karaa child neurology talk 10 29 2015 · 2015-10-29 · • mtp-131 bendavia:-peptide (stealth...

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