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MITOCHONDRIAL DISEASES
Introduction
• Mitochondria are crucial to the flow of energy in
cells.
• Mitochondria presumably originated as parasites

that formed a symbiotic relationship with
eukaryotic cells more than 2 billion years ago, in

response to an increase in atmospheric oxygen.
Mitochondrial Disorder
Primary cellular functions of mitochondria
 Supply energy to cell in form of ATP

 Generate and regulate reactive oxygen
species

 Buffer cytosolic calcium ions
 Regulate apoptosis through the

mitochondrial permeability transition pore
Serves as a cellular site for the following
metabolic pathways –

 Electron transport chain
 Tricarboxylic acid cycle or Krebs cycle

 Beta oxidation of fatty acids
 Gluconeogenesis

 Urea Synthesis
Mitochondrial Disorder
MITOCHONDRIA LIFE CYCLE :
FUSION, FISSION AND AUTOPHAGY
• Mitochondria can’t be synthesized

de novo, so new mitochondria must arise from
existing mitochondria.

• At any point of time, mitochondria are in a

dynamic flux between fission and fusion.
Unravelling the
genetics of
mitochondria
Mitochondrial Disorder
MITOCHONDRIAL DNA
• Circular, double stranded, and composed of
heavy and light chains or strands
• Contains 16,569 bp

• Encodes 13 proteins
22 tRNA

2rRNA
MITOCHONDRIAL VS NUCLEAR
GENOME
• Mitochondrial genome has
. smaller number of genes
. higher copy number
. less effective repair mechanisms
. higher mutation rates
Peculiarities of Mitochondrial Genetics

Maternal inheritance

 high copy number
 heteroplasmy

 bottleneck and segregation
 threshold
MATERNAL INHERITANCE
MATERNAL MODE OF INHERITANCE
HETEROPLASMY
• Cells contain hundreds of mitochondria , and
each mitochondria contains hundreds of mtDNA.
So cells contain thousands of copies of mtDNA.

• For the most parts ,their sequence will be

identical (homoplasmy )
Mitochondrial Disorder
Mutation arises in mtDNA

Mixed population of wild- type and mutant mtDNA within a single cell
( heteroplasmy )

Heteroplasmic cells divide and the mtDNA is distributed randomly to
daughter cells resulting in skewed populations of wild type or mutant
mtDNA
Random mitotic segregation of mtDNA causes varying proportions of
mutant mtDNA In daughter cells

Degree of heteroplasmy determines clinical phenotype
BOTTLENECK AND SEGREGATION
• Of the 1,50,000 mtDNA molecules in human oocytes
,only a small proportion of mtDNA is transmitted
during oogenesis and subsequently to embryo.

• Important implications in
high intrafamilial clinical variation
changing phenotype over time
THRESHOLD
• For heteroplasmic mtDNA mutations
• Cell can compensate for reduced wild-type mtDNA
until a certain threshold is met
- function of cell become compromised

• Disease occurs when enough cells in a tissue are
affected
• Threshold depends on specific mutation and cell types
Ex : neurons have a lower threshold for disease state
PATHOPHYSIOLOGY
•

Primary mitochondrial disease:

Diseases involving defects of oxidative phosphorylation.
• Tissues with high aerobic demands such as
brain tissue,
heart muscle ,
skeletal muscle

usually more severely affected.
• Mitochondrial disease can arise through :
1. defect in mtDNA
2. defect in nuclear-encoded mitochondrial

protein
mtDNA and disease
• Mutation creates two distinct classes of
mtDNA variants :
- single base pair variants
- mtDNA rearrangements (deletions and
insertions)
CLINICAL SYNDROMES
OF mtDNA mutations
mtDNA vs Nuclear DNA mutations
Feature

mtDNA mutations Nuclear DNA mutations

Mode of
inheritance

Maternal

Mendelian

Age of onset

Adults

Infancy / childhood

Severity of
disease

Less

More

Lactic acidosis

More common

Not seen
APPROACH TO MITOCHONDRIAL
DISORDERS
• Idiopathic, chronic, intermittent or progressive
illness involving at least two different high-energy
requiring tissues
– Neuron (brain, esp. basal ganglia, special senses

and autonomic neuron)
– Muscle (skeletal, cardiac, or smooth)
– Endocrine gland
– Renal tubule
• Examples
– Mental retardation and diabetes mellitus
– Migraine and hypotonia

