Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes

Abstract

Sirs,The ability to distinguish between sporadic presentationsof hereditary spastic paraparesis (HSP) and primary lateralsclerosis (PLS) is important in terms of prognostication andgenetic counseling, but clinical differentiation is problem-atic [6]. Primary lateral scherosis is a sporadic disorder ofprogressive spino-bulbar spasticity and may be part of theclinical spectrum of amyotrophic lateral sclerosis (ALS)[10]. Hereditary spastic paraparesis is a clinically andgenetically heterogeneous group of disorders characterizedby a slowly progressive spastic paraparesis [8, 12].To date, 15 genes and more than 20 additional loci havebeen identified for autosomal dominant (AD), autosomalrecessive and X-linked forms of HSP [5, 7]. The spastingene (SPG4) mutation is the most frequent cause of ADHSP (around 40% of families) and is also frequent insporadic HSP (13%), but not in PLS [3]. We recently foundpathogenic paraplegin gene (SPG7) mutations 11% ofpatients with sporadic HSP [4]. The role of other HSP genesin sporadic upper motor neuron (UMN) syndromes islargely unknown. Two known mutations (c.263G [A/p.N88Sand c.269C[T/p.S90L) in exon 3 of the seipin/BSCL2 gene(SPG17) can cause a range of AD (mixed) upper and lowermotor neuron disorders, including Silver syndrome (HSPwith amyotrophy of the hands), variants of Charcot–Marie-tooth disease type 2, distal hereditary motor neuropathy typeV(dHMNV),butalsopureandcomplicatedformsofHSP[1,13, 14]. Because of incomplete penetrance, the seipin/BSCL2 mutation can manifest as a sporadic disease [14].To investigate whether these two seipin/BSCL2 muta-tions are present in patients with sporadic HSP and PLS,we screened exon 3 of the seipin/BSCL2 gene in 86 Dutchpatients with a sporadic adult-onset UMN syndrome.Inclusion criteria were a gradually progressive UMN syn-drome, adult-onset, disease duration [6 months and anegative family history. Exclusion criteria were lowermotor neuron loss meeting the revised El Escorial criteriafor clinically definite, clinically probable or probable lab-oratory-supported ALS [2] and evidence of other causes ofa UMN syndrome based on a battery of laboratory inves-tigations, including serum biochemistry (including thyroid-stimulating hormone, angiotensin converting enzyme,vitamin B12, folate and vitamin E), analysis of very longchain fatty acids in plasma, serology (syphilis, borreliosis,human T cell lymphotrophic virus type 1 and humanimmunodeficiency virus) and bile alcohol analysis in urine,and cerebral and spinal magnetic resonance imaging(MRI). The presence of the SPG4 and SPG7 mutations wasexcluded in all patients. The study was approved by themedical ethics review board of the University MedicalCenter in Utrecht, and written informed consent wasobtained from all patients.Mutation screening of the seipin/BSCL2 gene was per-formed using automated forward and reverse directsequencing of exon 3. The BSCL2 exon 3 was amplified byPCR using intronic primers (primer sequences available onrequest), and the PCR products were loaded on an Applied