International Journal of Innovative Pharmaceutical Sciences and Research

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1 International Journal of Innovative Pharmaceutical Sciences and Research CASE REPORT OF LEIGH SYNDROME A RARE MITOCHONDRIAL DISORDER 1 Adhunika Marella*, 1 Shilpa Laxman*, 1 Srilatha Raparthi*, 1 Sandeep Ankam, 1 Dr.Ramya Bala Prabha, 1 Shushanta Kr.Das, 1 Dr.Uma Maheswara Rao.V Department of Pharm. D, CMR College of Pharmacy, Kandlakoya (V) Hyderabad, , Telangana state, INDIA Abstract Leigh Syndrome (LS) is a subacute necrotizing encephalomyelopathy characterized by bilateral symmetrical necrotic lesions of gray matter nuclei in the basal ganglia, diencephalon, cerebellum or brainstem. The onset is usually in early infancy and patients manifest a heterogeneous set of symptoms, such as regression or psychomotor delay, weakness, hypotonia, truncal ataxia, intention tremor associated with lactic acidosis in the blood, cerebrospinal fluid or urine. The diagnosis of Leigh s disease should be considered in appropriate clinical and laboratory settings whenever symmetrical hypodensities are encountered in the putamina and midbrain on CT and further investigated with MRI. Neuroradiological examinations, when performed, showed lesions in brainstem and basal ganglia in LS and dystonia patients. A positive result at MRI investigation could address the diagnosis of dystonia or LS although exceptions to this correlation have been reported. Key words: Leigh s Syndrome, MRI investigation, coenzyme Q10. Corresponding Author Adhunika Marella Department of Pharm.D, CMR College of Pharmacy, Hyderabad, Telangana state, INDIA adhunikamarella1@gmail.com Phone: Available online: September Issue 1366

2 INTRODUCTION Leigh Syndrome (LS) is a sub acute necrotizing encephalomyelopathy characterized by bilateral symmetrical necrotic lesions of gray matter nuclei in the basal ganglia, diencephalon, cerebellum or brainstem. The onset is usually in early infancy and patients manifest a heterogeneous set of symptoms, such as regression or psychomotor delay, weakness, hypotonia, truncal ataxia, intention tremor associated with lactic acidosis in the blood, cerebrospinal fluid or urine. It is the most frequent cause of inherited Mitochondrial disorder in infancy (1:40,000) [1]. LS inheritance is complex since patients may present mutations in mitochondrial DNA (mtdna) or in nuclear genes, which predominantly encode for proteins involved in respiratory chain structure and assembly or in coenzyme Q10 biogenesis [2]. Among maternally inherited forms, most of the mutations lay within genes encoding Complex I (ND1-6) and V (ATP6, ATP8) mitochondrial subunits [3]. However the genetic cause of a number of cases of Leigh syndrome remains unknown, despite the presence of a specific biochemical defect in many of them. Despite its considerable clinical, genetic and biochemistry heterogeneity, the basic neuropathological features in children affected are almost identical; which are focal, bilateral, and symmetric necrotic lesions associated with demyelination, vascular proliferation and gliosis in the brainstem, diencephalon, basal ganglia, and cerebellum [4]. It is possible to come to a diagnosis of probable SNE during life on the basis of clinical signs and symptoms, mode of inheritance, metabolic abnormalities, and neuroimaging findings [5,6]. We report a rare case which presented clinically as a neurodegenerative disorder and diagnosed as Leigh syndrome on MRI. CASE PRESENTATION A 8 months old male child admitted in Pediatrics department brought by mother as reliable information with chief complaints of developing of both eye lids since 8 days. Past history: Child was apparently asymptomatic 10 days back, had a history of vomiting for 3 days, multiple episodes/day, vomits milk, non projectile, non bilious, no blood in vomit and on further questioning to mother it was revealed that the child has loss of neck holding and dull activity positive. General examination: Child was dull, afebrile, pulse rate: 108 bpm, respiratory rate: 20 bpm, CFT < 3 seconds, Heart, Lungs were clear, par abdomen: soft, Liver 2cm decreased RCM, CNS:AF, Tone normal in all limbs, 180 Flip test - Normal. Available online: September Issue 1367

