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Variants associated with Gaucher disease in multiple system atrophy.

Mitsui J, Matsukawa T, Sasaki H, Yabe I, Matsushima M, Dürr A, Brice A, Takashima H, Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H, Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara Y, Momose Y, Takahashi Y, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Watanabe H, Ito M, Sobue G, Ishikawa K, Mizusawa H, Kanai K, Hattori T, Kuwabara S, Arai K, Koyano S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y, Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M, Kondo T, Murayama S, Hattori N, Yamamoto M, Murata M, Satake W, Toda T, Filla A, Klockgether T, Wüllner U, Nicholson G, Gilman S, Tanner CM, Kukull WA, Stern MB, Lee VM, Trojanowski JQ, Masliah E, Low PA, Sandroni P, Ozelius LJ, Foroud T, Tsuji S - Ann Clin Transl Neurol (2015)

Bottom Line: Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022.Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo Tokyo, Japan.

ABSTRACT

Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series.

Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.

Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).

Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

No MeSH data available.


Related in: MedlinePlus

Identification of Gaucher-disease-causing GBA variants in a multiplex family with MSA. The diagnosis of definite MSA in III-6 in Family 8 was confirmed by autopsy findings. Squares represent men; circles, women; black symbols, individuals with MSA; gray symbols, individuals with PD; open symbols, unaffected individuals; dots, genomic DNAs available. GBA, Glucocerebrosidase; MSA-P, multiple system atrophy with predominant parkinsonism; PD, Parkinson disease; NM, nonmutated allele.
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fig03: Identification of Gaucher-disease-causing GBA variants in a multiplex family with MSA. The diagnosis of definite MSA in III-6 in Family 8 was confirmed by autopsy findings. Squares represent men; circles, women; black symbols, individuals with MSA; gray symbols, individuals with PD; open symbols, unaffected individuals; dots, genomic DNAs available. GBA, Glucocerebrosidase; MSA-P, multiple system atrophy with predominant parkinsonism; PD, Parkinson disease; NM, nonmutated allele.

Mentions: Independent of the above analyses, we additionally analyzed affected members in six multiplex families with MSA reported previously.8 Of the six multiplex MSA families, we found that three of the four patients with MSA in Family 8 had GD variants, whereas we did not observe GD variants in other families. In Family 8, three patients with MSA-P (III-2, III-4, and III-6) including one (III-6) with autopsy-proven MSA (definite MSA) had the same heterozygous GD variant (L444R) (Fig.3), whereas the other patient with MSA-C (IV-1) did not carry the variant. In addition, one unaffected sibling (III-5) carried the variant, whereas the other unaffected sibling (III-1) did not carry the variant. Thus, although cosegregation of the GD variant with MSA was not complete in this family, the observation may also support some association of GD variants with MSA.


Variants associated with Gaucher disease in multiple system atrophy.

Mitsui J, Matsukawa T, Sasaki H, Yabe I, Matsushima M, Dürr A, Brice A, Takashima H, Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H, Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara Y, Momose Y, Takahashi Y, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Watanabe H, Ito M, Sobue G, Ishikawa K, Mizusawa H, Kanai K, Hattori T, Kuwabara S, Arai K, Koyano S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y, Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M, Kondo T, Murayama S, Hattori N, Yamamoto M, Murata M, Satake W, Toda T, Filla A, Klockgether T, Wüllner U, Nicholson G, Gilman S, Tanner CM, Kukull WA, Stern MB, Lee VM, Trojanowski JQ, Masliah E, Low PA, Sandroni P, Ozelius LJ, Foroud T, Tsuji S - Ann Clin Transl Neurol (2015)

Identification of Gaucher-disease-causing GBA variants in a multiplex family with MSA. The diagnosis of definite MSA in III-6 in Family 8 was confirmed by autopsy findings. Squares represent men; circles, women; black symbols, individuals with MSA; gray symbols, individuals with PD; open symbols, unaffected individuals; dots, genomic DNAs available. GBA, Glucocerebrosidase; MSA-P, multiple system atrophy with predominant parkinsonism; PD, Parkinson disease; NM, nonmutated allele.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402086&req=5

fig03: Identification of Gaucher-disease-causing GBA variants in a multiplex family with MSA. The diagnosis of definite MSA in III-6 in Family 8 was confirmed by autopsy findings. Squares represent men; circles, women; black symbols, individuals with MSA; gray symbols, individuals with PD; open symbols, unaffected individuals; dots, genomic DNAs available. GBA, Glucocerebrosidase; MSA-P, multiple system atrophy with predominant parkinsonism; PD, Parkinson disease; NM, nonmutated allele.
Mentions: Independent of the above analyses, we additionally analyzed affected members in six multiplex families with MSA reported previously.8 Of the six multiplex MSA families, we found that three of the four patients with MSA in Family 8 had GD variants, whereas we did not observe GD variants in other families. In Family 8, three patients with MSA-P (III-2, III-4, and III-6) including one (III-6) with autopsy-proven MSA (definite MSA) had the same heterozygous GD variant (L444R) (Fig.3), whereas the other patient with MSA-C (IV-1) did not carry the variant. In addition, one unaffected sibling (III-5) carried the variant, whereas the other unaffected sibling (III-1) did not carry the variant. Thus, although cosegregation of the GD variant with MSA was not complete in this family, the observation may also support some association of GD variants with MSA.

Bottom Line: Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022.Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo Tokyo, Japan.

ABSTRACT

Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series.

Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.

Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).

Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

No MeSH data available.


Related in: MedlinePlus