– Gastrointestinal dysmotility and stroke
– Hypothyroidism and cardiomyopathy

– Dysautonomia and deafness
– Depression and renal tubular acidosis
• Family history, intermittent disease, biochemical data
(lactic acidosis, elevated Krebs cycle intermediates)
can all increase suspicion of mitochondiral disease
• Mitochondrial disease affects tissues most
highly dependent on ATP production
– Nerves
– Muscles

– Endocrine
– Kidney
• Low energy-requiring tissues are rarely directly
affected, but may be involved secondarily
– Lung

– Connective tissue

• Symptoms can be intermittent
– Increased energy demand (illness, exercise)
– Decreased energy supply (fasting)
Mitochondrial Disorder
SYSTEM

CLINICAL MANIFESTATIONS

Cardiovascular






heart failure
arrhythmias
sudden death
left ventricular myocardial noncompaction

Pulmonary






dyspnea
orthopnea
respiratory failure
respiratory acidosis

neurologic









encephalopathy
ataxias
movement disorders
seizure disorder
mental retardation
stroke like episodes
migraine

endocrine







diabetes mellitus
diabetes insipidus
hypothyroidism
hypoparathyroidism
ACTH deficiency
Ocular

Musculoskeletal

Renal

 optic atrophy
 external opthalmoplegia
 ptosis
 retinitis pigmentosa
 cataract
 myopathy
•Skeletal muscle : ocular>axial/proximal>bulbar>distal
•Smooth muscle : dysphagia
•Cardiac : cardiomyopathy
 myalgias
 renal tubular defects
 benign renal cysts
 focal segmental glomerulosclerosis
 nephritic syndrome

Hematological

 anemia
 leukopenia
 thrombocytopenia
 eosinophilia

Gastrointestinal

 malabsorption
 villous atrophy
 pseudo-obstruction
LABORATORY EVALUATION
– Serum CK level: mildly elevated in mitochondrial
myopathies but are often normal,High-CPEO and
ptosis;Very high in limb weakness
– Lactate level: fasting blood lactate conc >3mm/l support
the diagnosis

– CSF lactate: fasting conce>1.5mm/l
• Normal level can be seen in NARP
• Elevated with short exercise
• Electrocardiography and echocardiography
– cardiac involvement
– (cardiomyopathy or atrioventricular conduction defects).
• Neuroimaging :
– suspected CNS disease.
• CT: basal ganglia calcification +/ diffuse atrophy
• MRI: focal atrophy of the cortex / cerebellum
high signal change on T2WI, particularly occipital
generalized leukoencephalopathy.
Cerebellar atrophy (pediatrics)
• Neurophysiologic studies:
– indicated in individuals with limb weakness,
sensory symptoms, or areflexia.
– Electromyography (EMG) is often normal but may

show myopathic features.
– Nerve conduction velocity (NCV)


may be normal or may show a predominantly
axonal sensorimotor polyneuropathy
• Electroencephalography (EEG)
– Indicated in suspected encephalopathy / seizures.

Encephalopathy: generalized slow wave activity on
the EEG.
Seizures : Generalized or focal spike and wave discharges
may be seen
MUSCLE BIOPSY
– More specific test of
mitochondrial myopathies
– analyzed for histologic or histochemical evidence
of mitochondrial disease.
– Respiratory chain complex studies are carried out
on skeletal muscle or skin fibroblasts.
– Ragged red fibers (RRFs) are seen on muscle
biopsy.
– Presence of more than 2% RRFs in skeletal muscle
biopsy is taken as one of the criteria for the
diagnosis of mitochondrial disease.
 Distinctive features of muscle biopsy in
mithochondrial myopathies :
• Succinate dehydrogenase (SDH) stain:
Increased staining of muscle fibers
Most sensitive & specific stain for
mitochondrial proliferation in muscle
fibers
• Cytochrome oxidase (COX) stain:
– Absent or reduced staining of muscle
fibers:
Reduced COX activity.
– May be diffuse or in scattered fibers.
IMMUNOHISTOCHEMISTRY
– Abnormal protein accumulation in ragged red fibers:

