Table 1 Clinical and molecular features of subjects with SCN8A variations
From: Expanding the genotype-phenotype spectrum in SCN8A-related disorders
Patient 1 | Patient 2 | Patient 2 - sibling | Patient 2 - father | Patient 3 | Patient 4 | Patient 5 | Patient 6 | |
|---|---|---|---|---|---|---|---|---|
Age (first seen) | 4 months | 3 months | 2 weeks | NA | 14 months | 3 years | 6–7 months | 10 years |
Age (last seen) | 17 yrs | 7 yrs | 4 yrs | 40 yrs | 6 yrs | 7 yrs | 8 yrs | 20 yrs |
Ethnicity | Caucasian | Caucasian | Caucasian | Caucasian | Caucasian | Caucasian | Indian | Indian |
Sex | Female | Female | Male | Male | Female | Female | Male | Female |
Family history | Paternal cousin with epilepsy | Father and brother with same condition | Sibling of Patient 2 | Father of Patient 2 | Father with 2 febrile seizures, on valproic acid till 4 years of age | NA | None | None |
Epilepsy diagnosis | DEE | Treatment responsive | Treatment responsive | Treatment responsive | Treatment responsive | Unclassified | DEE | Treatment responsive |
Genetic diagnosis (SCN8A)* | NM_001330260.2:c.1238C > A (p.(Ala413Asp) | NM_001330260.2:c.5630A > G (p.Asn1877Ser) | NM_001330260.2:c.5630A > G (p.Asn1877Ser) | NM_001330260.2:c.5630A > G (p.Asn1877Ser) | NM_001330260.2:c.4447G > A (p.Glu1483Lys) | NM_001330260.2:c.971G > A (p.Cys324Tyr) | NM_001330260.2:c.773C > T (p.(Thr258Ile)) | NM_001330260.2:c.986A > G (p.(Asp329Gly)) |
Zygosity | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous |
CADD score | 29 | 25.4 | 25.4 | 25.4 | 31 | 27.2 | 26.5 | 25 |
Inheritance | De novo | Paternal | Paternal | NA | De novo | De novo | De novo | De novo |
Function | Unknown | Gain-of-function | Gain-of-function | Gain-of-function | Gain-of-function | Loss-of-function | Unknown | Unknown |
Birth history | Uneventful | Maternal preeclampsia without complications | Maternal preeclampsia without complications | NA | Uneventul | NA | Maternal gestational hypothyroidism, diabetes and hypertension | Uneventful |
Novelty of the variant (ClinVar Variation ID) | Novel unreported | Known (130252), Anand 2016, Parrini 2016, Butler 2017 | Known (130252), Anand 2016, Parrini 2016, Butler 2017 | Known (130252), Anand 2016, Parrini 2016, Butler 2017 | Known (253195), Gardella 2016 | Known (1699202), Encinas 2020 | Known unreported (559632 - submitter BCCHR) | Known unreported (1518887) |
Intellectual disability | Profound | None | None | None | Normal | Yes | Yes | Normal |
Development | GDD | Normal | Normal | Normal | Normal | Severe GDD | GDD | Normal |
Age at seizure onset | 4 months | 3 months | 7 months | 6 months | 12 months | uncertain | 6–7 months | 10 yrs |
Seizure type at onset | IS, starring spells, hypsarrhythmia | Sudden arching of back, stiffness, choking sounds, frothing, greyish discoloration of the body | Stiffness, clicking sounds with eyes closed, body turned light gray | NA | Tonic stiffening with superimposed tremor with eyes open and unresponsive | possible clinical seizure | Arrest of activity with eyelid fluttering lasting for a few seconds | Head and eye deviation to the left, face pulling to the left, arched back and falling to the left side slowly to the ground, impaired awareness |
Course of seizure | LGS manifesting impaired awareness seizures, atypical absence seizures, GTCS, epileptic spasms, non-convulsive status epilepticus | Self resolving focal seizures followed by fatigue | Focal seizure | NA | Focal seizures. A couple of episodes occurred along with febrile illness. | - | Absence seizures | Focal seizures with impaired awareness |
Age at EEG | 12 yrs | 15 months | NA | NA | 18 months | 1 year - Normal | 1.5 yrs | 14 yrs |
EEG finding | Slow dysrhythmic background, bifrontal slowing, frontal spike and slow wave, L > R, left occipital sharp and slow waves, no subclinical seizures | Normal | NA | NA | Normal | 2 yrs - Dysrhythmic basal ganglia occasional generalized paroxysmal delta waves in sleep, frequent sharp waves in L temporal in drowsy/sleep with dipole configuration | Frequent generalized fragmentary spike and wave and atypical spike and wave activity maximal in the bilateral anterior quadrants of drowsiness and sleep | Normal |
Duration of seizure | 45min | 2-6min | 3min | NA | 2-3min | - | 3sec | 10-15sec |
Frequency of seizure | 2–3 a day | 2–3 a week | 1 episode | NA | 3–4 a month | - | 1–2 a day | 3 a month |
Seizure control | Treatment resistance for many years. Now under control. | Seizure-free | Seizure-free | Seizure-free | Seizure-free | No clinical seizures | Good | Seizure-free |
Other clinical findings | Hyperkinetic movements (choreo-athetoic), hypotonia, cortical visual impairment, sleep disorder, non-verbal, scoliosis, spastic quadraparesis, strabismus, G-tube fed | None | None | None | None | Overriding toes, drooling, microcephaly, corrected strabismus, far sighted, zoning out spells, one episode of lethargic, febrile, shaking, ?eyes rolling back | Previous history of ataxic gait | Hyperkinetic movement disorder, previously evaluated for daytime enuresis as a child |
Behavioral abnormalities | None | None | None | None | None | Autism. Behavior described as impulsive with high degree of motor activity. | ADHD | None |
Treatment response | Good | Good | Good | Good | Good | - | Good | Good |
Current treatment | Clonazepam | Carbamazepine | Carbamazepine | Carbamazepine | None. Weaned off topiramate. | None | Ethosuximide, acetazolamide, biphentin | Carbamazepine |
Past ASM | Vigabatrin, ACTH, carbamazepine, lamotrigine, leviteracetam, nitrazepam, oxcarbamazipine, topiramate, valproic acid, clonazepam, phenytoin, CBD oil, ketogenic diet | None | None | He was tried to wean on carbamazepine twice at 5 yrs and 19 yrs but failed both times. Now he takes 400 mg twice daily | Topiramate, clobazam | Valproic acid improved EEG abnormality | Lamotrigine, levetiracetam | None |
Brain MRI | White matter volume loss and delayed myelination | Normal | - | NA | Normal | - | Mild nonspecific T2 hyperintense changes within the peritrigonal white matter | Normal |
Age at brain MRI | 2 yrs | 8 months | - | NA | 2 yrs | - | 4 yrs | 10 yrs |
Chromosomal microarray | Normal | Normal | - | - | Normal | Normal | - | - |
Other relevant investigations | Newborn screening, plasma and CSF amino acids and lactate were normal | Incidental homozygous benign BTD variant. Acylcarnitine screen, metabolic screen with plasma amino acids, newborn screening were normal | CBC normal | NA | - | Additional heterozygous, de novo, missense VUS in KCNQ3, NM_004519, c.1120C > G (p.Pro374Ala) (CADD 25.7) | - | Ultrasound renal - small echogenic abnormality just to the right of the midline within the bladder dome. This may represent an urachal remnant. |