The mitochondrial cytopathies in children are clinically and genetically heterogeneous group of disorders caused by structural and/or functional abnormalities in mitochondria leading to involvement of nervous systems (mitochondrial encephalomyopathies) and other organ systems(1). The concept of mitochondrial disease was first introduced in 1962 by Luft et al. and the term mitochondrial encephalomyopathy was first used in 1977 by Shapira to describe cases with complex multisystem diseases with structurally and/or functionally abnormal mitochondria in brain or muscles. The discovery in 1988 of pathogenetic mutations in mitochondrial DNA (mtDNA) in Leber’s hereditary optic neuropathy (LHON) and in Kearns-Sayre Syndrome (KSS) revolutionized the diagnosis of mitochondrial disorders.

The precise relationship between mitochondrial DNA mutations, impairment of oxidative phosphorylation and clinical phenotypes is not well understood. The prevailing view is that defects in ATP generating capacity due to mitochondrial DNA defect leads to energy failure, cellular dysfunction and eventually cell death in the affected tissues. Recently, in-vitro evidence has indicated the central role of mitochondria in apoptosis. Apoptosis seems to play an important role in the pathogenesis of mitochondrial disorders associated with mtDNA defects affecting mitochondrial protein synthesis(2).

Mitochondrial encephalomyopathies can be subdivided into five groups depending on the area of mitochondrial metabolism affected(3). The defect may be of transport [CPT deficiency, and carnitine deficiency), defects of substrate utilization (pyruvate carboxylase deficiency, pyruvate dehydro-genase deficiency), defects of Kreb’s cycle (fumerase deficiency, alfa ketoglutarate dehydrogenase deficiency], defects of oxidation phosphorylation coupling (Luft’s syndrome) and defects of the respiratory chain (complex 1,2,3,4 and 5 deficiency).

Mitochondrial DNA is maternally inherited because information of zygote mtDNA is contributed by oocyte. Maternal inheritance is now well established as pattern of non-mendelian inheritance in mitochondrial ence-phalomyopathies. The causative mutation in mtDNA or nuclear DNA has been established in a number of cases of mitochondrial cytopathies. Di Nauro (1993) classification subdivides individual mitochondrial diseases on the basis of the site of defect of DNA molecule(3). The defect may be in the nuclear DNA (includes multisystem disorders with Mendelian hereditary pattern), in the mito-chondrial DNA (includes maternally inherited multisystem disorders, e.g., MERRF-myo-clonic epilepsy and red ragged fiber myopathy, MELAS-mitochondrial encephalopathy, lactic acidosis and stroke like episodes, NARP-neuropathy, ataxia and retinitis pigmentosa due to point mutations) and sporadic disorders, e.g., PEO-progressive external ophthalmo- plegia, KSS-Kearns-Sayre syndrome, Pearson syndrome due to deletion, etc.

In clinical classification of mitochondrial encephalomyopathies in children, two schools of thought can be distinguished, the ‘lumpers’ and ‘splitters’. Whereas, the lumpers do not recognize unique clinical entities (phenotypes), the splitters do. The manifestations of respiratory chain encephalomyopathies can be delivered into two groups. The first group comprises symptoms purely linked to skeletal muscles such as progressive external ophthalmoplegia (PEO) or mitochondrial myopathy and exercise intolerance usually without abnormalities of serum creatinine kinase(4). The second group encompasses multisystem manifestations (Table I).

It is caused by failure of brain oxidative metabolism during infancy or early childhood due to complex IV or V of respiratory chain enzyme deficiency secondary to joint mutation at nucleotide position 8993 in mtDNA. The lesions are found in basal ganglia, thalamus, midbrain (periaqueductal grey matter), and other parts of brain stem and cerebellum. The lesions are similar to those with Wernicke’s encephalopathy. The clinical onset is heterogenous. The usual onset in infancy is characterized by failure to thrive and developmental delay. The usual course is episodic neurological deterioration at the time of inter-current infection, ataxia, neuropathy, ophthalmoplegia and pyramidal signs which are frequent in children with Cytochrome Oxidase (COX) deficiency(5). The diagnosis is based on clinical and T2 weighted MRI scans which may show hyperintense signals in putamen and globus pallidus with mildly elevated blood and CSF lactate and pyruvate level.

