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Mitochondrial Disorders. Chenjie Xia (PGY-IV) Montreal Neurological Institute Wednesday, Jan. 25 th , 2012. Outline. Basic mitochondrial molecular biology Clinical implications of mitochondrial genetics Clinical approach to mitochondrial disorders General features

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mitochondrial disorders

Mitochondrial Disorders

Chenjie Xia (PGY-IV)

Montreal Neurological Institute

Wednesday, Jan. 25th, 2012

  • Basic mitochondrial molecular biology
  • Clinical implications of mitochondrial genetics
  • Clinical approach to mitochondrial disorders
    • General features
    • Visual loss, ophthalmoplegia, peripheral neuropathy, ataxia
mitochondrion basics
Mitochondrion Basics
  • 4 compartments:
    • outer mb
    • inner mb (folds into cristae)
    • intermembrane space
    • matrix

Larsson and Oldfors, Acta Physiol Scand 2001.

role of mitochondria energy production
Role of mitochondria = energy production

Berardo et al. Curr Neurol Neurosci Report, 2010

respiratory chain
Respiratory Chain

mitochondrion basics1
Mitochondrion Basics
  • Mitochondrial respiratory chain:
    • Most “lucrative” step for ATP production
    • 5 enzymes complexes (90 protein subunits)
    • complexes I, II, III, IV creates proton gradient (pump protons out of matrix)
    • complex V uses H gradient to generate ATP
    • Mobile electron carriers: CoQ, cyt c
mitochondria genetics
Mitochondria Genetics
  • mt components activity depend on:
    • nuclear DNA (nDNA)
    • mitochondrial DNA (mtDNA)

Larsson and Oldfors, Acta Physiol Scand 2001.

mitochondrial genetics
Mitochondrial Genetics
  • mt genome encodes only 37 genes
    • 13/90 proteins of the RC
    • 2 rRNAs, 22 tRNAs
  • Most mt proteins encoded by nDNA
    • e.g. complex II, CPTII, PDC
    • nDNA exerts +++ control on mt DNA & proteins
    • Concept of intergenomic communication
      • Replication of mtDNA depend on factors encoded by nDNA
mitochondrial genetics1
Mitochondrial Genetics
  • nDNA mutations
    • Usually manifest in childhood
    • More severe and diffuse
  • mtDNA mutations
    • Usually manifest in adulthood
    • More indolent and mosaic
  • These principles hold less well given recent discoveries showing increasing clinical and genetic heterogeneity of mt disorders
mitochondrial genetics2
Mitochondrial Genetics
  • Concept of heteroplasmy
    • Mitochondrion contain mix of mutant and wild-type mtDNA
    • Proportion of mutant mtDNA differs in different tissues or even cells of same tissue
  • Concept of threshold effect
    • Sx develop only when mutant mtDNAreaches certain threshold (usually high, >90%)
    • Threshold depends on energy metabolism of tissue
  • Concept of replicative segregation
    • Mutant mtDNA are “selected out” with repeated mitoses, but accumulate in tissues not undergoing mitoses (e.g. neurons, muscles)
mitochondria genetics1
Mitochondria Genetics
  • Mitochondrial disorders can be sporadic or inherited
  • If inherited, mainly maternally:
    • “Bottle-neck” effect in oogenesis
    • rare case report of paternally inherited
  • Often no clear genotype-phenotype correlation
mitochondrial genetics3
Mitochondrial Genetics
  • THM =phenotypic expression of mt disorders depend on many factors:
    • Nuclear versus mitochondrial mutation
    • Pathogenicity of mutation itself
    • Heteroplasmy
    • Threshold effect
    • Mitotic activity of tissue
    • Energy demand of tissue
    • Age
    • Etc…
general features of mid
General features of MID
  • Classic S/Sx:
    • Neurological:
      • stroke, seizure, dev. delay, dementia, visual impairment, EOMs, deafness, neuropathy, myopathy
    • Other:
      • DM, hepatopathy, cardiomyopathy, cardiac conduction defects, short stature
clinical manifestations systemic
Clinical Manifestations - Systemic

Nardin and Johns. Muscle and Nerve, 2001.

