Novel mutations of the SPG11 gene in hereditary spastic paraplegia with thin corpus callosum.

Background: Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a clinically and genetically heterogeneous neurodegenerative disorder with genetic linkage to multi-loci. Recently pathogenic mutations in the KIAA1840 (now named SPG11) for SPG11, the major HSP-TCC locus, were identified; at least 42 different mutations have been detected.

Objective: To study the clinical features and identify the SPG11 gene mutations in Chinese patients with HSP-TCC.

Methods: Three kindreds with an autosomal recessive HSP-TCC and 5 cases with sporadic HSP-TCC in Chinese Hans were recruited. Detailed clinical history, neurological examination, MRI, electromyography, Mini Mental State Examination (MMSE), Spastic Paraplegia Rating Scale (SPRS) were presented. DNA samples of the 8 families were collected and mutation analysis of SPG11 gene was carried out by direct DNA sequencing.

Results: Except for one patient whose age at onset was 3 years old, 10 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain MRI. We identified 10 novel and one known mutations in our 8 HSP-TCC families, which were two nonsense mutations (c.5977C>T/p.Q1993X, c.4668T>A/p.Y1556X), three small deletions (c.6898_6899delCT/p.L2300AfsX2338, c.3719_3720delTA/p.I1240VfsX263, c.733_734delAT/p.M245VfsX246), four small insertions (c.7088_7089insATTA/p.Y2363X, c.2163_2164insT/p.I722YfsX731, c.7101_7102insT/p.K2368X, c.6790_6791insC/p.L2264PfsX2339), one deletion/insertion (c.654_655delinsG/p.S218RfsX219), and one splice mutation (c.7151+4_7151+7delAGTA/p.K2384fsX2386). Each family has a different mutation and all the mutations are predicted to cause early protein truncation.

Conclusion: This study widens the mutation spectrum of the SPG11 gene and the mutations in the SPG11 gene are also the major causative gene for HSP-TCC in the Chinese Hans. Screening of the whole gene is recommended in clinical practice.