Mitochondrial Disorders Past Paper PDF - University of Central Lancashire

Molecular Medicine XY3121 Mitochondrial Disorders Dr Temba Mudariki  Learning Outcomes-Background 1. Understand the clinical presentation, diagnostic challenges, and management of adult-onset drug-resistant epilepsy, cortical myoclonu...

Molecular Medicine XY3121 Mitochondrial Disorders Dr Temba Mudariki  Learning Outcomes-Background 1. Understand the clinical presentation, diagnostic challenges, and management of adult-onset drug-resistant epilepsy, cortical myoclonus, and bilateral optic neuropathies due to m.14487T>C mitochondrial gene mutation. 2. Recognize the phenotypic variability and clinical features of mitochondrial diseases, emphasizing the significance of genetic testing and whole-genome sequencing in diagnosis. 3. Analyse the multidisciplinary approach and treatment modalities, including the use of onabotulinum toxin A injections, in addressing symptoms and improving the quality of life for patients with progressive myoclonic epilepsy secondary to mitochondrial disease. 4. Evaluate the continuum between seizures and cortical myoclonus, highlighting the link between abnormal neuronal hyperexcitability and the challenges in diagnosing mitochondrial diseases. 5. Discuss the implications of the case study, encouraging further exploration and research in the field of mitochondrial diseases and highlighting the importance of persistence in establishing a definitive diagnosis.  Overview Introduction Understanding Mitochondrial Diseases Case Presentation and Clinical Features Management and Treatment Discussion and Research Implications Recommended Reading Review Mitochondria are cytoplasmic organelles Involved in cellular respiration Possess their own chromosomes each with 65 569 bp Chromosomes arranged as a circular molecule mtDNA encodes – 22 tRNA, 2 ribosomal RNA rRNA, 13 protein subunits of the ETC/OXPHOS Sperm does not contribute mtDNA Pedigree for mitochondrial diseases – affected females pass own disease to all offspring Affected male does not pass own disease. Introduction Mitochondria are double membrane subcellular organelles. ATP production by OXPHOS ETC consists of 80 different polypeptides – organised into TMP complexes (I-V) Proton gradient generated by complexes I,II and IV Metabolic signal center of the cell- regulation of apoptosis, calcium homeostasis, lipid biosynthesis, iron Sulphur cluster biogenesis Mitochondria Respiratory Chain Complex Consists of multi-subunit structures Localised to the inner mitochondrial membrane Comprised of proteins, prosthetic groups – metal ions, iron-sulphur centers and cofactors ETC reduces molecular oxygen by NADH Process preserves energy released in the form of integral membrane protein complexes (I-IV) Mitochondria Respiratory Chain Defects mtDNA is a small 16.5kb circular molecular mtDNA encodes 22 tRNAs, 13 polypeptides, 2 rRNA mtDNA-encoded polypetides functionally important subunits of OXPHOS pathway Larger number of mitochondrial proteins (>1000) encoded in nDNA Mitochondria products of two genomes that can cause mitochondrial dysfunction.  Mitochondria Respiratory Chain Defects Mitochondria dysfunction – human disease- neurodegenerative disorders, cardiovascular, neurometabolic, cancer, obesity Heterogeneous groups of diseases – varying clinical features, tissue specific manifestations, affecting multiple organ systems mtDNA mutations – role in expression of disease phenotypes explored Rare class of disorders – recent studies show 1 in 5000 Individual mutations – 1 in 200 live births, small proportion harboring mutations develop disease. No cure Diagnosis important for prognosis and counselling Underlying mechanisms not fully understood – diagnosis challenge and treatment  Mitochondrial genetics Transmission of disease – heteroplasmic mother to offspring shows high degree of genetic and phenotypic variability between siblings Mitochondrial genetic bottleneck explains variability between siblings Comparison of heteroplasmic level in offspring and oocytes at different stages of development – bottleneck occurs early stages of oogenesis. Oogenesis - reduction in the number of mtDNA molecules (bottleneck) Fertilisation – heteroplasmic mtDNA mutation present in oocytes segregate to either of the two daughter cells Random process – generates variability in transmitted mutation load to offspring Unaffected heteroplasmic female can produce offspring unaffected, mildly or severely affected children  Mitochondrial genetics Indian Journal of Medical Research  Mitochondria Respiratory Chain Defects Heteroplasmy – Coexistence of wild type and mutant mtDNA molecules. Heteroplasmy due to presence of multiple copies of mtDNA in each cell Leber hereditary optic neuropathy (LHON) is an exception – mutations mostly present in homoplasmic conditions –symptomatic/asymptomatic individuals Biochemical defect, phenotypic expression - % of mutant mtDNA >tissue- specific critical threshold level (50-60% of mutant to wild type mtDNA) tRNA mutations – threshold level >90% some studies suggest 300 reported causing spectrum of diseases Failure in ATP production – main reason for most mitochondrial pathologies resulting in multi-systemic disorders Clinical presentations – extremely severe in high energy demand Skeletal muscle, CNS, Heart muscle, any organ Clinical presentation of mitochondria disorder – highly suggestive of particular disease phenotype, with well recognised clinical symptoms, specific mtDNA defect – see Table Large number of patients presented with group of clinical symptoms that are suggestive of a particular mitochondrial disorder but don’t fit in any disease category.  