Table 2.
Detailed Neurological Features of Individuals with PACS2 p.Glu209Lys
| Individual 1 | Individual 2 | Individual 3 | Individual 4 | Individual 5 | Individual 6 | Individual 7 | Individual 8 | Individual 9 | Individual 10 | Individual 11 | Individual 12 | Individual 13 | Individual 14 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Developmental Features | ||||||||||||||
| Sitting age | 8 mo | 20 mo | 6 mo | NA | 16 mo | 16 mo | NA | 10 mo | 18 mo | 12 mo | 9 mo | 7 mo | 12 mo | 11 mo |
| Walking age | 22 mo | NA | 18 mo | 18 mo | 18 mo | 22 mo | not walking | 27 mo | not walking | 24 mo | 24 mo | NA | 36 mo | 36 mo |
| Speech delay | + | + | + | + | + | + | + | + | + | + | + | NA | few single words | + |
| DD/ID | + | + | + | + | + | + | mild | + | + | + | + | + | mild | mild |
| Neurological Features | ||||||||||||||
| Hypotonia | + | NA | NA | NA | − | − | axial | − | diffuse | diffuse | − | + | axial | diffuse |
| Nystagmus | − | + | − | − | + | − | − | − | − | − | + (transient) | − | − | − |
| Stereotypies | − | + (transient) | − | − | − | + | − | − | + | + | − | + (transient) | + | − |
| Others | increased tendon reflexes | wide-based gait | − | − | visual problems | − | slightly increased tone in hands | − | − | − | − | − | increased tendon reflexes | wide-based gait |
| Psychiatric/behavioral features | − | sleeping and behavioral disturbances | − | mild autistic disorder | − | obsessive compulsive disorder | − | atypical social and behavioral features | atypical social and behavioral features | autism spectrum disorder | autism spectrum disorder | − | − | selective mutism |
| Epilepsy Details | ||||||||||||||
| Age of onset | 6 days | 4 days | 4 days | 7 days | 2 days | 2 days | 2 days | 2 weeks | 2 days | 1–2 mo | 1 day | 3 days | 2 weeks | 3 days |
| Seizure types | focal | GTCs | NA | GTCs | clonic and GTC | NA | focal with tonic stiffening and autonomic features, later clonic | focal, later tonic | focal tonic,tonic-clonic, and myoclonic, later GTCs and generalized tonic | clonic seizure with eye deviation, later GTC | focal (stopped at 2 months), later GTCs | focal tonic-clonic and tonic; status epilepticus | focal tonic-clonic, later focal or generalized | tonic, later tonic or GTCs |
| Longest seizure-free interval or age at last seizure | NA | 6 mo | NA | 2 years, immediate recurrence after withdrawal of valproate | 9 mo | status epilepticus 3 mo, 3.5 years; status epilepticus without fever: 3.5 year: | NA | 2 years, off AEDs since 3.5 year | 2 years | 2 years | NA | NA | NA | NA |
| EEG features | NA | neonatal to 3.5 mo: focal spikes, normal background; 1 year: normal | NA | neonatal: excess discontinuity, excessive multifocal sharp waves → generalized bursts of epileptic activity + MF sharp waves | neonatal: normal; 4 months: generalized slowing with MF sharp waves and frequent focal seizures | neonatal: left temporal spikes; 3.5 year (awake only): left paroxysmal temporal rolandic spikes, generalized slowing. | 6–7 wk: MF epileptiform activity; 9 mo: normal | 6 wk: subtle aberration R frontocentral and L temporal | neonatal: excess discontinuity, excess MF sharp waves; 2 year: intermittent generalized slowing, intermittent L temporal slowing | 4 mo: normal; 17 mo: rare generalized spikes | neonatal: epileptic discharges, Lrolandic region | neonatal: excess MF spikes and sharp waves, especially bilateral temporal regions; 2 mo: background poorly organized high amplitude background, lack of state change, MF spikes | 6 d: normal; neonatal/infantile: MF epileptiform activity, high amplitude slow spikes bilateral temporal; 17 mo: diphasic spikes at vertex, field to right frontocentral region, enhanced in sleep 3 year: ESES |
neonatal: excessive L and R central and temporal sharp waves; 10 mo: frequent L frontocentral region spikes; 22 mo: diffuse, frontally predominant 2-3 Hz spike or polyspike and wave, up to 500uV. 3 year: mild generalized slowing, frequent Left temporal epileptiform discharges |
| Brain MRI (age) | mild foliar distortion of the left cerebellar hemisphere, mega cisterna magna∗ (5 yr) | inferior vermian hypoplasia with prominent foramen Magendie and cisterna magna, severe foliar distortion of cerebellar hemispheres with centrifugal orientation, hypothalamic fusion anomaly (5 yr) | increased subarachnoid spaces∗ (NA) | mild inferior vermian hypoplasia with a patulous foramen Magendie and mega cisterna magna, mild distortion of the cerebellar folia (3 wk) | retrocerebellar arachnoidal cyst, inferior vermian hypoplasia with prominent foramen Magendie and a mega cisterna magna, severe foliar distortion of the left cerebellar hemisphere with centrifugal orientation, hypothalamic fusion anomaly (7 d) | normal∗ (10 d); normal∗ (4 mo) | inferior vermian hypoplasia, left retrocerebellar cyst, causing distortion of the smaller left cerebellar hemisphere and thinning of the overlying bones∗ (2 mo) | normal∗ (neonatal) | mega cisterna magna and patulous foramen Magendie, subtle cerebellar foliar distortion, hypothalamic fusion anomaly (1 wk) | mega cisterna magna, patulous foramen Magendie (1 mo) | thick corpus callosum, inferior vermian hypoplasia∗ (12.5 yr) | mega cisterna magna, severe foliar distortion with centrifugal orientation (3 mo) | moderate cerebellar foliar distortion (23 mo) | mild scattered subarachnoid hemorrhage structurally normal (2 mo); prominent cisterna magna and patulous foramen magendie with subtle foilar distortion (left side predominant) (31 mo) |
| Treatment | carbamazepine | phenobarbital, valproate | carbamazepine | phenobarbital, P5P, pyridoxine, valproate | levetiracetam, phenobarbital carbamazepine | topiramate | phenobarbital | phenobarbital sodium valproate | levetiracetam, phenobarbital | levetiracetam | valproate | levetiracetam, phenobarbital, oxcarbazepine | vigabatrin, levetiracetam, pyridoxalphosphate, pyridoxine, lamotrigine, valproate, clobazam | phenobarbital, pyridoxine, levetiracetam, lacosamide |
Abbreviations: d, day; DD/ID, developmental delay or intellectual disability; ESES, electrical status epilepticus of sleep; GTC, generalized tonic clonic seizure; L, left; m, months; MF, multifocal; mo, month; NA, not available; P5P, pyridoxal-5-phosphate; R, right; unsup., unsupported; ∗ brain MRI not reviewed by neurologist E.Y. from Boston Children’s hospital.