Journal of Neurology

, Volume 263, Issue 8, pp 1604–1611 | Cite as

A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings

  • Alexandros A. Polymeris
  • Alessandra Tessa
  • Katherine Anagnostopoulou
  • Anna Rubegni
  • Daniele Galatolo
  • Argirios Dinopoulos
  • Artemis D. Gika
  • Sotiris Youroukos
  • Eleni Skouteli
  • Filippo M. Santorelli
  • Roser Pons
Original Communication

Abstract

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. Adult case series dominate the literature, and there have been only a few studies in children. The purpose of this study is to describe our experience with pediatric HSP in Greece. We report the clinical and genetic findings in our patients and aim to offer insights into the diagnostic difficulties of childhood-onset disease. A series of 15 Greek children affected by pure HSP underwent extensive diagnostic investigations. Molecular analysis included whole exome sequencing (WES) or consecutive screening of candidate genes ATL1, SPAST, REEP1, and CYP7B1. WES performed in three cases yielded previously reported mutations in ATL1 and CYP7B1, and a variant c.397C>T of unknown significance in SPG7. Candidate gene screening performed in the remaining patients identified previously reported mutations in ATL1 (2), SPAST (2), and REEP1 (1), and two novel mutations, c.1636G>A and c.1413+3_6delAAGT, in SPAST. In six cases, the mutations were inherited from their parents, while in three cases, the mutations were apparently de novo. Our data confirm the genetic heterogeneity of childhood-onset pure HSP, with SPG4/SPAST and SPG3A/ATL1 being the most frequent forms. De novo occurrence of HSP does not seem to be uncommon. Candidate gene studies guided by diagnostic algorithms and WES seem both to be reasonable genetic testing strategies.

Keywords

Hereditary spastic paraplegia Pure Early onset Children Mutation screening 

Introduction

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness, resulting from the length-dependent, retrograde axonal degeneration of the corticospinal fibers. Traditionally, HSP is classified as pure (uncomplicated) and complicated. Pure HSP is characterized by spastic paraparesis occasionally accompanied by mild sensory deficits in the lower limbs and bladder dysfunction. In complicated HSP, spastic paraparesis is accompanied by variable combinations of other manifestations, such as extrapyramidal disturbances, ataxia, epilepsy, cognitive deficits, peripheral neuropathy, and neuroimaging abnormalities [1, 2]. HSP is rare, with prevalence estimates ranging from 1.2 to 9.6 per 100,000. The age of symptom onset varies widely from infancy to late adulthood [1].

The genetics of HSP are complex; the disorder can be inherited as an autosomal dominant (AD), autosomal recessive (AR), X-linked, or even maternal trait [2]. The number of genetic loci associated with the disease, designated as spastic paraplegia genes (SPGs), is continuously increasing. To date, over 70 SPG loci have been mapped and over 50 genes have been identified [2, 3].

The medical literature on HSP is dominated by adult case series, and there have been only a few studies in children [4, 5, 6, 7]. Diagnosing HSP in pediatric cases can be challenging in the absence of a positive family history. Indeed, sporadic cases seem to represent the majority of pediatric HSP patients, rendering HSP a diagnosis of exclusion, once structural lesions and neurometabolic disorders have been ruled out [4, 5].

Many SPGs have been reported to cause childhood-onset pure HSP. SPG4 (SPAST) is the most prevalent HSP subtype, accounting for 50 % of AD cases, and presents mostly as a pure form with variable age of onset, including childhood [8]. SPG3A (ATL1) accounts for 10 % of AD HSP, typically presenting as a pure form with infancy or early childhood onset. In fact, SPG3A accounts for 30 % of early onset AD HSP and is the most frequent cause of HSP with onset before age 10 years [8, 9]. Early onset pure AD HSP has also been linked to SPG31 (REEP1) and less frequently to SPG6, SPG10, and SPG12 among others [5, 8]. AR HSP forms are less common than the dominant ones and usually pertain to the complicated phenotype. Among them, SPG5A (CYP7B1) and SPG7 (paraplegin) have been associated with early onset presentation [2, 4, 8].