• Desmin
• αβcrystallin,
• Heat shock proteins,
• Dysferlin,
• Emerin,

• Caveolin.
• ELECTRON MICROSCOPY:
– Usually not specific or sensitive in adults with nondiagnostic histochemistry results ,
– Ultrastructure may be only evidence of
mitochondrial pathology in 6%
MOLECULAR GENETICS
• Testing carried out on genomic DNA
– Blood (suspected nuclear DNA mutations and
some mtDNA mutations)
– Muscle(suspected mtDNA mutations)
– Southern blot analysis may reveal a pathogenic
mtDNA rearrangement. The deletion or
duplication breakpoint may then be mapped by
mtDNA sequencing.
– If a recognized point mutation is not
identified, the entire mitochondrial genome may
be sequenced.
PRINCIPLES OF TREATMENT
Treat Underlying Neurologic Issues
– Seizures(antiepileptic drugs)
– Spasticity- baclofen, botulinium toxin
– Dystonia- diazepam, botulinium toxin, trihexyphenidyl
– headache –
acute: nonsteroidal anti-inflammatory drugs and
acetaminophen; avoid aspirin and triptans in MELAS,
chronic: amitriptyline, calcium blockers, riboflavin, coenzyme
Q10,
• Nutritional:
– Identify and treat deficiencies in vitamins (vitamins A, B12,
E, D, folate for red blood cells), minerals (iron, zinc,
selenium, calcium, magnesium), and protein calorie
(albumin).
Avoid Metabolic Stressors
• Extremes of heat and cold are not well tolerated. Fever

should be treated with acetaminophen (10 mg/kg every
4 hours to 15 mg/kg every 4 hours). Shivering is

metabolically expensive and should be avoided.
• Avoid unaccustomed strenuous exercise, especially in the
fasting state or with a concomitant illness.
• Avoid prolonged (greater than 12 hours) fasting.
MITOCHONDRIAL GENETIC
DISORDERS
REARRANGEMENTS

POINT MUTATIONS

CPEO

MELAS

Kearns-Sayre syndrome

MERRF

Pearson marrow pancreas syndrome

CPEO

Diabetes and deafness

Myopathy
Cardiomyopathy
NARP

LHON
Nuclear genetic disorder
• Autosomal dominant progressive ophthalmoplegia
• Mitochondrial neurogastrointestinal
enecephalomyopathy
• Leigh syndrome
• Cardioenecephalomyopathy
• Optic atrophy and ataxia
• Tubulopathy, encephalopathy and liver failure
MELAS
(Mitochondrial myopathy,
Encephalopathy, Lactic Acidosis and
Stroke like episodes)
– Most common mitochondrial encephalomyopathy
– Maternally inherited point mutation

– A3243G point mutation in tRNA-80%
– Onset in majority patients is before the age of 20 yrs
– Seizures: partial or generalized, may be first sign
– Stroke like episodes, do not conform to a vascular
distribution
– Hemiparesis, hemianopia and cortical blindness
– Associated condition, hearing loss, diabetes mellitus,

growth hormone deficiency
– Fatal outcome
Diagnosis of MELAS
CSF protein

Increased but <100mg/dl

Muscle biopsy

•Ragged red fibres
•SDH positive fibres
•COX positive fibres

CSF lactate

Increased

Imaging

•Grey and white matter involvement
•Basal ganglia calcification
•Focal lesion which mimic infraction are present in occipito-parietal

Genetics

80% have A3243G mutation in tRNA leucine
MUSCLE BIOPSY – SDH STAIN

Normal: Mild SDH staining of a
medium sized perimysial vessel.

Increased SDH staining of a
medium sized perimysial vessel
in a MELAS patient.
Scattered abnormal, vacuolated fibers
with clear rim: H & E

Scattered "ragged red" muscle fibers:
Gomori trichrome
KEARNS-SAYRE
SYNDROME
(KSS)
– Multiorgan disorder
– Triad-onset before 20yrs,CPEO ,pigmentary
retinopathy
– Plus one or more of following: complete heart

block, cerebellar ataxia, or increased CSF protein
100mg/dl
– Common 5-kb mtDNA deletion,

deletion/duplications, A3243G
– KSS/CPEO-like phenotype can be caused by
nuclear mutations in genes for mtDNA
maintenance (ANT1, Twinkle and POLG)
MERRF
(Myoclonic Epilepsy with
Ragged Red Fibres)
– Onset : childhood to middle adult
– Point mutation A8344G of tRNA lysine
– Characteristic : myoclonic epilepsy
cerebellar ataxia

progressive muscle weakness
– Others: dementia, peripheral neuropathy, optic

atrophy, hearing loss and diabetes mellitus
– Lipomas-cervical, symmetrical
Serum CPK

