PLCB1 – PLCB1-related Developmental and Epileptic Encephalopathy

PLCB1 encodes phospholipase C beta-1, a key enzyme in phosphoinositide signaling highly expressed in cortical and hippocampal neurons. Biallelic loss-of-function variants in PLCB1 have been linked to a severe infantile developmental and epileptic encephalopathy characterized by refractory seizures and profound global neurodevelopmental impairment.

Genetic evidence supports an autosomal recessive inheritance pattern. To date, seven unrelated probands across four families have been reported, including three newly described patients and four from earlier studies ([PMID:31883110]). Segregation analysis in one pedigree demonstrated co-segregation of homozygous variants in two affected cousins, providing additional confirmatory evidence ([PMID:31883110]).

The variant spectrum comprises predicted loss-of-function alleles: an intragenic homozygous deletion in one patient and a recurrent homozygous nonsense change, c.664C>T (p.Arg222Ter), in two cousins ([PMID:31883110]). No missense or hypomorphic alleles have been described to date.

Clinically, affected infants present at 3–5 months with infantile spasms and other seizure types, evolving into drug-resistant epilepsy. Profound intellectual disability is universal (6/7 unable to walk), and axial hypotonia is the most frequent neurological sign (HP:0008936), often accompanied by pyramidal or extrapyramidal hypertonia of the limbs. Microcephaly occurs variably.

Functional studies specific to PLCB1 in neural models are lacking. Targeted resequencing in malignant migrating partial seizures of infancy failed to identify pathogenic PLCB1 variants ([PMID:24315024]), and generic PLC beta isoform assays in vascular smooth muscle have characterized G-protein regulation but do not recapitulate neural phenotypes ([PMID:8799575]).

Together, the aggregation of seven probands with biallelic loss-of-function variants, segregation in affected relatives, and a consistent infantile epileptic encephalopathy phenotype warrants a Strong gene-disease association classification. Further disease-specific functional modeling is required. Key take-home: PLCB1 biallelic loss-of-function variants cause a distinctive autosomal recessive infantile epileptic encephalopathy with early onset, refractory seizures, and profound global developmental impairment.

References

• Clinical Genetics • 2020 • Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene. PMID:31883110
• Epilepsy Research • 2014 • Lack of pathogenic mutations in six patients with MMPSI. PMID:24315024
• British Journal of Pharmacology • 1996 • Phospholipase C isoforms in vascular smooth muscle and their regulation by G-proteins. PMID:8799575

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