Neurological symptoms, genotype-phenotype correlations and ethnic-specific differences in Bulgarian patients with Wilson disease.
OBJECTIVE
The aim of our study was to characterize the neurological symptoms in Bulgarian patients with Wilson disease (WD), to investigate genotype-phenotype correlations, and to test whether there are differences in phenotype between patients of different ethnic origin.


METHODS
A total of 126 Bulgarian patients with WD were included in the study. Detailed history, physical and neurological examination, laboratory investigation of copper metabolism, slit-lamp examination, abdominal ultrasound, magnetic resonance imaging/computed tomography of the brain, molecular genetic testing, and statistical analysis were performed.


RESULTS
Eighty-two patients demonstrated neurological signs. Tremor and dysarthria were most frequently observed. Rigidity, bradykinesia, and pyramidal signs were found in >25% of the patients. Dystonia, chorea, athetosis, ballismus, and epilepsy were rarely observed. We identified a total of 27 mutations of ATP7B. The most frequent mutation is p.H1069Q found on at least 1 allele in 78% of the patients. We did not find a significant correlation between p.H1069Q homozygosity and age of onset, ceruloplasmin level, and urinary copper excretion. The patients homozygous for p.H1069Q presented more frequently with hepatic signs. Mutations predicted to cause production of truncated protein are associated with earlier age at onset and lower ceruloplasmin level. In contrast to Bulgarian patients, Roma patients had an earlier disease onset and more frequent hepatic manifestation.


CONCLUSIONS
WD presents with a variety of neurological signs. The mutation p.H1069Q is not uniformly associated with late onset and neurological presentation. Frameshift and nonsense mutations lead to severe phenotype. There are ethnic-specific differences in disease manifestation.
Department of Neurology, University Hospital Alexandrovska, Bulgaria. violetamihaylova@yahoo.com
Violeta
V
Mihaylova
Teodor
T
Todorov
Hristo
H
Jelev
Iskren
I
Kotsev
Ludmila
L
Angelova
Olga
O
Kosseva
Georgi
G
Georgiev
Ralica
R
Ganeva
Silvia
S
Cherninkova
Ludmila
L
Tankova
Aleksei
A
Savov
Ivailo
I
Tournev
D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D002031:Bulgaria / Q000208:ethnology; D027682:Cation Transport Proteins / Q000235:genetics; D002648:Child; D000073840:Copper-Transporting ATPases; D005260:Female; D056726:Genetic Association Studies; D006527:Hepatolenticular Degeneration / Q000208:ethnology* / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases