Introduction
Hereditary spastic paraparesis (HSP) represents a group of central nervous system (CNS) diseases that mainly involve the spinal portion of upper motor neurons [
1]. Hallmark pathologic alteration in HSPs is diffuse axonal “dying-back” degeneration, most represented in the terminal segments of the longest axons, with possible involvement of dorsal columns [
2,
3]. Involvement of the lower motor neurons can also be observed [
4]. HSPs have an estimated prevalence ranging from 2 to 4.1 in 10
4 individuals [
5,
6], and they are classified according to inheritance (autosomal dominant, autosomal recessive, X-linked or mitochondrial with maternal trait transmission), to phenotype (“pure” or “complex”) and to onset (early or late) [
7,
8]. The pathogenesis of HSP is connected to a wide range of cellular processes, including membrane and axonal transport, modulation of the endoplasmic reticulum membrane, mitochondrial function, DNA repair, autophagy, lipid metabolism and myelination. Additionally, dysfunction in endosome membrane trafficking, oxidative stress and mitochondrial DNA polymorphisms have been implicated [
9].
Phenotypically, “pure” HSPs [
10] typically manifest with pyramidal signs starting in lower limbs, associated with variable disorders as sphincter dysfunctions and deep sensory loss. On the other hand, “complex” HSPs may display a broader range of neurological manifestations including cerebellar dysfunction, peripheral neuropathy, extrapyramidal features, seizures, deafness, cognitive impairment and psychiatric disorders [
1,
5]. Extraneurological manifestations can include cataracts, optic neuropathy, retinitis pigmentosa, facial dysmorphisms, scoliosis, hip dislocation and different foot deformities [
1,
11]. Furthermore, CNS neuroimaging reveals characteristic features, often related to a specific subtype: cerebellar atrophy, thin corpus callosum (TCC), white matter abnormalities (WMA), spinal cord atrophy, brain iron accumulation and hydrocephalus [
12‐
14]. Within the group of autosomal recessive hereditary spastic paraplegias (ARHSP), SPG11 is the most common, followed by SPG7, SPG15 and SPG56, whereas SPG46 seems more rare [
15‐
21].
SPG46 is a rare, early onset spastic paraparesis, classified as “complex” [
5]. It is inherited in an autosomal recessive manner, and its clinical presentation has appeared strikingly different from other ARHSP since its initial and seminal description [
22]. It is associated with biallelic mutations in the
GBA2 gene (locus 9p13.3) encoding for the non-lysosomal glucosylceramidase (GBA2) [
20,
23], a ubiquitous enzyme associated with the endoplasmic reticulum and the plasma membrane, which catalyzes conversion of glucosylceramide to glucose and ceramide [
24]. The other (non-homologous) enzyme degrading glucosylceramide is the lysosomal acid β-glucosidase (GBA), whose mutations cause Gaucher’s disease and a form of hereditary Parkinson’s disease [
25]. Glucosylceramide is the precursor component of gangliosides. Mutations in the
GBA2 lead to changes in enzymatic activity, which can be detected in lymphoblasts and leucocytes of affected subjects [
26], but also affect neurons [
23,
27], resulting in abnormal increase of glucosylceramide, although the pathogenic mechanism of neurodegeneration is still unclear [
24].
GBA2 mutations seem to lead to a clinical spectrum that encompasses different phenotypes, including HSP, autosomal recessive cerebellar ataxia (ARCA), or a more complex and severe condition like Marinesco-Sjögren Syndrome (MSS) [
18,
27,
28]. Clinically, HSP46 may show plethoric signs, both neurological and extraneurological, besides spastic paraparesis, such as: cerebellar dysfunction, peripheral neuropathy, distal amyotrophy, cognitive impairment, scoliosis, cataracts [
16,
20,
29], and there is still not a consensus basis about the overall definite phenotype. Furthermore, not all reports contain information about the features thought to be hallmarks, or at least common, in this disease (Table
1). Brain MRI may display WMA, TCC, cerebral, brainstem and cerebellar atrophy. To date, more than 90 genetic types of HSP have been identified [
5,
15] (
https://neuromuscular.wustl.edu/spinal/fsp.html;
OMIM), and 62 patients, between isolated cases and families, with SPG46 have been described worldwide. Since its clinical discovery [
22], when its genetic mutation was still unknown, and subsequent identification of the causative mutation [
16], 23 reports about SPG46 have been published. In over 15 years, different phenotypes have been described, pointing out a phenotypical heterogeneity and reinforcing the concept of “clinical spectrum” of this disease. Herein we report five novel
GBA2 pathogenic variants detected in unrelated SPG46 Italian patients. We also provide a comprehensive review of demographic, genetic, biochemical and clinical data from all SPG46 cases described in the existing literature, discussing about cases’ global distribution, overall phenotype’s characteristics, variable expressivity, possible hallmarks and the importance of GBA2 activity dosage.
