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Whole mitochondrial genome (mtDNA) sequencing

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Sequencing of mtDNA.

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Whole Mitochondrial Genome Sequencing - Comprehensive Medical Test Guide

  • Why is it done?
    • Test Description: This test sequences the entire mitochondrial genome (approximately 16,569 base pairs) to identify mutations, deletions, duplications, and other genetic variations in mitochondrial DNA (mtDNA). It provides complete nucleotide sequence information for comprehensive mutation detection.
    • Primary Indications: Suspected mitochondrial disease with progressive muscle weakness, unexplained neurological symptoms, or metabolic dysfunction
    • Confirmation of mitochondrial disorders such as MELAS, MERRF, Leber Hereditary Optic Neuropathy (LHON), or Leigh syndrome
    • Evaluation of matrilineal inheritance patterns in families with genetic disease
    • Assessment of hearing loss, vision problems, cardiac arrhythmias, or diabetes of unknown etiology
    • Pharmacogenetic testing to predict medication sensitivity and metabolic complications
    • Typical Timing: Performed when clinical presentation strongly suggests mitochondrial disease; often after initial screening tests, muscle biopsy, or biochemical studies are inconclusive. Can be ordered at any age but more commonly in childhood or adolescence when symptoms manifest.
  • Normal Range
    • Reference Values: A 'normal' result indicates the mitochondrial genome sequence matches the established reference sequence (Cambridge Reference Sequence or revised Cambridge Reference Sequence, rCRS) or contains only known benign variants.
    • Heteroplasmy Levels: Reported as percentage of mutant mtDNA relative to wild-type. Normal: 0-1% mutant burden (homoplasmic wild-type); Carrier: 1-50% heteroplasmy; Affected: typically >50% but variable penetrance. Threshold for disease expression varies by mutation type and tissue.
    • Interpretation Categories:
    • Negative/Normal: No pathogenic variants detected; sequence consistent with healthy population
    • Positive/Pathogenic: One or more definitively disease-causing mutations identified with appropriate heteroplasmy level
    • Variant of Uncertain Significance (VUS): Variant identified but pathogenicity unclear; requires functional studies or family correlation
    • Benign/Common Variant: Polymorphism present in general population with no disease association
    • Units of Measurement: Base pair positions (1-16,569); heteroplasmy expressed as percentage (%); copy number reported as integer values; depth of coverage in reads per base.
  • Interpretation
    • Pathogenic Mutations: Definitively disease-causing variants established through literature review and functional data. Examples: m.11778G>A (LHON), m.3243A>G (MELAS), m.8344A>G (MERRF), m.14484T>C (LHON). Homoplasmic status generally indicates symptomatic disease; heteroplasmic threshold varies (typically >60% for MELAS).
    • Point Mutations in Protein-Coding Genes: Non-synonymous changes affecting genes encoding oxidative phosphorylation (OXPHOS) complex proteins. Missense mutations may cause reduced enzyme activity; nonsense mutations typically result in truncated, non-functional proteins.
    • tRNA and rRNA Mutations: Alterations in ribosomal or transfer RNA genes impair protein synthesis machinery, reducing mitochondrial protein production. Often associated with MERRF and maternally inherited diabetes.
    • Large Deletions/Duplications: Loss or gain of multiple genes causing profound energy metabolism dysfunction. Single Large Deletion (SLD) syndrome presents with progressive external ophthalmoplegia (PEO), ptosis, and cardiac conduction abnormalities. Typically heteroplasmic.
    • Control Region Variants: Mutations in D-loop region affecting replication and transcription control. Often population-specific; pathogenicity assessment complex and context-dependent.
    • Factors Affecting Interpretation:
    • Heteroplasmy level and tissue distribution (peripheral blood vs. muscle vs. brain)
    • Age of symptom onset (congenital vs. adult-onset disease)
    • Ethnic background and population-specific variant frequencies
    • Biochemical parameters (serum lactate, CSF lactate, respiratory chain enzyme activity)
    • Imaging findings (MRI brain, muscle imaging patterns)
    • Segregation analysis and maternal inheritance confirmation
    • Clinical Significance of Patterns:
    • Homoplasmy: 100% mutant mtDNA typically associated with more severe/earlier disease manifestation
    • High-level heteroplasmy (>80%): Often symptomatic with disease features; prognosis generally more severe
    • Intermediate heteroplasmy (40-80%): Variable penetrance; symptoms may develop over time or remain stable
    • Low-level heteroplasmy (<40%): May be asymptomatic or present mild features; risk of segregation in offspring during oogenesis
  • Associated Organs
    • Primary Organ Systems Affected:
    • Central and Peripheral Nervous System: Progressive neurodegeneration, seizures, developmental delay, ataxia, peripheral neuropathy, stroke-like episodes
    • Skeletal and Cardiac Muscle: Progressive muscle weakness, myopathy, exercise intolerance, cardiomyopathy, arrhythmias, conduction abnormalities
    • Ocular System: Progressive external ophthalmoplegia (PEO), ptosis, optic nerve atrophy, retinal degeneration, cataracts
    • Endocrine System: Diabetes mellitus, thyroid dysfunction, parathyroid abnormalities, adrenal insufficiency
    • Auditory System: Sensorineural hearing loss, progressive deafness
    • Renal and Hepatic Systems: Chronic kidney disease, progressive renal failure, liver dysfunction, elevated transaminases
    • Associated Diseases and Conditions:
    • MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes): Most common mitochondrial disorder; characterized by stroke-like lesions, seizures, cognitive decline; m.3243A>G most frequent pathogenic variant
