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.</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.</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</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</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</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</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</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</p> Signup and view all the answers

    How does the structure of mitochondrial DNA enhance its function?

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

    What results from defects in mitochondrial respiratory chain complexes?

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

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

    <p>80</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.</p> Signup and view all the answers

    What is the primary consequence of mitochondrial dysfunction?

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

    Which of the following best describes the nature of mtDNA?

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

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

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

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

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

    What type of seizures did Mr. A experience?

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

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

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

    What kind of visual loss did Mr. A report?

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

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

    <p>Mindfulness</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</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</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</p> Signup and view all the answers

    What does heteroplasmy in mitochondrial genetics refer to?

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

    What is the primary reason for most mitochondrial pathologies?

    <p>Failure in ATP production</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</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%</p> Signup and view all the answers

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

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

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

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

    What is a common challenge in diagnosing mitochondrial disorders?

    <p>Phenotypic expression variability</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.</p> Signup and view all the answers

    What organ systems are particularly affected due to mitochondrial disorders?

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

    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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    Related Documents

    Mitochondrial Disorders Past Paper PDF - University of Central Lancashire

    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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