TY - JOUR
T1 - Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis
AU - Citterio, Andrea
AU - Arnoldi, Alessia
AU - Panzeri, Elena
AU - D'Angelo, Maria Grazia
AU - Filosto, Massimiliano
AU - Dilena, Robertino
AU - Arrigoni, Filippo
AU - Castelli, Marianna
AU - Maghini, Cristina
AU - Germiniasi, Chiara
AU - Menni, Francesca
AU - Martinuzzi, Andrea
AU - Bresolin, Nereo
AU - Bassi, Maria Teresa
PY - 2014
Y1 - 2014
N2 - Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/ p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (
AB - Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/ p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (
KW - Amplicon-based targeted resequencing
KW - CYP2U1
KW - DDHD2
KW - GBA2
KW - Spastic paraparesis
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U2 - 10.1007/s00415-013-7206-6
DO - 10.1007/s00415-013-7206-6
M3 - Article
C2 - 24337409
AN - SCOPUS:84899067023
VL - 261
SP - 373
EP - 381
JO - Journal of Neurology
JF - Journal of Neurology
SN - 0340-5354
IS - 2
ER -