Table 1
Clinical, demographic, radiological and biochemical details of our patients
Features |
Males/females | M | M | M | F | M | 4 M/1F |
Consanguinity | Yes | No | No | No | Yes | 2/5 |
World area | Morocco | Italy | Italy | Italy | Italy | |
Age last examination (y) | 36 | 33 | 56 | 21 | 47 | 38,6 |
Onset (y) | 10 | 0 | 12 | 2 | 10 | 6,8 |
Progression (y) | 26 | 33 | 44 | 20 | 37 | 32 |
Spasticity | Yes | Yes | Yes | Yes | Yes | 5/5 |
Sphincteric symptoms | Yes | Yes | No | Yes | No | 3/5 |
Cerebellar syndrome | Yes | Yes | No | Yes | Yes | 4/5 |
Peripheral neuropathy | Yes | Yes | Yes | No | Yes | 4/5 |
MCI | No | Yes | Yes | Yes | Yes | 4/5 |
Cataract | Yes | Yes | No | Yes | Yes | 4/5 |
Scoliosis | Yes | Yes | No | No | No | 2/5 |
Pes cavus | Yes | No | No | No | No | 1/5 |
Hypogonadism | No | No | No | - | No | 0/4 |
Movement disorders | No | No | Yes | No | No | 1/5 |
Head tremor | No | No | No | No | No | 0/5 |
Cervical/facial dystonia | No | No | No | No | No | 0/5 |
Facial myokimias | No | No | No | No | No | 0/5 |
Limb dystonia | No | No | Yes | No | No | 1/5 |
Limb tremor | No | No | Yes | No | No | 1/5 |
Other symptoms/signs | UGP | No | UGP | No | No | 2/5 |
SPRS | 23 | 31 | NA | 11 | 30 | 23.75 |
Overall phenotype | | | | | | |
HSP ph | Yes | Yes | Yes | Yes | Yes | 5/5 |
ARCA ph | - | - | - | - | - | 0/5 |
M-S ph | - | - | - | - | - | 0/5 |
MRI | | | | | | 5/5 |
TCC | Yes | No | No | Yes | No | 2/5 |
Cerebellar atrophy | Yes | No | No | No | No | 1/5 |
Brainstem atrophy | Yes | No | No | Yes | No | 2/5 |
Cerebral atrophy | No | No | No | No | No | 0/5 |
WMA | Yes | No | Yes | Yes | Yes | 4/5 |
GBA2 activity probands | 0.28 nmol/mg | 0.01 nmol/mg | Pending | Pending | NA | 0.145 nmol/mg |
Discussion
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‐
21,
27,
29,
35,
36,
38‐
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‐
21,
27,
29,
35,
36,
38‐
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 × 10
7 individuals. Similarly, in Italy, there have been 10 reported cases in approximately 5.9 × 10
7 individuals. Saudi Arabia has reported 8 cases, resulting in a prevalence of about 8 in 3.6 × 10
7 individuals. Lastly, in China, 4 cases have been documented, indicating a prevalence of around 4 in 140 × 10
7 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 × 10
7 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‐
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).
