Spastic Paraplegia Type 7 and Movement Disorders: Beyond the Spastic Paraplegia

Abstract

Background

Spastic paraplegia type 7 (SPG7) mutations can present either as a pure form or a complex phenotype with movement disorders.

Objective

Describe the main features of subjects with SPG7 mutations associated with movement disorders.

Methods

We analyzed the clinical and paraclinical information of subjects with SPG7 mutations associated with movement disorders.

Results

Sixteen affected subjects from 11 families were identified. Male sex predominated (10 of 16) and the mean age at onset was 41.25 ± 16.1 years. A cerebellar syndrome was the most frequent clinical movement disorder phenotype (7 of 16); however, parkinsonism (2 of 16), dystonia (1 of 16), and mixed phenotypes between them were also seen. The “ears of the lynx” sign was found in four subjects. A total of nine SPG7 variants were found, of which the most frequent was the c.1529C > T (p.Ala510Val).

Conclusion

This case series expands the motor phenotype associated with SPG7 mutations. Clinicians must consider this entity in single or familial cases with combined movement disorders.

The hereditary spastic paraplegias (HSPs) comprise a large and heterogeneous group of inherited neurologic disorders, with a defining and unifying feature of prominent lower extremity spasticity. Complex forms are associated with additional, often prominent, features including more severe neuropathy, seizures, parkinsonism, cognitive impairment, amyotrophy, short stature, and visual abnormalities, among others. A recent interesting finding in this field is the multiple modes of inheritance reported for variants of several causal genes. ¹ Pathogenic variants in the spastic paraplegia gene 7 (SPG7) account for approximately 5%–21% of autosomal recessive HSPs cases. However, several reports have proposed possible dominant inheritance for some variants of this gene. ² , ³

In large SPG7 cohorts most of the cases show pure phenotypes with only a small proportion of them exhibiting complex forms of the disease, combining spasticity with ataxia and parkinsonism as the main movement disorders. ⁴ , ⁵ Recently, new complex phenotypes have been described. The aim of this report is to describe the clinical and paraclinical features of patients with SPG7 mutations associated with movement disorders.

Methods

We retrospectively analyzed medical records of subjects who presented to four different movement disorders clinics in Canada, Portugal, Mexico, and Germany. Cases with SPG7 variants manifesting movement disorders were included. Clinical and paraclinical information, including demographic data, clinical assessment, imaging findings, genetic analysis, and additional available studies were analyzed.

Because the design of the study was retrospective, a full ethics review was not required. Written informed consent was obtained from all subjects. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Results

Sixteen subjects from twelve families native of Canada (n = 6), Portugal (n = 5), Mexico (n = 4) and Germany (n = 1) were included in the study (Table 1). Male sex predominated (10 of 16); mean age was of 56.5 ± 15.9 years (median, 59 years; range, 16–79 years) and mean age of onset was 41.25 ± 16.1 years (median, 40 years; range, 5–72 years). Overall, most of the subjects had gait and balance problems (11 of 16) as the presenting feature, followed by a combination of speech and balance abnormalities (2 of 16), dystonia (2 of 16), and parkinsonism (1 of 16).

TABLE 1.

