Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

Abstract

Background and PurposeA variety of hereditary diseases overlap with neurological phenotypes or even share genes with hereditary spastic paraplegia (HSP). The aim of this study was to determine the clinical features and genetic spectrum of patients with clinically suspected HSPs.MethodsA total of 52 patients with clinically suspected HSPs were enrolled in this study. All the patients underwent next-generation sequencing (NGS) and triplet repeat primed PCR to screen for the dynamic mutations typical of spinocerebellar ataxia (SCA). Multiplex ligation-dependent probe amplification (MLPA) was further conducted in patients with no causative genetic mutations detected to examine for large deletions and duplications in genes of SPAST, ATL1, REEP1, PGN, and SPG11. Clinical characteristics and findings of brain MRI were analyzed in patients with definite diagnoses.ResultsThe mean age of the patients studied was 36.90 ± 14.57 years. 75% (39/52) of patients manifested a phenotype of complex form of HSPs. A genetic diagnosis was made in 51.9% (27/52) of patients, of whom 40.3% (21/52) of patients had mutations in HSPs genes (SPG4/SPG6/SPG8/SPG11/SPG15/SPG78/SPG5A) and 11.5% (6/52) of patients had mutations in SCAs genes (SCA3/SCA17/SCA28). SPG4 and SPG11 were the most common cause of pure form of HSPs (5/6, 83.3%) and complex form of HSPs (5/15, 33.3%), respectively. Gait disturbance was the most common initial symptom in both the patients with HSPs (15/21) and in patients with SCAs (5/6). Dysarthria and cerebellar ataxia were detected in 28.5% (6/21) and 23.8% (5/21) of patients with HSPs, respectively, and were the most common symptoms in addition to progressive weakness and spasticity of the lower limbs. Cerebellar atrophy was seen on the brain MRI of patients with SPG5A, SCA3, and SCA28.ConclusionCausative genetic mutations were identified in 51.9% of patients with clinically suspected HSPs by NGS and triplet repeat primed PCR. A final diagnosis of HSPs or SCAs was made in 40.3% and 11.5% of patients, respectively. The clinical manifestations and neuroimaging findings overlapped between patients with HSPs and patients with SCAs. Dynamic mutations should be screened in patients with clinically suspected HSPs, especially in those with phenotypes of complex form of HSPs.

Copy number variations in SPAST and ATL1 are rare among Brazilians

“…In addition to the pattern of inheritance, differences related to the phenotype of cases may also have influenced the results, since 53.7% of our cohort had complex phenotype. A study carried out in China presented similar results to ours, having evaluated 52 families, 39 of them with a complex phenotype, 18 reinforcing this possibility.…”

Clinical and Genetic Spectrum in a Large Cohort of Hereditary Spastic Paraplegia

“…As a semiquantitative molecular technique, multiple ligation-dependent probe amplification (MLPA) is typically performed to detect abnormal CNVs escaping detection by conventional polymerase chain reaction (PCR) amplification sequencing, which has been widely applied in hereditary diseases caused by chromosome abnormalities, gene fragment deletions or rearrangements, such as Duchenne muscular dystrophy/ Becker's muscular dystrophy, spinal muscular atrophy, and HSP. [11][12][13][14] Although various HSP subtypes have been reported and studied elaborately, [15][16][17][18][19] information on the pattern in the HSP subgroup with rearrangements has yet to be fully defined, leading to a vague distinction between point mutation-and rearrangement-related groups. Here, we applied a combination of WES with MLPA to explore the genotype-phenotype correlations as well as the landscape and hallmarks of a Chinese cohort of 270 HSP patients.…”

Spastic paraplegia type 8: A first report from India

“…However, Japan Spastic Paraplegia Research Consortium (JASPAC) reported a 1% frequency of SPG8 analyzing 206 Japanese AD-HSP families, and a study from China on 52 patients with clinically suspected HSPs reported one patient with SPG8 (c.1725T>A p.N575K). [ 5 , 6 ] Ginanneschi et al . [ 7 ] (2020) from Italy reported four new mutations in the KIAA0196 gene.…”