Here, we report a series of 15 Greek children with pure HSP. The purpose of this study, which to the best of our knowledge is the first to report on pediatric HSP in Greece, is to describe the clinical features and genetic findings in our patients and offer insights into the diagnostic difficulties of childhood-onset HSP useful to the pediatric neurologist.

Patients and methods

This series includes 15 unrelated Greek children of non-consanguineous parents (patients 1–15), 12 males, and 3 females, who were referred to the Pediatric Neurology Unit, a third-level referring center at University Children’s Hospital Aghia Sophia, Athens from 2007 to 2015.

A detailed history, including perinatal events, developmental milestones, and family history, as well as a thorough neurological examination were taken in all patients. Siblings and parents were also examined. Walking disability was assessed using a four-grade functional status scale (modified from the original work published elsewhere [6,10]): grade 1, spastic gait with no or mild functional limitation; grade 2, spastic gait with moderate limitation (patient walks independently but is unable to run, and climbs stairs with difficulty); grade 3, spastic gait with severe limitation (patient needs assistance walking); and grade 4, patient is wheelchair bound most of the daytime.

Paraclinical investigations included brain and spinal MRI, an extensive biochemical workup in peripheral blood (vitamin B12, folic acid, vitamin E, lactic acid, ammonia, prolactin, lysosomal enzymes, very long chain fatty acids), urine (organic acids), and cerebrospinal fluid (cell count, glucose, protein, lactic acid, amino acids, and neurotransmitters), and molecular studies as described below.

Molecular studies

Genomic DNA was extracted from peripheral blood according to standard procedures, and either one of the following genetic testing strategies was used:
  1. 1.

    Whole exome sequencing (WES): WES was performed, following the standard procedures, and gene analysis was focused on all known SPGs available at the time of the test (http://www.ncbi.nlm.nih.gov/gtr/). All mutations detected were confirmed by Sanger sequencing on an ABI 3500xL (Life Technologies, Carlsbad, CA). Following WES, multiplex ligation-dependent probe amplification (MLPA) analysis was performed when indicated using the appropriate MLPA kits (MRC-Holland, Amsterdam, the Netherlands). All genetic investigations were performed at the commercial diagnostic laboratory Genomedica S.A., Piraeus, Greece.

     
  2. 2.

    Candidate gene screening: Consecutive screening of ATL1 (SPG3A), SPAST (SPG4), REEP1 (SPG31), and CYP7B1 (SPG5A), including Sanger sequencing of coding exons and flanking sequences. MLPA analyses of ATL1, SPAST, and REEP1 were also performed (MLPA kits P165-C2 and P213-B1, MRC-Holland). All genetic investigations were performed in a single neurogenetic laboratory (IRCCS Stella Maris, Pisa, Italy), following the standard procedures [11] under the direction of expert molecular geneticists (AT, FMS).

     
The diagnosis of pure HSP was made according to the following criteria:
  1. 1.

    Pure spastic paraparesis including pyramidal tract signs (spasticity, hyperreflexia, Babinski sign) with or without associated impairment of lower limb proprioception or vibration sense, pes cavus, urge incontinence, and upper limb hyperreflexia;

     
  2. 2.

    Uneventful perinatal history;

     
  3. 3.

    Positive family history or, in apparently sporadic cases, exclusion of brain or spinal cord lesions on MRI and exclusion of neurometabolic disorders.

     

Patients showing additional complicating neurological features were excluded from this study.

This study was performed in accordance with the Helsinki declaration. Informed written consent was obtained from the patients’ parents.

