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Questions and Answers
What is a significant characteristic of the epilepsy experienced by the 43-year-old man in the case report?
What is a significant characteristic of the epilepsy experienced by the 43-year-old man in the case report?
What type of seizures did the 43-year-old man initially experience?
What type of seizures did the 43-year-old man initially experience?
Which family member of the patient exhibited progressive gait abnormalities?
Which family member of the patient exhibited progressive gait abnormalities?
What was one of the later symptoms that the patient developed at age 42?
What was one of the later symptoms that the patient developed at age 42?
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Why are mitochondrial diseases considered diagnostic challenges?
Why are mitochondrial diseases considered diagnostic challenges?
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What is the primary clinical challenge associated with adult-onset drug-resistant epilepsy linked to the m.14487T>C mitochondrial gene mutation?
What is the primary clinical challenge associated with adult-onset drug-resistant epilepsy linked to the m.14487T>C mitochondrial gene mutation?
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Which of the following best describes the contribution of sperm to mitochondrial DNA (mtDNA)?
Which of the following best describes the contribution of sperm to mitochondrial DNA (mtDNA)?
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What is the significance of genetic testing and whole-genome sequencing in mitochondrial diseases?
What is the significance of genetic testing and whole-genome sequencing in mitochondrial diseases?
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Which treatment modality has shown effectiveness in managing symptoms of progressive myoclonic epilepsy in mitochondrial disease patients?
Which treatment modality has shown effectiveness in managing symptoms of progressive myoclonic epilepsy in mitochondrial disease patients?
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How do seizures and cortical myoclonus relate to abnormal neuronal hyperexcitability in mitochondrial diseases?
How do seizures and cortical myoclonus relate to abnormal neuronal hyperexcitability in mitochondrial diseases?
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What role do affected females play in the inheritance of mitochondrial diseases?
What role do affected females play in the inheritance of mitochondrial diseases?
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How does the structure of mitochondrial DNA enhance its function?
How does the structure of mitochondrial DNA enhance its function?
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What role do complexes I, II, and IV play in electron transport chain (ETC) functionality?
What role do complexes I, II, and IV play in electron transport chain (ETC) functionality?
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What is the primary function of mitochondrial DNA (mtDNA) in relation to the oxidative phosphorylation (OXPHOS) pathway?
What is the primary function of mitochondrial DNA (mtDNA) in relation to the oxidative phosphorylation (OXPHOS) pathway?
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What results from defects in mitochondrial respiratory chain complexes?
What results from defects in mitochondrial respiratory chain complexes?
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Which of the following statements accurately describes the structure of the mitochondrial respiratory chain?
Which of the following statements accurately describes the structure of the mitochondrial respiratory chain?
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How many polypeptides does the electron transport chain (ETC) consist of?
How many polypeptides does the electron transport chain (ETC) consist of?
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What is a significant feature of mitochondria in terms of genetic encoding?
What is a significant feature of mitochondria in terms of genetic encoding?
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What is the primary consequence of mitochondrial dysfunction?
What is the primary consequence of mitochondrial dysfunction?
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Which of the following best describes the nature of mtDNA?
Which of the following best describes the nature of mtDNA?
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What is the approximate prevalence of individual mutations in mitochondrial DNA within the population?
What is the approximate prevalence of individual mutations in mitochondrial DNA within the population?
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What was the main neurological symptom presented by Mr. A?
What was the main neurological symptom presented by Mr. A?
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Which mutation was identified in Mr. A's genetic testing?
Which mutation was identified in Mr. A's genetic testing?
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What type of seizures did Mr. A experience?
What type of seizures did Mr. A experience?
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What findings were observed in Mr. A's nerve conduction studies?
What findings were observed in Mr. A's nerve conduction studies?
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What kind of visual loss did Mr. A report?
What kind of visual loss did Mr. A report?
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Which aspect of Mr. A's health history was notable?
Which aspect of Mr. A's health history was notable?
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What technique was included in Mr. A's non-pharmacological intervention plan?
What technique was included in Mr. A's non-pharmacological intervention plan?
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What was demonstrated by the MRI scans in Mr. A's case?
What was demonstrated by the MRI scans in Mr. A's case?
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What role did genetic counseling play in Mr. A's treatment?
What role did genetic counseling play in Mr. A's treatment?
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What sensory loss pattern was noted during the examination of Mr. A?
