Anita Khalil

From the Department of Pediatrics, Maulana Azad Medical College & Associated Lok Nayak Hospital, New Delhi 110 002, India and Departments of Neurology* and Pathology** G.B. Pant Hospital, New Delhi 110 002, India.

Revision Accepted: March 1, 1998

Mitochondrial encephalomyopathies are a clinically and biochemically heterogeneous group of disorders sharing the common feature of structural mitochondrial abnormality on skeletal muscle biopsy(1). We report a case of Myoclonic Epilepsy with Red Ragged Fibres Syndrome (MERRF) which is a subtype of mitochondrial encephalomyopathy.

Case Report

A 6-year-old male child, product of a non consanguineous marriage, was admitted with choreiform movements of 8 days duration. There was no history of joint pains, sore throat, drug intake, neurological deficit or intellectual impairment, retrogression or retardation of milestones. The child had an attack of measles at 3 years of age. His birth history and developmental milestones both motor and mental, were normal. On tracing the pedigree no other family member was known to be similarly affected. On examination at the time of admission the child was found to be wasted, underweight (weight for age <3rd centile) but not stunted (height 112 cm). He was well oriented in time, space and person but had choreiform movements in all limbs. Rest of the general and systemic examination was within normal limits. Over the span of next 2 weeks, the child developed myoclonic movements which were quite severe, with inter-mittent increase in tone and dystonic posturing. There was intellectual impairment and emotional lability. The child was unable to stand or walk without support. By the third week of hospital stay the child had become nonambulatory and demented. In the fifth week he had three episodes of generalized tonic clonic convulsions. The choreoathetoid movements had been persisting throughout.

In the eight week of admission the child gradually showed signs of recovery. He started recognizing parents, indicated food needs, gradually regained bladder bowel control and started sitting with support. Within the next 2 weeks the child had become ambulatory, had a marked decrease in the abnormal involuntary movements, and started vocalizing.

On investigation, hemogram and ESR were within normal limits. ASO was less than 200 IU and CRP was negative. Blood culture and throat swab cultures were sterile. ECG and echocardiography were within normal limits. CSF microscopy and biochemistry was normal and was negative for measles antibody titres. Serum ammonia, copper, ceruloplasmin and CPK levels were normal. Serum lactate was 26 mg/dl (pre-exercise) and 28 mg/dl (post exercise), which were significantly elevated (normal values 5-18 mg/dl). Levels of serum pyruvate were 0.45 mg/dl and serum lactate 25.7 (mean�SD 16.6�4.4 laboratory value) The ratio of lactate: pyruvate was 57.1. Aminoacidogram as obtained by reversed phase HPLC was normal. EEG revealed slow background activity with right sided sharp wave discharges with secondary generalization. Serial cranial CT Scans and MRI T1 and T2 images were normal. Nerve conduction studies revealed left sural nerve sensory neuropathy. EMG however could not be carried out as the child was not co-operative. Snap frozen cryostat section of muscle biopsy from gastrocnemius muscle revealed a normal histology on HE stained section. Succinate dehydrogenase oxidative enzyme reaction showed 20% fibres with increased inter- myofibrillar and peripheral enzyme reactivity which were the ragged red fibres. Oil red O stain for lipid showed coarse granular staining. This histology was compatible with a diagnosis of mitochondrial myopathy. Electron microscopic study could not be carried out due to non availability. Mitochondrial DNA studies as performed by PCR-endonuclease digestion did not reveal any mutation at nucleotides 3243 and 8344 while mutation at nucleotide 8356 was not tested.

