Table 1.
Clinical features of the 17 individuals with TMEM63B variants
| Individuals’ ID/gender | TMEM63B varianta(cDNA and protein) | Age at last follow-up/death | Age at seizure onset/type | Seizure types/severity during follow-up | Treatment ever tried (+ efficacy, +/− transient efficacy, − worsening or not tolerated) | EEG | Brain magnetic resonance imaging | Clinical neurological phenotype | Hematological findings |
|---|---|---|---|---|---|---|---|---|---|
| 1/M | c.130G>A (p.Val44Met) |
8 years/deceased at 9 years (pneumonia) | 6 months/infantile spasms | spasms, myoclonic, focal with impaired awareness/daily | CZP, ESM, PB, VGB | 6 months–8 years: slow background, bilateral independent discharges; epileptic spasms and myoclonic szs | 5 months, 4 years: thin CC, colpocephaly, abnormal myelination, dysmorphic lateral ventricles, enlarged extracerebral spaces, progressive mild cerebellar atrophy, and watershed areas WM abnormality | threatened preterm labor at 35 weeks, global profound DD, generalized hypotonia, plagiocephaly, nystagmus, dysphagia (PEG 17 months), dyskinesias | mild anemia |
| 2/M | c.1298G>A (p.Arg433His) |
10 years | birth/focal | bilateral independent focal motor with impaired awareness, focal to bilateral tonic-clonic/weekly | CBZ, CLB, CZP, LEV, LCM, MDZ, PB, PHT, STP, TPM | 7−10 years: slow background, multifocal discharges; focal szs recorded | 6 years, 10 years: thin CC, multifocal WM abnormalities, ventricular asymmetry, progressive cerebellar atrophy | global profound DD, ataxic gait, lower limb hypertonia, nystagmus | mild abnormalities of RBCt, MCV, MCH |
| 3/M | c.1442C>A (p.Thr481Asn) |
15 years | 2 months/focal motor with asymmetric posturing | focal with impaired awareness and asymmetric posturing, focal to bilateral tonic-clonic/weekly | CBZ, CLB, PB, PER, STP, VGB, VNS | 15 years: slow background, focal epileptiform discharges | 4 years: thin CC, posterior predominant multifocal WM abnormalities, dysmorphic asymmetric lateral ventricles, enlarged cortical sulci | global profound DD, spastic asymmetric quadriparesis, severe cortical visual impairment | none |
| 4/Mb | c.130G>A (p.Val44Met) |
12 years/deceased at 12.5 years (pneumonia) | 4 months/focal | focal with impaired awareness; 9 months on: spasms and focal to bilateral tonic-clonic/daily; single episode of SE (14 months) | CBZ, CLB, KD, LTG, LEV, PRED, RFM, VGB, VPA, VNS | 8 months–10 years: slow background, bilateral independent or multifocal discharges; epileptic spasms recorded | 5 months, 7 years: thin CC, multifocal WM abnormalities, dysmorphic enlarged lateral ventricles, mild cortical and cerebellar atrophy, progressive trabecular bone thickening | global profound DD, wheelchair bound, cortical visual impairment, by 10 years knee fixed flexion contractures, dysphagia (PEG 5 years) | severe macrocytic anemia transfusion dependent |
| 5/M | c.130G>A (p.Val44Met) |
8 years | day 2/apnoeic | 4 months: epileptic spasms; 7 years: focal hyperkinetic motor with impaired awareness/sz-free | CBZ(+), CLB, LEV, PB(+), TPM(+) | 7 years: slow background, bilateral independent or multifocal discharges; focal szs recorded | 1 week, 7 months, 2 years: thin CC, abnormal myelination, dysmorphic asymmetric lateral ventricles, enlarged extracerebral spaces, progressive posteriorly predominant WM abnormality, and cerebellar atrophy | global profound DD, severe cortical visual impairment, nystagmus, spastic quadriparesis, dysphagia (PEG 2 years) | jaundice at birth |
| 6/Fb | c.130G>A (p.Val44Met) |