Table 3
Details about clinical and demographical findings in all HSP46 cases so far
Boukhris A et al. (2010) | 5 | 1 | Yes | 4,4 | NR | 5 | 5 | 5 | 5 | 5 | No | 5 | NR |
Hammer HB et al. (2013) | 10 | 4 | 4 yes | 8,4 | 26 | 10 | 10 | 10 | 1 | NR | 3 | 3 | No |
Martin E et al. (2013) | 11* | 4* | 3 yes, 1 no | 8,5 | 23 | 11* | 11* | 5 | 11* | 11* | No | 5* | 2 |
Votsi C et al. (2014) | 3 | 1 | Yes | 15,7 | 41 | 3 | 3 | 3 | 3 | 1 | NR | 3 | NR |
Citterio A et al. (2014) | 3 | 1 | Yes | 10 | 25 | 3 | 3 | No | 3 | No | No | 2 (flat foot) | No |
Kancheva D et al. (2016) | 2 | 1 | NR | NR | 14 | 2 | 2 | 2 | NR | NR | NR | NR | NR |
van de Warrenburg BP et al. (2016) | 1 | 1 | NR | 3 | NR | 1 | 1 | 1 | 1 | 1 | NR | NR | NR |
Yang YJ et al. (2016) | 1 | 1 | Yes | 8 | NR | 1 | 1 | NR | 1 (dementia) | NR | NR | NR | NR |
Haugarvoll K et al. (2017) | 3 | 2 | 2 no | 6 | NR | 3 | 3 | 3 | 3 | 3 | 1 | 1 | 1 |
Morais S et al. (2017) | 2 | 1 | NR | 10 | NR | 2 | 2 | 2 | NR | NR | NR | NR | NR |
Coutelier M et al. (2018) | 1 | 1 | NR | NR | NR | 1 | 1 | 1 | NR | 1 | NR | NR | NR |
Coarelli et al. (2018) | 1 | 1 | No | 6 | NR | 1 | 1 | 1 | 1 | No | no | 1 | No |
Wei Q et al. (2019) | 1 | 1 | NR | 22 | NR | 1 | 1 | 1 | NR | No | NR | NR | NR |
Algahtani H et al. (2019)* | 8 | 1 | Yes | 12 (proband) | NR | 8 | 8 | NR | NR | 1 | No | No | No (woman) |
Guan RY et al. (2020) | 2 | 2 | NR | NR | NR | 2 | 2 | 2 | 2 | NR | NR | NR | NR |
Spagnoli C et al. (2020) | 1 | 1 | NR | NR | NR | 1 | 1 | NR | NR | No | No | No | No (woman) |
Nakamura-Shindo K et al. (2020) | 2 | 1 | Yes | 23 | NR | 2 | 2 | NR | NR | 2 | No | No | No |
Kloth K et al. (2020) | 2 | 1 | NR | 25 | 14 | 2 | 1 | 1 | 2 | 1 | No | No | No (women) |
Holla VV et al. (2021) | 3 | 2 | 2 yes | 7 | 28 | 3 | 2 | NR | 1 | No | NR | NR | NR |
Gatti M et al. (2021) | 1 | 1 | NR | 2 | 15 | 1 | 1 | 1 | 1 | 1 | 1 | No | No (woman) |
Lan MY et al. (2022) | 2 | 1 | NR | 20,5 | 39 | 2 | 2 | NR | 2 | No | NR | NR | NR |
Gill et al. (2023) | 1 | 1 | NR | 9 | NR | 1 | 1 | NR | NR | NR | NR | NR | NR |
Cores Bartolomé C et al. (2023) | 1 | 1 | No | 10 | NR | 1 | 1 | 1 | NR | 1 | NR | 1 (+ equinus) | No (woman) |
Present report | 5 | 5 | 2 yes, 3 no | 6,8 | 44 | 5 | 5 | 4 | 4 | 4 | 2 | 1 | No |
Total | 67 | 36 | 16 yes, 8 no | 10,9 | 26,9 | 67 (100%) | 67 (100%) | 43 (87.76%) | 36 (75%) | 27 (64.3%) | 7 (17.5%) | 17 (38.6%) | 3 (16.7%) |
Table 4
Details about clinical and demographical findings in all HSP46 cases so far
Boukhris A et al. (2010) | 5 | No | | | | | | No | | | | | | | |
Hammer HB et al. (2013) | 10 | Yes | 3 | | | | | No | | | | | | | |
Martin E et al. (2013) | 11* | No | | | | | | Yes | | 3 | | | | | |
Votsi C et al. (2014) | 3 | No | | | | | | Yes | 3 | 3 | | | | | |
Citterio A et al. (2014) | 3 | NR | | | | | | Yes | | | 3 | | | | |
Kancheva D et al. (2016) | 2 | NR | | | | | | NR | | | | | | | |
van de Warrenburg BP et al. (2016) | 1 | NR | | | | | | NR | | | | | | | |
