The present study provides an overview about the frequency of mutations in the BSCL2, GARS, HSPB1 and HSPB8 genes in 33 patients diagnosed as dHMN-V, CMT2D or SS. The diagnostic yield gained in this series of probands with a well defined phenotype was 12% for BSCL2 mutations and 3% for GARS mutations. Moreover, we screened another series of 69 probands with an undefined dHMN phenotype or HSP complicated by pure motor neuropathy for mutations in exon 3 of BSCL2 but did not find any pathogenic mutations. These results strongly point to further, non-allelic heterogeneity in this group of disorders. This study further indicates that mutations in the HSPB1 and HSPB8 genes might not produce complicated phenotypes such as dHMN-V, SS and CMT2D but certainly more patients have to be screened before drawing any firm conclusions.
So far, only the two heterozygous mutations N88S and S90L in exon 3 of the BSCL2
gene have been reported in patients with dHMN [11
]. Our study highlights these two mutations as a cause of dHMN-V. Notably, the fourth patient carrying the S90L mutation exhibited prominent spastic paraparesis of the lower limbs in addition to axonal polyneuropathy and was originally diagnosed as HSP. Our findings confirm the marked phenotypic variation between the N88S and the S90L mutations as described earlier [2
] which both affect glycosylation of seipin, the protein encoded by BSCL2
]. Based on the previous reports and on the results presented in this study it seems most likely that the N88S and S90L substitutions are indeed the only two mutations in the BSCL2
gene that may cause dHMN-V or SS. We therefore suggest that an analysis of BSCL2
of patients with dHMN-V and SS may be restricted to exon 3. On the other hand, in non-classifiable dHMN and HSP cases this algorithm has no rationale.
Proband 2 is an offspring of a large Austrian dHMN-V/Silver syndrome family reported in 2005 [2
]. The phenotype of this patient, who shows the typical dHMN-V features in the hands and carries the N88S mutation, is highly unusual with regard to the severe ulcero-mutilating complications in the lower limbs and the lancinating pain attacks. This phenotype is difficult to explain on the basis of the present mutation only. Because other common causes of acquired and inherited sensory neuropathies (such as mutations in the HSN2
genes) have been excluded, it is possible that this patient is afflicted with a second rare genetic or acquired disease.
The GARS variant A57V identified in this study is novel, but its pathogenicity has to be confirmed in further CMT2D and dHMN-V patients because we did not have access to ethnic matched controls and there were no other family members available to show segregation with the phenotype. However, the initial phenotype in this case is typical for the phenotype described with GARS mutations and is the main evidence for considering A57V pathogenic. The finding of ptosis is unusual but since it is present in another family member who does not reportedly have other symptoms suggesting distal HMN or CMT2, it may be co-incidental and not related to the GARS phenotype.
The high phenotypic variation between and within families with BSCL2
mutations has already been documented very well [6
]. An overlapping of features consisting of uni- or bilateral selected hand muscle wasting and a variable degree of weakness in the lower limbs, which is often accompanied by pure motor neuropathy, has been demonstrated in both instances. Mild to severe pyramidal tract features are common in patients with BSCL2
mutations whereas they have only been observed in five patients with GARS
mutations to a mild degree [6
]. On the other hand, sensory abnormalities are more frequent in patients with GARS
mutations making the boundaries between hereditary motor and sensory neuropathies and distal HMN less clear. Having seen both patients with BSCL2
mutations we may state here that it is often impossible to distinguish the matching phenotypes on a clinical and electrophysiological basis particularly in the absence of pyramidal tract features. The latter strongly favour the diagnosis of SS and indicate that exon 3 of BSCL2
should be screened first. To avoid confusion of classification between these related diseases it might be important to use the term SS (which is also subcategorized as SPG17 among the group of hereditary spastic paraplegias) for cases with hand muscle involvement and additional spastic paraparesis only.
It still remains poorly understood how mutations in the BSCL2 and GARS genes lead to this broad spectrum of phenotypically overlapping disorders. It will be a challenge for future cellular and functional studies to detect the underlying mechanisms and maybe also to define common pathways between these two genes.