Metabolic epilepsies

Reetta KälviReetta Kälviäinen

ProfessorDirector of Kuopio Epilepsy Center

EEPILEPSYCENTER

Disclosures• Expert fee (Eisai, Finnish IBE chapter, Fennomedical,

GW Pharmaceuticals, SAGE Therapeutics, Takeda, UCB Pharma)

• Speaker’s fee (Eisai, Fennomedical, Orion, UCB Pharma)

• Travelling expenses for congresses/meetings (Eisai, Finnish IBE chapter, UCB Pharma)

• President of the Finnish ILAE Chapter• Co-Chair of the EAN Subspeciality Scientific panel on

Epilepsy• No financial support for this work

Unknown

Immune

Infectious

Structural

Etiology

Metabolic

Genetic

Co‐m

orbiditie

s

Epilepsy types

Focal GeneralizedCombinedGeneralized& Focal

UnknownFocal

Epilepsy Syndromes

Seizure typesGeneralized 

onsetUnknown onset

Focal onset

Etiology

GLUT1 deficiencyUnknown

Immune

Infectious

Structural

Metabolic

Genetic

Seizure typesGeneralized 

onsetUnknown onset

Focal onset

EpiCARE : An ERN for rare and complex epilepsies

Epilepsies of metabolic origin according to their pathogenesis

Epilepsies of metabolic origin according to the age of onset

Pyridoxine-Dependent Epilepsy• defect in α-aminoadipic semialdehyde (AASA)

dehydrogenase, with accumulation of products thatinactivate pyridoxal-5-phosphate (PLP)

• Mutations in the antiquitin gene, ALDH7A1 U,P, CSF AASA, CSF PLP• (Also mutations in PROSC gene encoding PLP-binding p.)• Early (even intrauterine) seizures not responding to AEDs,

but responding to pyridoxine– Multifocal and generalized myoclonic jerks, often intermixed with

tonic seizures,and focal onset motor seizures are typical• Infants may also develop emesis, abdominal distention,

sleeplessness presenting as sepsis,or with features of hyperalertness, hyperacusis, irritability, paroxysmal facialgrimacing, and abnormal eye movements

Pyridoxine-Dependent Epilepsy• If untreated/non-response to pyridoxine, affected

infants develop focal dyscognitive seizures, infantilespasms, and myoclonic seizures

• Late onset/atypical presentations of PDE 30%– a delayed presentation(usually with infantile spasms), infants

whose seizures initially respond to AEDs, but relapse later with refractory seizures, and patients whose seizures are notcontrolled by initial administration of pyridoxine but respondlater to a second trial

• EEG: multifocal discharges, slow-spike wavecomplexes, burst-suppression pattern, and hypsarrhythmia

• MRI:normal to white matter signal abnormalities, generalized cerebral atrophy, and hypoplasia ordysgenesis of corpus callosum

Pyridoxine-Dependent Epilepsy• Initial dose 100 mg of pyridoxine intravenously (ICU)

followed by oral pyridoxine supplementation (15-30 mg/kg/day in two divided doses) for 3–7 days(delayed responses occur)

• (Pyridoxal phosphate (PLP) is also effective)• If the treatment is successful and/or the diagnosis

confirmed by biochemical and/or molecular genetictesting, pyridoxine treatment continued indefinitely.

• If incomplete pyridoxine response, add-on treatmentwith folinic acid (3–5 mg/kg/day)

• + lysine-restricted diet– reduces the levels of the neurotoxic AASA

• + high-dose arginine supplementation– competitive inhibition of lysine uptake

Glucose Transporter Defect(GLUT1 Deficiency Syndrome)

• The deficiency of cerebral glucose transporter (GLUT1) leads to the GLUT1 deficiency syndrome, resulting in impaired glucose transport into the brain

• Mutations SLC2A1 geneCSF gluc, CSF/P gluc ratio (can be normal !)• Classical phenotype:infantile onset refractory seizures,

developmental delay, acquired microcephaly, abnormalities of muscle tone (hypotonia or spasticity), and movement disorders such as choreoathetosis, ataxia, and dystonia