Results

Medical history (Table 1)

The age of onset of the disease was difficult to ascertain in many cases. The first symptoms were reported at 3.5 ± 3.4 years (mean ± SD), and the diagnosis of HSP was reached at 6.9 ± 4.9 years.
Table 1

Medical history

Patient

Age at diagnosis (years)

Sex

Age at first symptoms (years)

Presenting symptom

Age at learning to walk (months)

Orthopedic history

Family history

Functional statusa at diagnosis

Therapeutic interventions

1

2.1

M

1.2

Abnormal gait

14

2

Botox

2

13.2

M

10.5

Abnormal gait

12

Hip osteochondritis

2

Baclofen, botox

3

14.2

M

3

Abnormal gait

14

flatfeet

2

Achilles lengthening, baclofen, botox

4

2.2

F

2

Delayed walking

24

+

2

Ankle–foot orthoses

5

10

M

6.5

Abnormal gait

18

Hip osteochondritis

1

Achilles lengthening

6

2.5

M

2

Delayed walking

22b

N/Ab

7

15.7

M

12

Abnormal gait

9

Flatfeet

+

2

Achilles lengthening

8

3.5

F

1.3

Abnormal gait

15

2

ankle–foot orthoses

9

2.8

F

1.5

Abnormal gait

24

1

botox

10

8.5

M

1

Abnormal gait

16

1

11

5

M

2.5

Abnormal gait

18

Hyperlordosis

1

12

2.5

M

2

Abnormal gait

17

+

1

Botox

13

3.5

M

2

Abnormal gait

10

+

1

14

6.7

M

4

Leg pain

9

+

1

15

11.3

M

1.5

Abnormal gait

48

2

Hamstring lengthening, botox, ankle–foot orthoses

M male, F female, N/A not applicable

aScale described in Patients and methods

bPatient 6 started walking with support at the age of 22 months and had not reached independent ambulation by the age of 2½ years. After his evaluation, he was lost to follow-up

Twelve children presented with abnormal gait and difficulty walking, two with delayed walking and one with ‘leg pain’. Other symptoms included ‘toe walking’, frequent falls, and ‘stiff legs’. Nine children showed gait difficulties immediately after walking skills were acquired, whereas the remaining (pts 2, 3, 5, 7, 13, 14) developed an abnormal gait later in childhood or adolescence. Acquisition of motor milestones was delayed in four children. Cognitive development was normal in all cases. Perinatal history was uneventful. Five children had a previous history of orthopedic problems.

A family history of HSP with AD inheritance was present in five patients. Four (pts 4, 12–14) had a parent with early onset spastic paraparesis and one (pt 7) had a family history of spastic paraparesis with variable age of onset in several members on the maternal side. His mother did not complain of motor symptoms, though brisk reflexes and bilateral Babinski sign were detected on examination.

Clinical features

Symmetric spasticity, hyperreflexia often with clonus in the lower limbs and bilateral Babinski sign were the predominant clinical findings in all cases. Muscle strength in the lower limbs was relatively preserved, with only five children presenting mild proximal weakness. Five patients developed Achilles tendon contractures and two had foot deformities, namely, pes cavus and pes equinus. Two patients had sensory disturbances in the lower limbs and two had occasional urinary symptoms. Brisk reflexes of the upper limbs were noted on examination in five children, one of whom also showed mild upper limb hypertonia. The clinical features of all patients are summarized in Table 2.
Table 2

Clinical features and genetic findings

Patients

Clinical features at diagnosis

Genetic testing

Lower limb muscle strength

Lower limb sensory disturbance

Lower limb deformities

Urinary symptoms

Upper limb involvement

Testing strategy

Altered gene

Nucleotide change

Aminoacid change

Parents’ status

1

Normal

Achilles contracture

WES

ATL1

c.1065C>A

p.Asn355Lys

Noncarriers

2

Normal

Vibration, proprioception

Achilles contracture

WES

CYP7B1

c.[266A>C];[250_250delC]

p.[Tyr89Ser];[Leu84PhefsX6]