Normal or increased

Lactate
(serum and CSF)

Elevated

EMG

Myopathic

EEG

May be abnormal, non specific

Muscle biopsy

•Ragged red fibres
•SDH positive fibres
•COX negative fibres

Genetics

•A8344G mutation
•Base pair substution-T8356C, G8363A
Leber’s hereditary optic
neuropathy (LHON)
– Onset in early 20s
– Maternally inherited
– Three mutation all are located within mtDNA
complex I genes
• G11778A mutation in ND4
• G3460A mutation
• T14484C mutation in ND6

– Characterized by acute and subacute bilateral
painless visual loss
– Visual loss is severe and permanent
– Dystonia or striatal degeneration
LEIGH’S
SYNDROME
– Subacute necrotising encephalomyopathy
– Onset: infancy and early childhood
– Most commonly caused by high mutant loads

(>95%) of T8993G/C
– Point mutations in ATP synthase gene, affects
complex V
– Other causes include complex I def
(NDUFV1), complex IV def (SURF1), PDHC

defenciency
– Progressive psychomotor deterioration,
respiratory failure

– MRI leukodystropy, changes in basal ganglia and
brain stem
Neuropathy, Ataxia, Retinitis
Pigmentosa(NARP)
– Onset :childhood
– Moderate heteroplasmy for T8993G/C in ATPase
6gene (same as Leigh but lower mutant load)
– Polyneuropathy, cerebellar ataxia, retinitis
pigmentosa

– Muscle biopsy -normal
Mitochondrial, Neurogastrointestinal
encephalomyopathy(MNGIE)
– Adolescent
– Autosomal recessive
– Mutation in thymidine phosphorylase in Ch 22

– Thymidine phosphorylase activity is reduced and
plasma thymidine levels are elevated

– Peripheral neuropathy,CPEO,gastrointestinal
dysmotility
 Toxin induced MtDNA myopathy
– Exogenous cause of mtDNA abnormalities is HIV infection
and antiretroviral therapy

– Zidovudine induced myopathy patient presents with
myalagia,weakness , atrophy of thigh and calf muscle
– S.CK- raised
– EMG-myopathic
– Muscle biopsy-ragged red fibres with minimal
inflammation
• Association with neurodegenerative disorders
– Parkinson disease
– Alzheimer disease
– Huntington disease

