Patient 1 - “Reflex seizures”

Patient 2 – “Novel frameshift”

Patient 3 – “Novel splice site”

Patient 4 – “Novel nonsense”

Seizure onset

6 months

2 months

2 months

3 months

Sex

Female

Female

Female

Female

Family history

Unremarkable

Unremarkable

Unremarkable

Unremarkable

Seizure semiology

6 months-18 months: startle spasms sometimes progressing to GTC only with bathing

18 months: tonic-spasms sequence sometimes progressing to GTC spontaneous or startle to submersion in water and loud noise. No hypermotor component.

2 months-2.5 years: Tonic, focal, autonomic symptoms

2.5 years: seizures in clusters

2 months-10 months: focal-tonic

10 months: hypermotor-tonic-spasm sequence

3 months-12 months: GTC

12 months-1.5 years: hypermotor-tonic-spasm sequence

1.5 years-2 years: tonic-spasm

2 years: GTC, focal

EEG findings

8 months: Excess high amplitude background slowing, somewhat poorly developed sleep features and parietal region hemispheric asymmetry

2 years: Multiple independent spike foci (MISF) and slow background activity for age

Delta slowing of the background followed by generalized attenuation during seizures and multifocal interictal epileptiform abnormalities

Bilateral independent frontal interictal discharges during sleep. During ictal event, there was high amplitude 2 Hz delta (hypermotor), followed by diffused attenuation (tonic) and spasms complex afterward. (refer to Figure 1.).

Bilateral independent frontal interictal discharges during sleep. No EEG of ictal events was ever captured.

Development

Severe delayed gross motor, fine motor, language and social

Severe delayed gross motor, fine motor, language and social

Severe delayed gross motor, fine motor and language

Mild delay social

Severe delayed gross motor, fine motor, language and social

Stereotypies

Abnormal hand movements to midline

Hyperoral

Hand flapping

Abnormal hand movements to midline

Abnormal hand movements to midline

Obsession with hands

Systemic disease

GERD

None

None

None

Physical examination

Normal growth parameters

Axial hypotonia, hyperreflexia

Poor tracking/eye contact

Microcephaly (<2 SD)

Axial hypotonia

Microcephaly (<2 SD)

Axial hypotonia

Intermittent dysconjugate strabismus

HC decreased growth velocity

Axial hypotonia

Investigations

NBS, lactate, uric acid, ammonia, plasma and urine amino acids, urine organic acids, succinylpurines, Batten disease screen of CLN1, CLN2 and ultrastructural examination for membrane bound inclusions, acylcarnitine profile, alpha galactosidase, chitotriosidase, galactocerebrosidase, urine and plasma creatine and guanidinoacetate, TIEF, lysosomal enzyme activities, palmitate oxidation and ATP synthesis, CSF analysis (neurotransmitters, lactate, glucose, protein, amino acids), MRI-brain with spectroscopy, array-CGH, MECP2 sequencing, CDKL5 MLPA and array-CGH

NBS, lactate, lipoprotein profile, plasma and urine amino acids, urine organic acids, acylcarnitine profile, total and free serum carnitine levels, plasma ammonia, total plasma homocysteine, serum CK, liver enzymes, urine alpha-AASA, creatine, biotinidase, VLCFA, Batten disease screen, CSF analysis (amino acids, lactate, glucose, protein, cell count, neurotransmitters), MRI-brain with spectroscopy, karyotype, gene sequencing (SCN1A, MECP2, CDKL5)

NBS, plasma and urine amino acids, total and free carnitine, acylcarnitine, urine organic acids, CBC, electrolytes, Ca, Mg, phosphate, lipase, liver enzymes, albumin, lactate, , uric acid, ammonium, VLCFA, homocysteine, CK, lysosomal enzyme activity, Krabbe, CLN1, CLN2, plasma pipecolic acid, CSF analysis (protein, glucose, lactate, neurotransmitters, pyridoxal 5’ phosphate, 5-HIAA, HVA), Vit E, Vit B12, Vit B6, urine methylmalonic acid, cholesterol, MRI-brain with spectroscopy, array-CGH, gene sequencing (PNPO, CDKL5)

NBS, plasma and urine amino acids, urine organic acids, lactate, total and free carnitine, TIEF, creatine, GAA, sialic acid, lipase, CBC, electrolytes, Ca, Mg, phosphate, lipoproteins, liver enzymes, albumin, lactate, uric acid, ammonia, LCFA, VLCFA, homocysteine, CK, MRI-brain with spectroscopy, array-CGH, gene sequencing (PNPO, MECP2, CDKL5)

Molecular diagnosis

c.162_99del261

c.2480_2486dupCAGATCT

c.99+1G>A

c.1238C>A

Age at diagnosis

2 years

2 years

<1 year

2 years

Antiepileptics

Phenobarbital, Topirimate, Clobazam, Valproate

Phenobarbital, Topirimate, Clobazam, Valproate, Keppra, Vitamin B6, Phenytoin, Lamotrigine, Nitrazepam, Oxcarbazepine, Mirtazipine, KCI, Levetiracetam, ketogenic diet

Phenobarbital, Topirimate, Clobazam, Levetiracetam, Lamotrigine, Vit B6, Vit B12, folate, ketogenic diet

Phenobarbital, Topirimate, Clobazam, Valproate, Levetiracetam, Oxcarbazepine, Gabapentin

Other medications

Ranitidine

Carnitine

None

None