    • MERRF (Myoclonic Epilepsy with Ragged Red Fibers): Progressive myoclonic seizures, myopathy with ragged red fibers, dementia, ataxia; m.8344A>G most common mutation
    • LHON (Leber Hereditary Optic Neuropathy): Acute vision loss in young adults; primarily affects central vision; three primary mutations account for 90% of cases
    • Leigh Syndrome: Progressive neurodegenerative disorder presenting in infancy with developmental regression, hypotonia, brainstem and basal ganglia involvement on imaging
    • PEO (Progressive External Ophthalmoplegia) Syndromes: Single or multiple large deletions; presents with ptosis, ophthalmoplegia, proximal muscle weakness, cardiac conduction defects
    • Potential Complications and Systemic Risks:
    • Sudden cardiac death from arrhythmias or complete heart block
    • Status epilepticus or intractable seizures leading to SUDEP (Sudden Unexpected Nocturnal Death in Epilepsy)
    • Lactic acidosis and metabolic derangement crisis
    • Progressive respiratory failure requiring ventilatory support
    • End-stage renal disease necessitating dialysis or transplantation
    • Stroke-like episodes and permanent neurological deficits
    • Blindness from progressive optic neuropathy or retinal degeneration
  • Follow-up Tests
    • Confirmatory and Supplementary Testing:
    • Tissue-Specific mtDNA Analysis: Repeat sequencing from muscle biopsy, blood, or other affected tissues to determine heteroplasmy distribution and tissue-specific mutation load
    • Respiratory Chain Enzyme Complex Assessment: Spectrophotometric measurement of Complex I, II, III, IV, and V activities in muscle tissue to confirm biochemical defect
    • Metabolic Testing: Serum and cerebrospinal fluid lactate levels (elevated indicating impaired oxidative metabolism); plasma amino acids; serum carnitine (free and acylated)
    • Muscle Biopsy with Histopathology: Ragged red fibers (RRF), cytochrome c oxidase (COX) deficiency, lipid accumulation; electron microscopy for abnormal mitochondrial morphology
    • Nuclear Gene Testing: If mtDNA sequencing negative but high clinical suspicion, sequence nuclear genes encoding mitochondrial proteins (e.g., POLG for PEO; SCO1, SCO2, COX10 for Complex IV deficiency)
    • Imaging Studies for Disease Assessment:
    • Brain MRI with spectroscopy: Detects stroke-like lesions, basal ganglia abnormalities, brainstem involvement, white matter changes, elevated lactate on MR spectroscopy
    • Cardiac evaluation: ECG, Holter monitoring, echocardiography to assess for cardiomyopathy, arrhythmias, and conduction abnormalities
    • Skeletal muscle MRI: Identifies pattern of muscle involvement and fatty infiltration
    • Genetic Counseling and Family Testing: Maternal relatives should be counseled and offered testing; risk assessment for offspring of affected women (100% transmission of mtDNA but heteroplasmy variable). Preimplantation genetic diagnosis (PGD) may be considered for family planning.
    • Ophthalmologic Assessment: Comprehensive eye examination, visual acuity testing, optical coherence tomography (OCT), fundus photography to document optic nerve changes and retinal involvement
    • Audiometry and Hearing Assessment: Pure tone audiometry and speech discrimination testing if hearing loss suspected; documentation of baseline for monitoring progression
    • Recommended Monitoring Frequency:
    • Pathogenic mutation confirmed: Annual to biannual clinical assessments with specialist evaluation (neurology, cardiology, ophthalmology)
    • Progressive symptoms or VUS: Follow-up sequencing of same gene from additional tissues; repeat biomarker testing at 6-12 month intervals
    • Asymptomatic carrier identified: Baseline imaging and functional testing; counseling regarding reproductive risks; annual monitoring if m.3243A>G or other mutation with age-dependent penetrance
    • Large deletions: Repeat quantitative PCR or next-generation sequencing annually to assess for clonal shifts or secondary deletions
  • Fasting Required?
    • Fasting Requirement: NO - Fasting is NOT required for whole mitochondrial genome sequencing
    • Sample Collection: Genetic testing using genomic DNA; food intake does not affect quality of genetic material
    • Specimen Types:
    • Peripheral blood (EDTA tube - most common): 3-5 mL venous blood; acceptable at any time of day
    • Muscle tissue: Obtained via biopsy (deltoid or vastus lateralis); no fasting requirement
    • Skin biopsy: For fibroblasts; minimal fasting impact
    • Saliva: Alternative non-invasive sample from collection kit; no fasting needed
    • Special Instructions:
    • No special preparation required; patient may eat and drink normally before collection
    • If muscle biopsy: Local anesthesia used; mild discomfort expected; no general anesthesia typically required; minimal recovery period
    • Avoid excessive heat exposure prior to blood draw (may affect sample quality)
    • Inform laboratory if recent transfusion or bone marrow transplant (may affect results due to chimeric mtDNA)
    • Medications - No Restrictions: Continue all regular medications; no need to adjust dosing or timing. However, if testing involves concurrent metabolic studies (lactate, amino acids), specific pre-test fasting may be required for those tests separately.
    • Sample Storage and Transport: Blood: Store at 2-8°C if delay >24 hours before DNA extraction; do not freeze whole blood in EDTA tubes. Submit to laboratory within 5-7 days of collection.
    • Muscle tissue: Immediately snap-freeze in liquid nitrogen or fix in formalin per laboratory protocol; transport on dry ice
    • Result Turnaround Time: Typically 2-4 weeks from receipt of sample; may be expedited to 1-2 weeks if marked 'Urgent'; complex cases with VUS interpretation may require additional 1-2 weeks for literature review and expert consultation

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