MITOCHONDRIAL DISORDER

These slides describe mitochondrial disorder and related genes name of the disorder and their symptoms.

1. PRESENTATION ON MITOCHONDRIAL DISORDERS PRESENTED BY VIBHA SINHA

2. INTRODUCTION Mitochondria is present in the cytoplasm of cell. It contains two membrane Mitochondria have round chromosome Multiple copy number in the cell Mutation rate is high .

3. Primary function of mitochondria Supply energy to cell in form of ATP Generate and regulate reactive oxygen species Regulate apoptosis Serves as cellular site for the following metabolic pathways- Electron transport chain Tricarboxylic acid cycle Beta oxidation of fatty acid Gluconeogenesis Urea synthesis

4. Genetics of mitochondria Circular double stranded , composed of heavy and light chains Contains 16,569 bp Encodes 13 protein, 22tRNA ,2rRNA Smaller number of gene Less effective repair mechanism Higher mutation rate

5. Unusual charcterstics of mitochondria Maternal inheritance Multiple copy number Heteroplasmy Bottleneck and segregation Threshold expression

6. Mitochondrial diseases can be arises Due to defects in mitochondrial DNA Due to defects in nuclear DNA Defects in mitochondrial DNA Single base pair variants Mitochondrial DNA rearrangement ( deletion, insertion)

7. S.N. MITOCHONDRIAL DNA DISORDER CLINICAL PHENOTYPE mtDNA GENOTYPE GENE STATUS INHERITANCE 1 Kearns-Sayre syndrome Progressive myopathy, ophthalmoplegia, cardiomyopathy A single, large scale deletion several deleted genes Heteroplasmic Usually sporadic 2 CPEO ophthalmoplegia a single, large scale deletion Several deleted genes heteroplasmic Usually sporadic 3 Pearson syndrome Pancytopoenia, Lactic acidosis A single, large scale deletion Several deleted genes Heteroplasmic Usually sporadic 4 MELAS Myopathy, encephalopathy lactic acidosis, stroke-like episodes 3243A>G; 3271T>C Individual mutations TRNL1 ND1 and ND5 Heteroplasmic heteroplasmic Maternal maternal

8. 5 MERRF Myoclonic epilepsy with red ragged fibers, myopathy 8344A>G; 8356T>C TRNK Heteroplasmic Maternal 6 NARP Neuropathy, ataxia, retinitis pigmentosa 8993T>G ATP6 Heteroplasmic Maternal 7 MILS (maternally inherited Leigh syndrome) Progressive brain stem disorder 8993T>C ATP6 Heteroplasmic Maternal 8 MIDD (maternally inherited diabetes and deafness) Diabetes, deafness 3243A>G TRNL1 Heteroplasmic Maternal 9 LHON (leber’s hereditary optic neuropathy ) Optic neuropathy 3460G>A 11778G>A 14484T>C ND1 ND4 ND6 Hetero - or homoplasmic Hetero- or homoplasmic Hetero- or homoplasmic Maternal Maternal Maternal

9. Classification of mitochondrial disorders caused by nuclear genes S.N. MECHANISM GENE INHERITANCE PHENOTYPE 1 Multiple mtDNA deletions TP ANT1 TWINKLE POLG AR AD AD, AR AD, AR MNGIE adPEO adPEO, IOSCA adPEO, arPEO, SANDO, parkinsonism 2 mtDNA depletion POLG TK2 SUCLA2 DGUOK MPV17 AR AR AR AR AR Alpers syndrome MM, SMA LS Alpers syndrome Alpers syndrome 3 RC subunit defect NDUSFx NDFVx SDHA AR AR AR LS, GRACILE LS LS

10. 4 Ancillary protein defect BCS1L SURF1 SCO2 COX15 ATP12 AR AR AR AR AR LS LS LS, hypertrophic cardiomyopathy, neuropathy Hypertrophic cardiomyopathy LS 5 CoQ synthesis defect COQ2, PDSS2 AR Encephalomyopathy, Tubulopathy, ataxia 6 Iron metabolism defect ALAS2, ABCB7 FRDA x- linked AR Sideroblastic anemia and ataxia Friedreich’s ataxia 7 Motility defect KIFSA AD Spastic paraplegia 8 Fusion defect MFN2 OPA1 AD AD CMT2A Optic nerve atrophy 9 Fission defect DLP1 AD Microcephaly, optic atrophy, lactic acidosis

11. KSS-Karnas Sayre Syndrome Introduction- KSS is an uncommon neuromuscular condition That affects those below age 20 years The condition is generally characterized by a progressive paralysis of the eye muscles Condition is a multi-systemic disorder that is progressive and can gravely affect the life of the affected child. Symptoms Eyelid drooping known as ptosis Pigmentation of retina External opthalmoplegia Cardiomyopathy Muscles weakness Deafness Seizure problems diabetes

12. CAUSES DIAGNOSIS Checking the pH and glucose level in the urine Check creatinine level in blood Confirmatory test is through muscles biopsy of the orbicularis KSS occurs spontaneously In some case inherited by mitochondria , autosomal dominant , or autosomal recessive inheritance KSS is the result of deletion in mitochondrial DNA Common 5kb mtDNA deletion, deletion/duplication ,A3242G Responsible gene are ANT1,TWINKLE,POLG

13. MELAS-Mitochondria Enchephaylopathy lactic asidosis stroke like syndrome INTRODUCTION Rare disorder affecting the muscles and nervous system The symptoms of this disorder begin as early as childhood And the signs became evident before the persons attains 15years SYMPTOMS It can cause seizures Intense headaches Muscles weakness Loss of vision and hearing Vomiting Fatigue and abdominal pain Loss of memory CAUSES This syndrome is caused due to defective mutation of mitochondrial DNA Repeated mutation Inherited by birth A3243G point mutation in tRNA-80% DIAGNOSIS Based on the symptoms of the affected person, the doctor would suspect MELAS syndrome. Brain biopsy

14. MNGIE- INTRODUCTION Mitochondrial Neurogastrointestinal Encephalopathy Syndrome MNGIE is rare multisystem disorder Characterized by progressive degeneration of the muscles of the gastrointestinal tract causing gastrointestinal dysmotility Weakness of extra – ocular muscles Degeneration of peripheral nerves causing altered sensation SYMPTOMS Vomiting Nausea Diarrhea Abdominal pain Numbness or sensation altered Ptosis CAUSES MNGIE is caused by changes in the TYMP gene encoding thymidine phosphorylase MNGIE caused by depletion,deletion or point mutation. DIAGNOSIS A diagnosis of MNGIE is suspected based upon detailed patient history MRI A diagnosis may be confirmed biochemically by demonstratating low TP enzyme activity in

15. fig.- Thymidine Phosphorylase mutation