Phenotypes of the N88S Berardinelli–Seip congenital lipodystrophy 2 mutation

Abstract

Recently, two missense mutations (N88S, S90L) in the Berardinelli-Seip congenital lipodystrophy gene have been identified in autosomal dominant distal hereditary motor neuropathy and Silver syndrome. We report the phenotypic consequences of the N88S mutation in 90 patients of 1 large Austrian family and two unrelated German families. Variation in the clinical and electrophysiological phenotype enabled us to distinguish six subtypes. In 4.4%, the disorder was not penetrant. Twenty percent of the patients were subclinically affected; some of these patients could only be detected by pathological nerve conduction studies. A distal hereditary motor neuropathy type V phenotype characterized by predominant hand muscle involvement was found in 31.1%, whereas 14.5% showed typical Silver syndrome with amyotrophy of the small hand muscles and spasticity of the lower extremities. Moreover, the phenotype present in 20% was compatible with Charcot-Marie-Tooth disease. In 10%, the clinical diagnosis of pure or complicated hereditary spastic paraparesis was made. Electrophysiological studies showed an axonal neuropathy but also chronodispersion of compound motor action potentials and conduction blocks. Sensory nerve conduction studies were rarely pathological. Our study indicates that the dominant N88S mutation in the Berardinelli-Seip congenital lipodystrophy gene 2 leads to a broad spectrum of motor neuron disorders.

Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome

“…In a number of families diagnosed as either dHMN-V or SS two heterozygous mutations (N88S, S90L) located in exon 3 in the Berardinelli-Seip congenital lipodystrophy gene (BSCL2) were identified [11]. Clinical examination of more than 90 patients with the BSCL2 N88S substitution showed that it is most often associated with a dHMN-V phenotype and less frequently, additional prominent spasticity and mild sensory disturbances are found in the lower limbs [2,[12][13][14][15]. Up to date, the S90L substitution was only described in three families and often resulted in a spastic paraplegia phenotype with marked weakness and wasting in the hands suggesting the clinical diagnosis of SS [11,15,16].…”

“…Silver syndrome (SS) is a rare motor neuron disease which also frequently resembles a dHMN-V phenotype as patients often show prominent amyotrophy of the small hand muscles [5]. The presence of mild to severe pyramidal tract signs is common in dHMN-V and SS whereas they have rarely been observed in patients with CMT2D [1,2,5,6]. Initially, the presence of spastic paraparesis has led to the subclassification of SS among the group of hereditary spastic paraplegias (HSP) and SS was thus termed as SPG17 [7].…”

“…Foot deformity and peroneal muscle weakness may also be present [1]. Sensory disturbances occur rarely in advanced stages of dHMN-V [1,2]. Recently, patients presenting with axonal hereditary motor and sensory neuropathy (HMSN type 2, i.e.…”

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

“…In families with the seipin/BSCL2 mutation, the frequency of an HSP phenotype has been observed to be as high as 10% of patients [1]. The other 46 patients in our study had symptomatic UMN involvement of the arms or bulbar region, which may suggest a diagnosis of PLS [6,10].…”

“…The role of other HSP genes in sporadic upper motor neuron (UMN) syndromes is largely unknown. Two known mutations (c.263G[A/p.N88S and c.269C[T/p.S90L) in exon 3 of the seipin/BSCL2 gene (SPG17) can cause a range of AD (mixed) upper and lower motor neuron disorders, including Silver syndrome (HSP with amyotrophy of the hands), variants of Charcot-Marietooth disease type 2, distal hereditary motor neuropathy type V (dHMNV), but also pure and complicated forms of HSP [1,13,14]. Because of incomplete penetrance, the seipin/ BSCL2 mutation can manifest as a sporadic disease [14].…”