Yang YJ et al. (2016) | 1 | Yes | | | | 1 | | Yes | 1 | | | | | | |
Haugarvoll K et al. (2017) | 3 | Yes | 2 | 1 (+ Athetosis) | | | 2 | No | | | | | | | |
Morais S et al. (2017) | 2 | Yes | | | | 2 | | NR | | | | | | | |
Coutelier M et al. (2018) | 1 | NR | | | | | | NR | | | | | | | |
Coarelli et al. (2018) | 1 | Yes | | | | | 1 | No | | | | | | | |
Wei Q et al. (2019) | 1 | No | | | | | | Yes | | | | | 1 | 1 | |
Algahtani H et al. (2019)* | 8 | Yes | 1 | | | | 1 | NR | | | | | | | |
Guan RY et al. (2020) | 2 | NR | | | | | | NR | | | | | | | |
Spagnoli C et al. (2020) | 1 | No | | | | | | Yes | | | | | | | 1 |
Nakamura-Shindo K et al. (2020) | 2 | No | | | | | | Yes | | | | | 1 | | |
Kloth K et al. (2020) | 2 | Yes | 1 | 2 | | 1 (writer cramp) | | Yes | 1 | | | | | | |
Holla VV et al. (2021) | 3 | Yes | 1 (no–no head tremor) | 1 | | 2 | 1 | Yes | 2 | | | 2 | | | |
Gatti M et al. (2021) | 1 | Yes | | | 1 | | 1 | No | | | | | | | |
Lan MY et al. (2022) | 2 | NR | | | | | | NR | | | | | | | |
Gill et al. (2023) | 1 | NR | | | | | | NR | | | | | | | |
Cores Bartolomé C et al. (2023) | 1 | Yes | | | | 1 | | No | | | | | | | |
Present report | 5 | Yes | | | | 1 | 1 | Yes | 2 | | | | | | |
Total† | 67 | 17/48 (35.4%) | 9/48 (18.75%) | 5/48 (10.4%) | 1/48 (2%) | 8/48 (16.7%) | 7/48 (14.6%) | 18/48 (37.5%) | 9/48 (18.8%) | 6/48 (12.5%) | 3/48 (6.25%) | 2/48 (4.2%) | 2/48 (4.2%) | 1/48 (2%) | 1/48 (2%) |
Table 5
Details about clinical and demographical findings in all HSP46 cases so far
Boukhris A et al. (2010) | 5 | x | | | Yes | 4 | 2 | 2 | | 1 | | NA |
Hammer HB et al. (2013) | 10 | | x | | Yes | 1 | 1 | | | | | NA |
Martin E et al. (2013) | 11* | x | | | Yes | 2 | 2 | 2 | | | | NA |
Votsi C et al. (2014) | 3 | | x | | Yes | 3 | | 3 | | | | 3(GBA2 activity almost undetectable)** |
Citterio A et al. (2014) | 3 | | x | | NA | | | | | | | NR |
Kancheva D et al. (2016) | 2 | x | | | NA | | | | | | | NR |
van de Warrenburg BP et al. (2016) | 1 | x | | | Yes | 1 | 1 | | | | 1 | NR |
Yang YJ et al. (2016) | 1 | x | | | Yes | 1 | | | | | 1 | NR |
Haugarvoll K et al. (2017) | 3 | | | x | 1 NA, 2 yes | 2 | 2 | 2 | | 2 | | 1 (7% residual GBA2 activity) |
Morais S et al. (2017) | 2 | x | | | NA | | | | | | | NR |
Coutelier M et al. (2018) | 1 | x | | | NA | | | | | | | NR |
Coarelli et al. (2018) | 1 | x | | | Yes | 1 | 1 | 1 | | | | NR |
Wei Q et al. (2019) | 1 | x | | | Yes | 1 neg | | | | | | NR |
Algahtani H et al. (2019)* | 8 | x | | | 7 NA, 1 yes | 1 | | 1 | | | | NR |
Guan RY et al. (2020) | 2 | x | | | NA | | | | | | | NR |
Spagnoli C et al. (2020) | 1 | x | | | Yes | 1 | 1 | | | | | NR |
Nakamura-Shindo K et al. (2020) | 2 | x | | | 1 NA, 1 yes | 1 | 1 | 1 | 1 | | | NR |
Kloth K et al. (2020) | 2 | x | | | 1 NA, 1 yes | 1 | | | 1 | | 1 | 2 (GBA2 activity severely reduced) |
Holla VV et al. (2021) | 3 | x | | | 1 NA, 2 yes | 2 | 2 | 2 | | | | NR |
Gatti M et al. (2021) | 1 | x | | | Yes | 1 neg | | | | | | 1 (almost indetectable GBA2 activity) |
