gms | German Medical Science

Introduction: NCL are severe inherited neurodegenerative diseases that occur in all ages. They manifest as refractory epileptic syndrome with progressive intractable seizures, visual failure, dementia, movement disorders, and early death. Mutations in 7/13 genes have been found in 9 pediatric patients admitted to the Translational Research Program of NCL in Argentina. Progressive neurodegeneration is a hallmark; it is associated with deposits of ceroid lipofuscin-like materials in the brain, which act by stimulating a cellular apoptotic cascade that leads to neuronal depletion. The correlation of the lipofuscin-like bodies (cytotypes) with the genotype was historically considered pathognomonic for 3 classical NCL diseases: Infantile (CLN1), Granular osmiophylic deposits (GROD); late infantile (CLN2), curvilinear bodies (CL); Juvenile (CLN3), fingerprint profiles (FP). Other cytotypes were also described, like rectilinear bodies (RL). Diseases CLN5, CLN6, CLN7, and CLN8 lacked definition of cytotype/genotype correlations in Argentinean patients.

Objective: To correlate the cytotypes/genotypes in CLN5, CLN6, CLN7 and CLN8 diseases in precise genetic defined subjects of Argentina.

Patients and Methods: In 9 patients suffering from the diseases CLN5, CLN6, CLN7 and CLN8 a study algorithm for NCL was applied including, clinical evaluation with complementary studies, PPT1/CLN1 -TPP1/CLN2 -enzyme activity tests, TEM and mutation screening.

Results: Enzyme activity tests ruled out diseases CLN1 and CLN2; lacking vacuolated lymphocytes ruled out CLN3. TEM lead to the suspicion of other NCL diseases through the observation of lipofuscin-like bodies and oriented the mutation screening. New phenotype/genotype correlations were established (Table 1 [Tab. 1]).

Conclusion: The use of TEM as a diagnostic tool is revalued in the context of a NCL translational study program. TEM analysis of a skin biopsy is recommended as a biomarker to guide decision-making for screening of mutations in patients with late infantile, juvenile or congenital phenotype through NCL gene containing-panels, once the enzyme deficiencies and vacuolated lymphocytes were ruled out. This may shorten the diagnostic time and reduce costs with respect to the gene by gene PCR and Sanger sequencing techniques used in the past, and whole exome sequencing (WES) without previous TEM.