Makindo Medical Notes

Related Subjects: |Dementias |DNA replication |DNA structure in Nucleus |Mitosis and Meiosis |Ribosomes |Microtubules |Mitochondria |Smooth and Rough Endoplasmic Reticulum

🔋 Mitochondrial diseases arise from defects in mitochondrial function. Although many are maternally inherited, around 95% of mitochondrial proteins come from nuclear DNA. Therefore, inheritance may be autosomal dominant, recessive, or even X-linked. Lynn Margulis first proposed their bacterial origin, highlighting the endosymbiotic theory.

About

• Energy failure disorders due to mitochondrial dysfunction, especially impacting high-energy tissues (muscle, brain, heart).
• Mitochondria have their own circular mtDNA, inherited maternally, but most proteins are nuclear-encoded.
• Prevalence: ~1 in 10,000 live births.
• Symptoms can affect multiple organ systems simultaneously (neuromuscular, ocular, endocrine, cardiac).

Aetiology

• Mutations in mtDNA or nuclear DNA → impaired oxidative phosphorylation (OXPHOS).
• Poor proofreading during mtDNA replication increases mutation risk.
• Mutations affect respiratory chain complexes I–V → ATP deficiency, lactic acidosis, and oxidative stress.

Mitochondrial Genetics

• Encodes 13 mRNAs (OXPHOS subunits), 22 tRNAs, 2 rRNAs.
• Defects commonly impair:
  • Complex I – NADH dehydrogenase
  • Complex II – Succinate dehydrogenase
  • Complex III – CoQ cytochrome reductase
  • Complex IV – Cytochrome oxidase
  • Complex V – ATP synthase
• Most mitochondrial proteins (95%) come from nuclear genes, imported into mitochondria post-translation.

Clinical Clues 🧩

• Sensorineural deafness
• Retinitis pigmentosa
• Recurrent “stroke-like” episodes
• Ataxia, seizures, or proximal myopathy
• Cardiomyopathy, conduction block, diabetes mellitus
• Lactic acidosis

Key Clinical Syndromes

• MELAS: Encephalopathy, lactic acidosis, stroke-like episodes, migraines, hearing loss, GI dysmotility.
• MERRF: Myoclonic epilepsy, ragged-red fibres, short stature, cardiomyopathy, lipomas.
• Kearns–Sayre Syndrome: Onset <20 yrs, ophthalmoplegia, pigmentary retinopathy, cardiac conduction block.
• PEO: Progressive external ophthalmoplegia, severe ptosis, overlap with other mitochondrial myopathies.
• Leigh’s Syndrome: Subacute necrotising encephalopathy of infancy/childhood, poor prognosis.

Investigations

• Muscle biopsy: Ragged-red fibres (trichrome stain), cytochrome oxidase deficiency.
• Blood: ↑Lactate ± CK, metabolic acidosis.
• CSF: ↑Protein, ±lactate.
• Imaging: MRI may show basal ganglia/brainstem lesions in Leigh’s.
• Genetics: Targeted mtDNA/nuclear DNA sequencing.

Management Principles

No cure – aim is symptom control and quality of life, with multidisciplinary care.

• 🔋 Supplements: CoQ10, L-carnitine, creatine, riboflavin, thiamine, antioxidants.
• 🏃‍♂️ Exercise: Light–moderate aerobic exercise may improve endurance. Avoid exhaustion and fasting.
• 🍽️ Nutrition: Adequate calories; consider enteral feeding if severe GI dysmotility.
• 💊 Avoid mitochondrial toxins: e.g. valproate, aminoglycosides in certain subtypes.

Symptom-Targeted Management

• Seizures → AEDs (avoid valproate; levetiracetam safer).
• Cardiac → Pacemaker for conduction block; monitor for cardiomyopathy.
• Endocrine → Insulin for diabetes, hormone replacement if adrenal/thyroid disease.
• GI dysmotility → Prokinetics, feeding tubes if required.

Genetics and Future

• Genetic counselling essential (maternal vs nuclear inheritance risks).
• Experimental: mitochondrial replacement therapy (“3-parent IVF”), gene therapy under investigation.

Prognosis

Highly variable. Some have mild multisystem disease with long survival; others (e.g. Leigh’s) face early neurodegeneration. Early diagnosis and multidisciplinary input improve quality of life.

Cases — Mitochondrial Diseases

• Case 1 — MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes) 🧠: A 14-year-old girl presents with recurrent “stroke-like” episodes causing hemiparesis and seizures. She also has short stature and sensorineural hearing loss. MRI shows cortical infarct-like lesions not confined to vascular territories. Serum lactate elevated. Diagnosis: MELAS syndrome. Management: Supportive — anti-epileptics (avoid valproate), arginine/citrulline supplements may reduce stroke-like episodes, MDT input (neuro, metabolic, genetics).
• Case 2 — MERRF (Myoclonic Epilepsy with Ragged-Red Fibres) ⚡: A 20-year-old man presents with progressive myoclonic jerks, ataxia, and generalised epilepsy. Family history: mother and maternal uncle with seizures and weakness. Muscle biopsy shows ragged-red fibres. Diagnosis: MERRF (due to mitochondrial tRNA mutation). Management: Symptomatic — anti-epileptics (avoid sodium valproate), physiotherapy, genetic counselling.
• Case 3 — Leber’s Hereditary Optic Neuropathy (LHON) 👁️: A 25-year-old man presents with subacute painless central vision loss in one eye, followed weeks later by the other. Fundoscopy: optic disc hyperaemia. Strong maternal family history of early blindness. Diagnosis: LHON due to mitochondrial DNA mutation affecting complex I. Management: Supportive (visual aids); idebenone sometimes used; genetic counselling; avoid mitochondrial toxins (tobacco, alcohol).

Teaching Commentary 🧠

Mitochondrial diseases are a heterogeneous group of disorders caused by defects in oxidative phosphorylation, often due to mtDNA mutations. 🔑 Key principles: - Maternal inheritance (mtDNA transmitted through oocytes). - Multisystem involvement: CNS (seizures, stroke-like episodes, ataxia), muscle (myopathy, weakness), eye (optic neuropathy, ophthalmoplegia), ear (hearing loss), endocrine (diabetes). - Common syndromes: MELAS, MERRF, LHON, Kearns–Sayre syndrome. Dx: lactate, muscle biopsy (ragged-red fibres), genetic testing. Mx: no curative therapy; focus on supportive management, avoidance of mitochondrial toxins, and genetic counselling. Prognosis varies by syndrome.