• early onset absence epilepsy, myoclonic astatic e.• an increase in seizures before meals, cognitive

impairment, or paroxysmal exercise-induced dyskinesia

Glucose Transporter Defect(GLUT1 Deficiency Syndrome)

• The ketogenic diet is an effective treatment– provides alternative sources of energy substrate in the form of

ketone bodies• Drugs that impair GLUT1 function, e.g., caffeine,

phenobarbital, diazepam, chloral hydrate, and tricyclicantidepressants should be avoided

• Triheptanoin, an anaplerotic agent that replenishes the Krebs cycle metabolites, has been found useful in reducing the non-epileptic paroxysmal manifestationsand normalizing the brain bioenergetics profile

10 family-members early onset epilepsy, paroxysmal exercise-indused dyskinesia andno or mild learning disability ; mild familiar forms are easily undiagnosed

Somatic mosaicism for a SLC2A1 mutation: The rate of mosaicism in the various tissues of the mother ranged from 28 to 34%, whereas the rate for the proband was about 50%, as expected

for a heterozygous mutation

Progressive myoclonus epilepsies (PMEs)

• Rare and heterogeneous disorders defined by the combination of action myoclonus, epileptic seizures, and progressive neurologic deterioration. 

• Neurologic deterioration may include progressive cognitive decline, ataxia, neuropathy, and myopathy

Progressive encephalopathies associated with 

seizures

Progressive myoclonic epilepsy

Progressive myoclonicataxia

First clinicalsymptoms

Cognitivearrest

Myocloniatonic‐clonic seizures

Ataxia and myoclonus

Late clinicalsymptoms Seizures or myoclonus

Progressionataxia, dementia

Dementia, mild or no seizures

Age at onset Early infancy Late infancy and adolescent Adults

Main etiology Hereditary‐metabolicdisease

ULD, LaforaMERRF, MIRAS, 

NCL, sialidosis

MERRF, MIRAS, Spinocerebellar

degeneration, coeliacdisease

Spectra of PMEs

Differential features of major PMEs

PME Onset Suggestive clinical sign Pathology

Unverricht Lundborgdisease (EPM1)

12‐15 yrs[5‐18]

Slow progressionMild cognitive impairment

None

Lafora disease(EPM2)

12‐16 yrs[6‐18]

Visual hallusinations Polyglycosan inclusionLafora body

NCLs Variable Macular degeneration and visual impairment(except in adult forms)

Lipopigmentdeposits and GRODs

MERFF Any age

Lactic acidosis Ragged red fibers

PMEs

Progressive myoclonic epilepsiescont

11. MEAK a. Gene test: KCNC1 mutation 12. CERS1‐Related PME (EPM8) a. Gene test: CERS1 mutation 13. LMNB2‐Related PME (EPM9) a. Gene test: LMNB2 mutation 14. PME with Neuroserpin Inclusion Bodies (FENIB)

a. Gene test: SERPINI1 mutation 

Unverricht‐Lundborg disease / Progressive myoclonus epilepsy (EPM1)

• Described by Unverricht in 1891 in Estonia and by Lundborg in 1903 in Sweden

• Rare autosomal recessively inherited neurodegenerative disorder

• Age of onset from 6 to 16 years• Action‐activated and stimulus sensitive myoclonus, tonic‐clonic 

epileptic seizures characteristic to ULD‐EPM1• Gradually ataxia, incoordination, intentional tremor, dysarthia 

develop• During the first 5 – 10 years the symptoms progress and about 

one‐third of the patients become severely incapacitated (wheelchair‐ bound)

Unverricht‐Lundborg disease (EPM1): epidemiology

Kälviäinen R et al. 2008

= Clustered cases= Affected families worldwide

Israel Arabian peninsulaMediterranean

myoclonus (Italy, southern France, Tunisia, Algeria, Morocco)

Reunion Island

North America

Cuba

SwedenNetherlands

Finland (4:100 000)

Genetics of EPM1 • Cystatin B (CSTB)mutations (15 different recognized)• Inhibitor of lysosomal cysteine protease (cathepsins B, H, L, S)• Most common expansion mutation (dodecamer 5‐CCCCGCCCCGCG‐

3) – Normal ‐ 2‐3 repeats– Disease – minimum of  30 repeats (largest ‐ 125)– Unclear ‐ 12‐17 repeats– Not found ‐ 4‐11 and 18‐29 repeats

Rare stop-mutation

expansionmutation

Courtesy of Saara Tegelberg, PhD.

