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TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

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TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus Supplementary Information for: TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus Adeline Ngoh1,2*, Jose Bras*3, Rita Guerreiro*3, Amy McTague1,2, Joanne Ng1,2, Esther Meyer1, W. Kling Chong4, Stewart Boyd5, Linda MacLellan6, Martin Kirkpatrick7, Manju A Kurian1,2 Supplementary Tables Supplementary Table 1 ……………………………………………………………… 2 Supplementary Table 2 ……………………………………………………………… 7 Supplementary Figures Supplementary Figure 1……………………………………………………………... 18 Supplementary Figure 2 …………………………………………………………….. 19 Supplementary References ……………………………………………………….. 20 ! ! ! ! ! 1! Supplementary,Table,1:,,Approach,to,Paediatric,Myoclonus, Anatomical, Neurophysiological, Examples,of,Conditions/Causes, Associated,Genes,if, DISTRIBUTIO TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment, Origin, findings, to,consider, any, N, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, Options, H,Focal, ! Acute,Or,Insidious" FACTORS, H,Multifocal, ! Progressive,Or, H,Segmental, Static, CORTICAL, Cortical"myoclonus"is" 1. EPILEPTIC,MYOCLONUS" characterised"by1:!" A. Progressive,Myoclonic, EPM1A/, Multifocal" Late" Triggering"factors:" Generalised"tonic"clonic" Piracetam29" " Epilepsy,(EPM)2,,,3, UnverrichtHLundborg, Often" Childhood/Adolescence" !"""Voluntary"action" seizures" Levetiracetam" • Brief"EMG" (i) Unverricht!Lundborg" Disease:"!CSTB4" involving" Insidious"onset" !"Postural" Progressive"ataxia" Sodium"Valproate1" discharges"lasting" disease"EPM1$ EPM1B:"PRICKLE15,6,7!" distal"limbs" Progressive" !"Stimulus"(light," Neurodevelopmental" " less"than"70ms" " EPM2A/B(Lafora, and"face" touch,"noise)" regression" Benzodiazepines" " (ii) Lafora"body"disease$ Body,Disease):" sensitive, Varying"degrees"of" e.g."Clonazepam" • EEG"spikes" (EPM2A/B)$ EPM2A/Laforin8," cognitive"decline" " associated"with" " NHLRC18!" Avoid:" EMG"myoclonic" (iii) Myoclonic"Epilepsy" EPM3:"KCTD79,10,11!" Phenytoin" bursts"and" with"Ragged"Red"Fibres" EPM4:"SCARB212" Carbamazepine" preceding" (MERRF)$ EPM5:"PRICKLE27" Lamotrigine" myoclonus"by"brief" " EPM6:"GOSR213"" Vigabatrin" interval"(20ms"for" (iv) Neuronal"ceroid" EPM7:"KCNC114! hand"muscles"and" lipofuscinosis"(NCL)$ " 35ms"for"calf" " MERRF:"MTTK15,!! muscles)" (v) Dentatorubropallidolu MTTL116,!!MTTH17," " ysian"atrophy"(DRPLA)"$ MTTS118,"MTTS219," " " MTTF20,"MTTP21! • Enhancement"of" (vi) Sialidosis$ " 22 22 early"cortical" $ NCL:"CLN1 ,!CLN2 ,! 22 22 component"of"SSEPs" (vii) Familial" CLN3 ,!CLN5 ,! 22 22 –"giant"SSEPs" encephalopathy"with" CLN6 ,!CLN8 ,! 23 24 " neuroserpin"inclusion" CTSD !MFSD8 ,!! 25 10! • Back"averaging"of" bodies"(FENIB)$ ATP13A2 ,!!KCTD7 ! EEG"time!"locked"to" " 26! myoclonic"Jerks"may" " DRPLA:""ATN1 ! disclose"cortical" " 27! origin"of"myoclonic" Sialidosis:"NEU1 ! jerks" 28! " FENIB:,SERPINI1 ! 