15 months/deceased at 23 months (pneumonia in progressive respiratory failure) | day 10/apnoeic | focal onset with impaired awareness, focal to bilateral tonic-clonic, epileptic spasms/daily | Alimemazine, CBZ, CLB, PB(+/−), paraldehyde, PRED, TPM, VGB, VPA, VNS(+), biotin, pyridoxine | 2–23 months: slow background, multifocal or generalized discharges with burst suppression; focal szs recorded | 2 months: thin CC, enlarged extracerebral spaces, diffusely abnormal myelination | global profound DD, quadriparesis with generalized hypotonia, cortical visual impairment, nystagmus, dysphagia (PEG 16 months) | macrocytic anemia, transfusion dependent |
| 7/Ma | c.130G>A (p.Val44Met) |
20 months | birth/apnoeic | 2 weeks: stiffening episodes; 9 months: epileptic spasms/sz-free | LEV, steroids, VGB | birth–20 months: normal background, then hypsarrhythmia, slow background, focal discharges | 1 week, 5 months, 11 months: thin CC, widespread WM abnormalities, enlarged dysmorphic lateral ventricles, mild progressive cerebellar atrophy | global profound DD, asymmetric quadriparesis, generalized hypotonia, cortical visual impairment, nystagmus, dysphagia (no PEG yet) | scleralicterus |
| 8/F | c.130G>A (p.Val44Met) |
17 years | 4 months/infantile spasms | 1 year: generalized tonic, focal motor with impaired awareness/daily | ACTH, CBZ, CLB, CZP, ESM, GBP, ivIg, LCM, LEV, PB, PER, PIR, PLP, PRM, STP, TPM, VPA, ZNS | 4 months–12 years: hypsarrhythmia, then slow background, multifocal epileptiform discharges | 4 months, 2 years, 10 years: thin CC, abnormal myelination, dysmorphic asymmetric lateral ventricles, enlarged extracerebral spaces, progressive widespread WM abnormality, ventricular dilatation, cerebellar atrophy, and trabecular bone thickening | global profound DD, quadriparesis, dysphagia (PEG 12 years) | severe anemia requiring occasional transfusions |
| 9/M | c.130G>A (p.Val44Met) |
15 years | 2 years 6 months/febrile seizures | 3 years: epileptic spasms in small clusters/weekly | CZP, VPA | slow background, no epileptiform discharges in 4 EEG recordings | 4 months: thin CC with absent splenium and delayed myelination; 6 years 7 months: increased signal of WM in watershed areas, generalized decrease of white matter volume | global profound DD, wheelchair bound, quadriparesis, pseudobulbar signs, jerky involuntary movements, stereotypical movements and behavior, dysphagia (PEG 3 years), cortical visual impairment, nystagmus | mild anemia |
| 10/F | c.1377C>G (p.Asp459Glu) |
3 years | 2 weeks/focal | bilateral independent focal, epileptic spasms/daily | CBD, KD, LEV, VGB, VNS, ZNS | 2–9 months: slow background, hypsarrhythmia, multifocal discharges; focal szs and epileptic spasms recorded | 2 months: thin CC, enlarged extracerebral spaces, abnormal myelination more pronounced posteriorly, Rathke cleft cyst | global profound DD, quadriparesis, generalized hypotonia, cortical blindness with roving eye movements, dysphagia | mild macrocytic anemia |
| 11/M | c.1387G>A (p.Val463Ile) |
7 years | 2 years/focal | occasional focal with impaired awareness/during fever | VPA | 4–6 years: normal background, bilateral independent discharges | 6 years: multifocal, posteriorly predominant WM abnormality | global severe DD, motor impairment, generalized hypotonia | none |
| 12/M | c.1387G>A (p.Val463Ile) |
23 months | first few weeks/myoclonic jerks | 14 months; intractable focal seizures | LEV, CLB, ESM, CLZ, TPM(+/−), VPA(−) | 14 months: normal background, generalized and focal discharges | 14 months: mild prominence of ventricular system and extra-axial CSF spaces | global DD, dysphagia | none |
| 13/F | c.1424_1426del (p.Ile475del) |