Baseline characteristics of cases with SPG7 pathogenic variants

Subject	Country	Sex	Age, y	Age at onset, y	Initial features	MD phenotype	Clinical features	Family background	MRI findings	SPG7 variant	Genotype status	Pathogenicity	Type
1	Mexico	M	64	49	Balance and gait problems	Cerebellar syndrome	Skew deviation, hyperreflexia in lower limbs	Sibling of case 2	Ears of the lynx sign, cerebellar atrophy, bilateral parietal atrophy	c.1529C > T p.(Ala510Val)	Homozygous	Pathogenic	Single nucleotide
2	Mexico	M	54	35	Gait and balance problems	MSA‐C‐like	Skew deviation, multidirectional gaze limitation, spastic paraparesis, erectile dysfunction, incontinence	Sibling of case 1	Cerebellar atrophy	c.1529C > T p.(Ala510Val)	Homozygous	Pathogenic	Single nucleotide
3	Portugal	F	43	36	Gait and balance problems	Cerebellar syndrome	Square wave jerks, spastic paraparesis, lower limb hypestesia, cerebellar ataxia, pes cavus	Consanguinity among parents and paternal grandparents; daughter of case 4	Cerebellar atrophy	c.1454_1462del p.(Arg485_Glu487del)	Homozygous	Pathogenic	Deletion
4	Portugal	M	69	40	Gait and balance problems	Cerebellar syndrome	Square wave jerks, spastic paraparesis, neuropathy, cerebellar ataxia	Consanguinity among parents; father of case 3	NA	c.1454_1462del p.(Arg485_Glu487del)	Homozygous	Pathogenic	Deletion
5	Canada	M	64	32	Spasmodic dysphonia and writers' cramp	Dystonia‐ataxia	Upgaze limitation, spasmodic dysphonia, writer's cramp, action tremor, spastic paraparesis, cerebellar ataxia, urinary urgency	Sibling of case 6 and 7	Cerebellar atrophy	c.1529C > T p.(Ala510Val) and c.2096dupT p.(Met699fs)	Compound heterozygous	Pathogernic	Duplication
6	Canada	M	55	40	Slurred speech and gait problems	Dystonia‐ataxia	Upgaze limitation, postural/intention tremor, foot dystonia, spastic paraparesis, cerebellar ataxia	Sibling of case 5 and 7	Cerebellar atrophy	c.1529C > T p.(Ala510Val) and c.2096dupT p.(Met699fs)	Compound heterozygous	Pathogenic	Duplication
7	Canada	F	57	37	Balance and gait problems.	Parkinsonism‐ dystonia‐ataxia	Multidirectional diplopia, upgaze limitation, spastic paraparesis, foot dystonia, action and rest tremor, freezing, cerebellar ataxia. Responsiveness to L‐dopa, epilepsy	Sibling of case 5 and 6	Ears of the lynx sign	c.1529C > T p.(Ala510Val) and c.2096dupT p.(Met699fs)	Compound heterozygous	Pathogenic	Duplication
8	Portugal	F	58	52	Gait problems	Cerebellar syndrome	Spastic tetraparesis, cerebellar ataxia, pes cavus, subcutaneous nodules at hips	None	Cerebellar atrophy	c.1529C > T p.(Ala510Val) and c.184‐?_376 +?del(p.?)	Compound heterozygous	Pathogenic	Single nucleotide/deletion
9	Germany	F	63	40	Gait and balance problems	Cerebellar syndrome	External ophthalmoplegia, spasticity, neuropathy, cerebellar ataxia	Gait and balance problems in her mother	Cerebellar atrophy	c.1045G > A; p.(Gly349Ser) and c.1454_1462del; p.(Arg485_Glu487del)	Compound heterozygous	Pathogenic	Single nucleotide/9 bp deletion
10	Mexico	M	16	5	Right leg dystonia	Generalized dystonia	Dysarthria, anxiety, nocturnal cramps	None	Ears of the lynx sign	c.1468G > T, p.(Glu490Ter)	Heterozygous	Likely pathogenic	Nonsense
11	Mexico	F	29	25	Clumsiness micrographia tremor	Dystonia‐parkinsonism	Cervical dystonia and parkinsonism. Responsiveness to dopaminergic therapy (pramipexole and rasagiline)	Maternal grandfather with parkinsonism	Ears of the Lynx sign	c.1468G > T, p.(Glu490Ter)	Heterozygous	Likely pathogenic	Nonsense
12	Canada	M	65	30	Gait problems	Parkinsonism	Spastic paraparesis, urinary urgency	Gait disturbance in mother, 3 siblings and 1 child. One sibling had a diagnosis of Lewy Body Dementia	None	c.1053dupC p.(Gly352fs)	Heterozygous	Pathogenic	1 bp duplication
13	Canada	F	74	72	Gait problems, jaw tremor, micrographia	Parkinsonism	Mild external ophthalmoplegia with ptosis, jaw tremor, mild cerebellar symptoms, RBD, constipation, hyposmia, anxiety. Responsiveness to L‐dopa, motor and non‐motor fluctuations	None	Mild cerebellar atrophy	c.861dup p.(Asn288)	Heterozygous	Pathogenic	1 bp duplication
14	Portugal	M	60	50	Gait problems	Dystonia‐ataxia	Dementia, cervical and truncal dystonia, spastic tetraparesis, neuropathy, cerebellar ataxia	None	Cortical global atrophy	c.‐9C > T‐5'UTR	Heterozygous	Pathogenic	Single nucleotid
15	Portugal	M	54	48	Speech and gait problems	Cerebellar syndrome	Cerebellar ataxia, right pyramidal syndrome	None	Cerebellar atrophy	c.397C > T p.(Arg133Trp)	Heterozygous	Pathogenic	SNV single nucleotide variation/missense variant
16	Canada	M	79	69	Balance and gait problems	Cerebellar syndrome	Cerebellar ataxia	Father with AD, 2 siblings with memory problems	Cerebellar atrophy (vermis). Amyloid angiopathy, periventricular white matter changes	c. 1450‐446_1779 + 746 delinsAAAGTGCT	Heterozygous	Pathogenic	Deletion

Abbreviations: F, female; M, male; MD, movement disorder; MRI, magnetic resonance imaging; NA, not available; RBD, REM sleep behavior disorder; SPG7, spastic paraplegia type 7.

