Table 1.

Phenotypic features of patients with WDR45 mutations

Case ID Age, Gender	Epilepsy syndrome	Mutation* (skewed X-inactivation)	Development prior to seizure onset	Age and seizure type at onset	Development after seizure onset/Regression	Other seizure types	Seizure offset	EEG	Neuroimaging MRI/FDG PET	Other features	Medications (current medication underlined)
#1 8y, F	IS evolving to LGS	c.629delG p.Ser210X (mildly 84:16)	Delayed: fixed and followed by 6w, never rolled over or sat	7m: IS (ceased by 18m, recurred at 5y)	Profound ID: non-verbal, non-ambulatory, cannot sit Regression with seizure onset: stopped smiling, reduced eye contact	Myo (onset uncertain, by 15m) Abs Tonic FIAS (onset 5y)	6y 10m - following bilateral femoral osteotomy	Posterior quadrant epileptiform discharges evolving to abundant posterior spike-wave discharges, PSW and low voltage PFA, L>R Multifocal epileptiform activity Diffuse background slowing Spasms associated with bilateral slow & fast paroxysms (10m and 15m) Tonic seizures lasting 2–40 seconds associated with low voltage fast activity, R>L Myo jerks in sleep associated with PSW	1y 4m: large ventricles especially frontal horns, small incompletely rotated hippocampi, thin CC, decreased white matter volume, delayed myelination (approx 9m), large extra axial spaces 4y 1m: larger ventricles, round hippocampi, no internal architecture in hippocampi, bright on T2 and improved rotation, very thin CC, decreased white matter volume and very delayed myelination, blooming in cerebral peduncles and both globus pallidi FDG-PET 2y 4m: extensive bilateral frontal cortical hypometabolism, L > R	Profound myopia Cortical visual impairment Asymmetric spastic quadriparesis Dislocated left hip Kyphosis Scoliosis No dysmorphic or behavioral features	TPM, prednisolone (after 2 weeks stopped spasms for 4m), VPA, LTG, CZP (increased tonic seizures), VGB, CLB, ETX, LCM, ZNS, KD, VNS (more alert, fewer tonic seizures), GBP (5 weeks seizure free post-surgery)
#2 7y, F	LGS	c.1007_1008del p.Tyr336CysfsX5 recurrent (ND)	Delayed: sat with support 6–8m, “babbling” and sitting independently at 16m	16m: Tonic seizures	Profound ID: non-verbal, non-ambulatory, cannot sit Regression with seizure onset: lost ability to sit, roll over, “babble”, use a fork	Myo (onset 18m) FIAS (onset 3.5y) Abs (onset 4.5y) FIAS evolving to bilateral TCS (3y 10m)	Ongoing	Occipital slowing and sharp waves evolving to GSW in sleep followed by decrements, fast activity in wakefulness. Then posterior predominant SSW, PSW and PFA in sleep. Tonic seizures associated with diffuse fast activity and bilateral PFA	1y 2m: large ventricles especially frontal horns, very thin CC, decreased white matter volume and delayed myelination 1y 11m: large ventricles especially frontal horns, round hippocampi but no internal architecture, thin CC, decreased white matter volume and severe myelination delay, large extra axial CSF spaces	Peripheral spasticity No behavioral features Brachycephaly	ZNS, VPA (worse), CLB (increased duration tonic seizures, respiratory difficulties), LTG, TPM, LEV, prednisolone, 6m of no medication with no increase in seizures at 3.5y, Baclofen (seizures ceased), nil
#3 11y, F	DEE	c.700C>T p.Arg234X recurrent (No 49:50)	Delayed speech acquisition	12m: Myo	Severe ID: single words 18m, rare word combinations 9y, currently has 20 single words and follows simple commands Regression with frequent seizures: loss of speech, less response to painful stimuli	Febrile NCSE (14m) FIAS with clonic component	10.5y	Frequent irregular GSW. Background slowing with occipital predominance Myo jerks associated with irregular GSW. Staring episodes with irregular GSW with variable lead from central and posterior regions. Focal clonic seizures emanating from L or R central region.	9y 4m: mild ventriculomegaly, thin CC in posterior body and splenium, subtle white matter volume reduction, normal myelination, SWI blooming in cerebral peduncles and globus pallidi 10y 5m: mild subtle white matter volume reduction, normal myelination	Sleep disturbance Dental issues Oro-motor apraxia Moderate pes planus Peripheral hypotonia Intoeing with wide-based gait Poor coordination High pain threshold Seizure trigger: fever, head flexion Aggression Broad nasal bridge Hypertelorism Mild facial asymmetry	VPA (irritable), VGB, TPM, LEV, CLB (seizures ceased when added to VGB + TPM + LEV, VGB then weaned)
#4 2y, F	IS	c.627del p.Ser210GlnfsX78 (Yes 92:8)	Delayed: rolled over 5m, sat unsupported 10m	8m: IS	Delayed: nonverbal, pulls to stand, cruising, eats with spoon No regression	FIAS (9m) IS with head deviation to L (16m)	Ongoing	8m: modified hypsarrhythmia 9m: bi-temporal epileptiform activity during sleep, hypsarrhythmia resolved From 10m: multifocal epileptiform activity, GSW	7m: prominence of ventricles and extra axial CSF spaces, incomplete rotation of L hippocampi, generally thin CC, normal white matter volume and myelination	Hypertension (frusemide 1mg/kg daily) Diarrhoea No behavioral features Cushingoid features	Prednisolone (stopped spasms and hypsarrhythmia), VGB, TPM, pyridoxine, ACTH, medical cannabis, KD (metabolic acidosis requiring potassium bicarbonate supplementation)
#5 7y, F	MAE	c.454delT p.Cys152AlafsX9 (ND)	Delayed smiling	17m: Febrile seizure	Severe ID: few single words, walks independently Regression with seizure onset: loss of speech	Atonic (onset 24m) Myo (onset uncertain) NCSE (onset 2y 10m) Atypical Abs (onset 27m)	5y Rare febrile TCS from 4y 2m	GSW, PSW Biposterior quadrant epileptiform activity, L > R Slow background Atypical absence seizure with 1.5–2.5 Hz GSW	23m: normal 5y: mild cerebellar atrophy, mild reduction in white matter volume	Genua valgum (knock knees) No dysmorphic or behavioral features	LEV, LTG, VPA (stopped seizures)
#6 4y, F	Focal seizures with fever	c.726C>G p.Tyr242X (ND)	Delayed speech acquisition: no spontaneous speech, could repeat and imitate intonation and speech sounds at 12m	12m: Focal seizure with fever	Severe ID: few single words, walks independently Regression with seizure onset: loss of “babble”	Febrile FIAS (onset 1y)	3y	No definite epileptiform discharges Background slowing	1y 6m: thin CC, normal white matter volume and myelination 3y 6m: mild cerebellar atrophy of superior vermis, prominent ventricles and extra axial CSF spaces, thin CC, mild reduction in white matter, myelination normal	Sleep disturbance No dysmorphic or behavioral features	VPA (no change in seizure frequency),TPM (stopped seizures but withdrawn due to side effects), LEV (no seizures for 11m)
#7 3y, F	DEE	c.614G>A p.Gly205Asp (no 34:66)	Delayed: sat 2.5y, non-verbal, standing with support, not walking	36m: Drop attacks	Severe ID: 2 single words, walks with assistance, reaches for spoon	FIAS	Ongoing	Diffuse moderate background slowing Multifocal discharges, GSW, GPFA	Normal	Episodes of hyperventilation Severe autistic behavior No dysmorphic features	LEV, LTG, VPA, CLB, OCBZ, TPM, ZNS, RFM, LCM, no change to seizure frequency), KD, nil