3 Power Right Left UL 3/5 3/5 LL 3/5 3/5 DTR'S B T K A Planters - B/L Pupils - NSRL. Laboratory investigations Serum electrolytes, complete blood count: RBC, Hemoglobin were found to be normal, WBC - 13,000; differential count: Neutrophils - 30 (40-75%), Lymphocytes - 65(20-45%), were found to be abnormal, Eosinophils, Monocytes, Basophils were found be normal. Peripheral blood smear revealed an impression of RBC: Normocytic & Hypochromic. WBC- Leucocytosis. Platelets Thrombocytosis and count was found to be normal. Differential diagnosis CT scan brain plain done which show an impression of bilateral basal ganglia hypo-density, inborn errors of metabolism-leigh, hallervorden-spatz syndrome. Magnetic resonance imaging was performed and which finally revealed an impression of Symmetrical T 2 / Flair hyper intensity with diffusion restriction in bilateral caudate and lenti form nucleus medial peri ventricular thalami and periadeductal white matter. s/o Leighs disease. Based on the above complaints and laboratory investigations the condition was finally confirmed as LEIGH S disease. Treatment Initially symptomatic treatment was given, which was followed by Tab.Thiamine (vitamin B 1 ) - 75mg/PO/OD, Cap.Coenzyme Q 10-30mg/PO/TID, Inj.Optineuron - 3ml/IV/OD 3days with oral feeds which was continued for 15 days and patient was discharged with the same medications. Available online: September Issue 1368

4 Fig.1 Fig.2 Figure 1 & 2 Denotes Symmetrical T 2 / Flair hyper intensity with diffusion restriction in bilateral caudate and lenti form nucleus medial peri ventricular thalami and periadeductal white matter. DISCUSSION Leigh s disease or SNE is a rare progressive neurological disorder of the childhood. Age of onset of symptoms is usually less than 2 years (infantile form), but others may present in childhood (juvenile form) and unusually in adulthood. It presents early in life with psychomotor regression, abnormal muscle tone, weakness, dystonia, brainstem and cerebellar dysfunction (ataxia), visual loss, missed milestones or regression of the achieved milestones, tachypnea, and seizures [7-9]. Neuroimaging plays an important role in diagnosis of patients with Leigh syndrome. These high T2 signals on MRI reflect the spongiform changes and vacuolation in the affected brain structures. Specific therapy for mitochondrial disorders in children is not available. The results and prognosis are variable. A high-fat, low-carbohydrate diet may be followed if a gene on the X chromosome is implicated. Thiamine (vitamin B 1 ) may be given if a deficiency of pyruvate dehydrogenase is known or suspected [10-12]. Marked improvement was observed with riboflavin, which nearly normalized the adenosine triphosphate production. Rapid clinical and biochemical improvement was observed in patients with acute central respiratory failure with the use of intravenous soya bean oil (Ketogenic emulsion). Ketogenic diet has been found to improve the outcome in those with a deficiency of pyruvate dehydrogenase. The use of coenzyme Q10, thiamine, and carnitine may cause a decrease in severity of symptoms in a few cases. Available online: September Issue 1369

5 CONCLUSION The diagnosis of Leigh s disease should be considered in appropriate clinical and laboratory settings whenever symmetrical hypodensities are encountered in the putamina and midbrain on CT and further investigated with MRI. Neuroradiological examinations, when performed, showed lesions in brainstem and basal ganglia in LS and dystonia patients. A positive result at MRI investigation could address the diagnosis of dystonia or LS although exceptions to this correlation have been reported. With appropriate investigations, accurate diagnosis and prompt institution of adequate supportive therapy, symptomatic amelioration can be achieved, thereby adding life to the limited years of survival of these children. Further research aimed at prenatal identification of the responsible mutations and prevention of the disease is warranted. REFERENCES 1. Rahman S, Blok RB, Dahl HH, Leigh syndrome. Clinical features and biochemical and DNA abnormalities. Ann Neurol, 1996; 39: Tucker EJ, Compton AG, Thorburn DR. Recent advances in the genetics of mitochondrial encephalopathies. Curr Neurol Neurosci Rep, 2010; 10: Wong LJ. Pathogenic mitochondrial DNA mutations in protein-coding Rahman S, Blok RB, Dahl HH, Leigh syndrome, et al: Clinical features and biochemical and DNA abnormalities. Ann Neurol, 1996; 39: Van Erven PM, Cillessen JP, Eekhoff EM. Leigh syndrome, a mitochondrial encephalo (myo)pathy. A review of the literature. Clin Neurol Neurosurg, 1987; 89: Castro-Gago M, Blanco-Barca MO, Campos-Gonzalez Y, Arenas-Barbero J, Pintos- Martinez E, Eiris-Punal J: Epidemiology of pediatric mitochondrial respiratory chain disorders in northwest Spain. Pediatr Neurol, 2006; 34(3): Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M: The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol, 2001; 49(3): Leigh D: Sub acute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry, 1951; Medina L, Chi T, DeVivo D, et al: MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. Am J Neuroradiol, 1990; 11: Available online: September Issue 1370

6 9. Davis PC, Hoffman JC Jr, Braun IF. MR of Leigh s disease (subacute necrotizing encephalomyelopathy). Am J Neuroradiol, 1987; 8: Carroll J, Fearnley I, Skehel JM. Bovine complex I is a complex of 45 diff erent subunits. J Biol Chem, 2006; 281: Distelmaier F, Koopman W, van den Heuvel L. Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain, 2009; 132: Dunning CJ, McKenzie M, Sugiana C. Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO J, 2007; 26: Available online: September Issue 1371