Overview of mitochondrial diseases and their phenotypic heterogeneity Group of genetic disorders Phenotypic heterogeneity Clinical Presentations Diagnostic Challenges Adult-Onset Progressive Myoclonic Epilepsy with m.14487T>C Mutation Patient Information: Mr. A, a 45-year-old male, presented with a history of progressive myoclonic epilepsy, bilateral optic neuropathies, and muscle weakness. He reported experiencing focal to bilateral tonic-clonic seizures, refractory myoclonus, and episodes of right upper limb jerking. Additionally, he developed bilateral simultaneous progressive visual loss over a period of weeks, leading to legal blindness. Mr. A reported an escalating frequency of myoclonic jerks, impacting his speech and swallowing abilities. His medical history was unremarkable, with no prior history of childhood convulsions.  Clinical Findings Upon examination, Mr. A exhibited high-frequency, stimulus-sensitive multifocal myoclonus predominantly affecting the right side of his face and right upper limb. Ankle reflexes were absent, and he displayed a glove-and-stocking distribution of sensory loss. Initial visual testing revealed bilateral central scotomata with corrected visual acuities of 6/60 in the right eye and 6/18 in the left eye, with relatively preserved peripheral vision and pallor of both optic discs. Subsequent MRI scans demonstrated cortical hyperintensities involving both hemispheres. Nerve conduction studies revealed a symmetrical, length-dependent axonal neuropathy.  Genetic Testing and Diagnosis Given the complex clinical presentation and the suspicion of mitochondrial disease, genetic testing was initiated. Whole mitochondrial gene sequencing on a muscle sample revealed a 98% heteroplasmic m.14487T>C p. (Met63Val) mutation. This mutation, located in the NADH dehydrogenase 6 (ND6) subunit, is known for its implication in mitochondrial respiratory chain dysfunction.  Treatment and Management The patient's treatment journey involved a multidisciplinary approach, including the administration of various antiseizure medications and targeted onabotulinum toxin A injections. Non-pharmacological interventions such as mindfulness and respiratory physiotherapy were integrated to address the associated complications. Genetic counselling was provided to Mr. A and his family members to understand the inheritance pattern and potential implications.  Significance of Understanding Adult-Onset Progressive Myoclonic Epilepsy Adult-onset progressive myoclonic epilepsy (PME) Diagnostic Challenges Impact on Quality of Life Therapeutic Implications Genetic Implications Research and Advancements  Understanding Mitochondrial Diseases Phenotypic variability and clinical presentation of mitochondrial diseases Diagnostic challenges in identifying mitochondrial diseases Significance of genetic testing and whole-genome sequencing in diagnosis  CASE REPORT A 43-year-old man was referred with a 4-year history of drug-resistant epilepsy character- ised by focal to bilateral tonic-clonic seizures and refractory myoclonus. There was no other medical history. He had been born at term, attained all developmental milestones normally and had no history of childhood convulsions. He had two sisters, both of whom had child- hood epilepsy. One sister had experienced global developmental delay, had never talked and been wheelchair-bound following a diag- nosis of congenital muscular dystrophy. The other sister had reached normal milestones until the age of 3 years, after which she devel- oped progressive gait abnormalities. Both sisters had died from pneumonia aged 13 and 16 years old.  CASE REPORT When he was 42 years old he had one daughter, aged 8 years old, with no neurological symptoms. Our patient reported developing symptoms when he was 39 years old, initially with episodes of right elbow cramping, which evolved to paroxysmal episodes of right upper limb jerking lasting approximately thirty seconds on each occasion. With time, these attacks became more frequent, and he also began to experience episodes of twitching over the right side of his face. He reported violent episodes lasting up to fifteen minutes with jerking of all four limbs with preserved awareness. He had one episode associated with loss of consciousness, followed by right upper and lower limb weakness lasting several days.  