Other organs in EPM1

• Skull is thickened 10.0±2.0mm ( EPM1) and 7.6±1.2mm (contr) (p<0.001) and patients have frequently scoliosis and multiple fractures– Suoranta S, et al. Bone. 2012 Dec;51(6):1016‐24. 

• Diabetes ?• Pulmonary function ? Swallowing ?• Cataract ?• Risk of SUDEP ? 

Genetics of EPM1 • Cystatin B (CSTB)mutations (14 different recognized)• Most common expansion mutation (dodecamer 5‐CCCCGCCCCGCG‐

3) – Normal ‐ 2‐3 repeats– Disease – minimum of  30 repeats (largest ‐ 125)– Unclear ‐ 12‐17 repeats– Not found ‐ 4‐11 and 18‐29 repeats

Rare stop-mutation

expansionmutation

Courtesy of Saara Tegelberg, PhD.

13.12.2018 28

Comparison of the EPM1 patients homozygous for the expansion mutation with the compound heterozygous patients for the 

expansion and c.202C>T mutations

• Five compound heterozygous patients were compared with 21 age and gender matched homozygous patients

• Age at onset was lower in compound heterozygotes compared with homozygous patients:

– 7 ±1 yr vs. 10 ±1 yr, P = 0.005• UMRS myoclonus with action score also was higher in compound heterozygous 

patients compared with homozygous patients

– 67 ±32 vs. 33 ±17, P = 0.006• In neuropsychological testing compound heterozygous patients also had lower 

VIQ and PIQ results compared with homozygous patients

Koskenkorva et al. Neurodegener Dis. 2011;8(6):515-22.

• CSTB mutations c.67-1G>C ;c.168+1_18del; c.133C>T; c168+2_169+21delinsAA• The protein dose (cystatin B/b-actin) was 0.24 ± 0.02, which is not different from

that assessed in patients bearing the homozygous dodecamer expansion.• The compound heterozygous patients had a significantly earlier disease onset (7.4

± 1.7 years) than the homozygous patients, and their disease presentations included frequent myoclonic seizures and absences, often occurring in clusters throughout the course of the disease.

• Action myoclonus progressively worsened and all pts older than 30 years were in wheelchairs. Most of the pts showed moderate to severe cognitive impairment,and six had psychiatric symptoms.

Hypothesis that disease severity is inversely correlatedwith the amount of residual functional cystatin B protein

Lafora disease / Progressive myoclonus epilepsy (EPM2)

• autosomal recessive PME with an adolescent onset• mutations of the EPM2A gene encoding laforin or 

NHLRC1/EPM2B encoding malin• medication‐refractory generalized tonic–clonic or visual seizures 

and spontaneous and stimulus‐sensitive myoclonus;• followed by rapidly progressive dementia with apraxia and visual 

loss. • patients finally become wholly incapacitated and usually die 

within a decade of symptom onset.

Lafora diseaseGenotype/Phenotype variability

• Mild course; maintain >10 years gait autonomy – NHLRC1 mutations; most carried the homozygous or the compound 

heterozygous p.D146N missense

– was found in none of the patients– The D146N missense mutation lies in the first NHLRC1 domain and is known to affect ubiquitination of glycogen synthesis activator protein PTG and interaction with laforin

Lafora diseaseGenotype/Phenotype variability

• Early‐onset Lafora disease presenting at 5 years of age with dysarthria, myoclonus, and ataxia suggesting LIvNCL cinically

• The subsequent course is a typical PME, though much more protracted than any infantile neuronal ceroid lipofuscinosis, or Lafora disease, with patients living into their fourth decade. 

• The mutation, c.781T > C (F261L), is in a gene of unknown function, PRDM8.

