Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene

Abstract

Biallelic mutations in the PLCB1 gene, encoding for a phospholipase C beta isoform strongly expressed in the brain, have been reported to cause infantile epileptic encephalopathy in only four children to date. We report here three additional patients to delineate the phenotypic and genotypic characteristics of the disease. Our three patients were one sporadic case with an intragenic homozygous deletion and two cousins with the homozygous p.(Arg222*) nonsense variant in PLCB1. These patients had severe to profound intellectual disability, epileptic spasms at age 3‐5 months concomitant with developmental arrest or regression, other seizure types and drug‐resistant epilepsy. With this report, we expand the clinical, radiologic and electroencephalographic knowledge about the extremely rare PLCB1‐related encephalopathy. Since the first report in 2010, the overall number of reported patients with our additional patients is currently limited to seven. All seven patients had epileptic encephalopathy, mainly infantile spasms and 6/7 had profound intellectual disability, with one only being able to walk. Truncal hypotonia was the most frequent neurological sign, sometimes associated with pyramidal and/or extrapyramidal hypertonia of limbs. Microcephaly was inconstant. In conclusion, the phenotypical spectrum of PLCB1‐related encephalopathy is relatively narrow, comprises infantile spasms and severe to profound intellectual disability, and does not seem to define a recognizable clinical entity.

Phospholipase C families: Common themes and versatility in physiology and pathology

“…Inhibitory interneurons are stimulated by cholinergic input and loss of PLCβ1 results in disruption of PKC activity leading to a deficit in GABAergic inhibition [174]. In J o u r n a l P r e -p r o o f human patients, loss of PLCβ1 also results in infantile epileptic encephalopathy [175][176][177] (Table 2). This is a rare event and to date, only seven cases have been identified.…”

Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease

“…Li et al [62], Kowalczyk et al [63] and Sun et al [64] revealed that the expression of ADCYAP1, NPAS4, NPSR1, HTR2C, GABRB2, ALOX12B, ADRB3, EGR3, HSPA1A and IL3RA are associated with progression of schizophrenia, but these genes might be novel target for AD. GABRA6 [65], GABRA1 [66], GABRG2 [67], SLC4A10 [68], HCN1 [69], GABRA4 [70], KCNC2 [71], SCN2A [72], SYN2 [73], FGF12 [74], SCN8A [75], OLFM3 [76], PLCB1 [77], KCNQ5 [78], TUBB2A [79], SIK1 [80], ABCC2 [81], SLC6A12 [82] and COL6A2 [83] have been reported to be closely related to the occurrence and development of epilepsy, but these genes might be novel target for AD. Previous investigation demonstrates that RGS4 [84] [92], NRN1 [93], SYT1 [94], GRIN2B [95], AVP (arginine vasopressin) [96], VSNL1 [97], HTR2A [98], PAK3 [99] [108], IGF1 [109], PLK2 [110], CBLN4 [111], CAP2 [112], SV2B [113], CAMK4 [114], INA (internexin neuronal intermediate filament protein alpha) [115] KIF5A [179] are associated with amyotrophic lateral sclerosis, but these genes might be novel target for AD.…”

“…Matsuzaki et al [55], Shepard et al [56], Lennertz et al [57], Klemettilä et al [58], Ullah et al [59], Kim et al [60], Sasayama et al [61], Li et al [62], Kowalczyk et al [63] and Sun et al [64] revealed that the expression of ADCYAP1, NPAS4, NPSR1, HTR2C, GABRB2, ALOX12B, ADRB3, EGR3, HSPA1A and IL3RA are associated with progression of schizophrenia, but these genes might be novel target for AD. GABRA6 [65], GABRA1 [66], GABRG2 [67], SLC4A10 [68], HCN1 [69], GABRA4 [70], KCNC2 [71], SCN2A [72], SYN2 [73], FGF12 [74], SCN8A [75], OLFM3 [76], PLCB1 [77], KCNQ5 [78], TUBB2A [79], SIK1 [80], ABCC2 [81], SLC6A12 [82] and COL6A2 [83] have been reported to be closely related to the occurrence and development of epilepsy, but these genes might be novel target for AD. Previous investigation demonstrates that RGS4 [84], CXCL11 [85], EGR1 [86], CALB1 [87], BDNF (brain derived neurotrophic factor) [88], TERT (telomerase reverse transcriptase) [89], NEFL (neurofilament light) [90], SNAP25 [91], RPH3A [92], NRN1 [93], SYT1 [94], GRIN2B [95], AVP (arginine vasopressin) [96], VSNL1 [97], HTR2A [98], PAK3 [99], STXBP5L [100], HCRTR2 [101], SYP (synaptophysin) [102], SYT10 [103], PRKCE (protein kinase C epsilon) [104], NRG1 [105], KISS1 [106], NRXN3 [107], RAB3A [108], IGF1 [109], PLK2 [110], CBLN4 [111], CAP2 [112], SV2B [113], CAMK4 [114], INA (internexin neuronal intermediate filament protein alpha) [115], GAP43 [116], TTR (transthyretin) [117], CXCR2 [118], IL1R2 [119], CXCR4 [120], CCR2 [121], MYOCD (myocardin) [122], S100A12 […”

“…Matsuzaki et al [54], Shepard et al [55], Lennertz et al [56], Klemettilä et al [57], Ullah et al [58], Kim et al [59], Sasayama et al [60], Li et al [61], Kowalczyk et al [62] and Sun et al [63] revealed that the expression of ADCYAP1, NPAS4, NPSR1, HTR2C, GABRB2, ALOX12B, ADRB3, EGR3, HSPA1A and IL3RA are associated with progression of schizophrenia, but these genes might be novel target for AD. GABRA6 [64], GABRA1 [65], GABRG2 [66], SLC4A10 [67], HCN1 [68], GABRA4 [69], KCNC2 [70], SCN2A [71], SYN2 [72], FGF12 [73], SCN8A [74], OLFM3 [75], PLCB1 [76], KCNQ5 [77], TUBB2A [78], SIK1 [79], ABCC2 [80], SLC6A12 [81] and COL6A2 [82] have been reported to be closely related to the occurrence and development of epilepsy, but these genes might be novel target for AD. Previous investigation demonstrates that RGS4 [83], CXCL11 [84], EGR1 [85], CALB1 [86], BDNF (brain derived neurotrophic factor) [87], TERT (telomerase reverse transcriptase) [88], NEFL (neurofilament light) [89], SNAP25 [90], RPH3A [91], NRN1 [92], SYT1 [93], GRIN2B [94], AVP (arginine vasopressin) [95], VSNL1 [96], HTR2A…”

Cryptic mutations of PLC family members in brain disorders: recent discoveries and a deep-learning-based approach

“…A change in the next base after the exon (c.99+1G>A) in early infantile epileptic encephalopathy 177 and (c.2930+1G>A) in patients with West syndrome has been identified. 178 Additionally, recent studies have shown several novel nonsense mutations associated with epileptic encephalopathy, including c.550C>T (p.Arg184*), 179 c.664C>T (p.Arg222*) 180 and c.1332T>A (p.Tyr444*) 178 within West syndrome.…”