神经元蜡样质脂褐质沉积病(NCL)的基因型与表型相关性研究(英文)

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.

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 osmiophilie deposits （GRODs） or mixed-GROD-containing EM profiles; 94% of NCI2 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 in51.3% 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 NCLI-3 via their characteristic clinical features.