2! Anatomical, Neurophysiological, Examples,of,Conditions/Causes,to, Associated, DISTRIBUTION, TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment,Options, Origin, findings, consider, Genes,if,any, H,Focal, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, H,Multifocal, ! Acute,Or,Insidious" FACTORS, H,Segmental, ! Progressive,Or, Static, CORTICAL, Cortical"myoclonus" B. Generalised,Myoclonic, EJM1/JAE1:! Multifocal" Adolescence" Triggering"factors" Seizures, Sodium"valproate42" is"characterised" Epilepsies, EFHC131,32" Insidious"onset" !"EJM:" Usually"normal" Levetiracetam" by1:!" , EJM2:"Linked"to" Static" Photosensitivity, neurodevelopment"or" Lamotrigine"with" " (i) Juvenile"Myoclonic" 15q1433,34" mild" clonazepam"" 30 41 • Brief"EMG" Epilepsy"(EJM) " EJM3:"Linked"to" neurodevelopmental" Avoid :" discharges" (ii) Myoclonic"Absence" 6p2135" impairment, Gabapentin" lasting"less" Epilepsy/Juvenile" EJM4:"Linked"to" Normal"neurological" Phenytoin" than"70ms" Absence"Epilepsy" 5q12!q1436" examination" Carbamazepine" " (JAE)" EJM5:!GABRA137" Vigabatrin" 38" • EEG"spikes" EJM6:"CACNB4 39 associated" EJM7:"GABRD !! with"EMG" EJM8/JAE2:" 40 myoclonic" CLCN2 !! bursts"and" EJM9:"Linked"to" 41" preceding" 2q33!q36 myoclonus"by" " brief"interval" C. Childhood,Myoclonic,Epilepsy, Dravet’s43, Multifocal" Infancy"to"childhood" Photosensitivity" Several"seizure"types"" Dravet’s43, (20ms"for" " syndrome, common"in"Dravet’s" Usually"various"degrees" syndrome, hand"muscles" (i) Severe"myoclonic" SCN1A! syndrome"and" of"neurodevelopmental" Topiramate" and"35ms"for" epilepsy"of"Infancy"!" PCDH19,!GABRA! present"in"some" impairment" Stiripenthol" calf"muscles)" Dravet"Syndrome" GABRG2,!HCN1,! with"Doose’s" Clobazam" " (ii) Myoclonic!"Astatic" STXBP1! syndrome" Levetiracetam" " Epilepsy"Doose" , Ketogenic"diet" " • Enhancement" syndrome" Doose’s " 43, of"early" syndrome Avoid:" cortical" SLC2A1,!SLC6A1! Carbamazepine" component"of" CHD2,!GABRA1,! Lamotrigine" SSEPs"–"giant" GABRG2,!SCN1A,! " 43 SSEPs" SCN1B,!KCNA2! Doose’s " " , syndrome, • Back"averaging" Ketogenic"diet" of"EEG"time!" Usually"refractory" 44 45,46" locked"to" 2. PROGRESSIVE,MYOCLONIC, GOSR2 " Multifocal" Childhood/Adolescence" Triggered"by:" Progressive"ataxia" Similar"to"EPM myoclonic" ATAXIA, Insidious" Voluntary" Intention"tremor" jerks"may" Progressive" movement" Mild"or"no"seizures" disclose" Stress" /cognitive""decline" " cortical"origin" Stimulus"sensitive of"myoclonic" jerks" " ! 3! Anatomical, Neurophysiological, Examples,of,Conditions/Causes,to, Associated, DISTRIBUTION, TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment,Options, Origin, findings, consider, Genes,if,any, H,Focal, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, H,Multifocal, ! Acute,Or,Insidious" FACTORS, H,Segmental, ! Progressive,Or, Static, CORTICAL, Cortical"myoclonus" 3. TOXIC/METABOLIC,CAUSES, !" Focal"or" Any"age" ! Usually" Encephalopathy, Remove"toxic"cause" is"characterised" " multifocal, Acute"Onset" stimulus" Negative"myoclonus" Correct"metabolic" by1:!" A. Drugs1,47"" ! Csensitive" may"be"a"feature" disturbance" " ! Levodopa" a (Asterixis)" " • Brief"EMG" ! Bismuth"salicylate" n Symptomatic" discharges" ! Antidepressants" " treatment"for" lasting"less"than" ! Anticonvulsants" b myoclonus"similar" 70ms" (Gabapentin," e to"EPM45" " pregabalin," " • EEG"spikes" lamotrigine," p associated"with" phenytoin)" r EMG"myoclonic" ! Antibiotics" o bursts"and" " g preceding" " r 1,47 myoclonus"by" B. Metabolic , e brief"interval" disturbance/Disorders, s (20ms"for"hand" ! Organ"dysfunction"–" s muscles"and" hepatic,renal" i 35ms"for"calf" ! Electrolyte"or" v muscles)" glycaemic" e" " disturbance" " ! Hyper/" • Enhancement"of" hypothyroidism" early"cortical" ! Storage"disorders" component"of" ! Tay"Sachs"" SSEPs"–"giant" ! Gauchers"Type"3" SSEPs" 4. CENTRAL,NERVOUS,SYSTEM, !" Focal" Any"age."Static"or" Triggered"by" History"of"headache" Surgery"if"possible" 1,47 , " LESION , progressive" voluntary"action Focal"neurological"signs" Symptomatic" • Back"averaging" A. Tumour" treatment"for" of"EEG"time!" B. Vascular"malformation, myoclonus"similar" 46" locked"to" to"EPM 1,47 46" myoclonic"Jerks" 5. POSTH,HYPOXIC , !" Multifocal" Any"age"–"Static"or" Triggered"by" Negative"myoclonus" Similar"to"EPM " may"disclose" –,Lance,Adams,Syndrome, improvement"with"time" voluntary"action common" cortical"origin"of" myoclonic"Jerks" " ! ! ! ! 4! Anatomical, Neurophysiological, Examples,of,Conditions/Causes,to, Associated, DISTRIBUTION, TIME, TRIGGERING/, OTHER,ASSOCIATED, Treatment,Options, Origin, findings, consider, Genes,if,any, H,Focal, ! Age,of,Onset" ALLEVIATING, SYMPTOMS/SIGNS, H,Multifocal, ! Acute,Or,Insidious" FACTORS, H,Segmental, ! Progressive,Or, Static, SUBCORTICAL, No"sign"of" 1. ESSENTIAL,MYOCLONUS,+/H, DYT11:, Multifocal!" Childhood" Dramatic"alleviation" Dystonia" Clonazepam" hyperexcitability"on" DYSTONIA, SGCE48! more"often"in" Insidious" of"myoclonic" Psychiatric"symptoms"–" Bilateral"pallidal"or" EEG"or"SSEP1,45" A. DYT11, " head,"neck" Static" symptoms"with" anxiety,"depression," deep"brain" " B. DYT15, and"upper" alcohol" OCD" stimulation49" Myoclonus"duration" limbs," on"EMG"ranges"from" occasionally"in" 25!300ms45" lower"limbs" " 2. HYPEREKPLEXIA50, GLRA151" Non! Onset"in"infancy" Triggered"by" Hypertonia"(usually" Clonazapam50" A. Genetic, GLRB52" segmental" Insidious" sensory"stimuli"to" transient)" B. Brainstem, GPHN53" Bilateral," Static" the"mantle"area""or" Hypokinesia" encephalitis/ischaemia1,55, ARHGEF953" synchronous" auditory"stimuli" C. Vascular,lesions, SLC6A553,54" involvement"of" without"habituation" D. Multiple,sclerosis56, " facial" (grimacing)," neck"(flexion)," arms" (abduction)" trunk"and"legs" (flexion)" movements" 3. OPSOCLONUSHMYOCLONUS, !" Multifocal" Childhood"onwards" Can"be"triggered"by" Opsoclonus"–" Immuno! SYNDROME57, Insidious/subacute" voluntary"action," involuntary"arrhythmic" modulation57" A. Associated,with, Static" tactile,"visual"or" multi!directional" Steroid"therapy" Neuroblastoma,in,40H,65%, auditory"" saccades" Rituximab" of,children,45,58, stimulus"."" Ataxia" IVIG" , Exacerbated"by" Encephalopathy" stress"or"crying." Irritability"and" behavioural"change" 4. RETICULAR,REFLEX, !" Axially" Any"age" Sensitivity"to"stimuli" Encephalopathy" Clonazepam1,46" MYOCLONUS, localised9" Sub!acute" in"distal"limbs" " A. PostHhypoxic,brain,injury, Non! Static" instead"of"mantle" B. Brain,stem,encephalitis, segmental" area"in"contrast"to" C. Uraemia1, hyperekplexia" 5. PALATAL,MYOCLONUS, " Segmental" Childhood"onwards" H" Ear"clicking/tinnitus" Clonazepam45,46" A. Essential,palatal, involving" Piracetam" myoclonus:,, rhythmic" Carbamazepine" ! Idiopathic, contractions"of" Sodium"valproate" , the"soft"palate" Botulinum"toxin" B. Symptomatic,palatal, injection46"
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