Genotype-phenotype correlation in Italian children with Wilson's disease.
OBJECTIVE
Wilson's disease phenotype is very variable for clinical and laboratory features. Our aim was to assess the role of the type of ATP7B disease causing mutations on Wilson's disease phenotype.


METHODS
We retrospectively evaluated the data of children with Wilson's disease from eight pediatric departments.


RESULTS
Fifty-eight patients (34 male, median age at diagnosis 7.4 years) from 47 unrelated families were studied, carrying 34 different mutations. The most common mutations were the missense p.H1069Q and p.M769V, the nonsense p.R1319X, the frameshift c.2299delC, c.2298_2299insC and c.2530delA, and the splice site mutation c.2447+5G>A. Serum ceruloplasmin and copper were lower among the patients' homozygotes for nonsense and frameshift mutations than in patients with missense mutations. A normalization of serum alanine aminotransferase after therapy was not achieved in 23.6% of patients with missense mutations versus 45.5% of patients with nonsense/frameshift mutations. A direct linear correlation was found between age at diagnosis and urinary copper excretion at diagnosis.


CONCLUSIONS
The type of mutation explains at least a part of Wilson's disease phenotype, and mutation analysis should be considered as an integrative tool for such a challenging diagnosis. Urinary copper excretion appears to be correlated to the age at diagnosis rather than genotype.
Nicastro
Emanuele
E
Department of Pediatrics, University of Naples Federico II, Naples, Italy.
Loudianos
Georgios
G
Zancan
Lucia
L
D'Antiga
Lorenzo
L
Maggiore
Giuseppe
G
Marcellini
Matilde
M
Barbera
Cristiana
C
Marazzi
Maria Grazia
MG
Francavilla
Ruggiero
R
Pastore
Maria
M
Vajro
Pietro
P
D'Ambrosi
Mariangela
M
Vegnente
Angela
A
Ranucci
Giusy
G
Iorio
Raffaele
R
D019943:Amino Acid Substitution; D002570:Ceruloplasmin / Q000235:genetics; D002648:Child; D018389:Codon, Nonsense; D003300:Copper / Q000097:blood / Q000652:urine; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006527:Hepatolenticular Degeneration / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007558:Italy; D008111:Liver Function Tests; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D012189:Retrospective Studies; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics
D018389:Codon, Nonsense; D003300:Copper; D004247:DNA; D002570:Ceruloplasmin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human