general features of mid1
General features of MID
  • Key points:
    • +++ multisystemic
    • +++ overlap b/w different syndromes
    • same mutation can cause different phenotypes
      • proportion of 3243tRNA mutation determines CPEO vs MELAS vs Leigh’s
    • same phenotype can result from different mutations
      • MELAS can result from 3243tRNA, 3271tRNA, 11084 ND4
classification of mids
Classification of MIDs
  • 1.Affected structure or pathway w/i mito.
    • RC subunits, tRNA, mt transport machinery, mt maintenance, etc
  • 2.Mono- vs multi-systemic
  • 3. Syndromic vs non-syndromic
    • +++ genetic & phenotypic overlap b/w the two
    • Syndromic better known for acronyms and for understanding of mito medicine
    • But non-syndromic more common, probably less recognized in clinical practice (atypical & less spectacular presentations)
presenting phenotypes
Presenting Phenotypes
  • Visual Loss
  • Ptosis / opthalmoplegia
  • Neuropathy
  • Ataxia
  • (Myopathy)
  • (Seizures)
  • (Stroke)
genetic defects of mids
Genetic Defects of MIDs

Finsterer, CJNS, 2009

presenting phenotypes1
Presenting Phenotypes
  • Visual Loss
  • Ptosis / opthalmoplegia
  • Neuropathy
  • Ataxia
  • (Myopathy)
  • (Seizures)
  • (Stroke)
visual loss lhon
Visual Loss – LHON
  • Leber’s Hereditary Optic Neuropathy
    • Degeneration of retinal ganglion cells
    • Most common disease caused by mtDNA mutation
  • Clinical presentation
    • Bilateral sequential acute or subacute visual failure
    • Central vision lost before peripheral, blue-yellow perception lost early on (red-green more preserved)
    • Disc swelling and hyperemia followed by atrophy
    • Predominantly in young men
    • Little or no recovery (altho visual impairment seldom complete)
visual loss lhon1
Visual Loss = LHON
  • When to think of LHON for visual loss:
    • Young men
    • no vascular comorbidities (less likely ischemic)
    • Painless (less likely optic neuritis, either viral or demyelinating)
    • No toxic or deficiency state (B12, thiamine, tobacco-alcohol amblyopia, sildenafil)
genetic defects of mids1
Genetic Defects of MIDs

Finsterer, CJNS, 2009

visual loss rp
Visual Loss - RP
  • Retinitis Pigmentosa
    • All retinal layers affected
    • Predominance in males
    • 1st Sx = nyctalopia (impairment of twilight vision)
    • Usu both eyes affected simultaneously
    • Perimacular zones affected first  partial to complete ring scotoma
    • Pigmentary changes spare fovea  eventually pt perceives world as if seeing through tubes
visual loss rp1
Visual Loss - RP
  • DDx
    • Bardet-Biedl syndrome, Laurence-Moon syndrome, Freidreich’s ataxia, Refsum, Cockayne syndrome, Bassen-Kornzweig disease
    • Kearn-Sayre syndrome
presenting phenotypes2
Presenting Phenotypes
  • Visual Loss
  • Ptosis / opthalmoplegia
  • Neuropathy
  • Ataxia
  • (Myopathy)
  • (Seizures)
  • (Stroke)
ophthalmoplegia kss
Ophthalmoplegia – KSS
  • Kearns-Sayre syndrome
    • Obligatory triad: onset before 20, pigmentary retinopathy, progressive external opthalmoplegia
    • Other features:cardiac conduction abnormalities, can also have high  CSF protein, cerebellar ataxia, seizures, sensorineural deafness, pyramidal signs
genetic defects of mids2
Genetic Defects of MIDs

Finsterer, CJNS, 2009

ophthalmoplegia cpeo
Ophthalmoplegia – CPEO
  • Chronic progressive external ophthalmoplegia
  • Clinical manifestations
    • Ptosis, can be asym.; ophthalmoplegia, more symm. (rare diplopia, transient if occurs)
    • Long durat’n of Sx before presentation (mean 26 years)
    • majority presents for ptosis (1/2 have less than 10% of ocular motility fxn!!!)
    • Sx may worsen in the evening
    • Often no FMHx
genetic defects of mids3
Genetic Defects of MIDs

Finsterer, CJNS, 2009

ophthalmoplegia cpeo1
Ophthalmoplegia – CPEO
  • DDx
    • KSS (ECG, age of onset, severity)
    • MG (anti-AchR, response to Mestinon)
    • OPMD (muscle biopsy)
presenting phenotypes3
Presenting Phenotypes
  • Visual Loss
  • Ptosis / opthalmoplegia
  • Neuropathy
  • Ataxia
  • (Myopathy)
  • (Seizures)
  • (Stroke)
classification of mids causing pnp
Classification of MIDs causing PNP