Discussion

The term mitochondrial encephalomyo-pathy was first used in 1977 to describe cases with complex multisystem disease with structurally and/or functionally abnormal mitochondria in brain or muscles(1). Mitochondria contain their own DNA (mt DNA) and are capable of synthesizing a small but vital set of proteins all of which are components of respiratory chain complexes. Certain alterations (deletions, point mutations or duplications) in the mtDNA lead to specific disease profiles(2). These encephalomyopathies have specific interitance pattern(3), most of the childhood encephalomyopathies including MERRF have a maternal mode of inheritance whereas the others have an autosomal mode of inheritance. The common presenting features in a patient of MERRF are quite variable. The major clinical features are presence of myoclonic seizures and muscle weakness which are present in all cases. Apart from this the range of clinical features may extend from severe CNS dysfunction (dementia, ataxia, spasticity) to a asymptomatic myopathy with red-ragged fibres on muscle biopsy. In severe forms of mitochondrial encephalomyopathies there may be multisystem involvement in form of growth retardation, cardiomyopathy, pigmentary retinopathy, renal tubular dysfunction, hepatic failure and signs of hormonal insufficiency.

Our patient had most of the classical features of MERRF, in the form of myoclonus, dementia, lactic acidosis and ragged red fibres on muscle biopsy. Short stature and a positive family history though observed in most of the cases were not seen. A newer diagnostic classification(3) has been proposed with major and minor diagnostic criteria to categorize the disease as possible, probable or certain. Using this classification our patient was diagnosed as having probable mitochondrial disease, a certain diagnosis could not be made as age adjusted biochemical or polarographic assessment of respiratory chain complex activity was not done due to non-availability. However the clinical features, progression of the disease, presence of elevated serum lactate and abnormal muscle biopsy with red ragged fibres established the diagnosis of MERRF. Two important differential diagnosis were considered initially, namely SSPE and aminoacidemias. The features which suggested a possibility of SSPE were a history of measles at 3 years of age, presence of myo-clonic jerks and dementia. SSPE was subsequently ruled out after investigations which revealed absence of measles antibody in CSF and absence of classical EEG changes. Moreover the patient showed improvement in clinical condition during his hospital stay. Aminoacidemias were ruled out by absence of hyperammonemia, hypoglycemia, and a normal aminoacidogram.

Treatment options for patients with respiratory chain diseases are limited. Treatment is generally non specific and unsatisfactory till date. The effort of the treating physician should be to decrease energy demands on dysfunctional mitochondria. The patient should avoid extremes of temperature, over exercise and drugs like barbiturates and phenytoin_ which inhibit respiratory chain function and chloramphenicol, tetracycline_which inhibit mitochondrial protein synthesis. Recently, artificial electron acceptors like Vitamin K3, and Vitamin C have been used(4). Anti- oxidants have also been used to protect against mtDNA free radical damage. Corticosteroids and riboflavin have been used with limited success. Our patient was initially put on phenobarbitone and phenytoin both of which were later withdrawn due to the above mentioned reason. Nitrazepam and valproic acid were later added to which the patient responded well and seizures were relatively well controlled. Other agents like Vitamins C, E, K and riboflavin were supplemented in usual doses. Complete bed rest was ensured with adequate nutrition.

The prognosis is variable as the disease may have an episodic and fluctuating course. The main morbidity is due to muscle weakness, CNS dysfunction or systemic involvement. Mortality is usually due to cardiac conduction defects. Our patient has been under follow up for last 6 months. His mental status has improved; the child is more interactive and has meaningful vocalization.No further episodes of generalized tonic clonic seizures occured but occasional brief myoclonic jerks are persisting.

References

1. Petty RKH, Harding AE, Morgan-Hughes JA. The clinical features of mitochondrial myopathy. Brain 1986; 109: 915-938.

2. Mauro S, Moraes CT. Mitochondrial encephalomyopathies. Arch Neurol 1993; 50: 1197-1208.

3. Walker UA, Collins S, Byrne E. Respiratory chain encephalomyopathies: A diagnostic classification. Eur Neurol 1996; 36: 260-267.

4. Peterson PL, Martens ME, Lee CP. Mitochondrial encephalomyopathies. Neurologic Clin 1988; 6: 529-545.