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Inborn Errors of Metabolism and Epilepsy

Sabine'Grnborg,'MD'

Overlge'

Center'for'Sjldne'Sygdomme'og'Center'for'Medfdte'Stofski=esygdomme'

BrneUngeKlinikken'og'Klinisk'GeneAsk'Klinik'

Rigshospitalet'

'

'

NNPS'mde'preGcourse'

September'2018'

Speaker honoraria from Novo Nordisk and Actelion Travel grants from Sanofi Genzyme and Merck

PI - Arimoclomol prospective study in patients diagnosed with Niemann Pick disease type C, Orphazyme SI - Phase 2/3 study on Glut1 deficiency, Ultragenyx

SI - Phase 1/2 study on MLD, Shire SI Phase 2 study alpha-mannosidosis, Zymenex/Chiesi

Disclosures' Sabine Grnborg NNPS pre-course, 2018.09.05

Inborn Errors of Metabolism (IEM)

Genetic defects in the biosynthesis or breakdown of substances in specific pathways

Historically identified by specific biochemical test

Total number of identified IEM increasing exponentially (currently 1015!)

CDG syndromes: (1983-2013)

O-Fucose

O-GalNAc / O-GlcNAc

Glycolipid

Dystroglycanopathy Glycosaminoglycan N-Linked

10

20

30

40

50

60

70

80

Number of Disorders

GPI-Anchor

1983 1990 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

90

IN 2013 A NEW DISORDER EVERY 11.79 DAYS June 26,2013

Courtesy: Prof. H. Freeze

June 2013: towards 100 glycosylation diseases

Ferreira'CR'et'al.'GeneAcs'in'

Medicine'2018.'A'proposed'nosology'

of'IEM.''

Freeze'HH'et'al.'AJHG'2014.''

Solving'glycosylaAon'disorders:''''

Sabine Grnborg NNPS pre-course, 2018.09.05

Inborn Errors of Metabolism (IEM)

Genetic defects in the biosynthesis or breakdown of substances in specific pathways

Historically identified by specific biochemical test

Total number of identified IEM increasing exponentially (currently 1015!)

Increasing number of IEM can be treated by metabolic interventions

Phenylketonuria (PKU):

Treatment with protein reduced diet

amino acid substitution

phe monitoring

! excellent outcome

Biotinidase deficiency

Treatment with biotin supplementation

09/11/16 00:44untreated-pku.jpg 700469 pixels

Page 1 of 1http://www.phedup.co.uk/images/untreated-pku.jpg

Sabine Grnborg NNPS pre-course, 2018.09.05

Inborn Errors of Metabolism - Categories

Intermediary metabolism

standard metabolic tests

fluctuating symptoms, acute presentations

therapeutic interventions often possible

Biosynthesis/breakdown of complex molecules

slowly progressive

specific analyses necessary for diagnostics

Neurotransmitter diseases

Metabolism of vitamines og co-factors

Metabolism of metals

amino acids, carbohydrates, fatty acids, mitochondrial

energy metabolism, urea cycle, !

Metabolism of purins/pyrimidines, lysomomal and

peroxisomal diseases, isoprenoids/sterols, !

Epilepsy can manifest in all

groups

Sabine Grnborg NNPS pre-course, 2018.09.05

IEM neurological symptoms

Onset at all ages acute or chronic/chronic-progressive +/- developmental delay (DD) and ID +/- seizures +/- encephalopathy +/- syndromic/multiple congenital anomalies +/- autism +/- muscular +/- movement disorder, CP mimic +/- psychiatric +/- neurodegenerative (WM, GM, BG, cerebellum)

IEM as cause probably underdiagnosed (e.g. found in 5-15% of patients with ID)'

'

Sabine Grnborg NNPS pre-course, 2018.09.05

IEM neurological symptoms

Onset at all ages acute or chronic/chronic-progressive +/- developmental delay (DD) and ID +/- seizures +/- encephalopathy +/- syndromic/multiple congenital anomalies +/- autism +/- muscular +/- movement disorder, CP mimic +/- psychiatric +/- neurodegenerative (WM, GM, BG, cerebellum)

IEM as cause probably underdiagnosed (e.g. found in 5-15% of patients with ID)'

'

with comm

on neurologic

al co-morbidit

y

Sabine Grnborg NNPS pre-course, 2018.09.05

IEM and CNS manifestations - Challenges

'

Increasing number of IEM Overlapping and unspecific symptoms

Possible lack of biochemical markers (or unavailable) ! Making a diagnosis is challenging

! Consider IEM early on ! Define at risk-patient population

! Optimize diagnostic strategy

because timely diagnosis has the potential to improve outcome

'

'

Sabine Grnborg NNPS pre-course, 2018.09.05

IEM and Epilepsy

> 370 IEM disease genes have been associated with epilepsy and seizures

25% of these IEM have a specific treatment option

Defects in energy metabolism, metabolism of amino acids, CDGs, lysosomal disorders,

How often does IEM underlie pediatric epilepsies?