A cerebellar syndrome (lower limb predominant) was the most frequent movement disorder phenotype, present in seven subjects, followed by a mixed phenotype of dystonia‐ataxia in three subjects, parkinsonism in two, dystonia‐parkinsonism in one, and a combination of parkinsonism‐dystonia‐ataxia in one. Finally, one subject developed a multiple system atrophy type C (MSA‐C) phenotype, while another showed an isolated dystonia as the main clinical feature. Among those with coexistent parkinsonism, improvement in their symptoms with dopaminergic therapy was observed, and one of them developed motor fluctuations from levodopa therapy.

Upper motor neuron signs were found in 11 subjects, spastic paraparesis was the most common form of presentation, seen in six individuals. There were two cases in which spastic tetraparesis were found. Two subjects had signs of sensory neuropathy, whereas another showed a sensorimotor axonal neuropathy on electrophysiological studies.

Ocular movement abnormalities were found in 10 subjects; up gaze limitation was the most common finding, followed by ophthalmoparesis/ophthalmoplegia (one of these subjects had also ptosis), skew deviation, and square wave jerks. None of them had optic atrophy.

Imaging studies were available in 15 subjects, with global cortical cerebellar atrophy being the most frequent finding in 10 of them. Interestingly four subjects revealed hyperintensities in the frontal horns of the lateral ventricles (“ears of the lynx” sign) (Fig. 1).

FIG. 1.

Axial MRI from subjects 1 (A), 7 (B), 10 (C) and 11 (D) showing frontal horn hyperintensities at FLAIR and T2 sequences, consistent with “ears of the lynx” sign.

We found a total of 11 different SPG7 variants; whole exome sequencing was used in all patients. Seven cases were heterozygous, compound heterozygous in five and homozygous in four. The c.1529C > T (p.Ala510Val) genetic variant was the most frequent finding, present either as homozygous, heterozygous, or compound heterozygous state.

Main clinical features from these subjects are shown in the (Video 1).

Video 1.

Main clinical features from 16 cases with movement disorders associated to SPG7 pathogenic variants.

Discussion

SPG7 is typically an autosomal recessive pure or complicated HSP resulting from homozygous or compound heterozygous mutations in the SPG7 gene. A dominant/heterozygous mode of inheritance has also rarely been reported, ⁴ however, a recent report challenged this notion finding that one such patient with ataxia and spastic paraplegia carried a second deep intronic variant only identified by whole‐genome sequencing. ⁶ Although this disease is associated with mutations in the SPG7 gene, the distribution of expression of this gene in different tissues suggests that other mutations of SPG7 may exist that are associated with different phenotypes. ⁷

In addition to spastic paraplegia, large cohorts of SPG7 subjects have shown complex phenotypes. However, additional movement disorders such as cervical dystonia, myoclonus, and parkinsonism have also been reported. ⁴ , ⁵ More recently, single cases of spasmodic dysphonia, ⁸ limb dystonia, ⁹ palatal tremor, ¹⁰ and two cases of MSA‐C like ¹¹ , ¹² have widened the spectrum with most of these new cases, showing little or no spasticity (Table 2). Large cohorts have also included cases without any sign of spastic paraplegia. ⁴

TABLE 2.

Uncommon movement disorders associated with SPG7 pathogenic variants

Author	Age at onset, y	Sex	Clinical features	MRI	SPG7 variant	Genotype status
Hall et al 8	17	M	Spasmodic dysphonia, spasticity, dysphagia	Normal	c.233 T4A (p.Leu78X)	Homozygous
Schaefer et al 9	40	M	Limb dystonia, cerebellar ataxia, mild spasticity	Normal	c.2096dupT, p.(Met699Ilefs*4) c.1529C > T (p.Ala510Val)	Compound heterozygous
van Gassen et al 5	16	F	Cervical dystonia, spasticity	NA	c.2115‐2131del (p.Leu706fs)	Homozygous
	48	F	Cervical dystonia, spasticity	NA	c.861dup, p.Asn288X c.2228 T > C (p.Ile743Thr)	Compound heterozygous
De la Casa‐Fages et al 4	30	M	Myoclonus, head dystonia, tremor	Cerebellar and cortical atrophy	c.1529C > T, p.(Ala510Val)	Homozygous
	50	M	Pisa Syndrome, parkinsonism	Cortical atrophy	c.1529C > T, p.(Ala510Val)	Homozygous
Gass et al 10	41	M	Palatal tremor, macrocephaly, cognitive decline, lower limb weakness/spasticity	Mild cerebellar atrophy	p.Ala510Val (c.1529C > T) p.Arg485_Glu487del (c.1454_1462del)	Compound heterozygous
Campins‐Romeu et al 16	17	M	Multifocal dystonia with prominent bulbar and cervical involvement	Mild cerebellar atrophy and T2‐weighted hyperintensities of the cerebral peduncles	c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val)	Homozygous
Coarelli et al 17	NA	NA	Dystonia	NA	NA	NA
	NA	NA	Parkinsonism	NA	NA	NA

