitochondrial Disorders Caused by Nuclear DNA Defects




Leigh syndrome 

Complex I NDUFS4
Complex II NDUFS7
Complex II SDHA

Leukodystrophy and myoclonic epilepsy

Complex I NDUFV1


Complex I NDUFS2

Optic atrophy and ataxia

Complex II SDHA

Leigh syndrome

Complex IV SURF1

Complex IV COX10


Complex IV SCO2

Hepatic failure and encephalopathy

Complex IV SCO1

Autosomal dominant External ophthalmoplegia


Autosomal recessive external ophthalmoplegia


Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)


Table 2. Genetic Classification of Some Mitochondrial Disorders Caused by mtDNA Defects


Type of Gene

mtDNA Mutation

•  Chronic progressive external    ophthalmoplegia (CPEO)
•  Kearns-Sayre syndrome
•  Pearson syndrome
•  Diabetes and deafness


Rearrangement (deletion/duplication)  


Protein encoding

G11778A, T14484C, G3460A

NARP/Leigh syndrome

Protein encoding


Exercise intolerance and myoglobinuria

Protein encoding

Cyt b mutations



A3243G, T3271C, A3251G



A8344G, T8356C



A3243G, T4274C



T14709C, A12320G



G1606A, T10010C



A3243G, A4269G

Diabetes and deafness


A3243G, C12258A

Nonsyndromic sensorineural deafness



Aminoglycoside-induced nonsyndromic deafness



Diagnostic Modalities
Mitochondrial dysfunction should be considered in the differential diagnosis of any progressive multisystem disorder. Diagnostic criteria are shown in Table 3.

Table 3. Genetic Classification of Some Mitochondrial Disorders Caused by mtDNA Defects

Major Criteria

Minor Criteria

Clinical Clinically complete RC
encephalomyopathy* or a mitochondrial cytopathy defined as fulfilling all 3 of the following**
Symptoms compatible with a RC
Histology >2% ragged red fibers in skeletal muscle Smaller numbers of RRF, SSAM, or widespread electron microscopy abnormalities of mitochondria
Enzymology Cytochrome c oxidase negative fibers or residual activity of a RC complex <20% in a tissue; <30% in a cell line, or <30% in 2 or more tissues Antibody-based demonstration of an RC defect or residual activity of an RC complex 20% 30% in a tissue, 30% 40% in a cell line, or 30% 40% in 2 or more tissues
Functional Fibroblast ATP synthesis rates >3 SD below mean Fibroblast ATP synthesis rates 2-3 SD below mean, or fibroblasts unable to grow in galactose media
Molecular Nuclear or mtDNA mutation of undisputed pathogenicity Nuclear or mtDNA mutation of probable pathogenicity
Metabolic   One or more metabolic indicators of impaired metabolic function

ATP indicates adenosine triphosphate; SSAM, subsarcolemmal accumulation of mitochondria.
Patients with 2 major or 1 major and 2 minor criteria were assigned with a definite diagnosis.
*Leigh disease, Alpers disease, LIMD, Pearson syndrome, Kearns-Sayre syndrome, MELAS, MERRF, NARP, MNGIE, and LHON.
**Unexplained combination of multisystemic symptoms that is essentially pathognomic for an RC disorder, a progressive clinical course with episodes of exacerbation or a family history strongly indicative of a mtDNA mutation, other possible metabolic or non-metabolic disorders have been excluded by appropriate testing.
***Added pediatric features: stillbirth associated with a paucity of intrauterine movement, neonatal death or collapse, movement disorder, severe failure to thrive, neonatal hypotonia, and neonatal hypertonia as minor clinical criteria.

Mitochondrial evaluation is often warranted in children with a complex neurologic picture or a single neurologic symptom and other system in involvement.

Mitochondrial evaluation is often warranted in children with a complex neurologic picture or a single neurologic symptom and other system involvement

Following tests should be done in suspected cases:
  1. Measurement of plasma or CSF lactic acid concentration - Arterial Lactate>2 mmol/L or CSF lactate>1.5 mmol/L is suggestive. Normal plasma or CSF lactic acid concentration does not rule out the presence of a mitochondrial disorder.
  2. Ketone bodies are usually present.
  3. Plasma acylcarnitines and urine organic acids.
  4. Cardiac . Both electrocardiography and echocardiography may indicate cardiac involvement (cardiomyopathy or atrioventricular conduction defects)
  5. If these studies are abnormal, the clinician should proceed with Muscle biopsy and assessment of the respiratory chain enzymes. The muscle biopsy should be carried out either in a center with special expertise or in close collaboration with such a center. Respiratory chain complex studies are then usually carried out on skeletal muscle or skin fibroblasts. Modified Gomori stain, lipid stains, succinate dehydrogenase (SDH) and cytochrome oxidase histochemistry is carried out in addition to hematoxylin stain. Electron microscopic finding of subsarcolemmal accumulation of mitochondria is the most common finding.

