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Leigh Syndrome in an Adolescent Girl: A Case Report

ABSTRACT Leigh syndrome (LS) is a disorder of infancy and rarely late childhood. It presents with regression of mental and motor skills. Here, we present LS in an adolescent girl who presented with generalized dystonia and cognitive decline. Her infective, metabolic, endocrinal and autoimmune work up was normal. The neuroimaging showed progressive symmetric involvement of basal ganglia with focal intensity over bilateral lentiform nucleus and thalamic region. The cerebrospinal fluid (CSF) lactate level was elevated. Genetic test could not be performed; however the history of neuro-regression with extrapyramidal involvement with CSF and neuroimaging finding led to the diagnosis of Leigh’s syndrome.


INTRODUCTION
L eigh syndrome (LS) was first described in 1952 by a British neuro-psychiatrist, Archibald Denis Leigh. The condition is an inherited neurometabolic disease affecting the central nervous system. 1 The prevalence of Leigh disease (LD) is about of 1:100,000 to 1:140,000 births. It is a familial or sporadic mitochondrial disorder characterized by psychomotor regression and lesions in the basal ganglia and brainstem. Onset of Leigh syndrome typically begins during infancy with progression and death by 2 years of age. 2 Late onset disease during adolescence and adult is not common. 3

CASE PRESENTATION
A 13-year girl presented with insidious progression of symptoms for 18 months. It started with gradual onset of tremor in the hands, slurring of speech and increased salivation. There was no history of fever, headache or vomiting at the onset of symptoms. For the past 8 months, she started to develop gradually progressive dystonia of upper limbs involving the entire body aggravated by stress or stimulus. Because of the dystonia, her daily activities were restricted but could walk around with support, eat by herself and take self care. For last one month, she developed motor aphasia along with swallowing difficulty. There was neither history of seizure or impairment of consciousness.
There was also no prior history of jaundice, joint pain, rash or abnormal behavior or altered sleep pattern or any history of head trauma. Other personal and family history was unremarkable. She was the only child and product of her non -consanguineous marriage.
On examination child was alert and oriented with generalized and oro-motor dystonia. Her vitals were normal. She had extrapyramidal signs along with exaggerated knee and ankle reflexes. Her vision and hearing was grossly intact at the time of admission; however detail auditory and visual assessment could not be performed. After about one week of hospital admission, she gradually deteriorated with increasing dystonia and cognitive decline. She started to become drowsy, failed to recognize parents and also developed urinary and bowel incontinence.
Her hemogram, renal and liver function tests were normal. Metabolic work up revealed normal serum copper, ceruloplasmin, and urine copper levels. Thyroid profile, anti-nuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA) and serum lactate were also normal. Tandem mass spectroscopy including screening for abnormal urinary metabolites was also normal. Cerebrospinal fluid (CSF) analysis showed lymphocytes of 65 cells/dl with slight increase in protein level of 60mg/ dl. CSF N-methyl-D-asparate (NMDA) receptor antibody was negative; however CSF lactate was increased. Her magnetic resonance imaging (MRI) of head showed hyper signal intensity over bilateral basal ganglia predominantly bilateral lentiform nucleus and thalamus; and electroencephalogram (EEG) showed generalized slowing with theta delta dysrhythmia.
She was started on supplements of thiamine, carnitine, pyridoxine, coenzyme-Q and trihexyphenyldyl for her dystonia. During hospital stay, her dystonia decreased slightly however her cognition and incontinence remained static. With the available reports, the diagnosis of late onset Leigh disease was made.

DISCUSSION
Leigh disease is considered as a disease in infancy or early childhood. Defects in mitochondrial oxidative phosphorylation (OXPHOS) is usually associated with early onset disease. 4 It can be inherited as an autosomal recessive mitochondrial trait due to mutations in nuclear genes encoding mitochondrial respiratory chain complex subunits or complex assembly proteins. 5 X-linked related to defects in pyruvate dehydrogenase complex (PDHc) due to mutations in the PDHA1 gene is also found to be associated with LD. 6 In young infants, LD presents with motor delay, mental retardation and/or progressive cognitive decline, hypotonia, ataxia and dystonia. Because of involvement of brainstem, the children might present with respiratory abnormalities and swallowing dysfunction along with ophthalmological manifestations and abnormal thermoregulation. 7 The late onset LD is not common. In older children and adults, it presents with cranial nerve disturbance, pyramidal signs, and cerebellar dysfunction.  metabolic diseases were differential diagnosis for the patient and were excluded by investigations. During her hospital stay of almost 4 weeks, we treated her with pulse dose of methylprednisolone for five days. Mega dose of thiamine and supplementation of carnitine, pyridoxine and coenzyme-Q was continued. However, she did not respond to any of the treatment. Her cognition and consciousness level gradually started to deteriorate. She was then discharged with above medications on parents request.
The prognosis of LD is brim and there is no definitive treatment for LD till now. Poor survival is predicted by disease onset before 6 months of age, failure to thrive, brainstem lesions on neuroimaging and requirement for intensive care treatment. The major cause of mortality is due to disease progression with progressive brain stem involvement with respiratory insufficiencies. 10

CONCLUSION
Leigh disease should be considered in an adolescent if they present with progressive extrapyramidal symptoms and neuroimaging findings of bilateral symmetric involvement of multiple brainstem nuclei/ structures. In such condition, further investigations including blood and/or CSF lactate, respiratory chain enzymes activities and genetic studies should be considered to support the diagnosis . Though the complete cure for LD is not available, accurate diagnosis with appropriate investigations followed by prompt institution of adequate supportive therapy helps in amelioration of apparent symptoms as well parental dilemma of the disease.