Abbreviations: F, female; M, male; MRI, magnetic resonance imaging; NA, not available; SPG7, spastic paraplegia type 7.

Cerebellar ataxia is a common finding in SPG7 variants. ¹³ The combination of cerebellar ataxia and autonomic features (MSA‐C‐like phenotype), as shown in case 2, seems to be even more unusual. Beyond ataxia, parkinsonism is the most common movement disorder described in SPG7 pathogenic variants and has been reported to be present in 21% of SPG7 subjects. ⁴ In case 11, parkinsonism and dystonia had a remarkable response to the combination of pramipexol and rasagiline.

With respect to dystonia, focal type (cervical) has been one of the most frequent findings in large SPG7 cohorts. ⁵ However, generalized forms, as shown in case 10 have not been previously reported. The latter started at the age of 5 years with dystonia in the lower extremities that generalized by the time he was 7 years old, dystonic features were not responsive to levodopa. Moreover, case 5 had both spasmodic dysphonia and writer's cramp, which have been described separately in single case reports. ⁸ , ⁹

Multiple radiologic findings can be seen, including cerebellar and brain atrophy, ⁴ , ⁵ as shown in some of our cases. The “ears of the lynx” sign, consisting in T2 and fluid attenuated inversion recovery (FLAIR) hyperintensities at the frontal horns of the lateral ventricles, have been commonly described among SPG11 and SPG15 cases; however, some SPG7 cases can also present this magnetic resonance imaging (MRI) sign. ¹³

Functional imaging of cases with dopa‐responsive parkinsonism associated with SPG7 mutations have demonstrated bilateral nigrostriatal presynaptic dopaminergic denervation, which provides clear evidence that SPG7 subjects have a more widespread brain involvement besides the pyramidal tracts. ⁴ , ¹⁴

Although a clear mechanism by which SPG7 pathogenic variants could cause disease is uncertain, evidence indicates that SPG7 mutations induce mitochondrial biogenesis, possibly causing the clinical abnormalities commonly found among these subjects. The mechanisms involved are upregulation of mitochondrial gene expression, protein synthesis, and increased mitochondrial mass, which are typical for a mitochondrial disorder. In accordance with this, progressive external ophthalmoplegia and ptosis fall within the spectrum of complex SPG7 phenotypes, which are classical presenting features of mitochondrial disease. ¹⁵

The wide spectra of age at onset, progression, and symptoms, together with the clinical overlap with other neurological diseases and the high degree of genetic heterogeneity, has made it difficult to establish phenotype–genotype correlations in large cohorts carrying SPG7 variants. ¹ However, in our case series, two unrelated subjects with dystonia (cases 10 and 11) had the same SPG7 heterozygous likely pathogenic variant (c.1468G > T, p.Glu490Ter). The related cases 1 and 2 showed the most frequent variant encountered in SPG7 cases, the homozygous variant (c.1529C > T p.[Ala510Val]) ⁴ , ⁵ and more often associated with ataxia than with spastic paraplegia, ¹ nevertheless one of these cases showed both clinical features, perhaps associated with a longstanding disease. Case 12 showed a heterozygous pathogenic variant (c.1053dupC [p.Gly352fs]) that has been reported in compound heterozygous state in individuals with HSP ⁵ and cases 5–9 carried the same compound heterozygous variants that were reported in three quarters of all patients in a large case series. ⁴

Although heterozygous variants had been previously described among SPG7 cases, some of these could manifest disease throughout different genetic mechanisms, mainly those manifesting parkinsonism as a core feature. Whole exome sequencing (WES) and panels designed for parkinsonism, dystonia, and other neurodegenerative diseases were sought in most of our heterozygous cases, but additional information was not obtained from them. However, we cannot confirm at this point if the aforementioned heterozygous variants are completely responsible for the phenotype found among those subjects. Further, we did not perform WES, so we cannot exclude the possibility of an additional deep intronic variant as reported recently. ⁶ In addition to the intronic variants, another possibly implicated mechanism in our heterozygous SPG7 variants is digenic inheritance (carrying two mutations in different HSP genes). Recently, in a large Canadian SPG7 cohort, 6.5% carried biallelic SPG7 variants. We found that the number of pathogenic/likely pathogenic SPG7 alleles in HSP cases is higher than in controls, suggesting potential dominant or digenic inheritance in some. ³