Carrier mother; father

3

Proximal weakness

Achilles contracture, pes cavus

Urgency

Hyperreflexia

Candidate gene screening

SPAST

c.1413+3_6delAAGT

 

N/A

4

Proximal weakness

Candidate gene screening

ATL1

c.715C>T

p.Arg239Cys

Carrier mother

5

Normal

Vibration

Achilles contracture

WES, MLPA for SPG7

SPG7

c.[397C>T];[=]a

p.Arg133Trpa

Carrier mother

6

Proximal weakness

pes equinus

Candidate gene screening

   

7

Normal

Achilles contracture

Hyperreflexia

Candidate gene screening

   

8

Proximal weakness

Candidate gene screening

   

9

Normal

Hyperreflexia

Candidate gene screening

SPAST

c.1636G>A

p.Gly546Arg

Noncarriers

10

Proximal weakness

Incontinence

Candidate gene screening

SPAST

c.1245+5G>A

 

Carrier father

11

Normal

Parental refusal

    

12

Normal

Candidate gene screening

   

13

Normal

Candidate gene screening

ATL1

c.715C>T

p.Arg239Cys

Carrier father

14

Normal

Hyperreflexia

Candidate gene screening

REEP1

c.166G>A

p.Asp56Asn

Carrier father

15

Normal

Hypertonia, hyperreflexia

Candidate gene screening

SPAST

c.1496G>A

p.Arg499His

Noncarriers

WES, whole exome sequencing; candidate gene screening: consecutive screening of ATL1, SPAST, REEP1, and CYP7B1, described in patients and methods; MLPA, multiplex ligation-dependent probe amplification; N/A, not available

aProbably benign variant (see “Discussion”)

Disease severity and progression

According to the functional status scale aforementioned, walking disability was estimated as mild (grade 1) in seven children and moderate (grade 2) in another seven. One patient had not acquired independent ambulation by the time of our latest examination. All patients received physical therapy, while further therapeutic interventions were less commonly needed: three children underwent Achilles tendon and one hamstring lengthening, three used ankle–foot orthoses, two received oral baclofen and six Botox injections (Table 1).

Clinical follow-up was available in eight patients (pts 1–5, 8, 9, 12), ranging from 0.6 to 8 years (3 ± 2.7 on average). Patients were generally stable clinically, exhibiting either a static or a very slowly progressive disease course. None of them showed significant additional functional limitations.

Genetic testing

Genetic testing was performed on all patients but one (pt 11) due to parental refusal. The testing strategies used and their results in the patients and their parents are summarized in Table 2.

WES analyses in three cases yielded a previously reported [12] heterozygous mutation c.1065C>A/p.Asn355Lys in ATL1, two already reported [13] mutations c.250_250delC/p.Leu84Phefs*6 and c.266A>C/p.Tyr89Ser in CYP7B1, and a heterozygous point variant c.397C>T/p.Arg133Trp in SPG7. This SPG7 variant is listed twice in the ExAC Browser [14], and according to in silico analyses adopting prediction software SIFT, PolyPhen and Mutation Taster may be deleterious. MLPA analysis of SPG7 (MLPA kit P213-B1, MRC-Holland) did not detect the presence of deletion or duplication in the other allele.

Candidate gene screening in the remaining patients identified pathogenic mutations in seven cases:

In ATL1, two patients harbored a previously reported heterozygous mutation c.715C>T/p.Arg239Cys [10].

In SPAST, two patients carried the previously reported heterozygous mutations c.1245+5G>A [15] and c.1946G>A/p.Arg499His [16], one patient carried a novel heterozygous mutation c.1413+3_6delAAGT that predictably affects the splicing sequence of intron 11, and another patient carried a novel heterozygous missense mutation c.1636G>A/p.Gly546Arg. The latter mutation is located in the spastin AAA domain, a protein domain where additional pathogenic variants have been associated with SPG4 HSP.

