2011.06.03
Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia
（Brain. 2011 May;134(Pt 5):1387-99. doi: 10.1093/brain/awr069. Epub 2011 Apr 12.）
Yokoseki A1, Ishihara T1, Koyama A1, Shiga A1, Yamada M2, Suzuki C3, Sekijima Y4, Maruta K5, Tsuchiya M6, Date H7, Sato T1, Tada M1, Ikeuchi T6, Tsuji S7, Nishizawa M1, Onodera O6.
1Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University
2Department of Clinical Research, National Hospital Organization, Saigata National Hospital
3Department of Neurology, Aomori Prefectual Chuo Hospital
4Department of Neurology and Rheumatology, Division of Clinical and Molecular Genetics, Shinshu University Hospital
5Department of Neurology, National Hospital Organization, Minamikyushu Hospital
6Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Centre for Bioresource-based Research, Brain Research Institute, Niigata University
7Department of Neurology, Graduate School of Medicine, The University of Tokyo
Abstract
Early onset ataxia with ocular motor apraxia and hypoalbuminaemia/ataxia-oculomotor apraxia 1 is a recessively inherited ataxia caused by mutations in the aprataxin gene. We previously reported that patients with frameshift mutations exhibit a more severe phenotype than those with missense mutations. However, reports on genotype-phenotype correlation in early onset ataxia with ocular motor apraxia and hypoalbuminaemia are controversial. To clarify this issue, we studied 58 patients from 39 Japanese families, including 40 patients homozygous for c.689_690insT and nine patients homozygous or compound heterozygous for p.Pro206Leu or p.Val263Gly mutations who were compared with regard to clinical phenotype. We performed Kaplan-Meier analysis and log-rank tests for the ages of onset of gait disturbance and the inability to walk without assistance. The cumulative rate of gait disturbance was lower among patients with p.Pro206Leu or p.Val263Gly mutations than among those homozygous for the c.689_690insT mutation (P=0.001). The cumulative rate of inability to walk without assistance was higher in patients homozygous for the c.689_690insT mutation than in those with p.Pro206Leu or p.Val263Gly mutations (P=0.004). Using a Cox proportional hazards model, we found that the homozygous c.689_690insT mutation was associated with an increased risk for onset of gait disturbance (adjusted hazard ratio: 6.60) and for the inability to walk without assistance (adjusted hazard ratio: 2.99). All patients homozygous for the c.689_690insT mutation presented ocular motor apraxia at <15 years of age. Approximately half the patients homozygous for the c.689_690insT mutation developed cognitive impairment. In contrast, in the patients with p.Pro206Leu or p.Val263Gly mutations, only ∼50% of the patients exhibited ocular motor apraxia and they never developed cognitive impairment. The stepwise multivariate regression analysis using sex, age and the number of c.689_690insT alleles as independent variables revealed that the number of c.689_690insT alleles was independently and negatively correlated with median motor nerve conduction velocities, ulnar motor nerve conduction velocities and values of serum albumin. In the patient with c.[689_690insT]+[840delT], p.[Pro206Leu]+[Pro206Leu] and p.[Pro206Leu]+[Val263Gly] mutations, aprataxin proteins were not detected by an antibody to the N-terminus of aprataxin. Furthermore Pro206Leu and Val263Gly aprataxin proteins are unstable. However, the amount of the 689_690insT aprataxin messenger RNA was also decreased, resulting in more dramatic reduction in the amount of aprataxin protein from the c.689_690insT allele. In conclusion, patients with early onset ataxia with ocular motor apraxia and hypoalbuminaemia homozygous for the c.689_690insT mutation show a more severe phenotype than those with a p.Pro206Leu or p.Val263Gly mutation.