It is progressive grey matter degeneration of infancy characterized by seizures, developmental regression and progressive motor abnormalities(6).

This non-neurological disease of childhood is characterized by sideroblastic anemia, vascularization of marrow precursors and pancreatic dysfunction. Exceptionally some patients develop signs of Kearns-Sayre syndrome in adolescents.

It is a sporadic multisystem disorder where diagnostic features are childhood onset, progressive external ophthalmoplegia, cardiac conduction block, atypical pigmentary retinal degeneration, dementia, CSF protein >100 mg/dl and red ragged fibers on muscles biopsy. Other features are deafness, ataxia, episodic coma, and endocrine abnormalities (diabetes mellitus, hypoparathyroidism and growth hormone deficiency). MRI shows white matter degeneration. The prognosis is poor due to progressive downhill course(7).

Episodic seizures, vomiting and recurrent stroke like episodes of hemiparesis and hemianopia begin in childhood with severe neurological decline often with dementia until adolescence. The majority of patients have lactic acidosis and red ragged fibers in muscle biopsy. Most cases are caused by point mutation in mtDNA at nucleotides 3243 and 3271(8).

The major clinical features are childhood onset muscle weakness with seizures extending from severe central nervous system dys-function (deafness, ataxia, spasticity, myo-clonus, dementia and peripheral neuropathy) to asymptomatic with red ragged fibers(9). Various seizure types occur including focal seizures, atypical absences, drop attacks, and photosensitive tonic clonic seizures. It occurs due to point mutation at nucleotide 3256 and 8344 of mtDNA.

The point mutation of T to G at nucleotide portion 8893 of mtDNA affects complex V leading to maternally inherited sensory neuropathy, ataxia and retinitis pigmentosa in children. It may be associated with seizures as well(10).

TABLE II–Major and Minor Diagnostic Criteria

PET - Positron emission tomography; 
P-MRS-31 - Phosphate magnetic resonance spectroscopy;
RC - Respiratory chain; RRF - Red Ragged Fiber.

Major and minor diagnostic criteria have been proposed(11) which are outlined in Table II. The presence of one major and one minor criterion or at least 3 minor criteria allows diagnosis of probable mitochondrial disease, while two major or one major and two minor allow definite diagnosis.

Metabolic evaluation: Rise in serum and CSF lactate is not a sole indicator of mitochondrial cytopathy. It may be spuriously raised in ischemia due to tourniquet during collection, diabetic ketoacidosis, liver failure, glycogen storage disease, hypoxic ischemic injury.

Markers of increased mitochondrial content: Red ragged fiber (RRF) is the histological hallmark of muscle biopsy shown by Gommori Trichome staining. Succinate dihydrogenase (SDH) or NADH tetrazolium reductase activity provides a sensitive indicator of mitochondrial proliferation. More intense reaction is seen in red ragged fibers. RRF occurs in high percentage in progressive external opthalmo-plegia (PEO), may be less prominent in MELAS, MERRF and are generally absent in Leigh’s syndrome.

Dietary manipulations including high carbohydrate intake has been recommended to compensate for impaired gluconeogenesis and to decrease lipolysis. Anecdotal success has been reported with a number of vitamins and co-factors [riboflavin, vitamin K, vitamin C(12, 13), thiamin, nicotinamide, carnitine] and glucocorticosteroids. Coenzyme Q10 has been used most extensively in varied doses (10-120 mg/day) and found to be more consistently beneficial in some studies(14) clinically and on investigation (decrease in serum lactate, nerve conduction velocities, muscle metabolism measured by magnetic resonance spectro-scopy). On the other hand other workers obtained no response.

In conclusion, neurological mitochondrial disorders in children have a wide range of age of onset and clinical manifestations. Heightened awareness of these disorders would help towards proper diagnosis and treatment in many previously undiagnosed cases.

Man Mohan Mehndiratta,
Puneet Aggarwal,
Department of Neurology,
GB Pant Hospital,
New Delhi 110 002, India,
E-mail: [email protected]