Mitochondrial Disorders
Chenjie Xia (PGY-IV)
Montreal Neurological Institute
Wednesday, Jan. 25th, 2012
Outline
• Basic mitochondrial molecular biology
• Clinical implications of mitochondrial
genetics
• Clinical approach to mitochondrial
disorders
– General features
– Visual loss, ophthalmoplegia, peripheral
neuropathy, ataxia
Basic mitochondrial molecular
biology
Mitochondrion Basics
• 4 compartments:
– outer mb
– inner mb (folds into
cristae)
– intermembrane
space
– matrix
Larsson and Oldfors, Acta Physiol Scand
2001.
Berardo et al. Curr Neurol Neurosci Report, 2010
Role of mitochondria = energy production
Respiratory Chain
http://www.photobiology.info/Hamblin.html
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
Overview of clinical implications
of mitochondrial genetics
Mitochondria Genetics
• mt components
activity depend on:
– nuclear DNA (nDNA)
– mitochondrial DNA
(mtDNA)
Larsson and Oldfors, Acta Physiol Scand
2001.
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 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 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 mtDNA reaches 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 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 Genetics
• THM = phenotypic expression of mt
disorders depend on many factors:
–
–
–
–
–
–
–
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Nuclear versus mitochondrial mutation
Pathogenicity of mutation itself
Heteroplasmy
Threshold effect
Mitotic activity of tissue
Energy demand of tissue
Age
Etc…
Clinical Approach to
Mitochondrial Disorders
A few words on mitochondrial
disorders in general
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
Nardin and Johns. Muscle and Nerve, 2001.
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
• 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
•
•
•
•
•
•
•
Visual Loss
Ptosis / opthalmoplegia
Neuropathy
Ataxia
(Myopathy)
(Seizures)
(Stroke)
Genetic Defects of MIDs
Finsterer, CJNS, 2009
Presenting Phenotypes
•
•
•
•
•
•
•
Visual Loss
Ptosis / opthalmoplegia
Neuropathy
Ataxia
(Myopathy)
(Seizures)
(Stroke)
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 = 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 MIDs
Finsterer, CJNS, 2009
Visual Loss - RP
• Retinitis Pigmentosa
–
–
–
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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 - RP
• DDx
– Bardet-Biedl syndrome, Laurence-Moon
syndrome, Freidreich’s ataxia, Refsum,
Cockayne syndrome, Bassen-Kornzweig
disease
– Kearn-Sayre syndrome
Presenting Phenotypes
•
•
•
•
•
•
•
Visual Loss
Ptosis / opthalmoplegia
Neuropathy
Ataxia
(Myopathy)
(Seizures)
(Stroke)
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 MIDs
Finsterer, CJNS, 2009
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 MIDs
Finsterer, CJNS, 2009
Ophthalmoplegia – CPEO
• DDx
– KSS (ECG, age of onset, severity)
– MG (anti-AchR, response to Mestinon)
– OPMD (muscle biopsy)
Presenting Phenotypes
•
•
•
•
•
•
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Visual Loss
Ptosis / opthalmoplegia
Neuropathy
Ataxia
(Myopathy)
(Seizures)
(Stroke)
Classification of MIDs causing PNP
Finsterer, Journal of Neurological Sciences, 2011
PNP in MIDs – Leigh syndrome
• Clinical manifestations
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–
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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
• 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 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 MIDs
Finsterer, CJNS, 2009
Presenting Phenotypes
•
•
•
•
•
•
•
Visual Loss
Ptosis / opthalmoplegia
Neuropathy
Ataxia
(Myopathy)
(Seizures)
(Stroke)
Finsterer, CJNS, 2009
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 MIDs
Finsterer, CJNS, 2009
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 MIDs
Finsterer, CJNS, 2009
Young adult woman with Alpers syndrome
Saneto et al. Mitochondrion, 2008
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 nonsyndromic 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
References
• 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
Finsterer, Journal of Neurological Sciences, 2011