THE CLN7 / MFSD8 GENOTYPIC AND PHENOTYPIC SPECTRUM IN THE CORDOBA COHORT OF NEURONAL CEROID LIPOFUSCINOSES (NCL)

VENIER, ANA CLARA; CISMONDI, INÉS ADRIANA; GUELBERT, GUILLERMO; PESAOLA, FAVIO; BECERRA, ADRIANA; DE PAUL, ANA LUCÍA; VAZQUEZ, JUAN CARLOS G.; FERNANDEZ, ELMER; GUELBERT, NORBERTO; NOHER, INÉS

St. Louis

Congreso; The 17th International Congress on Neuronal Ceroid Lipofuscinosis (NCL 2021); 2021

MFSD8/CLN7 is located on chromosome 4q28.2 having 13 exons, and a continuously growing number of pathological, likely pathological and benign DNA variants recorded in international data bases. The disease was first described in a Turkish consanguineous family, and later one the geographical distribution was expanded. Pathogenic DNA variants probably cause alterations in protein function rather than structural alterations. CLN7p is a lysosomal membrane transporter with suggested topology of 12 transmembrane domains. It belongs to the major facilitator superfamily (MFS) domain-containing proteins, single-polypeptide carriers that are able to transport small solutes by using chemiosmotic gradients. However, the specific molecules that MFSD8 transports across the lysosomal membrane have not been identified. Recent studies performed in Mfsd8-knockout mice demonstrated that MFSD8-deficient cells presented enlarged lysosomes, impaired outward movement, and decreased lysosomal exocytosis that would be related to activity of mTOR. Furthermore, MFSD8 was associated to decrease lysosomal proteins Cln5, Ppt1 and Ctsd, which cause other NCL diseases. AIM: observational retrospective study of CLN7/MFSD8 disease (OMIM #610951) in the Cordoba cohort, adding knowledge to the phenotypic/ genotypic spectra in Latin America. SUBJECTS: clinically compatible individuals and their parents (as possible) with TPP1 activity in control?s interval under informed consent. METHODS: clinical, enzymatic, morphological, and genotypic (NGS and PCR+Sanger sequencing) assessment. RESULTS AND DISCUSSION: Four children with compatible clinical phenotypes were diagnosed with CLN7/MFSD8 disease through genetic assessment, after excluding enzymatically the CLN2 disease. The 2 boys and 2 girls belong to non-consanguineous families of Argentina and Paraguay. It is possible that one Argentinean and one Paraguayan child are related without knowing because they share the same last name as well as one of the DNA variants. One girl and one boy were homozygous for the E3 c.103C>T, pArg35*nonsense pathogenic variant, which is the prevalent in the cohort. One boy had the same variant in heterozygosity with the likely pathogenic splice site variant I9 c.863+1G