5. Mitochondrial Disorders
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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?

  • It was primarily resistant to medication. (correct)
  • It only occurred during sleep.
  • It manifested solely as absence seizures.
  • It was easily controlled with anticonvulsants.
  • What type of seizures did the 43-year-old man initially experience?

  • Focal to bilateral tonic-clonic seizures. (correct)
  • Generalized tonic-clonic seizures.
  • Absence seizures only.
  • Myoclonic seizures exclusively.
  • Which family member of the patient exhibited progressive gait abnormalities?

  • His daughter.
  • His mother.
  • His second sister. (correct)
  • His first sister.
  • What was one of the later symptoms that the patient developed at age 42?

    <p>Bilateral simultaneous progressive visual loss. (D)</p> Signup and view all the answers

    Why are mitochondrial diseases considered diagnostic challenges?

    <p>They present with a wide range of symptoms and phenotypic variability. (D)</p> Signup and view all the answers

    What is the primary clinical challenge associated with adult-onset drug-resistant epilepsy linked to the m.14487T>C mitochondrial gene mutation?

    <p>Management of symptoms and diagnosis (A)</p> Signup and view all the answers

    Which of the following best describes the contribution of sperm to mitochondrial DNA (mtDNA)?

    <p>Sperm does not contribute to mtDNA at all (B)</p> Signup and view all the answers

    What is the significance of genetic testing and whole-genome sequencing in mitochondrial diseases?

    <p>They assist in confirming diagnoses due to phenotypic variability (C)</p> Signup and view all the answers

    Which treatment modality has shown effectiveness in managing symptoms of progressive myoclonic epilepsy in mitochondrial disease patients?

    <p>Onabotulinum toxin A injections (C)</p> Signup and view all the answers

    How do seizures and cortical myoclonus relate to abnormal neuronal hyperexcitability in mitochondrial diseases?

    <p>Both are outcomes of similar underlying neuronal dysfunction (B)</p> Signup and view all the answers

    What role do affected females play in the inheritance of mitochondrial diseases?

    <p>They pass the disease to all of their offspring (B)</p> Signup and view all the answers

    How does the structure of mitochondrial DNA enhance its function?

    <p>The circular arrangement reduces mutation rates (D)</p> Signup and view all the answers

    What role do complexes I, II, and IV play in electron transport chain (ETC) functionality?

    <p>They generate a proton gradient. (D)</p> Signup and view all the answers

    What is the primary function of mitochondrial DNA (mtDNA) in relation to the oxidative phosphorylation (OXPHOS) pathway?

    <p>Encoding tRNAs, rRNA, and essential polypeptides. (C)</p> Signup and view all the answers

    What results from defects in mitochondrial respiratory chain complexes?

    <p>A wide range of human diseases. (B)</p> Signup and view all the answers

    Which of the following statements accurately describes the structure of the mitochondrial respiratory chain?

    <p>It is comprised of proteins and metal ions in multi-subunit structures. (B)</p> Signup and view all the answers

    How many polypeptides does the electron transport chain (ETC) consist of?

    <p>80 (B)</p> Signup and view all the answers

    What is a significant feature of mitochondria in terms of genetic encoding?

    <p>mtDNA and nDNA both encode mitochondrial proteins. (D)</p> Signup and view all the answers

    What is the primary consequence of mitochondrial dysfunction?

    <p>Potential development of various diseases. (B)</p> Signup and view all the answers

    Which of the following best describes the nature of mtDNA?

    <p>It is a small circular molecule. (B)</p> Signup and view all the answers

    What is the approximate prevalence of individual mutations in mitochondrial DNA within the population?

    <p>1 in 200 live births. (C)</p> Signup and view all the answers

    What was the main neurological symptom presented by Mr. A?

    <p>Bilateral optic neuropathies (C)</p> Signup and view all the answers

    Which mutation was identified in Mr. A's genetic testing?

    <p>m.14487T&gt;C p.(Met63Val) (C)</p> Signup and view all the answers

    What type of seizures did Mr. A experience?

    <p>Tonic-clonic seizures (B)</p> Signup and view all the answers

    What findings were observed in Mr. A's nerve conduction studies?