    Normal plasma or CSF lactic acid concentration does not rule out the presence of a mitochondrial disorder

  6. Neuroimaging . Indicated in individuals with suspected CNS disease. CT may show basal ganglia calcification and/or diffuse atrophy. MRI may show focal atrophy of the cortex or cerebellum, or high signal change on T2-weighted images, particularly in the occipital cortex. There may also be evidence of a generalized leukoencephalopathy.
  7. Neurophysiological studies. Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy or seizures. Encephalopathy may be associated with generalized slow wave activity on the EEG. Generalized or focal spike and wave discharges may be seen in individuals with seizures. Peripheral neurophysiologic studies are indicated in individuals with limb weakness, sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show myopathic features. Nerve conduction velocity (NCV) may be normal, or may show a predominantly axonal sensorimotor polyneuropathy. Magnetic resonance spectroscopy and exercise testing (with measurement of blood concentration of lactate) may be used to detect evidence of abnormal mitochondrial function non-invasively.
  8. Magnetic resonance spectroscopy and exercise testing may also be of use to detect an elevated lactate level in brain or muscle at rest, or a delay in the recovery of the ATP peak in muscle after exercise.

When the presentation is classic for a maternally inherited mitochondrial syndrome, such as MELAS, MERRF, or Leber hereditary optic neuropathy, appropriate mtDNA studies should be obtained first Molecular genetic testing may be carried out on genomic DNA extracted from blood (suspected nuclear DNA mutations and some mtDNA mutations), or genomic DNA extracted from muscle (suspected mtDNA mutations). Studies for mtDNA mutations are usually carried out on skeletal muscle DNA because a pathogenic mtDNA mutation may not be detected in DNA extracted from blood.
  • Southern blot analysis may reveal a pathogenic mtDNA rearrangement. The deletion or duplication breakpoint may then be mapped by mtDNA sequencing.
  • Mutation analysis of a panel of genes may be performed.
  • If a recognized point mutation is not identified, the entire mitochondrial genome may be sequenced. In many individuals in which molecular genetic testing does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function.

Diagnostic criteria are well established for adults, modified diagnostic criteria are used in children in some studies.
Genetic Counseling
Mode of Inheritance
Mitochondrial disorders may be caused by defects of mtDNA or nuclear DNA . MtDNA defects are transmitted by maternal inheritance. Nuclear gene defects may be inherited in an autosomal recessive manner or an autosomal dominant manner.

Risk to Family Members - mtDNA
Parents of a proband
  • mtDNA deletions
  • mtDNA deletions generally occur de novo and thus affect only one family member with no significant risk to other family members.
  • mtDNA point mutations and duplications
  • mtDNA point mutations and duplications may be transmitted through the material line.
  • The father of a proband is not at risk of having the disease-causing mtDNA mutation.
  • The mother of a proband (usually) has the mitochondrial mutation and may or may not have symptoms.

Sibs of a proband: The risk to the sibs depends upon the genetic status of the mother. If the mother has the mitochondrial DNA mutation, all sibs are at risk of inheriting it.

Offspring of a proband:
  • Offspring of males with an mtDNA mutation are not at risk. All offspring of females with an mtDNA mutation are at risk of inheriting the mutation.

Other family members of a proband: The risk to other family members depends upon the genetic status of the proband's mother. If she has a mitochondrial DNA mutation, her siblings and mother are also at risk.

Nuclear DNA mutations will have the usual risk for autosomal dominant and recessive inheritance.

Prenatal diagnosis prenatal diagnosis is available for some of the autosomal recessive mutations at specialized centers.
The management of mitochondrial disease is largely supportive. A variety of vitamins and co-factors have been used in individuals with mitochondrial disorders, but clinical evidence supporting their use is lacking. Food supplements such as ubiquinone (co-enzyme Q10, ubidecarenone) are generally well tolerated and some individuals report a subjective benefit on treatment. Individuals with complex I and/or complex II deficiency may benefit from oral administration of riboflavin. Management includes early diagnosis and treatment of diabetes mellitus, cardiac pacing, ptosis correction, and intraocular lens replacement for cataracts.
Food supplements such as ubiquinone (co-enzyme A10, ubidecarenone) are generally well tolerated and some individuals report a subjective benefit on treatment.
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