– Friedreich ataxia
THANK YOU

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Mitochondrial Disorder

  • 2. Introduction • Mitochondria are crucial to the flow of energy in cells. • Mitochondria presumably originated as parasites that formed a symbiotic relationship with eukaryotic cells more than 2 billion years ago, in response to an increase in atmospheric oxygen.
  • 4. Primary cellular functions of mitochondria  Supply energy to cell in form of ATP  Generate and regulate reactive oxygen species  Buffer cytosolic calcium ions  Regulate apoptosis through the mitochondrial permeability transition pore
  • 5. Serves as a cellular site for the following metabolic pathways –  Electron transport chain  Tricarboxylic acid cycle or Krebs cycle  Beta oxidation of fatty acids  Gluconeogenesis  Urea Synthesis
  • 7. MITOCHONDRIA LIFE CYCLE : FUSION, FISSION AND AUTOPHAGY
  • 8. • Mitochondria can’t be synthesized de novo, so new mitochondria must arise from existing mitochondria. • At any point of time, mitochondria are in a dynamic flux between fission and fusion.
  • 11. MITOCHONDRIAL DNA • Circular, double stranded, and composed of heavy and light chains or strands • Contains 16,569 bp • Encodes 13 proteins 22 tRNA 2rRNA
  • 12. MITOCHONDRIAL VS NUCLEAR GENOME • Mitochondrial genome has . smaller number of genes . higher copy number . less effective repair mechanisms . higher mutation rates
  • 13. Peculiarities of Mitochondrial Genetics Maternal inheritance  high copy number  heteroplasmy  bottleneck and segregation  threshold
  • 15. MATERNAL MODE OF INHERITANCE
  • 16. HETEROPLASMY • Cells contain hundreds of mitochondria , and each mitochondria contains hundreds of mtDNA. So cells contain thousands of copies of mtDNA. • For the most parts ,their sequence will be identical (homoplasmy )
  • 18. Mutation arises in mtDNA Mixed population of wild- type and mutant mtDNA within a single cell ( heteroplasmy ) Heteroplasmic cells divide and the mtDNA is distributed randomly to daughter cells resulting in skewed populations of wild type or mutant mtDNA Random mitotic segregation of mtDNA causes varying proportions of mutant mtDNA In daughter cells Degree of heteroplasmy determines clinical phenotype
  • 19. BOTTLENECK AND SEGREGATION • Of the 1,50,000 mtDNA molecules in human oocytes ,only a small proportion of mtDNA is transmitted during oogenesis and subsequently to embryo. • Important implications in high intrafamilial clinical variation changing phenotype over time
  • 20. THRESHOLD • For heteroplasmic mtDNA mutations • Cell can compensate for reduced wild-type mtDNA until a certain threshold is met - function of cell become compromised • Disease occurs when enough cells in a tissue are affected • Threshold depends on specific mutation and cell types Ex : neurons have a lower threshold for disease state
  • 21. PATHOPHYSIOLOGY • Primary mitochondrial disease: Diseases involving defects of oxidative phosphorylation. • Tissues with high aerobic demands such as brain tissue, heart muscle , skeletal muscle usually more severely affected.
  • 22. • Mitochondrial disease can arise through : 1. defect in mtDNA 2. defect in nuclear-encoded mitochondrial protein
  • 23. mtDNA and disease • Mutation creates two distinct classes of mtDNA variants : - single base pair variants - mtDNA rearrangements (deletions and insertions)
  • 25. mtDNA vs Nuclear DNA mutations Feature mtDNA mutations Nuclear DNA mutations Mode of inheritance Maternal Mendelian Age of onset Adults Infancy / childhood Severity of disease Less More Lactic acidosis More common Not seen
  • 27. • Idiopathic, chronic, intermittent or progressive illness involving at least two different high-energy requiring tissues – Neuron (brain, esp. basal ganglia, special senses and autonomic neuron) – Muscle (skeletal, cardiac, or smooth) – Endocrine gland – Renal tubule
  • 28. • Examples – Mental retardation and diabetes mellitus – Migraine and hypotonia – Gastrointestinal dysmotility and stroke – Hypothyroidism and cardiomyopathy – Dysautonomia and deafness – Depression and renal tubular acidosis
  • 29. • Family history, intermittent disease, biochemical data (lactic acidosis, elevated Krebs cycle intermediates) can all increase suspicion of mitochondiral disease
  • 30. • Mitochondrial disease affects tissues most highly dependent on ATP production – Nerves – Muscles – Endocrine – Kidney