In REEP1, one patient harbored a previously reported heterozygous mutation c.166G>A/p.Asp56Asn [17].

In three patients, the mutations found were apparently de novo, including the c.1065C>A in ATL1 and the c.1946G>A and c.1636G>A in SPAST.

Discussion

Cerebral palsy manifesting as spastic paraparesis in children with a history of premature birth is caused by an acquired insult to the developing brain and is a common problem in pediatric neurology practice. Structural spinal or cerebral lesions and rare metabolic or demyelinating disorders, including l-dopa responsive dystonia and leukodystrophies, may also present with spastic paraparesis [2, 5, 18]. HSP underlies spastic paraparesis in a limited number of cases. Reaching the HSP diagnosis in pediatric cases is challenging, especially in the absence of a positive family history. Many patients are misdiagnosed with cerebral palsy, even when there is no antecedent of a perinatal sentinel event and no lesions detected on brain imaging [19, 20].

In our series, all children showed an insidious onset and static or very slowly progressive course, leading to mild or moderate disability. These observations are in accordance with other pediatric series of pure HSP [4, 6], in which patients did not worsen significantly over the years, contrary to late-onset patients who gradually worsen over time [3]. This non-progressive or slow course of pure early onset HSP can also contribute to the misdiagnosis of cerebral palsy in sporadic cases [20].

The majority of reported early onset pure HSP cases follow an AD pattern of inheritance [5, 6]. However, only 1/3 of our patients had a family history consistent with an AD transmission. Intrafamilial variability with differences in age of onset and disease severity is observed in HSP [3, 6], and apparent genetic anticipation, whereby a child becomes symptomatic before his parents, has been described [1]. It is therefore important to examine the asymptomatic parents and search for pyramidal signs [5], as in the case of the mother of patient 7.

In our cohort, 2/3 of the cases were sporadic. Researchers increasingly recognize that the apparently sporadic occurrence of HSP is not uncommon [4, 8]. Truly sporadic cases due to de novo mutations can occur [19, 20]. Furthermore, somatic mosaicism in unaffected parents has also been described [21]. In our series, three patients (one with SPG3A and two with SPG4) harbored mutations that were absent in their parents, and their siblings were healthy. Unfortunately, we did not obtain consent for paternity testing to ensure the lack of hereditability of these mutations.

In addition to the age of onset and disease severity, variability in HSP can also occur in the type of presentation. While mutations in common HSP genes have been associated with different hereditary neuropathies [12, 22], other SPGs can present as either a pure or a complicated HSP form [3]. In our series, the mutation in ATL1 in patient 1 had been previously reported in a family with hereditary sensory neuropathy type I and variable upper motor neuron involvement [12]. In patient 2, the two mutations detected in CYP7B1 had also been previously reported in a patient with marked sensory ataxia and mild lower limb pyramidal signs [13].

In contrast with the pediatric series described elsewhere, where all patients showed normal gross motor development [4], delay in motor milestones was noted in about 1/4 of our patients. Furthermore, in more than half of our cases, gait difficulties were evident, since the child first attempted walking. Our data indicate that childhood-onset HSP may often manifest itself as early as the first 2 years of life and that delayed gross motor development may be the first such manifestation.

An excess of males over females (12:3) was noted in our series, similar to larger HSP case series [17, 23]. In a recent meta-analysis, it has been suggested that HSP caused by mutations in SPAST occurs more often in males, speculating on the neuroprotective role of estrogens [24]. Future studies in larger case series will help determine whether gender-dependent penetrance applies to other early onset HSPs [25].

Several children in our study had first consulted an orthopedist due to variable orthopedic problems and two had been diagnosed with hip osteochondritis prior to their HSP diagnosis. To the best of our knowledge, this arthropathy is not characteristic of spastic paraplegia and has not been previously reported in HSP. It is likely that the occurrence of osteochondritis in our patients is incidental.

