Case Reports

Indian Pediatrics 2000;37: 545-549

Mitochondrial encephalomyopathies (ME) comprise a heterogenous group of neuro-degenerative disorders caused by defects of mitochondrial metabolism. In the recent years these disorders have emerged as a major cause of certain hitherto undiagnosed progressive neurological syndromes. Myoclonic epilepsy with ragged red fibres (MERRF) is an infrequently encountered maternally inherited ME. We present 3 cases of this uncommon condition.

Cases 1 and 2: A 10-year-old male child, product of a nonconsanguineous marriage, presented with gait disturbance and slurring of speech for five years. He had a normal development till five years of age when he started swaying while walking, with inter-mittent falling to either side. Slurring of speech was also noticed around the same time. Three months later, he developed generalized tonic-clonic seizures, which had since been recurring every 15-20 days. In addition, jerky movements of the body were noticed occurring infrequently initially, but gradually increasing in frequency to 6-7 per day at the time of presentation. There was no mental deterioration or visual/auditory symptoms. Similar symptoms were also noticed in a younger sibling of the patient (Case 2). No other family members were similarly affected. On examination, the patient had a normal height, weight and head circumference. There were no oculo-cutaneous telangiectasiae and the fundus was normal. Frequent myoclonias, involving neck, trunk and proximal portions of limbs were observed during awake state with cessation during sleep. Marked ataxia with broad based gait, intention tremors, dys-diadochokinesia, pastpointing and scanning speech was present. There was no muscle wasting or weakness and no sensory impairment.

The patient had a normal hemogram, serum electrolytes, liver and kidney function tests, serum copper, ceruloplasmin and alpha fetoprotein level. Fasting serum and CSF lactate were both elevated at 40 mg/dl (normal 8-22 mg/dl) and 14.7 mg/dl (3–12mg/dl), respect-ively. The CT scan skull, BERA and VER were normal. The EEG showed generalized epi-leptiform discharges. Muscle biopsy from Vastus lateralis showed 20% fibres with increased peripheral and intermyofibrellar reactivity on succinic dehydrogenase enzyme reaction (Fig. 1). Modified Gomori trichrome stain showed ragged red fibres corresponding to those seen on SDH stain.

The 5-year-old younger brother of this child also developed similar complaints of unsteady gait and involuntary jerks from the age of three and half years. He had a normal development prior to onset of symptoms. On examination he had dysarthria, ataxia and frequent multifocal myoclonic jerks. There was no motor or sensor abnormality, no deafness and the fundus was normal. He was also found to have an elevated serum and CSF lactate concentraton (30 mg/dl and 16 mg/dl, respectively). All other laboratory investigations were normal. EEG showed diffuse slowing of background activity. The CT scan was normal. Muscle biopsy was not done since his clinical presentation was similar to that of his brother. Blood examination for mitochondrial DNA of both brothers did not reveal any mutation.

Case 3: A 2½-year-old boy with a normal prior development presented with progressive impairment in walking with frequent falls, followed by inability to stand without support for 1½ months. This was associated with clumsiness in hand movements and inability to feed self. Shortly after presentation he developed sudden jerks involving the whole body occurring with the frequency to 10-15/day. There was no family history of any neurological illness. On examination, he had a normal stature and head circumference. There was bilateral coarse nystagmus, intention tremors, truncal ataxia and unsteady gait. Frequent multifocal myoclonic jerks, at times generalized and leading to fall were noticed. There was no wasting but mild proximal weakness in lower limbs was present. The fundus was normal. Investigations revealed normal levels of serum CPK, ammonia and AFP. The urinary aminoacidogram was normal. Serum lactate levels were elevated (24.6 mg/dl). Muscle biopsy from Vastus lateralis muscle showed presence of ragged red fibres in 10% of muscle fibres. The EEG, BERA and the MRI scan were normal.

The diagnosis of MERRF was made in the three cases on the basis of clinical and histopathological features. They were given Vitamin B complex, C and E in the usual doses and adequate dietary intake was ensured. Case 1 also received sodium valproate. Due to economic constraints Coenzyme Q10 and methyl prednisolone could not be given. They are presently on regular follow up for the last 1 year. The seizures of Case 1 are under control. The cerebellar signs and myoclonias are however persisting in all of them. No deterioration of intellect has been noticed so far.

