neonatal-onset encephalopathy with rigidity and seizures and neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures

[galyea123]

Hi! I wanted to notice that both of these conditions are caused by mutations in the BRAT1 gene (there are some publications about BRAT1 related disorders and Orphanet links both OMIM entries in their page).

"Biallelic BRAT1 variants were first described by Puffenberger et al. in 2012, after sequencing the exome of two individuals from an endogamous population of Amish origin in Pennsylvania. These individuals had a combination of severe drug-resistant epilepsy, limb rigidity, brain injury, and early death [5]. In 2015, Hanes et al. reported a patient with compound heterozygous BRAT1 variants and a less severe clinical phenotype characterized by global developmental delay and cerebellar atrophy [6]. Biallelic BRAT1 variants have therefore been associated with two distinct clinical pictures: BRAT1-related rigidity and multifocal seizure syndrome (RMFSL; MIM 614498) and BRAT1-related neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS; MIM 618056). A correlation between the severity of the disorder and the type of BRAT1 mutations has been suggested, with biallelic truncating variants appearing to be associated with the more severe phenotype" Source: https://www.nature.com/articles/s41431-023-01410-z

I think it will be useful to make clear the relation among these conditions.

Thank you! Gioconda

[nicolevasilevsky]

Hi @galyea123 both of these terms have the subclass axiom that states there are germline mutations in the BRAT1 gene. Is there another specific action you would like us to take to demonstrate the relationship between these two disease entities?

Thanks!

[galyea123]

Hi Nicole! I apologize for not being clear here.
Because we had an inquiry and the possibility of having a NORD report for "BRAT1-related disorders" I was thinking if we could mention in the respective definitions that both are related to biallelic BRAT1 gene mutations. In the MONDO page (MONDO:0020841)for the Neurodevelopmental disorder with cerebellar atrophy and with or without seizures there is no definition yet but it is linked to OMIM 618056. In the OMIM page they have the definition for the disease and they mention that "Biallelic mutations in the BRAT1 gene can also cause lethal neonatal rigidity and multifocal seizure syndrome (RMFSL; 614498), a more severe disorder with overlapping features."
The definition for lethal neonatal rigidity and multifocal seizure syndrome in MONDO (MONDO:0013784) comes from Orphanet but it is also linked to OMIM. I suggest adding in this page that: "Biallelic mutations in the BRAT1 gene can also cause neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS; 618056), a somewhat less severe disorder with overlapping features."

Anyhow, thank you for letting me know about the subclass axiom (this may be enough if the definition clarification is not possible).

Thank you! Gioconda