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.


CONCLUSIONS
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.
Ju
Weina
W
SCL-Molecular Neurogenetic Diagnostic Laboratory, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Wronska
Anetta
A
Moroziewicz
Dorota N
DN
Zhong
Rocksheng
R
Wisniewski
Natalia
N
Jurkiewicz
Anna
A
Fiory
Michael
M
Wisniewski
Krystyna E
KE
Johnston
Lance
L
Brown
W Ted
WT
Zhong
Nanbert
N
D017668:Age of Onset; D000626:Aminopeptidases / Q000235:genetics; D003594:Cytoplasmic Granules; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D057057:Serine Proteases / Q000235:genetics; D013869:Thiolester Hydrolases; D000091346:Tripeptidyl-Peptidase 1
C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D000091346:Tripeptidyl-Peptidase 1; D013869:Thiolester Hydrolases; C416054:PPT1 protein, human; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human