Mitochondrial Disorders

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.

Role of mitochondria = energy productionBerardo et al. Curr Neurol Neurosci Report, 2010

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


• 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


• 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


• 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…

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


• Visual Loss


• 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)

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 - RP

• DDx– Bardet-Biedl syndrome, Laurence-Moon

syndrome, Freidreich’s ataxia, Refsum, Cockayne syndrome, Bassen-Kornzweig disease

– Kearn-Sayre syndrome


• Visual Loss


• 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

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

Ophthalmoplegia – CPEO

• DDx– KSS (ECG, age of onset, severity)– MG (anti-AchR, response to Mestinon)– OPMD (muscle biopsy)


• Visual Loss


• Neuropathy

• Ataxia

• (Myopathy)

• (Seizures)

• (Stroke)

Classification of MIDs causing PNP

Finsterer, Journal of Neurological Sciences, 2011

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

• 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)

Saneto et al. Mitochondrion, 2008

Boy with LS: 7 mos

Boy with LS: 19 mos

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


• Visual Loss


• 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

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

Saneto et al. Mitochondrion, 2008

Young adult woman with Alpers syndrome

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

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

Finsterer, Journal of Neurological Sciences, 2011

Classification of MID

Mitochondrial Disorders

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