Mitochondrial encephalopathies are degenerative disorders which result from progressive decline in cellular energy, due to biochemcial defects affecting one or more of mitochodrial respiratory chain complexes I, III and IV(1). MERRF is an infrequently encountered ME characterized by myoclonus, ataxia and convulsions(2). Other less common manifestations include muscle weakness and wasting, dementia, hearing loss, progressive intellectual deterioration and stroke like episodes. Short stature and lipomas may also be associated(2). However, the clinical spectrum is wide, including those with minimal involvement at one end and with severe disability at the other(3). The affected individuals usually have a normal development in early years of life, with the age at onset of symptoms varying from early childhood to the 4th decade of life. Biochemically, elevated blood and CSF levels of lactate, pyruvate and/or alanine are seen indicating oxidative phosphorylation defect(4). Results of imaging studies are non-specific and may reveal intra cerebral calcification or cerebellar atrophy(2). The EEG may show diffuse background slowing with generalized epileptiform discharges and photosensitivity or giant somato sensory evoked potentials(5).

The histological hallmark of all ME including MERRF is the ragged red fibre (RRF) in muscle biopsy. The RRF reflects the over production of abnormal mitochondria and can be visualized histochemically with succinic dehydrogenase or the Gomori trichrome stain(6,7). Identification of any RRF in a young person (< 30 years old) is suspicious of ME and levels above 2% can be regarded as a major diagnostic indicator at any age(4). Electron microscopy reveals evidence of abnormal mitochondria (inclusions, crystal abnormalities, giant mitochondria) or proliferation of mitochondria normal in structure and size(8). The defect in respiratory chain can be measured by histo/biochemical assay of individual enzyme components(9). These assays are however not available here.

MERRF is usually a maternally inherited genetic disease with a mitochondrial DNA point mutation at 8344th nucleotide position. Mutations at nucleotide positions 3243 and 8356 have also been reported. However, acquired causes cannot be excluded specially in sporadic cases(10). Also, mutations may not be observed in all cases(11). In some cases, deletions may be found only in muscle DNA with little deleted DNA in blood. In the first two cases we have been unable to demonstrate the mutation in blood; the DNA studies could not be carried out in the 3rd case.

The main differential diagnosis in these cases was from ataxia telengiectasia, Wilsons Disease, and in the first case, other disorders presenting like progressive myoclonus epilepsy (PME) including Lafora disease and neuronal ceroid lipofuscinosis. These were excluded by appropriate laboratory investigations. Certain organic acidemias producing similar clinical picture may also be associated with elevated serum lactate levels. These were ruled out by absence of hypoglycemia, hyper-ammonemia and a normal urinary aminoacidogram.

Recently, an approach which delineates major and minor criteria for diagnosis of ME has been proposed(4). Our cases satisfy the clinical and histological criteria described for definite diagnosis of MERRF.

Management of MERRF is mainly supportive and includes prevention and treatment of catabolic stresses like infections, fever, starvation and excessive physical exertion which may exacerbate the condition. Seizures should be controlled and adequate caloric intake ensured. Drugs compromising mitochondrial function (phenytoin, pheno-barbitone, chloramphenicol, etc.) should be avoided. Drug treatment includes use of agents which may act as electron transfer mediators to circumvent reduced activity of respiratory enzymes (Vitamin K3, C), or antioxidants (Vitamin C, E and Co Q10). Steroids may help by increasing muscle strength(12). Recent reports have also found encouraging results with use of cytochrome C, Vitamin B1 and B2(13) and 21 aminosteroids.

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11. Hammans SR, Sweeney MG, Brockington M, Morgan Hughes JA, Hardinge AE. Mito-chondrial encephalopathies: Molecular genetic diagnosis from blood samples. Lancet 1991; 337: 1311-1312.

12. Peterson PL. The treatment of mitochondrial myopathy and encephalomyopathies. Biochem et Biophys Acta 1995; 1271: 275-280.

13. Tanaka J, Nagai T, Arai H, Iniu K, Yamanouchi H, Goto Y, et al. Treatment of mitochondrial encephalomyopathy with a combination of cytochrome C and vitamins B1 and B2. Brain Dev 1997; 19: 262-267.