    <p>Symmetrical, length-dependent axonal neuropathy (C)</p> Signup and view all the answers

    What kind of visual loss did Mr. A report?

    <p>Bilateral simultaneous progressive visual loss (A)</p> Signup and view all the answers

    Which aspect of Mr. A's health history was notable?

    <p>Unremarkable medical history with no childhood convulsions (C)</p> Signup and view all the answers

    What technique was included in Mr. A's non-pharmacological intervention plan?

    <p>Mindfulness (B)</p> Signup and view all the answers

    What was demonstrated by the MRI scans in Mr. A's case?

    <p>Cortical hyperintensities in both hemispheres (B)</p> Signup and view all the answers

    What role did genetic counseling play in Mr. A's treatment?

    <p>To understand the inheritance pattern and implications (A)</p> Signup and view all the answers

    What sensory loss pattern was noted during the examination of Mr. A?

    <p>Glove-and-stocking distribution of sensory loss (D)</p> Signup and view all the answers

    What does heteroplasmy in mitochondrial genetics refer to?

    <p>Coexistence of wild type and mutant mtDNA molecules (C)</p> Signup and view all the answers

    What is the primary reason for most mitochondrial pathologies?

    <p>Failure in ATP production (D)</p> Signup and view all the answers

    How does the mitochondrial genetic bottleneck affect siblings?

    <p>It generates a high degree of genetic and phenotypic variability (C)</p> Signup and view all the answers

    What percentage of mutant mtDNA is often required to surpass critical thresholds in tissues for symptoms to manifest?

    <p>50-60% (C)</p> Signup and view all the answers

    Which specific condition is noted to predominantly present in homoplasmic conditions?

    <p>Leber hereditary optic neuropathy (LHON) (A)</p> Signup and view all the answers

    What describes the process occurring during fertilization regarding heteroplasmic mtDNA mutations?

    <p>Random segregation to daughter cells (D)</p> Signup and view all the answers

    In mitochondrial genetics, what does the term 'oogenesis' refer to?

    <p>Reduction in the number of mtDNA molecules (A)</p> Signup and view all the answers

    What is a common challenge in diagnosing mitochondrial disorders?

    <p>Phenotypic expression variability (B)</p> Signup and view all the answers

    Which of the following statements about unaffected heteroplasmic females is true?

    <p>They may have children with varied health impacts. (D)</p> Signup and view all the answers

    What organ systems are particularly affected due to mitochondrial disorders?

    <p>Skeletal muscle, CNS, and heart muscle (C)</p> Signup and view all the answers

    Flashcards

    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)

    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

    mtDNA is inherited maternally, meaning that offspring inherit their mitochondrial DNA solely from their mother. Fathers do not contribute mtDNA.

    Mitochondrial Diseases

    Genetic mutations in mtDNA can lead to various mitochondrial diseases. These diseases often affect energy production, leading to a range of symptoms, including muscle weakness, fatigue, and neurological problems.

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    Mitochondrial Gene Mutations

    Adult-onset drug-resistant epilepsy, cortical myoclonus (muscle spasms), and bilateral optic neuropathies (vision loss) are examples of neurological conditions that can be caused by mutations in mitochondrial genes.

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    Genetic Testing for Mitochondrial Diseases

    Genetic testing, including whole-genome sequencing, is essential for diagnosing mitochondrial diseases. These tests can identify mutations in mtDNA that are responsible for the symptoms.

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    Management of Mitochondrial Diseases

    Treatment for mitochondrial diseases focuses on managing symptoms and improving quality of life. This may involve multidisciplinary approaches, such as medication for seizures, physical therapy for muscle weakness, and supportive care.

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    Adult-Onset Progressive Myoclonic Epilepsy (PME)

    A type of epilepsy that begins in adulthood, characterized by progressive muscle spasms (myoclonus) and seizures.

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    Diagnostic Challenges in PME

    The challenges faced in accurately diagnosing adult-onset progressive myoclonic epilepsy, often due to its varied symptoms and similarities to other neurological disorders.