Finsterer, Journal of Neurological Sciences, 2011

pnp in mids leigh syndrome
PNP in MIDs – Leigh syndrome
  • Clinical manifestations
    • Dev. delay, seizures
    • Ophthalmoparesis, nystamus
    • cerebellar ataxia, chorea, dystonia
    • Spasticity, muscle weakness
    • Brainstem involvement: respiratory insufficiency, dysphagia, recurrent vomiting, abnormal thermoregulation
    • Non-neurological: short stature, cardiomyopathy, anemia, RF, vomiting, diarrhea
ataxia in mids leigh syndrome
Ataxia in MIDs – Leigh syndrome
  • Other features
    • Most frequent childhood MID
    • Wide variety of abnormalities (from severe to absence of neurological problems)
    • Wide genetic heterogeneity
  • Features of peripheral neuropathy (collateral)
    • Sensori-motor, demyelinating
    • Can be confused with GBS (due to severe demyelination)
genetic defects of mids4
Genetic Defects of MIDs

Finsterer, CJNS, 2009


Boy with LS: 19 mos

Boy with LS: 7 mos

Saneto et al. Mitochondrion, 2008

pnp in mids mngie
  • Mitochondrial neuro-gastrointestinal encephalopathy
    • Severe gastrointestinal dysmotility (nausea, postprandial emesis, early satiety, dysphagia, reflux, abdo pain, diarrhea, cachexia)
    • Others: confusion, PEO, deafness, dysarthria, short stature
  • Features of peripheral neuropathy (collateral)
    • Sensori-motor, with distal weakness, predominantly affects lower limbs (may be confused with CIDP)
    • Mixed axonal and demyelinating on NCS
genetic defects of mids5
Genetic Defects of MIDs

Finsterer, CJNS, 2009

presenting phenotypes4
Presenting Phenotypes
  • Visual Loss
  • Ptosis / opthalmoplegia
  • Neuropathy
  • Ataxia
  • (Myopathy)
  • (Seizures)
  • (Stroke)
pnp in mids narp
  • Neurogenic weakness with ataxia and retinitis pigmentosa
  • Clinical manifestations
    • Proximal muscle weakness due to PNP
    • Ataxia due to cerebellar atrophy
    • Visual impairment (optic atrophy, salt&pepper retinopathy, bull’s eye maculopathy, or RP)
    • Others: short stature, opthalmoplegia, learning difficulties, dementia, seizures, cardiac arrhythmias
genetic defects of mids6
Genetic Defects of MIDs

Finsterer, CJNS, 2009

ataxia in mid ahs
Ataxia in MID – AHS
  • Alpers-Huttenlocher Syndrome
    • Severe hepatocerebral syndrome
  • Clinical manifestations
    • Starts in first years of life, early death
    • Neurological: intractable seizures, dev. delay, psychomotor regression, stroke-like episodes, hypotonia, cortical blindness, ataxia
    • Other: hepatic failure (avoid valproic acid!!), fasting hypoglycemia
genetic defects of mids7
Genetic Defects of MIDs

Finsterer, CJNS, 2009


Young adult woman with Alpers syndrome

Saneto et al. Mitochondrion, 2008

take home messages
Take Home Messages
  • Main role of mitochondria = energy production; mitochondrial disorders predominantly affect high metabolism (energy dependent) tissues
  • Both mtDNA and nDNA abnormalities are implicated in mitochondrial disorders
  • Absence of FMHx by no means preclude Dx of mt disorder
  • Syndromic mt disorders are better known, but non-syndromic mt disorders are more common
  • There is no clear genotype-phenotype correlation in mitochondrial disorders
  • Mitochondrial disorders are often multisystemic
  • There is +++ overlap in phenotype b/w different mt disorders
  • Caballero et al. Chronic progressive exertnal ophthalmoplegia, The Neurologist, 2007, 33-36.
  • Finsterer, Mitochondrial ataxias, CJNS, 2009, 36, 543-553.
  • Finsterer, Inherited mitochondrial neuropathies, Journal of Neurological Sciences, 304, 2011, 9-16
  • N.-G. Larsson and A. Oldfors. Mitochondrial myopathies, Acta Physiol Scand 2001, 171, 385-393.
  • Rachel Nardin and Donald Johns. Mitochondrial dysfunction and neuromuscular disease. Muscle and Nerve, 2001, 24: 170-191.
  • Saneto et al. Neuroimaging of mitochondrial disease, Mitochondrion, 2008, 396-413.
  • Schapira, Mitochondrial disease, Lancet, 2006, 70-82
classification of mid
Classification of MID

Finsterer, Journal of Neurological Sciences, 2011