  • 31. • Low energy-requiring tissues are rarely directly affected, but may be involved secondarily – Lung – Connective tissue • Symptoms can be intermittent – Increased energy demand (illness, exercise) – Decreased energy supply (fasting)
  • 33. SYSTEM CLINICAL MANIFESTATIONS Cardiovascular     heart failure arrhythmias sudden death left ventricular myocardial noncompaction Pulmonary     dyspnea orthopnea respiratory failure respiratory acidosis neurologic        encephalopathy ataxias movement disorders seizure disorder mental retardation stroke like episodes migraine endocrine      diabetes mellitus diabetes insipidus hypothyroidism hypoparathyroidism ACTH deficiency
  • 34. Ocular Musculoskeletal Renal  optic atrophy  external opthalmoplegia  ptosis  retinitis pigmentosa  cataract  myopathy •Skeletal muscle : ocular>axial/proximal>bulbar>distal •Smooth muscle : dysphagia •Cardiac : cardiomyopathy  myalgias  renal tubular defects  benign renal cysts  focal segmental glomerulosclerosis  nephritic syndrome Hematological  anemia  leukopenia  thrombocytopenia  eosinophilia Gastrointestinal  malabsorption  villous atrophy  pseudo-obstruction
  • 36. – Serum CK level: mildly elevated in mitochondrial myopathies but are often normal,High-CPEO and ptosis;Very high in limb weakness – Lactate level: fasting blood lactate conc >3mm/l support the diagnosis – CSF lactate: fasting conce>1.5mm/l • Normal level can be seen in NARP • Elevated with short exercise
  • 37. • Electrocardiography and echocardiography – cardiac involvement – (cardiomyopathy or atrioventricular conduction defects). • Neuroimaging : – suspected CNS disease. • CT: basal ganglia calcification +/ diffuse atrophy • MRI: focal atrophy of the cortex / cerebellum high signal change on T2WI, particularly occipital generalized leukoencephalopathy. Cerebellar atrophy (pediatrics)
  • 38. • Neurophysiologic studies: – indicated in individuals with limb weakness, sensory symptoms, or areflexia. – Electromyography (EMG) is often normal but may show myopathic features. – Nerve conduction velocity (NCV)  may be normal or may show a predominantly axonal sensorimotor polyneuropathy
  • 39. • Electroencephalography (EEG) – Indicated in suspected encephalopathy / seizures. Encephalopathy: generalized slow wave activity on the EEG. Seizures : Generalized or focal spike and wave discharges may be seen
  • 41. – More specific test of mitochondrial myopathies – analyzed for histologic or histochemical evidence of mitochondrial disease. – Respiratory chain complex studies are carried out on skeletal muscle or skin fibroblasts. – Ragged red fibers (RRFs) are seen on muscle biopsy. – Presence of more than 2% RRFs in skeletal muscle biopsy is taken as one of the criteria for the diagnosis of mitochondrial disease.
  • 42.  Distinctive features of muscle biopsy in mithochondrial myopathies : • Succinate dehydrogenase (SDH) stain: Increased staining of muscle fibers Most sensitive & specific stain for mitochondrial proliferation in muscle fibers • Cytochrome oxidase (COX) stain: – Absent or reduced staining of muscle fibers: Reduced COX activity. – May be diffuse or in scattered fibers.
  • 44. – Abnormal protein accumulation in ragged red fibers: • Desmin • αβcrystallin, • Heat shock proteins, • Dysferlin, • Emerin, • Caveolin.
  • 45. • ELECTRON MICROSCOPY: – Usually not specific or sensitive in adults with nondiagnostic histochemistry results , – Ultrastructure may be only evidence of mitochondrial pathology in 6%
  • 47. • Testing carried out on genomic DNA – Blood (suspected nuclear DNA mutations and some mtDNA mutations) – Muscle(suspected mtDNA mutations) – Southern blot analysis may reveal a pathogenic mtDNA rearrangement. The deletion or duplication breakpoint may then be mapped by mtDNA sequencing.
  • 48. – If a recognized point mutation is not identified, the entire mitochondrial genome may be sequenced.
  • 50. Treat Underlying Neurologic Issues – Seizures(antiepileptic drugs) – Spasticity- baclofen, botulinium toxin – Dystonia- diazepam, botulinium toxin, trihexyphenidyl – headache – acute: nonsteroidal anti-inflammatory drugs and acetaminophen; avoid aspirin and triptans in MELAS, chronic: amitriptyline, calcium blockers, riboflavin, coenzyme Q10,
  • 51. • Nutritional: – Identify and treat deficiencies in vitamins (vitamins A, B12, E, D, folate for red blood cells), minerals (iron, zinc, selenium, calcium, magnesium), and protein calorie (albumin).