Regarding clinical features, comparing between heterozygous and biallelic variant carriers, some differences have been found. As in a recently published SPG7 case series, ¹⁶ our compound heterozygous subjects (and even those with heterozygous variants) showed more complex phenotypes including dystonia, parkinsonism, tremor, and external ophthalmoplegia, than those with homozygous variants, which showed mainly cerebellar syndromes. However, there are also single SPG7 cases with movement disorders reported in the literature, in a homozygous state (Table 2).

In accordance with this, a study of 585 HSP subjects from 372 families and 1175 controls, upper extremity ataxia (37.9%) and intent tremor (30%) were relatively common in biallelic carriers of SPG7 variants, but none of the heterozygous carriers showed these symptoms. On the other side, subjects with heterozygous SPG7 variants had younger age at onset compared to those with biallelic variants (16.5 vs. 33.8 years; P = 0.021). ³

Finally, single heterozygous SPG7 mutations have also been identified in cases with chronic progressive external ophthalmoplegia, ataxia and lower limb spasticity. ¹⁵

This case series widens the spectrum of SPG7 mutations. Clinicians must consider SPG7 mutations as a possible etiology in movement disorders of unknown origin or in single or familial cases with combined movement disorders, and alternatively, clinicians must look for movement disorders in this entity, because these clinical features could have been previously underreported.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

M.S.F.: 1A, 1B, 1C, 3A

A.E.L.: 1A, 2B, 2C, 2C, 3A 3B

L.K.: 1B, 1C, 3A

I.C.:1B, 1C, 3A

M.S.: 1B, 1C, 3A

G.K.: 1B, 1C, 3A

C.G.: 1B, 1C, 3A

R.M.: 1A, 3A, 3B

A.F.:1A, 2C, 3A 3B

C.E.P.A.: 3B

C.Z.R.: 1A, 1B, 1C, 2A, 2B, 3A, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. This study was approved by the local Ethics Committee from each hospital. Patients have signed consent for video acquisition and publication.

Funding Sources and Conflicts of Interest: The authors declare no funding sources or conflicts of interest.

Financial Disclosures for the Previous 12 Months: M.S.F. has no disclosures to declare. A.E.L. has served as an advisor for AbbVie, Acorda, AFFiRis, Biogen, Denali, Janssen, Lilly, Lundbeck, Maplight, Paladin, Retrophin, Roche, Sun Pharma, Sunovion, Theravance, and Corticobasal Degeneration Solutions; received honoraria from Sun Pharma, AbbVie and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J. Safra Philanthropic Foundation, the Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; received publishing royalties from Elsevier, Saunders, Wiley‐Blackwell, Johns Hopkins Press, and Cambridge University Press. L.K. has received salary support for this work from Canadian Health Institutes of Research (CIHR) Clinician–Scientist Award. In the past year, L.K. has received research support from CIHR, the Michael J. Fox Foundation for Parkinson's Research, Natural Sciences, and Engineering Research Council of Canada (NSERC), Ontario Brain Institute, Parkinson Canada, and Toronto General and Western Hospital Foundation; held contracts with ApoPharma and UCB; and, received honoraria from National Institutes of Health (NIH) and Takeda. I.C. has no disclosures to declare. M.S. has no disclosures to declare. G.K. has no disclosures to declare. C.G. is supported by a VolkswagenStiftung Fellowship (Freigeist). He received honoraria for serving as ad hoc advisory board for Biomarin pharmaceutical and Orphazyme, and for educational activities of the Movement Disorder Society. R.P.M. has no disclosures to declare. A.F. has served as an advisor for Apple, AbbVie, Abbott, Medtronic, Boston Scientific, Sunovion, Chiesi Farmaceutici, UCB, Ipsen, and Rune labs; received honoraria from American Academy of Neurology, AbbVie, Abbott, Medtronic, Boston Scientific, Sunovion, Chiesi Farmaceutici, UCB, Ipsen, Paladin Lab, and Movement Disorders Society; received grants from University of Toronto, AbbVie, Medtronic, Boston Scientific, MSA Coalition, and McLaughlin Centre. C.E.P.A. has no disclosures to declare. C.Z.R. has no disclosures to declare.