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    Impact of PME on Quality of Life

    The profound impact PME has on the quality of life of individuals, affecting their physical well-being, social interactions, and overall sense of independence.

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    Therapeutic Implications of PME

    The implications of PME for therapeutic approaches, considering the challenges of managing seizures and mitigating the progression of the disease.

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    Genetic Implications of PME

    The role of genetics in understanding the causes and inheritance patterns of PME, aiding in genetic testing and counseling for affected families.

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    Electron Transport Chain (ETC)

    A series of protein complexes embedded in the inner mitochondrial membrane that transfer electrons and pump protons, ultimately generating a proton gradient used for ATP synthesis.

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    ETC Complexes (I-IV)

    Integral membrane proteins in the inner mitochondrial membrane that facilitate the movement of electrons and protons during oxidative phosphorylation.

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    Proton Gradient Generation

    The process by which the ETC generates a proton gradient across the inner mitochondrial membrane.

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    ATP (Adenosine Triphosphate)

    The primary source of energy for most cellular activities, produced by the ETC and ATP synthase.

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    mtDNA (Mitochondrial DNA)

    The circular DNA molecule found within mitochondria, encoding essential components of the oxidative phosphorylation pathway.

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    Mitochondrial Respiratory Chain Defects

    Mitochondrial disorders caused by mutations in mtDNA, affecting various tissues and organs.

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    Mitochondrial Dysfunction

    A group of diseases caused by disruptions in the ETC and ATP production, leading to various symptoms, from muscle weakness to neurodegeneration.

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    nDNA (Nuclear DNA)

    The genetic material found in the nucleus of cells, separate from mtDNA.

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    Apoptosis (Programmed Cell Death)

    A type of cell death triggered by various stimuli, including mitochondrial dysfunction, apoptosis contributes to normal development and disease.

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    Myoclonic Epilepsy

    A type of epilepsy characterized by sudden, involuntary muscle jerks.

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    Optic Neuropathies

    A condition where the optic nerve, which transmits visual information from the eye to the brain, is damaged, leading to vision loss.

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    Bilateral Tonic-Clonic Seizures

    Seizures that involve both sides of the brain.

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    Focal to Bilateral Seizures

    A type of seizure that starts in one part of the brain but can spread to other parts.

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    Central Scotomata

    A condition where a person experiences progressive loss of vision in the center of their field of vision.

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    Axonal Neuropathy

    A type of nerve damage that affects the peripheral nerves, leading to weakness, numbness, and tingling.

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    m.14487T>C p.(Met63Val)

    A genetic mutation that leads to a change in the amino acid sequence of the ND6 subunit of the mitochondrial respiratory chain.

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    Multidisciplinary Approach

    A treatment approach that uses a combination of medications and therapies to manage symptoms.

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    Onabotulinum Toxin A Injections

    A type of therapy that uses injections of botulinum toxin A to reduce muscle spasms and improve movement.

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    Heteroplasmy

    The coexistence of both normal and mutated mitochondrial DNA (mtDNA) molecules within a single cell.

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    Homoplasmy

    A condition where almost all mtDNA copies within a cell are mutated, often leading to symptoms.

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    Mitochondrial Genetic Bottleneck

    The process where the number of mtDNA molecules is significantly reduced during early oogenesis. This can lead to variations in the number of mutated mtDNA passed on to offspring.

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    Threshold Effect

    A critical threshold level of mutated mtDNA (often 50-60%) in a specific tissue that triggers the development of clinical symptoms.

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    Mitochondrial Disorders

    A group of genetic disorders affecting the mitochondria characterized by a wide range of clinical presentations.

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    Leber Hereditary Optic Neuropathy (LHON)

    An inherited eye disorder caused by mutations in mtDNA, often present in homoplasmic conditions.

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    Phenotypic Heterogeneity

    A clinical feature of mitochondrial disorders where the symptoms don't fit into any specific disease category.

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    Diagnostic Challenges

    The challenge faced by clinicians in diagnosing mitochondrial disorders due to the complex nature of the diseases and the wide variety of clinical presentations.

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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
    • A list of articles and books.

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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.

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