What sensory loss pattern was noted during the examination of Mr. A?
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What does heteroplasmy in mitochondrial genetics refer to?
What does heteroplasmy in mitochondrial genetics refer to?
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What is the primary reason for most mitochondrial pathologies?
What is the primary reason for most mitochondrial pathologies?
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How does the mitochondrial genetic bottleneck affect siblings?
How does the mitochondrial genetic bottleneck affect siblings?
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What percentage of mutant mtDNA is often required to surpass critical thresholds in tissues for symptoms to manifest?
What percentage of mutant mtDNA is often required to surpass critical thresholds in tissues for symptoms to manifest?
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Which specific condition is noted to predominantly present in homoplasmic conditions?
Which specific condition is noted to predominantly present in homoplasmic conditions?
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What describes the process occurring during fertilization regarding heteroplasmic mtDNA mutations?
What describes the process occurring during fertilization regarding heteroplasmic mtDNA mutations?
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In mitochondrial genetics, what does the term 'oogenesis' refer to?
In mitochondrial genetics, what does the term 'oogenesis' refer to?
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What is a common challenge in diagnosing mitochondrial disorders?
What is a common challenge in diagnosing mitochondrial disorders?
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Which of the following statements about unaffected heteroplasmic females is true?
Which of the following statements about unaffected heteroplasmic females is true?
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What organ systems are particularly affected due to mitochondrial disorders?
What organ systems are particularly affected due to mitochondrial disorders?
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Flashcards
Mitochondria Function
Mitochondria Function
Mitochondria are subcellular organelles found in the cytoplasm of cells. They play a crucial role in cellular respiration, which is the process of converting food into energy.
Mitochondrial DNA (mtDNA)
Mitochondrial DNA (mtDNA)
Mitochondria have their own DNA called mtDNA, which is distinct from the DNA found in the nucleus. mtDNA is circular and contains genes that encode for essential proteins involved in cellular respiration.
Mitochondrial Inheritance
Mitochondrial Inheritance
mtDNA is inherited maternally, meaning that offspring inherit their mitochondrial DNA solely from their mother. Fathers do not contribute mtDNA.
Mitochondrial Diseases
Mitochondrial Diseases
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Mitochondrial Gene Mutations
Mitochondrial Gene Mutations
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Genetic Testing for Mitochondrial Diseases
Genetic Testing for Mitochondrial Diseases
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Management of Mitochondrial Diseases
Management of Mitochondrial Diseases
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Adult-Onset Progressive Myoclonic Epilepsy (PME)
Adult-Onset Progressive Myoclonic Epilepsy (PME)
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Diagnostic Challenges in PME
Diagnostic Challenges in PME
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Impact of PME on Quality of Life
Impact of PME on Quality of Life
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Therapeutic Implications of PME
Therapeutic Implications of PME
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Genetic Implications of PME
Genetic Implications of PME
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Electron Transport Chain (ETC)
Electron Transport Chain (ETC)
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ETC Complexes (I-IV)
ETC Complexes (I-IV)
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Proton Gradient Generation
Proton Gradient Generation
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ATP (Adenosine Triphosphate)
ATP (Adenosine Triphosphate)
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mtDNA (Mitochondrial DNA)
mtDNA (Mitochondrial DNA)
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Mitochondrial Respiratory Chain Defects
Mitochondrial Respiratory Chain Defects
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Mitochondrial Dysfunction
Mitochondrial Dysfunction
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nDNA (Nuclear DNA)
nDNA (Nuclear DNA)
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Apoptosis (Programmed Cell Death)
Apoptosis (Programmed Cell Death)
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Myoclonic Epilepsy
Myoclonic Epilepsy
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Optic Neuropathies
Optic Neuropathies
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Bilateral Tonic-Clonic Seizures
Bilateral Tonic-Clonic Seizures
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Focal to Bilateral Seizures
Focal to Bilateral Seizures
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Central Scotomata
Central Scotomata
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Axonal Neuropathy
Axonal Neuropathy
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m.14487T>C p.(Met63Val)
m.14487T>C p.(Met63Val)
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Multidisciplinary Approach
Multidisciplinary Approach
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Onabotulinum Toxin A Injections
Onabotulinum Toxin A Injections
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Heteroplasmy
Heteroplasmy
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Homoplasmy
Homoplasmy
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Mitochondrial Genetic Bottleneck
Mitochondrial Genetic Bottleneck
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Threshold Effect
Threshold Effect
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Mitochondrial Disorders
Mitochondrial Disorders
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Leber Hereditary Optic Neuropathy (LHON)
Leber Hereditary Optic Neuropathy (LHON)
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Phenotypic Heterogeneity
Phenotypic Heterogeneity
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Diagnostic Challenges
Diagnostic Challenges
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Study Notes
Molecular Medicine XY3121: Mitochondrial Disorders
- Learning Outcomes - Background:
- Understand adult-onset drug-resistant epilepsy, cortical myoclonus, and bilateral optic neuropathies due to m.14487T>C mitochondrial gene mutation.