16 years | 6 months/infantile spasms | tonic/daily; GTCs/monthly | ACTH, CBD, CLB, CZP, LEV, LTG, OXC, TPM(−), VGB(−), VPA | 4 months–16 years: hypsarrhythmia, then slow background, bilateral independent or multifocal discharges; epileptic spasms and tonic szs recorded | 7 months, 2 years, 4 years, 8 years: thin CC, multifocal WM abnormalities, asymmetric dysmorphic lateral ventricles, progressive trabecular bone thickening | global profound DD, generalized hypotonia, microcephaly, visual impairment, nystagmus, squint, spastic quadriparesis, dysphagia (PEG 12 years) | severe hemolytic anemia, transfusion dependent |
| 14/M | c.1738G>A (p.Gly580Ser) |
5 years | 10 months/focal | GTCs/occasional during fever | VPA | 2 years: slow background, focal discharges | 1 year 7 months: thin CC, widespread WM abnormality, especially periventricular, asymmetric dysmorphic lateral ventricles, mild cerebellar atrophy | global profound DD, spastic quadriparesis, axial hypotonia, upper limb dystonia, visual impairment, dysphagia (PEG 3 years) | none |
| 15/F | c.1738G>T (p.Gly580Cys) |
30 years | 3 years/focal | focal with impaired awareness, GTCs/yearly | CBZ, CZP, PHT(+), VPA, ZNS | 15 years: slow background, focal discharges; focal szs recorded | 15 years, 21 years, 24 years, 27 years, 28 years: thin CC, widespread WM abnormality, especially periventricular/posterior, progressive cerebellar atrophy, and trabecular bone thickening | global moderate DD, cerebellar ataxia, tremor, dysarthria, limited mobility, bipolar disorder | mild hyperbilirubinemia |
| 16/F | c.1979G>C (p.Arg660Thr) |
25 years | 11 months/focal | focal with posturing and impaired awareness, recurrent SE/yearly | CBZ(−), LMT(−), OXC, PB(−), TPM, VNS(+) | 17 months–22 years: background mildly abnormal, diffuse beta activity, multifocal discharges; focal szs recorded | 1 year, 2 years, 10 years: thin CC, multifocal WM abnormality | global moderate DD, spastic quadriparesis, ASD | macrocytic anemia |
| 17/M | c.2089T>C (p.Phe697Leu) |
15 years | 11 months/focal | focal with eye deviation; jerking, GTCs, recurrent SE/sz-free at last FU | CLB, LTG(−), LEV(−), OXC, PHT, VPA | 5–17 months: normal background; focal discharges | 1 year, 12 years: thin CC, abnormal myelination, colpocephaly, dysmorphic lateral ventricles, increased WM signal with posterior/periventricular predominance | global, severe DD, toe walking, ASD | none |
Abbreviations and symbols: ASD, autism spectrum disorder; CBD, cannabidiol; CBZ, carbamazepine; CC, corpus callosum; CLB, clobazam; CZP, clonazepam; DD, developmental delay; ESM, ethosuximide; F, female; GBP, gabapentin; GTCS, generalized tonic-clonic seizures; ivIg, intravenous immunoglobulin; KD, ketogenic diet; LCM, lacosamide; LEV, levetiracetam; LTG, lamotrigine; M, male; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; MDZ, midazolam; NA, not available; OXC, oxcapazepine; PB, phenobarbital; PEG, percutaneous endoscopic gastrostomy; PER, perampanel; PHT, phenytoin; PIR, piracetam; PLP, pyridoxal 5′-phosphate; PRED, prednisolone; PRM, primidone; RBCs, red blood cells; RFM, rufinamide; SE, status epilepticus; STP, stiripentol; sz, seizure; TGP, targeted gene panel; TPM, topiramate; VGB, vigabatrin; VNS, vagus nerve stimulation; VPA, valproic acid; WM, white matter; ZNS, zonisamide.
a
Variants’ nomenclature is based on the GenBank: NM_018426.3 reference sequence.
b
IDs 4, 6, and 7 are mentioned in Cacheiro et al.14 (Table S8: DDD subject 1, 100KGP subject 2, and100KGP subject 1); treatment ever tried: +, efficacy; +/−, transient efficacy; −, worsening or not tolerated.