?

REVIEW ARTICLE

Contemporary scope of inborn errors of metabolism involvingepilepsy or seizures

Birut Tumien1,2 & Borut Peterlin3 & Ale Maver3 & Algirdas Utkus1

Received: 25 February 2018 /Accepted: 10 July 2018# Springer Science+Business Media, LLC, part of Springer Nature 2018

AbstractMany inborn errors of metabolism may present with epilepsy or seizures, however, current scope of these diseases is unknown.Due to available precision medicine approaches in many inborn errors of metabolism and sophisticated traditional diagnostics,this group of disorders is of special relevance to clinicians. Besides, as current treatment is challenging and unsuccessful in morethan 30% of all epilepsy patients, these diseases may provide valuable models for ictogenesis and epileptogenesis studies andpotentially pave the ways to identification of novel treatments. The aim of this study was to elucidate genetic architecture ofinborn errors of metabolism involving epilepsy or seizures and to evaluate their diagnostic approaches. After extensive search,880 human genes were identified with a considerable part, 373 genes (42%), associated with inborn errors of metabolism. Themost numerous group comprised disorders of energy metabolism (115, 31% of all inborn errors of metabolism). A substantialnumber of these diseases (26%, 97/373) have established specific treatments, therefore timely diagnosis comes as an obligation.Highly heterogenous, overlapping and non-specific phenotypes in most of inborn errors of metabolism presenting with epilepsyor seizures usually preclude phenotype-driven diagnostics. Besides, as traditional diagnostics involves a range of specializedmetabolic tests with low diagnostic yields and is generally inefficient and lengthy, next-generation sequencing-based methodswere proposed as a cost-efficient one-step way to shorten Bdiagnostic odyssey . Extensive list of 373 epilepsy- or seizures-associated inborn errors of metabolism genes may be of value in development of gene panels and as a tool for variants filtration.

Keywords Metabolic epilepsy . Next-generation sequencing . Inheritedmetabolic disease . Diagnostics

Introduction

Epilepsy affects 12% of population, approximately 50 millionpeople worldwide. The treatment of epilepsy is extremely chal-lenging. More than 30% of epilepsy patients are refractory to

treatments with current antiepileptic drugs (AED). Besides,many patients experience adverse effects that may compromisetreatment adherence. Even in individuals who finally obtainseizure control, it is usually achieved through Btrial and error^approach for to find appropriate AED, dose or combination ofAEDs. Development of the vast majority of current AED wasbased on a prevailing dogma B that epilepsy is primarily achannelopathy (Greenberg and Subaran 2011) and relied onestablished animal models (e.g., pentylenetetrazol, electroshockor kindling) reflecting mostly acute stages of seizures andictogenesis and not the chronic nature of epilepsy andepileptogenesis (Bialer and White 2010). Failure of currentAED to affect epileptogenesis is exemplified by 47 clinicaltrials of AED administration after an epileptogenic trigger eventthat could not prevent the development of epilepsy (Avanzini etal. 2013). Moreover, despite the introduction of more than 15new antiepileptic drugs (AED) since 1990, efficacy and tolera-bility of AED treatment has not substantially improved, there-fore, conceptually novel strategies for the development of AEDare highly required (Lscher and Schmidt 2011).

Electronic supplementary material The online version of this article(https://doi.org/10.1007/s11011-018-0288-1) contains supplementarymaterial, which is available to authorized users.

* Birut Tumientumbir@gmail.com

1 Institute of Biomedical Sciences, Faculty of Medicine, VilniusUniversity, Santariskiu 2, LT-08661 Vilnius, Lithuania

2 Vilnius University Hospital Santaros Klinikos, Santariskiu 2,LT-08661 Vilnius, Lithuania

3 Clinical Institute for Medical Genetics, Division of Gynecology,University of Ljubljana Medical Centre, Ljubljana, Slovenia

Metabolic Brain Diseasehttps://doi.org/10.1007/s11011-018-0288-1

Sabine Grnborg NNPS pre-course, 2018.09.05

Treatable epileptic IEMs

Metabolic crisis of different IEM

e.g. urea cycle defects, MSUD

Vitamin responsive metabolic epilepsies Pyridoxin

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