- Recognize phenotypic variability and clinical features of mitochondrial diseases, emphasizing the importance of genetic testing and whole-genome sequencing in diagnosis.
- Analyse the multidisciplinary approach and treatment modalities (e.g., onabotulinum toxin A injections) for progressive myoclonic epilepsy secondary to mitochondrial disease to improve patients' quality of life.
- Evaluate the link between seizures, cortical myoclonus, and abnormal neuronal hyperexcitability in diagnosing mitochondrial diseases.
- Discuss the implications of case studies, highlighting the importance of persistence in establishing definitive diagnoses.
Overview
- Introduction:
- Understanding Mitochondrial Diseases
- Case Presentation and Clinical Features
- Management and Treatment
- Discussion and Research Implications
- Recommended Reading
Review
-
Mitochondria:
- Cytoplasmic organelles involved in cellular respiration.
- Possess their own chromosomes (65 569 bp) arranged in a circular molecule.
- mtDNA encodes 22 tRNA, 2 rRNA, and 13 protein subunits of the electron transport chain (ETC)/oxidative phosphorylation (OXPHOS).
- Sperm does not contribute mtDNA
- Mitochondrial diseases are often passed down through mothers.
- Affected females pass disease to all offspring
- Affected males do not pass the disease.
-
Mitochondrial structure:
- Two membranes: inner membrane (cristae), outer membrane,
- Intermembrane space,
- Inner mitochondrial membrane consists Lamellae
- Outer membrane contain Porins,
- Mitochondrial DNA granules,
- Matrix granules,
- Ribosomes,
- ATP synthase.
-
Mitochondrial Respiratory Chain Complex:
- Multi-subunit structures located in the inner mitochondrial membrane.
- Composed of proteins, prosthetic groups (metal ions, iron-sulfur centers), and cofactors.
- Reduces molecular oxygen by NADH.
- Preserves energy released in the form of integral membrane protein complexes (I-IV).
Mitochondrial Respiratory Chain Defects
-
mtDNA:
- Small, 16.5kb circular molecule.
- Encodes 22 tRNAs, 13 polypeptides, and 2 rRNAs.
- mtDNA-encoded polypeptides are subunits of the OXPHOS pathway
- Larger number of mitochondrial proteins (>1000) are encoded in nDNA.
- Multifactorial origins cause mitochondrial dysfunction.
-
Mitochondrial Diseases:
- Result from mitochondrial dysfunction, leading to a range of neurodegenerative, cardiovascular, neurometabolic, cancer, and obesity disorders.
- Heterogeneous groups of diseases with varying clinical features, primarily affecting tissue-specific manifestations affecting multiple organ systems.
- Rare, with a frequency seen in 1 in 5000 individuals. Mutations often develop in 1 in 200 live births.
- No cure currently exists.
- Diagnosis is important for prognosis and counselling.
- There is still much uncertainty regarding the underlying mechanisms for these diseases.
Mitochondrial Genetics
-
Transmission of Disease:
- Heteroplasmic mothers transmit disease with high variability among offspring.
- Mitochondrial genetic bottleneck explains variability among siblings
- Comparison of heteroplasmic level in offspring and oocytes at different stages shows bottleneck in early oogenesis.
- Oogenesis—reduction in the number of mtDNA molecules.
- Fertilization—mtDNA mutations in oocytes segregate to either of the two daughter cells by random process.
-
Heterolamplasmy:
- Coexistence of wild-type and mutant mtDNA molecules in a cell.
- A large number of mtDNA molecules that can result in a range in severity as well as a diversity of diseases.
