Dados do Trabalho

Título

DRUG-RESISTANT SEIZURES IN A TEENAGER WITH A VARIANT OF UNCERTAIN SIGNIFICANCE IN PCDH19

Apresentação do caso

The case reported is about a 15 years old girl who presents drug-resistant epilepsy (currently
using four different antiepileptic drugs), besides Intellectual disability. Her parent reported her
first seizure at 6 months of age, during sleep, afebrile, with ocular version and behavioural
arrest. Another four episodes occurred that day (some evolving to tonic postures). After a brief
hospitalisation, she was discharged with multiple antiepileptic drugs. No relevant perinatal
history was found. After a new increased frequency of seizures, she was hospitalised again.
Magnetic resonance imaging showed no abnormalities and initial screening for inborn errors of
metabolism was normal. Electroencephalogram registered paroxysmal discharges consisting of
diffuse sharps and waves. The patient’s evolution was unfunded, presenting different types of
seizures (some of them starting with screaming), sometimes sustaining four months with no
seizures, sometimes presenting thirty seizures on the same day. Antiepileptic drugs
combinations (sodium valproate, carbamazepine, phenobarbital, phenytoin, vigabatrin and
lamotrigine) were readjusted multiple times during follow up and benzodiazepines were added
both for synergism and for emergency uses. She was two and a half years old at her first
evaluation with a neurologist: significant speech impairment was recorded, despite normal
gross motor development. Intellectual disability is present. The Epilepsy and Ataxia Genetic
Panel’s report describes a variant of uncertain significance (VUS), c.365A>G: p.(Leu122Pro), in
heterozygosity in the PCDH19 gene.

Discussão

The PCDH19 gene is located on Xq22 but despite being positioned as a X-linked mode of
inheritance, the pedigree exhibits a peculiar pattern: affected females were connected
through unaffected male relatives. This gene encodes the protein protocadherin-19 and is
constituted by six exons. Pathogenic variants (in heterozygosity) were associated with early
onset epilepsy (before three years of age), in clusters, typically induced by fever, often drug-
resistant and also with a significant risk of intellectual disability and autism spectrum disorder.

Comentários finais

The variant of uncertain significance found in this patient genetic panel is absent in about 62
thousand individuals of the population bank and was not previously described in literature.
Pathogenic variants were described in neighbour codons of the reported VUS.

Referências (se houver)

Hynes K, Tarpey P, Dibbens LM, Bayly MA, Berkovic SF, Smith R, Raisi ZA, Turner SJ, Brown NJ, Desai TD, Haan E, Turner G, Christodoulou J, Leonard H, Gill D, Stratton MR, Gecz J, Scheffer IE. Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families. J Med Genet. 2010 Mar;47(3):211-6. doi: 10.1136/jmg.2009.068817. Epub 2009 Sep 14. PMID: 19752159.
Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, Bomar J, Sutton E, Vandeleur L, Shoubridge C, Edkins S, Turner SJ, Stevens C, O'Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Jones D, Lee R, Madison M, Mironenko T, Varian J, West S, Widaa S, Wray P, Teague J, Dicks E, Butler A, Menzies A, Jenkinson A, Shepherd R, Gusella JF, Afawi Z, Mazarib A, Neufeld MY, Kivity S, Lev D, Lerman-Sagie T, Korczyn AD, Derry CP, Sutherland GR, Friend K, Shaw M, Corbett M, Kim HG, Geschwind DH, Thomas P, Haan E, Ryan S, McKee S, Berkovic SF, Futreal PA, Stratton MR, Mulley JC, Gécz J. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008 Jun;40(6):776-81. doi: 10.1038/ng.149. Epub 2008 May 11. PMID: 18469813; PMCID: PMC2756413.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. PMID: 25741868; PMCID: PMC4544753.
Zuberi SM, Wirrell E, Yozawitz E, Wilmshurst JM, Specchio N, Riney K, Pressler R, Auvin S, Samia P, Hirsch E, Galicchio S, Triki C, Snead OC, Wiebe S, Cross JH, Tinuper P, Scheffer IE, Perucca E, Moshé SL, Nabbout R. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022 Jun;63(6):1349-1397. doi: 10.1111/epi.17239. Epub 2022 May 3. PMID: 35503712.

Declaração de conflito de interesses de TODOS os autores

No conflit of interest is declared