Muscle strength in the legs was relatively preserved, with only 1/3 of patients presenting mild proximal weakness. Similar observations are reported elsewhere, particularly in patients with early onset disease [6, 23]. Additional findings frequently described in pure HSP [1] were also noted in our patients, including posterior column sensory deficits, bladder disturbances, upper limb hyperreflexia, and pes cavus. Of note, SPG3A HSP seems to be less frequently associated with such features [26], which was also our experience with none of our SPG3A patients presenting additional findings.

We reached a genetic diagnosis in about 2/3 of our patients, which is relatively high compared with other studies [4, 17]. WES identified pathogenic mutations in 2 out of 3 patients and candidate gene screening in 7 out of 11. Bearing in mind the limitation of our small sample size, both genetic testing strategies seemed to have a similar diagnostic yield.

Our data confirm the genetic heterogeneity of childhood-onset pure HSP. SPG4 was the most common HSP form (29 %) in our cohort, followed by SPG3A (21 %). This is in contrast to the previous observation that SPG3A is twice as frequent as SPG4 in patients with onset before age 10 years [9]. A study of Italian children with sporadic pure HSP also reported a similar frequency of SPG4, but no SPG3A cases. The authors postulated that SPG3A was underrepresented in their sporadic HSP cohort, since it is most often associated with a recognizable familial occurrence [4]. This might also be the case for our cohort, which comprised mostly of sporadic cases. A recent study of adult Greek HSP patients suggests that SPG3A is altogether rarer in the Greek population compared with other western European populations [17]. SPG31 and SPG5A were rarer HSP forms in our cohort, consistent with other reports [5, 8, 17].

Patient 5 in our series carried a heterozygous variant in SPG7 which was inherited from his presently asymptomatic mother. A second mutation could not be found. It is probable that this is an incidental finding of a benign variant. Other possibilities include the presence of a second mutation in an as yet unknown regulatory region, including the promoter or internal intron sequences. A mutation acting dominantly, or the possibility of digenic inheritance, as speculated in other cases with heterozygous mutations in SPG7 [27, 28], might be an alternative explanation.

In summary, we described our experience with a series of 15 Greek children affected by pure HSP. This study confirms the genetic heterogeneity of childhood-onset pure HSP and further corroborates the notion that the disease might, not uncommonly, arise de novo. The absence of a positive family history should not deter pediatric neurologists from considering HSP when more obvious etiologies have been excluded. Pediatric HSP patients can present with delayed walking or variable gait difficulties even in toddlerhood. Investigating asymptomatic first-degree relatives would be sensible in both suspected and definitively diagnosed cases of HSP. The diagnostic yield of well-thought algorithms for candidate gene screening [2, 4, 5, 8], first targeting both SPAST and ATL1, does not seem to be inferior to that of WES. Both genetic testing strategies seem to be reasonable in pediatric pure HSP.

Notes

Compliance with ethical standards

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards

This study was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. Informed written consent was obtained from the patients’ parents.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Alexandros A. Polymeris
    • 1
  • Alessandra Tessa
    • 2
  • Katherine Anagnostopoulou
    • 3
  • Anna Rubegni
    • 2
  • Daniele Galatolo
    • 2
  • Argirios Dinopoulos
    • 4
  • Artemis D. Gika
    • 1
  • Sotiris Youroukos
    • 1
  • Eleni Skouteli
    • 5
  • Filippo M. Santorelli
    • 2
  • Roser Pons
    • 1
  1. 1.First Department of PediatricsAghia Sophia Children’s Hospital, University of AthensAthensGreece
  2. 2.Molecular Medicine and NeurogeneticsIRCCS Stella MarisPisaItaly
  3. 3.Molecular Genetics DepartmentGenomedica S.A.PiraeusGreece
  4. 4.Third Department of PediatricsAttikon Hospital, University of AthensAthensGreece
  5. 5.Neonatal Intensive Care UnitIASO, MITERA and REA HospitalsAthensGreece

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