  • 52. Avoid Metabolic Stressors • Extremes of heat and cold are not well tolerated. Fever should be treated with acetaminophen (10 mg/kg every 4 hours to 15 mg/kg every 4 hours). Shivering is metabolically expensive and should be avoided. • Avoid unaccustomed strenuous exercise, especially in the fasting state or with a concomitant illness. • Avoid prolonged (greater than 12 hours) fasting.
  • 54. REARRANGEMENTS POINT MUTATIONS CPEO MELAS Kearns-Sayre syndrome MERRF Pearson marrow pancreas syndrome CPEO Diabetes and deafness Myopathy Cardiomyopathy NARP LHON
  • 55. Nuclear genetic disorder • Autosomal dominant progressive ophthalmoplegia • Mitochondrial neurogastrointestinal enecephalomyopathy • Leigh syndrome • Cardioenecephalomyopathy • Optic atrophy and ataxia • Tubulopathy, encephalopathy and liver failure
  • 56. MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke like episodes)
  • 57. – Most common mitochondrial encephalomyopathy – Maternally inherited point mutation – A3243G point mutation in tRNA-80% – Onset in majority patients is before the age of 20 yrs
  • 58. – Seizures: partial or generalized, may be first sign – Stroke like episodes, do not conform to a vascular distribution – Hemiparesis, hemianopia and cortical blindness – Associated condition, hearing loss, diabetes mellitus, growth hormone deficiency – Fatal outcome
  • 59. Diagnosis of MELAS CSF protein Increased but <100mg/dl Muscle biopsy •Ragged red fibres •SDH positive fibres •COX positive fibres CSF lactate Increased Imaging •Grey and white matter involvement •Basal ganglia calcification •Focal lesion which mimic infraction are present in occipito-parietal Genetics 80% have A3243G mutation in tRNA leucine
  • 60. MUSCLE BIOPSY – SDH STAIN Normal: Mild SDH staining of a medium sized perimysial vessel. Increased SDH staining of a medium sized perimysial vessel in a MELAS patient.
  • 61. Scattered abnormal, vacuolated fibers with clear rim: H & E Scattered "ragged red" muscle fibers: Gomori trichrome
  • 63. – Multiorgan disorder – Triad-onset before 20yrs,CPEO ,pigmentary retinopathy – Plus one or more of following: complete heart block, cerebellar ataxia, or increased CSF protein 100mg/dl
  • 64. – Common 5-kb mtDNA deletion, deletion/duplications, A3243G – KSS/CPEO-like phenotype can be caused by nuclear mutations in genes for mtDNA maintenance (ANT1, Twinkle and POLG)
  • 66. – Onset : childhood to middle adult – Point mutation A8344G of tRNA lysine – Characteristic : myoclonic epilepsy cerebellar ataxia progressive muscle weakness – Others: dementia, peripheral neuropathy, optic atrophy, hearing loss and diabetes mellitus – Lipomas-cervical, symmetrical
  • 67. Serum CPK Normal or increased Lactate (serum and CSF) Elevated EMG Myopathic EEG May be abnormal, non specific Muscle biopsy •Ragged red fibres •SDH positive fibres •COX negative fibres Genetics •A8344G mutation •Base pair substution-T8356C, G8363A
  • 69. – Onset in early 20s – Maternally inherited – Three mutation all are located within mtDNA complex I genes • G11778A mutation in ND4 • G3460A mutation • T14484C mutation in ND6 – Characterized by acute and subacute bilateral painless visual loss – Visual loss is severe and permanent – Dystonia or striatal degeneration
  • 71. – Subacute necrotising encephalomyopathy – Onset: infancy and early childhood – Most commonly caused by high mutant loads (>95%) of T8993G/C – Point mutations in ATP synthase gene, affects complex V – Other causes include complex I def (NDUFV1), complex IV def (SURF1), PDHC defenciency
  • 72. – Progressive psychomotor deterioration, respiratory failure – MRI leukodystropy, changes in basal ganglia and brain stem
  • 74. – Onset :childhood – Moderate heteroplasmy for T8993G/C in ATPase 6gene (same as Leigh but lower mutant load) – Polyneuropathy, cerebellar ataxia, retinitis pigmentosa – Muscle biopsy -normal
  • 76. – Adolescent – Autosomal recessive – Mutation in thymidine phosphorylase in Ch 22 – Thymidine phosphorylase activity is reduced and plasma thymidine levels are elevated – Peripheral neuropathy,CPEO,gastrointestinal dysmotility
  • 77.  Toxin induced MtDNA myopathy – Exogenous cause of mtDNA abnormalities is HIV infection and antiretroviral therapy – Zidovudine induced myopathy patient presents with myalagia,weakness , atrophy of thigh and calf muscle – S.CK- raised – EMG-myopathic – Muscle biopsy-ragged red fibres with minimal inflammation
  • 78. • Association with neurodegenerative disorders – Parkinson disease – Alzheimer disease – Huntington disease – Friedreich ataxia