Lan MY et al. (2022) | 2 | x | | | Yes | 2 | | 2 | | | | NR |
Gill et al. (2023) | 1 | x | | | Yes | 1 | 1 | | | | | NR |
Cores Bartolomé C et al. (2023) | 1 | x | | | Yes | 1 neg | | | | | | NR |
Present report | 5 | x | | | Yes | 5 | 2 | 0 | 1 | 0 | 4 | 2 |
Total† | 67 | | | | 46/67 (68,6%) | 29/46 (63%) | 16 (35%) | 16 (35%) | 3 (7%) | 3 (7%) | 7 (15%) | 9/14 |
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‐
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‐
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‐
67]. Its clinical hallmarks are child-onset hypotonia and muscle weakness but not spasticity in lower limbs [
68]. The Norwegian patients did not exhibit hypotonia or myopathy during childhood and instead presented with early onset-spastic paraparesis. Therefore, SPG46 may start with diverse symptoms sometimes different from spasticity in lower limbs, like cerebellar ataxia and may seldom show different phenotypes [
17‐
19,
27]. Regardless of different onset or dominant symptoms, the disease is primarily described in most reports as a complex form of ARHSP. Considering the long disease duration (mean 26.9 years—Tables
1 and
3), the overall phenotype gradually manifests as a “typical” complex ARHSP over time, exhibiting distinct features that serve as hallmarks of SPG46 (Tables
1,
3,
4 and
5). At times, the differentiation between cerebellar ataxia and HSP seems artificial, as it reveals a phenotypic continuum linked to specific genes, which can be better understood through the concept of variable expressivity: indeed, little is known about any cis–trans regulatory elements of
GBA2.
Our MRI findings demonstrate slight variations compared to those reported in the literature (Tables
1 and
5). Specifically, we observed a lower incidence of cerebellar atrophy (0/5), a higher incidence of brainstem atrophy (40% versus 7%), and significant differences concerning WMA (80% versus 15%). These findings highlight the importance of WMA sign in our cohort. However, it is worth noting that our study includes a limited number of cases, and further expansion of the cohort is necessary to enable a more meaningful comparison (Tables
1 and
5).
We have noted a significant reduction in GBA2 activity, as confirmed by tests conducted in our study as well in a few others [
20,
23,
26,
27,
29,
47]. Importantly, previous reports and mice studies suggest that this enzyme, despite being relatively understudied, may affect axonal differentiation and branching [
69] and locomotor function [
20,
24]. Also, GBA2 shows species-specificity [
70,
71], especially regarding male reproduction [
72,
73], implying that there is more than meets the eye. GBA2 activity test is undoubtedly useful from a diagnostic point of view (Table
1). In our congenital case, it is noteworthy that GBA2 activity was nearly absent, exhibiting a significant reduction compared to proband A, who presented a more typical onset and progression (Table
1).