title: Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis.
abstract: 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 (<1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes.
authors: Laboratory of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Via D. L. Monza 20, Bosisio Parini, 23842, Lecco, Italy.
authors: Andrea
authors: A
authors: Citterio
authors: Alessia
authors: A
authors: Arnoldi
authors: Elena
authors: E
authors: Panzeri
authors: Maria Grazia
authors: MG
authors: D'Angelo
authors: Massimiliano
authors: M
authors: Filosto
authors: Robertino
authors: R
authors: Dilena
authors: Filippo
authors: F
authors: Arrigoni
authors: Marianna
authors: M
authors: Castelli
authors: Cristina
authors: C
authors: Maghini
authors: Chiara
authors: C
authors: Germiniasi
authors: Francesca
authors: F
authors: Menni
authors: Andrea
authors: A
authors: Martinuzzi
authors: Nereo
authors: N
authors: Bresolin
authors: Maria Teresa
authors: MT
authors: Bassi
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005962:Glucosylceramidase; D006801:Humans; D007223:Infant; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010740:Phospholipases / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D014481:United States; D055815:Young Adult; D001617:beta-Glucosidase / Q000235:genetics*
chemical_list: D003577:Cytochrome P-450 Enzyme System; C484320:CYP2U1 protein, human; D000072467:Cytochrome P450 Family 2; D010740:Phospholipases; C541017:DDHD2 protein, human; D001617:beta-Glucosidase; C517537:GBA2 protein, human; D005962:Glucosylceramidase