Mitochondrial Dz & Epilepsy: The Basics

Sumit Parikh, MDBit.ly/mitoarticles

disclosures

Employment - Cleveland Clinic

LAVENDER/LILAC, Acadia Pharmaceuticals

MAT, Minovia Therapeutics

NAMDC, NIH U54

Pearson Natural History Study, Minovia & CHAMP Foundation

Natural History Study of CDKL5, IFCR and NIH RDCRN

Natural History Study of PTEN, CO-I, NIH RDCRN

Mitochondrial Medicine Society, Board

Mitochondrial Care Network, Co-Chair

Speaker’s Bureau - Cleveland Clinic and UMDF

Scientific Boards – UMDF

Editor – Mitochondrial & Metabolic Medicine (M3)

BasicsRed Flags

DiagnosticsSeizure Types

TreatmentA Few Cases

TODAY

Basics

key rolesATP production

combat free radicals

cell death cascade

lesser known roles

cell signaling

cell differentiation

cell division & growth

transport

inflammatory cascade

non-shivering thermogenesis

iron metabolism

calcium storage and signaling

steroid synthesis

hormonal signaling (mt estrogen receptor)

Two sets of blueprints

nuclear & mitochondrial DNA

mtDNA

This Photo by Unknown Author is licensed under CC BY

1500+ genesbuild & maintain mitochondria

5-10% of all human genes

>350 linked to disease

Mitocarta/Mitominer

nDNA

so what is mitochondrial disease

why does it happen

when should you worry about it?

Pathogenic DNA variant

mtDNA or nDNA

Red Flag Symptoms

mitosoc.org

Myoclonus & EPC

StrokesDeep Gray Matter DiseaseCerebellar Disease

Ophthalmoplegia

PtosisRetinal Pigment DzOptic Atrophy

Sensorineural Hearing Loss

Cardiomyopathy

Heart Block

Renal Tubular Acidosis

Tubulopathy

Dysmotility

Pseudo-obstruction

Ataxia

Cognitive DeclineDevelopmental DelayEpilepsy

Myopathy/NeuropathyWhite Matter Disease

Early Onset Cataracts

Adrenal Insufficiency

DiabetesGrowth Hormone DefHypothyroidism/PTH

Short Stature

Arrhythmia

Focal Sclerosing Glomerulonephritis

Liver dysfunction

Pancreatic insufficiency

Diagnostic Approach

Crummy Biomarkers

DNA testing is a better but still imperfect answer

Next-gen Sequencing

Nuclear Gene Panels (100+ genes)

Whole Exome Sequencing

mtDNA Genome Sequencing

Whole Genome Sequencing

bit.ly/mitopcp

MMS consensus criteria bit.ly/mitoconsensus

MitochondrialEpilepsy

35-60% have epilepsy

Debray et al, Pediatrics 2007; Khurana et al, Neuropediatrics 2008;

El Sabbagh et al, Epilepsia 2010; 1225–Lee et al, Epilepsia 2008

80% have other features when epilepsy occurs

El Sabbagh S, Lebre AS, Bahi-Buisson N, et al. Epileptic phenotypes in children with respiratory chain disorders. Epilepsia 2010; 51: 1225–3

Seizure Types

Myoclonus and EPC are historically sine qua non

Focal and generalized

Infantile Spasms

Ohtahara, Lennox Gastaut & Landau Klefner

• Kang et al., 2007; Lee et al. 2007

• Castro-Gago et al., 2009; El Sabbagh et al. 2010

Case 1

16-year-old female

Onset of left temporal headaches with migrainous features

Associated left visual auras (bright lights)

10 months later develops twitching of left arm and leg -> focal status

Alper-Huttenlocher

Disease

myo-cerebro-hepatopathy

Onset birth - 3 years; second peak in late adolescence

Acute neurologic and/or hepatic decompensation with illness (can include new onset epilepsy)

Recurrent neuro-degeneration with illness

POLG-spectrum

Mitochondrial Disease

Alpers or Myo-cerebro-hepatopathy

Chronic Progressive External Ophthalmoplegia (CPEO)

Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA)

Ataxia-Neuropathy Spectrum (ANS)

POLG-spectrum

Mitochondrial Disease

Early onset form is an autosomal recessive disease

Two pathogenic variants - on separate alleles

POLG & Epilepsy

Focal motor or myoclonic seizures evolving to generalized seizures with or without EPC or status epilepticus

If occipital origin - positive or negative visual phenomena often presenting manifestation

Present at onset in 50-89%

Hikmat & Rahman 2016Anagnostou & McFarland 2016

POLG & the EEG

Occipital predilection

Continuous high amplitude slow waves when awake

Intermixed low amplitude, high frequency polyspikes

Hikmat & Rahman 2016Anagnostou & McFarland 2016

POLG Disease & Valproic

Acid

Do not give Valproic Acid

Catastrophic liver failure

POLG Variant Q1236H & Valproic Acid

Case 2

37-year-old female with

diabetes

Presents with a h/o focal epilepsy with impairment of awareness

Has a prior diagnosis of diabetes beginning in her 20s that seems difficult to control

Mother also has diabetes and a history of hearing loss

37-year-old female with

diabetes

Maternal aunt with early onset strokes (now deceased)

Migraines in maternal family members

Strokes in a nonvascular distribution

37-year-old female with

diabetes

Lactate of 3.5 mM (normal < 2.2)

Mild sensorineural hearing loss detected

Mitochondrial DNA genome sequencing showed a 3243A>G pathogenic variant

MELAS

Mitochondrial Encephalomyopathywith Lactic Acidosis & Strokes

MIDD

Maternally Inherited Diabetes & Deafness +/-Cardiomyopathy

Other Key Features

Sensorineural Hearing Loss

Diabetes (mitochondrial type) - 1% of all diabetes

Hypothyroidism

Cardiomyopathy

Retinal disease and night vision difficulties

Focal sclerosing glomerulonephritis (FSGS)

Ovarian insufficiency

L-ArginineGiven IV acutely

Given orally preventatively

Decreased stroke morbidity, mortality and frequency?

RCT underway (Dr. Scaglia, Baylor)

Mitochondrial SeizureTreatment & Cautions

Valproic Acid

Caution in more than just POLG disease/Alpers

MELAS - increase in stroke

Disease worsening in other mtDNA & nuclear mutations

Carnitine may be protective

Lin et al, Metab Brain Dis 2007; Lam et al, Eur J Pediatr 1997; Galimberti et al, Neurology 2006; Chabrol et al, Eur J Pediatr 1994; Lheureux et al, Clin Toxicol (Phila) 2009

Ketogenic Diet

May benefit some per retrospective analysis (seizures and other symptoms)

Possibly more so in those with mtDNA deletions (in cell lines & mice)

May worsen acidosis or other metabolic parameters

Several deaths reported

Santra et al, Ann Neurol 2004; Ahola-Erkkila et al, Hum Mol Genet 2010; Joshi et al, Pediatr Neurol 2009; Kang et al, Epilepsia 2007; 48: 82–8

VigabatrinInhibits conversion of nucleosides in the mitochondria and may induce mtDNA depletion

Besse et al. 2015

Topiramate Worsening acidosis

Mirza et al, Pharmacogenet Genomics. 2011 May; Mirza et al, Br J Clin Pharmacol. 2009; Belotti et al, Eur J Paediatr Neurol. 2010; Dodgson et al, Epilepsia. 2000; Shiber et al, J Emerg Med. 2010

Others

Lamotrigine – protective?

Leveteracetam – better for mitochondrial myoclonus?

VNS – no data

Arpin et al, Metab Brain Dis 2009; 24: 453–61

Active Surveillance

MMS consensus criteriabit.ly/mitocare

Coordinated & Standardized Care

mitosoc.orgFounded by Dr.’s Haas & Naviaux at UCSD

Mitochondrial Care Networkmitonetwork.org