-
Leber hereditary optic neuropathy (LHON):
- Results in mutations mostly present in homoplasmic conditions.
- Mutations give rise to symptomatic and asymptomatic individuals.
Mitochondrial DNA Mutations and Diseases
- Mutations:
-
300 mutations reported causing a spectrum of diseases.
- Failure in ATP production is a primary cause of various mitochondrial pathologies. leading to serious multisystemic disorders.
- Clinical presentation is often severe in high-energy-demand tissues like skeletal muscle, CNS, and heart muscle
-
Overview of Mitochondrial Diseases and Their Phenotypic Heterogeneity
- Group of Genetic Disorders:
- Various genetic disorders causing mitochondrial diseases.
- Phenotypic Heterogeneity:
- Wide variations in disease presentation.
- Clinical Presentations:
- Diverse set of symptoms.
- Diagnostic Challenges:
- Difficulty in identifying specific causes.
Adult-Onset Progressive Myoclonic Epilepsy with m.14487T>C Mutation
- Patient Information:
- 45-year-old male with progressive myoclonic epilepsy.
- Bilateral optic neuropathies and muscle weakness
- Focal to bilateral tonic-clonic seizures.
- Refractory myoclonus and episodes of right upper limb jerking.
- Bilateral simultaneous progressive visual loss (legal blindness).
- Escalating frequency of myoclonic jerks impacting speech and swallowing.
- Unremarkable medical history with no prior childhood convulsions
Clinical Findings
- Examination findings:
- High-frequency, stimulus-sensitive multifocal myoclonus affecting the right side of the face and right upper limb.
- Absent ankle reflexes.
- Glove-and-stocking distribution of sensory loss.
- Bilateral central scotomata (6/60 right, 6/18 left).
- Relatively preserved peripheral vision and optic discs pallor.
- Cortical hyperintensities on MRI scans.
- Symmetrical, length-dependent axonal neuropathy.
Genetic Testing and Diagnosis
- Whole mitochondrial gene sequencing.
- Revealling 98% heteroplasmic m.14487T>C p. (Met63Val) mutation in NADH dehydrogenase 6 (ND6) subunit which is known for its implications in mitochondrial respiratory chain dysfunction.
Treatment and Management
- Multidisciplinary approach:
- Antiseizure medications (e.g., levetiracetam, carbamazepine).
- Targeted onabotulinum toxin A injections.
- Non-pharmacological interventions (e.g., mindfulness, respiratory physiotherapy).
- Genetic counseling for the patient and family members regarding the inheritance pattern and implications.
Significance of Understanding Adult-Onset Progressive Myoclonic Epilepsy
- Diagnostic Challenges
- Impact on Quality of Life
- Therapeutic Implications
- Genetic Implications
- Research and Advancements
Understanding Mitochondrial Diseases
- Phenotypic variability and clinical presentation:
- Diagnostic challenges:
- Significance of genetic testing and whole-genome sequencing:
Case Reports
- Multiple cases outlined with specific presentation, findings and observations.
Muscle Biopsy and Enzyme Analysis
- Muscle Biopsy: Minor nonspecific changes.
- Cytochrome Oxidase Negative Fibres: Few deficient fibres in complex I and IV evident (no definite diagnosis.
- Complex I/II + III/IV and Ubiquinone Deficiency: Rule out by enzyme analysis.
Management
- Antiseizure medications: Levetiracetam, carbamazepine, zonisamide, perampanel, and clonazepam.
- Non-Pharmacological interventions mindfulness and respiratory physiotherapy
- Videofluoroscopy: Oropharyngeal myoclonus affecting swallowing ability.
- Endoscopic gastrostomy: For nutritional support.
- Onabotulinum toxin A injections: Improved myoclonus in multiple areas (70% subjective)
Discussion and Research Implications
- Challenges and importance of diagnosing mitochondrial diseases.
- Link between seizures, cortical myoclonus and abnormal neuronal hyperexcitability
- Continuum between seizures and cortical myoclonus
Recommended Reading
- A list of articles and books.
Studying That Suits You
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Description
This quiz explores various aspects of mitochondrial disorders, particularly focusing on the m.14487T>C mutation and its clinical implications. It aims to enhance understanding of drug-resistant epilepsy, cortical myoclonus, and the importance of genetic testing. Participants will analyze treatment modalities and evaluate connections between seizures and mitochondrial diseases.