Early DNA screening by wes diminishes the diagnostic delay of CLN6-disease in Argentina

PESAOLA FAVIO; CISMONDI INÉS ADRIANA; BECERRA ADRIANA; LEYES CLAUDIA; VENIER ANA CLARA; GUELBERT NORBERTO; NOHER INES

Congreso; SSIEM 2018; 2018

CLN6-disease is a Neuronal Ceroid Lipofuscinosis (NCL) type appearing at late infantile/adult ages whose etiological diagnosis may suffer delay. Three Argentinean individuals were recognized and the time lapse to diagnosis evaluated. METHODS: phenotypic and genotypic study of 3 individuals; 2/3 were genotyped through gene by gene PCR and Sanger sequencing, and 1/3 through WES. RESULTS: onset 2-3.3y with motor function decline, frequent falls 2-4.5y, assisted walking 4.4-6.11y, total prostration 5.11-9.6y. Language failure 3.3-4y, speech difficulties 4.4-4.5y, speech loss 5.11-9.6y. Visual loss 3-7y and blindness (only reported in 1/3 cases) 5y. Refractory seizures with generalized atonic myoclonic movements and lateralization of the trunk 3-5.9y. Death 1/3 15y, 1/3 >18, and 1/3 living with 10.3y. Electron microscopy in skin biopsy: 2/3, ceroid lipofuscin-like bodies of dense structure, with fingerprint profiles combined with curvilinear bodies, and 1/3 curvilinear bodies. Gene CLN6 variants and time lapse from onset of symptoms to etiological diagnosis were evaluated. Case1: PCR+Sanger: E4c.486 + 8C> T/ E7 c.755G>A, time to diagnosis: 21.3y. Case 2: PCR+Sanger: E4c.307 C> T/ E6 c.556dupC, time to diagnosis: 8y. Case 3: WES: E4c.461_463delTCA/ E3 c.250T>A, time to diagnosis 6.8y. DISCUSSION: The set of symptoms in CLN6-disease was characterized in 3 cases of Argentina with late infantile onset. Identified were 5 DNA pathological variants and 1 probably pathological in the CLN6 gene in heterozygous combinations. The time lapse to etiological diagnosis diminished ~75% integrating WES and clinical hallmarks. The methodology of systematical establishment of phenotypic/genotypic hallmarks for rare neurological disease meets increasingly the current needs to abbreviate the diagnostic time lapse.