Mutation co-ordinates based on WDR45: NM_007075.3and protein NP_009006.2 # effect of frameshift mutation predicted by mutalyzer (see URLs).

^*All mutations arose de novo

Abs, Absence; ACTH, acetylcholinesterase; CC, corpus callosum; CLB, clobazam; CSE, status epilepticus; CSF, cerebrospinal fluid; CZP, clonazepam; ETX, ethosuxamide; F, female; FDG-PET, fluoro-deoxyglucose positron emission tomography; FIAS, focal impaired awareness seizure; FS, febrile seizures; GBP, gabapentin; GPFA, generalised paroxysmal fast activity; GPS, generalised polyspike; GSW, generalized spike-wave; ID, intellectual disability; IS, infantile spasms; KD, ketogenic diet; L, left; LCM, lacosamide; LGS, Lennox-Gastaut syndrome; LEV, levetiracetam; LTG, lamotrigine; m, months; MRI, magnetic resonsnace imaging; Myo, myoclonic; NCSE, non-convulsive status epilepticus; ND, not determined; OCBZ, oxcarbazepine; PET, positon emission tomography; PFA, paroxysmal fast activity; PPR, photoparoxysmal response; PSW, polyspike wave; R, right; sec, seconds; RFM, rufinamide; SE, status epilepticus; sec, seconds; SSW, slow spike and wave; SW, slow-wave; SWI, susceptibility weighted imaging; TCS, tonic-clonic seizures; TPM, topiramate; VGB, vigabatrin; VNS, vagal nerve stimulator; VPA, valproate; w, weeks; y, years; ZNS, zonisamide

Current medications underlined