• The PRDM8 protein interacts with laforin and malin and causes translocation of the two proteins to the nucleus.

Neuronal ceroid lipofuscinoses

• Most common group of neurodegenerative disorders associated with lysosomal storage

• In the pregenetic era, they were divided into infantile, juvenile, and adult according to the age of onset, the order of presentation of the main symptom (myoclonus and seizures, cognitive and motor decline, and retinal pathology and visual loss), and electron microscopic features.

• The length of survival is related to the specific type, but they all lead to early death.

Neuronal ceroid lipofuscinoses

• Molecular genetics has emerged as a useful tool for enhancing subtype classification of neuronal ceroid lipofuscinoses.

• There are 14 genetic forms (CLN1 to CLN14) described to date and 360 etiological mutations, most of which have been included in the neuronal ceroid lipofuscinoses mutation database26 (www.ucl.ac.uk/ncl/mutation).

• myoclonic seizures may be infrequent during their disease course 

• However, in the late phases of progressive neurodegeneration and brain atrophy, most patients experience some form of myoclonus, tremor, or involuntary movements

Myoclonus epilepsy and ataxia due to pathogenic variants in the potassium channel (MEAK)

Muona et al.

• caused by a recurrent de novo missense mutation in KCNC1

• resembles at disease onset EPM1

highlights the usefulness of exome sequencing as a diagnostic tool in affected PME individuals previously subjected to negative molecular analyses because it identified a dominantly inherited recurrent de novo mutation in contrast to the recessive inheritance model of most PMEs.

Treatable metabolic epilepsies

EpiCare : A network for rare and complex epilepsies 

Eurooppalaiset osaamisverkostot

13.12.2018 42

• Komission delegoitu päätös ja toimeenpanosäädös• Edistävät eri maiden terveysalan ammattilaisten ja

osaamiskeskusten tiedonvaihtoa• Soveltavat EU:n yhteisiä periaatteita

erityishoitoa edellyttäviin harvinaisiin sairauksiin• Toimivat tutkimuksen ja asiantuntemuksen

keskuksina muista EU-maista tulevien potilaiden hoidossa

• Varmistavat tarvittaessa palveluiden saatavuuden

WP IV: Research

WP II: E-guidelines

WP I: E-database

WP III: Education & Training

WP V: Clinical trials

Diagnostic Modules

WP11: Dissemination

WP1: Network Coordination GOSH, UK

EAE GOSH, UK

WP2: Laboratory diagnostics

WP3: Neuroimaging

Necker, FrKuopio UH, FI

WP5: Neuropsychology

WP4: Clin Neurophysiology

FN Motol, CZUMCU, NL

Filadelfia, DKCarlo Besta Milan, IT

UH Bonn, D

Therapeutic Modules

WP7: Targeted medical therapies

WP8: E-pilepsy (surgery)

WP10: Diet

WP9: Neonatal seizures

UH Bonn, DE

Lausanne, CH

GOSH, UKUCC, IE

GOSH, UKMatthews Friends, UK

WP6: E-neuropathologyUK Erlangen, D

UZ Leuven, BE

Paracelsus MU, AUBambino Gesù, IT

GHE-HCL, FR

Meyer, IT

Necker, FrMondino, IT

E- panel discussion

ERC Healthcare providers

E-database

Specialized panel

Patient

Registry

Intervention

Clinical trials

Vaikean epilepsian diagnostiikan ja hoidon 

valtakunnallinen yhteensovittaminen

Take home• Metabolic etiology and treatment may be the solution

to drug-resistant seizures and should not be missed• Metabolic etiologies are not only present in infants;

milder phenotypes do exist in many diseases(depending on specific mutations, compoundheterozygotes, mosaicism, etc.)

• Diagnoses cannot be made on seizure types orelectroclinical grounds

• Imaging findings nonspecfic; neuronal loss and hypomyelination, occasionally malformative lesions

• Even when structural lesions exist, they may fail to explain the entire electroclinical phenotype

• The clinical context and biochemical testing (includingCSF studies) lead to preliminary diagnosis confirmed bygenetic testing (New mutations always possible !!!)