Genotype-phenotype analyses of classic neuronal ceroid lipofuscinosis (NCLs): genetic predictions from clinical and pathological findings.

Objective: Genotype-phenotype associations were studied in 517 subjects clinically affected by classical neuronal ceroid lipofuscinosis (NCL).

Methods: Genetic loci CLN1-3 were analyzed in regard to age of onset, initial neurological symptoms, and electron microscope (EM) profiles.

Results: The most common initial symptom leading to a clinical evaluation was developmental delay (30%) in NCL1, seizures (42.4%) in NCL2, and vision problems (53.5%) in NCL3. Eighty-two percent of NCL1 cases had granular osmiophilic deposits (GRODs) or mixed-GROD-containing EM profiles; 94% of NCL2 cases had curvilinear (CV) or mixed-CV-containing profiles; and 91% of NCL3 had fingerprint (FP) or mixed-FP-containing profiles. The mixed-type EM profile was found in approximately one-third of the NCL cases. DNA mutations within a specific CLN gene were further correlated with NCL phenotypes. Seizures were noticed to associate with common mutations 523G>A and 636C>T of CLN2 in NCL2 but not with common mutations 223G>A and 451C>T of CLN1 in NCL1. Vision loss was the initial symptom in all types of mutations in NCL3. Surprisingly, our data showed that the age of onset was atypical in 51.3% of NCL1 (infantile form) cases, 19.7% of NCL2 (late-infantile form) cases, and 42.8% of NCL3 (juvenile form) cases.

Conclusion: Our data provide an overall picture regarding the clinical recognition of classical childhood NCLs. This may assist in the prediction and genetic identification of NCL1-3 via their characteristic clinical features.