We present five previously unreported Italian patients with SPG46. These patients were found to have five novel GBA2 variants, all of which were determined to be pathogenic based on in silico predictors. This report represents the 24th documented study on the disease (Table 3, 4 and 5). Thus far, a total of 67 cases (30 men, 34 women, sex not specified in three) from 36 families have been described worldwide (Tables 2 and 3; Fig. 2) [16,17,18,19,20,21, 27, 29, 35, 36, 38,39,40,41,42,43,44,45,46,47,48,49,50] since the seminal description of Boukhris et al. in 2008 [22]. Patients with GBA2 pathogenic variants have been described in Tunisia, Belgium, Turkey, Portugal, Cyprus, Italy, Romania, Netherlands, China, Norway, France, Saudi Arabia, Japan, Germany, India, Taiwan, USA and Spain [16,17,18,19,20,21, 27, 29, 35, 36, 38,39,40,41,42,43,44,45,46,47,48,49,50] (Fig. 2 and Table 2). Based on the worldwide distribution, the prevalence of the disease seems to be higher in the Mediterranean area (Fig. 2). It ought to be considered the prevalence in each country where the highest number of cases has been reported (Table 2). In Tunisia, for instance, there have been 15 cases reported, with a prevalence of approximately 15 in 1.2 × 107 individuals. Similarly, in Italy, there have been 10 reported cases in approximately 5.9 × 107 individuals. Saudi Arabia has reported 8 cases, resulting in a prevalence of about 8 in 3.6 × 107 individuals. Lastly, in China, 4 cases have been documented, indicating a prevalence of around 4 in 140 × 107 individuals. Considering these prevalence rates, the Mediterranean area exhibits the highest concentration of SPG46 cases due to its smaller population (Fig. 2). For instance, this is particularly notable when comparing it with countries like the USA, which has a significantly larger population (approximately 33 × 107 inhabitants) but a minimal prevalence of the disease, with only one reported case so far [35]. Since ARHSPs are more common in countries with a higher rate of consanguinity, this may provide an explanation for the higher number of reported cases in these areas. A thorough demographical, clinical, radiological and biochemical comparison was conducted, examining the features of our cases in relationship with the available literature (Tables 1, 3, 4 and 5). Two out of five patients included in this study belonged to consanguineous families, where the parents were found to be relatives (Fig. 1; Table 1). Consanguinity is commonly observed in recessive diseases, and SPG46 makes no exception. Among the available reports in literature with this information (12 out of 23), consanguinity was investigated in 19 families (out of 31) and was found in 14 of them (73.68%) (Table 3). This highlights the prevalence of consanguineous marriages within the context of SPG46 and underscores the significance of genetic factors in the disease’s inheritance patterns. In all cases reported so far, the presence of both spastic paraparesis and cerebellar syndrome has been consistently observed (Table 3). In our study, all patients had early onset (6.8 year) and slow progression over time. Remarkably, one case had congenital onset (Table 1; proband B), and one had the longest progression so far (Table 1; proband C—44 years of disease); it is the second reported with such disease duration [47, 50]. Additional clinical features, commonly regarded as characteristic signs of this rare HSP [16,17,18,19,20, 22] such as neuropathy, MCI, bilateral cataracts, scoliosis, pes cavus and hypogonadism are observed with varying prevalence among the SPG46 population (Table 3). MCI is a common feature (Tables 1 and 3), but it may show very lately [18]. About half of the cases described so far show MCI, but its prevalence may turn out to be higher, due to later onset, as in our proband C (Table 1).

Movement disorders, like head and upper limbs’ tremor, cranial and upper limbs’ dystonia, can be observed with moderate occurrence, and they appear to be part of the clinical presentation in several described cases (17 out of 55—Table 4). Cervical dystonia has been outlined as the onset symptom in one patient, later evolved into a complex athetotic-dystonic disorder which involved the UL (initially described as “writer’s cramp”); at brain MRI she showed brainstem atrophy, also involving basal ganglia [47]. Facial myokymias were reported too [29]. Other neurological signs and symptoms emerged (Tables 1 and 4). Six cases of hearing loss have been reported. This is a symptom frequently found in mitochondrial diseases [51, 52]. Since a role in mitochondrial fragmentation has been already outlined in GBA2 mutation [53], we may suppose a similar mechanism in SPG46. Four cases of psychiatric disorders are also described [36, 43, 46]: in one case, the disease onset was represented by delusions [43]. Among the other neurological signs, UGP is the most frequent (19%—Tables 1 and 4) [18, 21, 47, 48]. Interestingly, this phenomenon is frequently observed in Gaucher’s Disease Type 3 (GD3). It is attributed to ceramide accumulation in cerebellar and brainstem areas controlling vertical gaze: floccular lobe, vestibular system, pontine paramedian reticular formation, rostral interstitial nucleus of the medial longitudinal fascicle and motor neurons of the abducens nucleus [54, 55]. GD3 is a neurodegenerative disease caused by pathological accumulation of glucosylceramide in the CNS due to lysosomal GBA dysfunction [56], similarly to what happens in SPG46. GBA and GBA2 do not have the same location or functioning [57]. However, it has been pointed out not only an akin role (i.e. glucosylceramide metabolism), but also an indirect action synergy [58]. Malekkou et al. biochemically characterized the same Cypriot SPG46 family described in 2014 [18], and, besides abolished GBA2 activity, they highlighted a compensatory effect of GBA, since its activity was threefold higher in SPG46 patients compared to controls [26]. Thus, the two enzymes not only share a similar role, but seem also to be related. Since UGP seems to be recurrent in SPG46 (Tables 1 and 4), we hypothesize a similar role of GBA2, resulting in brainstem and cerebellar dysfunction, and thus leading to UGP.

With exception of peripheral neuropathy and cognitive assessment, many reports lack additional clinical data or do not provide negative results (Tables 3, 4 and 5). As shown in Table 3, features such as scoliosis, foot abnormalities and hypogonadism should undergo more comprehensive investigation to determine their status as defining characteristics. This presents a challenge in further delineating the phenotypic profile of SPG46. Furthermore, manifestations like movement disorders (dystonia), ocular movements abnormalities and skeletal deformities might have a higher occurrence (Table 4). In future reports, recognizing and considering these features can aid diagnosis.

In most reports (20 out of 24, which includes our own study—Table 5) patients and families are primarily described with a phenotype consistent with HSP. Only few descriptions classify the disease as ARCA [17,18,19], and just one report identifies it as MSS [27]. That may often depend on predominant symptoms, or on signs and symptoms at onset. In 2013, Hammer et al. discovered the second group of GBA2-mutated patients, and initially diagnosed the condition as autosomal recessive ataxia, as the first presentation involved cerebellar syndrome. However, shortly thereafter, in addition to peripheral neuropathy, significant spasticity emerged, initially in the lower limbs and subsequently extending to the upper limbs, becoming highly pronounced and dominating the overall clinical presentation [19]. Later, Votsi et al. discovered a new GBA2-mutated family, in Cyprus, and classified it as ARCA. However, their phenotype description involves a typical HSP onset and progression (with spasticity in lower limbs) [18]. The first Italian description of SPG46, depicted as ARCA, involved three affected individuals from the same family. Still, a predominantly cerebellar phenotype was evident in a single case, while the other members displayed HSP, and significant intrafamilial variability [17]. Curiously, the variant discovered by Hammer et al. (c.2618G > A) [19] is the same of the Saudi SPG46 family from 2019 [44], which was described mainly as a HSP, complicated by cerebellar ataxia. Thus, different phenotypes may arise from same identical mutations, as also evidenced by the intrafamilial variability observed by Citterio et al. [17]. There are cases where the same genotype causes different degrees of phenotypical expression, even in the same family, as seen in diseases like neurofibromatosis, Van der Woude syndrome or holoprosencephaly [59,60,61]. Differently from incomplete penetrance, in which the expected phenotype manifests or not, this phenomenon is referred to as “variable expressivity”, which quantifies the degree to which a genotype displays its phenotypic expression [62]. Variable expressivity appears to be caused by a range of factors, including common variants, variants in regulatory regions, gene-modifiers, epigenetics, environmental factors and lifestyle [63]. In the two Norwegian families described in 2017, the probands presented at examination with early onset cerebellar ataxia, also with bilateral cataract, mental retardation and late spastic paraparesis [27]. Clinical diagnosis of MSS was made (one of the families was visited and diagnosed in 1977) [64]. MSS is an AR disorder, caused by mutations in SIL1, characterized by cerebellar atrophy with ataxia, early-onset cataracts, and it also may include mild to severe intellectual disability, hypogonadism and skeletal abnormalities [65,66,67]. Its clinical hallmarks are child-onset hypotonia and muscle weakness but not spasticity in lower limbs [