karaa child neurology talk 10 29 2015 · 2015-10-29 · • mtp-131 bendavia:-peptide (stealth...
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MITOCHONDRIAL DISEASE
Amel Karaa, MD Mitochondrial Disease Program
Massachusetts General Hospital
Disclosures & Disclaimers• United Mitochondrial Disease Foundation Research Grant
• North American Mitochondrial Disease Consortium (RDCRN/NIH)
• Advisory Board of:• Mitochondrial Medicine Society• MitoAction• Stealth BioTherapeutics
• Overview of the mitochondria• Overview of mitochondrial function & genetics• Overview of mitochondrial disease:
SymptomsDiagnosis Management
Outline:
http://biology.tutorvista.com/animal-and-plant-cells/mitochondria.html
Overview: the mitochondria1 to 1000s/cell
Overview: The mitochondria
Vafai et al. Nature 2013:491, 374–383
Overview: the mitochondria
Modified from Wallace D. Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXVI
Nat Rev Genet. 2012 December ; 13(12): 878–890
Overview: the mitochondriaThe electron transport chain
Overview: the mitochondria
mtDNAnDNA
The Mitochondrial Organelle
Bi-genomic Input
Unique mtDNA genetics• Maternal inheritance
Overview of mtDNA
Unique mitochondrial genetics• Maternal inheritance• Double stranded circular DNA
Overview of mtDNA
} 16,569 bp} Encodes 37 proteins:
} 22 tRNAs} 13 respiratory chain peptides} 2 ribosomal
} 5–10 copies/mitochondrion, 100–1000s/cell} Limited DNA repair (↑mutation rate)
Unique mitochondrial genetics• Maternal inheritance• Double stranded circular DNA• Random segregation
Threshold expression and Heteroplasmy
Overview of mtDNA
Overview of mtDNA
http://clinicalgate.com/the-human-microbiome/
Unique mitochondrial genetics• Maternal inheritance• Double stranded circular DNA• Random segregation, Threshold expression and
Heteroplasmy
Overview of mtDNA
jcb.rupress.org
The EMBO Journal VOL 32 | NO 1 | 2013
Overview of nDNA
Mendelian inheritance patterns
• Autosomal recessive (most common)• Autosomal dominant• X-linked
Overview of nDNA
Sporadic/De novo
Hundreds of genes
• Prevalence in children 6.2/100,000*,• At least 1 in 4,300 of adults will develop mitochondrial disease
Overview of mitochondrial disease
* D. Skladal, J. Halliday, D. R. Thorburn, Brain 126, 1905–1912 (2003).
Overview of mitochondrial disease
• Any age – infancy to adulthood• Multi-organ dysfunction• Variable severity• Progressive• Episodic
‘…any organ, any symptom, any age’
Episodic Phenotype
TIME
OBSERVABLE
DYSFUNCTION
normal
aging mild
severe
moderate OrganFailure
Metabolic Stress à
Overview of mitochondrial disease
0 10 20 30 40 50 (%)0102030(%)
EncephalopathyMyopathy
Myocardiopathy
Exercise intolerance
Kidney disease
Leigh syndrome
Ophthalmoplegia
Intestinal disease
DysmorphyBone marrow dysfunction
Retinopathy
Peripheral neuropathyAtaxia
MERRF/MELASDeafness
Alpers syndrome
Diabetes
Optic atrophy
Liver disease
Adults (n = 390) Children (n = 220)SIMD/NAMA :Courtesy of Dr A Lombes Hopital La SalpétrièreUniversité Paris VI
Overview of mitochondrial disease
Most common reasons for referralChildren Adults
HypotoniaSeizuresDevelopmental delayElevated lactate levelsAbnormal MRI imagesLiver diseaseFailure to thriveGI dysmotility
Fatigue +++Shortness of breath, air hungerMuscle painGI dysmotilityDysautonomia/POTSMultiple symptoms in many organ system that do not seem to be related
Overview of mitochondrial disease
Overview of mitochondrial diseaseWhen should I suspect mitochondrial disease?
• Atypical features• Multisystemic involvement• Recurrent setbacks or “flare-ups” occur with stressors
DiMauro S, Schon EA. Am J Med Genet 2001;106(1): 18–26
Overview of mtDNA disease
Overview of mtDNA disease
• MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokes
• MERRF: Myoclonic Epilepsy with Ragged Red Fibers• LHON: Leber’s Hereditary Optic Neuropathy• KSS/PEO: Kearns Sayre syndrome/Progressive external ophthalmoplegia.
MELAS:
• Symptoms before age 40• Neurosensory hearing loss• Migraine headaches• Peripheral neuropathy• Myopathy • Depression and other psychiatric disorders
Overview of mtDNA disease
MELAS:• Endocrine• Cardiac involvement• Kidney dysfunction
Overview of mtDNA disease
MELAS:• Polygenetic disorder caused by at least 29 mutations in
mtDNA• A3243G (tRNA gene): most common mutation (80%)• Overlap with MERRF
Overview of mtDNA disease
Overview of mtDNA disease
Symmetric signal prolongation in both occipital lobes involving the medial aspects.
