Dados do Trabalho

Título

EARLY-ONSET EPILEPTIC ENCEPHALOPATHY ASSOCIATED WITH PPP3CA GENE MUTATION: A POSSIBLE NOVEL PATHOGENIC VARIANT WITH AN ATYPICAL PHENOTYPE

Apresentação do caso único

The boy of unrelated parents, with no family history of neurological disorders, was born at 41 week gestational age without complications. Hypotonia and poor interaction were noticed early. At 6 months, he developed epileptic spasms and EEG showed hypsarrhythmia (West Syndrome). His global developmental delay (GDD) had worsen progressively and started choreoathetosis and dystonias. Vigabatrin was initiated and then high dose of prednisolone with poor control and no EEG change. ACTH was performed, with good seizure control and EEG response. Evolved polymorphic seizures types: tonic, myoclonic seizures, and abnormal eye movements with autonomic features. Daily seizures persisted and EEG reveals a multifocal epileptic encephalopathy pattern. He underwent different trials of anti-seizures medication (ASM). Haloperidol, biperiden and clonazepam were used to improve the movement disorders without success. Brain MRI showed diffuse atrophy without spectroscopy abnormalities. Metabolic, ocular and auditory evaluations were unremarkable. Whole exome sequencing showed a heterozygous change in PPP3CA gene related to epileptic encephalopathy and developmental type 91. At 2 years-old, he is on many ASM, presenting with repeated involuntary movements and profound GDD.

Discussão

The protein encoded by the PPP3CA gene located on chromosome 4 (4q24), is related to intracellular regulation of endocytosis and synaptic vesicle transmission. Depending on type of mutation (gain or loss of function), different phenotypes are observed. The gain of function is related of intellectual disability and malformations and the loss of function, early-onset epileptic encephalopathy. The mutation described in our patient has not been reported yet. This allele has an extremely low frequency in population data, with a high rate of pathogenic missense variants, in addition to reports that other variants involving the same codon but with different amino acid changes cause pathogenicity, configuring our patient’s mutation as probably pathogenic until now.

Comentários finais

PPP3CA gene mutation is a rare recognized disorder. The typical reported presentation of patients with loss of function mutation type is developmental and epileptic encephalopathy. There is no report of a marked and early movement disorder symptoms in these patients, been this case an atypical presentation. Otherwise, this could be a feature related to this new possible pathogenic variant never described before.

Referências

Li J, Cao J. Case report: A novel PPP3CA truncating mutation within the regulatory domain causes severe developmental and epileptic encephalopathy in a Chinese patient. Front Neurol. 2022 Sep 7;13:889167. doi: 10.3389/fneur.2022.889167

Panneerselvam S, Wang J, Zhu W, et al. PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy. Clin Genet. 2021 Aug;100(2):227-233. doi: 10.1111/cge.13979

Yang S, Shen X, Kang Q, et al. Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report. BMC Pediatr. 2020 Jun 27;20(1):315. doi: 10.1186/s12887-020-02213-7

Myers CT, Stong N, Mountier EI, et al. De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures. Am J Hum Genet. 2017 Oct 5;101(4):516-524. doi: 10.1016/j.ajhg.2017.08.013.

Palavras Chave

PPP3CA gene; Developmental and epileptic encephalopathy; movement disorders