CASE REPORT When he was 42 years old, he developed bilateral simultaneous progressive visual loss over a period of weeks, to the extent that he had been registered legally blind. On examination, there was high-frequency, stimulus- sensitive multifocal myoclonus predominantly affecting the right side of his face and right upper limb. Awareness was preserved. Facial myoclonus grew more pronounced when talking to the extent he was unable to speak or swallow. Ankle reflexes were absent and there was a glove-and-stocking distribution of sensory loss. Initial visual testing revealed bilateral central scotomata with corrected visual acuities of 6/60 in the right eye and 6/18 in the left eye, relatively preserved peripheral vision and pallor of both optic discs. Optical coherence tomography showed bilateral symmetric thinning of the nerve fibre layer in the papillomacular bundles. Six months later, there had been considerable deterioration in central vision, with acuities in both eyes at the level of hand movements only. This did not improve despite a trial of high dose intravenous steroids with an oral taper.  CASE REPORT MRI scans over a 2-year period demonstrated interval development of multifocal cortical and subcortical T2/ FLAIR hyperintensities involving both cerebral hemi- spheres. Nerve conduction studies revealed a symmetrical, length-dependent axonal neuropathy. Prolonged video electroencephalography (EEG) revealed episodes of twitching involving the face, upper body and right arm with no epileptiform correlate. Although excessive muscle artefact made back-averaging impossible, short- duration myoclonic jerks with craniocaudal spread, followed by brief periods of atonia were consistent with cortical myoclonus. Giant somatosensory evoked potentials (N20-P25 24.4µV) were also found, supporting the presence of cortical hyperexcitability.  CASE REPORT A muscle biopsy was performed, which showed minor non-specific changes. Although there were no definite cytochrome oxidase negative fibres (which may be subject to variation in level of sections), rare fibres deficient in complex I and complex IV components were evident. These changes were not diagnostic, but were in keeping with the clinical impression of a mitochon- drial disorder. On the contrary, muscle respiratory chain enzyme analysis showed no evidence of complex I/II+III/ IV or ubiquinone deficiency. A 21-gene panel for patho- genic mitochondrial gene mutations was negative. Given clinical suspicion, we proceeded to whole mitochondrial gene sequencing on the muscle sample that revealed a 98% heteroplasmic m.14487T>C p. (Met63Val) mutation. This is a pathological variant which results in an amino acid substitution in NADH dehydrogenase 6 (ND6), a complex 1 subunit of the mitochondrial respiratory chain.  MANAGEMENT A number of different antiseizure medications including levetiracetam, carbamazepine, zonisamide, perampanel and clonazepam (up to 2 mg four times per day) were trialled. These were associated with initial improvement in myoclonus, however, benefit was not sustained. Leveti- racetam was tapered to cessation and replaced with pirac- etam (4 g three times per day), with mild benefit. Videofluoroscopy revealed oropharyngeal myoclonus impacting on his ability to safely swallow and a percuta- neous endoscopic gastrostomy was inserted to assist with nutritional demands. Onabotulinum toxin A was administered to a number of right-sided facial, neck and upper limb muscles (80 units orbicularis oculi, 10 units nasalis, 10 units risorius, 20 units levator anguli oris, 60 units platysma) with a 70% subjective improvement in myoclonus.  Discussion and Research Implications The challenges and importance of diagnosing mitochondrial diseases The link between seizures, cortical myoclonus, and abnormal neuronal hyperexcitability The continuum between seizures and cortical myoclonus  Recommended Reading 1. DiMauro, S., & Schon, E. A. (2003). Mitochondrial respiratory-chain diseases. New England Journal of Medicine, 348(26), 2656-2668. 2. Gorman, G. S., Chinnery, P. F., DiMauro, S., Hirano, M., Koga, Y., McFarland, R.,... & Turnbull, D. M. (2016). Mitochondrial diseases. Nature Reviews Disease Primers, 2, 16080. 3. Rahman, S., & Thorburn, D. (2020). Nuclear gene‐encoded Leigh syndrome overview. In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, & Amemiya A (Eds.), GeneReviews®. University of Washington, Seattle. 4. Ylikallio, E., & Suomalainen, A. (2012). Mechanisms of mitochondrial diseases. Annals of Medicine, 44(1), 41-59. 5. Parikh, S., Goldstein, A., Koenig, M. K., Scaglia, F., Enns, G. M., Saneto, R.,... & Cohen, B. H. (2015). Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genetics in Medicine, 17(9), 689-701. 6. Schon, E. A., DiMauro, S., & Hirano, M. (2012). Human mitochondrial DNA: roles of inherited and somatic mutations. Nature Reviews Genetics, 13(12), 878-890. 7. Munnich, A., & Rustin, P. (2001). Clinical spectrum and diagnosis of mitochondrial disorders. American Journal of Medical Genetics, 106(1), 4-17.