à IV Arginine Protocol
MELAS:
MERRF:• Ataxia, weakness and dementia• Sensorineural hearing loss• Exercise intolerance, seizures, dystonia• Optic atrophy, pigmentary retinopathy, ophthalmoparesis• Cardiomyopathy• Multiple lipomas
Overview of mtDNA disease
MERRF:
Overview of mtDNA disease
The most common mutation (> 80%): m.8344A>G
LHON:
• Degeneration of retinal ganglion cells and their axons
• Acute or subacute loss of central vision
• Affects predominantly young adult males
Overview of mtDNA disease
http://www.lhon.org/lhon/LHON.html
Overview of mtDNA diseaseDNA deletion syndromes/PEO:
http://www.neurology.org/content/51/6/1525.2/F4.medium.gif
Overview of mtDNA diseaseDNA deletion syndromes/KSS:Clinical triad– Onset < 20 yrs– CPEO– Retinal degenerationOther features– Cerebellar ataxia– Sensorineural deafness– Complete heart block– Elevated CSF protein (100 mg/dl)– Endocrinopathies– Nearly always sporadic
http://www.stlukeseye.com/conditions/RetinitisPigmentosa.html
The EMBO Journal VOL 32 | NO 1 | 2013
Overview of nDNA
Overview of nDNA
Clinical Presentation of Mitochondrial Diseases in Children with PIND Christopher M Verity et al.
2493 cases of progressive ID112 (69 males, 43 females) with mitochondrial diseases
Ages birth to 14 yearsMedian age 12moMost with non-specific:
Developmental delayHypotoniaFailure to thriveSeizures
Mortality was high 36%Abnormal CSF lactate 77%Abnormal MRI (increased basal ganglia signal) 60%
Primary mitochondrial disease Vs.
Secondary mitochondrial dysfunction
Common in cancer, chronic diseases, Parkinson’s disease, ALS, Pompe, other neurodegenerative disorders, and normal aging.
Overview of 2ry mitochondrial disease
Overview of 2ry mitochondrial disease
Lancet 2012; 379: 1825–34
Diagnostic Evaluation: The problem• Nonspecific symptoms• There is no universally accepted diagnostic algorithm for
mitochondrial disorders• There is no gold standard diagnostic method.• Enzyme (ETC) testing may produce false positive and
false negative results.• Molecular testing is positive in 25-45% of the cases at
best.
Diagnostic Evaluation
Morava et al Neurology 2006
Annals of Medicine, 2013; 45: 4–16
Diagnostic Evaluation: Other
Diagnostic EvaluationIMAGING TESTING
Leigh MELAS KSS ETC defMNGIEMERRF– Bilateral deep gray [putamen, GP, caudate]
– Metabolic stroke [non-vascular territory]– Diffuse white matter abnormalities– Lactate on MRS (abnl choline, NAA)– Cerebral and/or cerebellar volume loss E.Grant
Diagnostic EvaluationEM
RRF
Histochemistry
COX SDH
Molecular Testing: ? New Gold standard• mtDNA
• Screen point mutations • Whole genome screen • Deletion/duplication analysis • Depletion
• nDNA• Specific gene selection • Screening – NGS
• panel• whole exome/whole genome or dual genome analysis
Diagnostic Evaluation
Treatment and Management
• No single treatment. • Management is tailored for each individual.
Lifestyle changes are very important and can be effective.
Treatment and ManagementEnergy balance equation:
Minimize energy losses Avoid physical stresses
Emotional stressesAdequate rest
Optimize energy gains. Sleep
NutritionExercise
Treatment and Management
§Avoid toxins: • Drugs, cigarette smoking, alcohol
§“Mitochondrial cocktail”:• Variety of vitamin and cofactor supplementation.
Therapy in trials:
• EPI-743:- Small molecule (Edison Pharmaceuticals) for the treatment of Leigh syndrome, Pearson syndrome and other ETC deficiency.
• MTP-131 Bendavia:- Peptide (Stealth Biotherapeutics) that targets mitochondria
for the treatment of mitochondrial myopathy.
Treatment and Management
Therapy in trials:
• RTA- 408:- Small molecule (Reata Pharmaceuticals) for the treatment of mitochondrial myopathy.
• RP-103:- Cysteamine (Raptor Pharmaceuticles) for children with
confirmed mitochondrial disease.• Ultragenix:
- Triheptanoin
Treatment and Management
Science. 2015, VOL 349 ISSUE 6255
Prevention: Mitochondrial Donations
• Thank you, and any questions?
Amel Karaa, MDAdult Mitochondrial Disease Program
Massachusetts General Hospital