First Clinicogenetic Description of Parkinson's Disease Related to GBA Mutation S107L

ABSTRACT

Background

Mutations in the glucocerebrosidase gene (GBA) are a common genetic risk factor for Parkinson's disease (PD). Mutations in the N‐terminus part of GBA are less commonly found in association with PD than those in the C‐terminus. Phenotypic characterization of GBA‐related PD has been challenging, in part attributed to differential impact of distinct GBA mutations.

Aim

To provide a phenotypic description of two patients with PD heterozygous for the GBA mutation S107L. The S107L mutation is located in the catalytic domain of glucocerebrosidase and has not previously been reported in patients with PD.

Methods

Motor and nonmotor symptoms (NMS) of PD were evaluated using established rating scales and questionnaires. The genotype was determined by Sanger sequencing.

Results

Two half‐brothers, both heterozygous carriers of S107L, exhibited an early PD onset with several NMS.

Conclusions

In these patients, heterozygosity for S107L was associated with an early onset of PD with NMS.

Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase deficient in Gaucher disease (GD), are a common genetic susceptibility factor for Parkinson's disease (PD).1 More than 300 mutations have been identified in GBA, several of which are associated with PD, but the pathological mechanisms underlying this association remain largely unknown.2 For individual cases, GBA‐related PD (GBA‐PD) and idiopathic PD (iPD) are indistinguishable.2 However, overall in cohorts, an earlier age of onset and increased risk of cognitive decline are reported in GBA‐PD compared to iPD.3, 4 For carriers of severe GBA mutations, the correlation with the GBA‐PD phenotype is more apparent, with an increased odds ratio for PD, earlier age of disease onset, and increased risk of dementia, compared to carriers of mild mutations.5, 6

S107L (p.Ser146Leu) is a rare GBA mutation in exon 4, and only 5 cases of GD with this mutation appear in the literature.7, 8, 9, 10, 11 Two cases were compound heterozygotes with L444P (p.Leu483Pro), leading to acute neuronopathic GD (type 2) and death before the age of 1. Two cases suffered from chronic neuronopathic GD (type 3), one with genotype S107L/N188S (p.Asn227Ser) who survived until the age of 19, and the fourth with genotype F213I (p.Phe252Ile)/S107L, who died at age 3.5. The fifth case, with genotype N370S (p.Asn409Ser)/S107L, had non‐neuronopathic GD (type 1) with symptomatic bone disease and massive splenomegaly, treated by a splenectomy at age 12. Based on these case reports, S107L is categorized as a rare and severe GBA mutation.12 S107L is located in an α‐helix in the catalytic domain of glucocerebrosidase,13 possibly causing a dramatic reduction in enzymatic activity resulting in severe disease.

Here, we report, for the first time, the clinical and genetic findings of two half‐brothers with relatively early‐onset PD, both heterozygous for the GBA mutation S107L.

Materials and Methods

The study was approved by the local research ethics committee (2016/19‐31/2), and participants provided written informed consent. The family members included in the study is marked by an asterisk (“*”) in the pedigree in Figure 1. They underwent standardized neurological examination as well as testing for several nonmotor symptoms (NMS). Genotype was determined by Sanger sequencing. For details see Supporting Information Methods S1.

Figure 1.

(A) Family pedigree for S107L mutation in GBA. Squares and circles indicate males and females respectively; slash deceased; ^*individuals genotyped. Age indicates the age at neurological examination. (B) Example of Sanger sequencing result from healthy control and case II (II:5) showing the heterozygote mutation.

Results

Demographic and clinical data for both cases are summarized in Table 1.

Table 1.

Demographic and clinical findings in two S107L heterozygotes with PD

	Case 1	Case 2
Sex/age	M/44	M/53
Ethnicity	Swedish	Swedish
Age of onset	37	47
Disease duration	8 years	6 years
Presenting symptom	Asymmetrical resting tremor	Asymmetrical impaired alternating hand movements
Motor symptoms	Bilateral rigidity, freezing, dystonia, bradykinesia, motor fluctuations	Rigidity, myoclonus, impaired alternating hand movements
Autonomic dysfunction	Yes	Yes
Depression	Yes	No significant
Signs of RBD	No	Yes
Environmental risk factors/protective factors	None/premorbid 8 cups of coffee per day	Chemical exposure (painter)/nicotine use (“snus”) 40 years, 2 to 3 cups of coffee per day
Total UPDRS on/off (UPDRS‐III)	74/101 (43/61)	30 (17)
H & Y stage	4	2
MoCA	25/30	25/30
UPSIT	18/40	22/40
MADRS‐S	14/54	4/54
BDI‐II	20/63	9/63
HADS	18/42	10/42
NMS‐Quest	4/30	12/30
PDQ‐39SI	66,5/100	24,5/100
PSQI	9,5/21	3/21
EQ‐5D‐5L/EQ VAS	22222/80/100	22212/80/100
Mental fatigue	10,5/44	10/44

Signs and Symptoms

Case 1 (II:4)

A previously healthy 37‐year‐old man, of Swedish descent, presented with signs of retrobulbar neuritis and, self‐reported, tremor. During the medical investigation, the patient developed parkinsonian symptomatology with asymmetric bradykinesia and rigidity as dominating symptoms. No resting tremor was documented. Neurofilament light protein (NFL) was slightly elevated in cerebrospinal fluid (CSF), while dementia markers (Tau, phospho‐Tau and Aβ_1‐42) were within the normal range. In addition, there was one strong and two to three weak oligoclonal bands, as well as an elevated immunoglobulin G index. Magnetic resonance imaging (MRI) showed three nonspecific periventricular high‐intensity T₂ lesions. However, he did not fulfill the diagnostic criteria for multiple sclerosis, and the symptoms of retrobulbar neuritis were not detected at follow‐up. Moreover, his MRI picture is unchanged after 8 years. ¹²³I‐FP‐CIT single‐photon emission computed tomography (DaTSCAN) revealed a pronounced reduction in dopamine uptake bilaterally, but more augmented on the right side, consistent with PD or other parkinsonian syndrome. He was diagnosed with early onset PD and treated with a dopamine D2 receptor agonist, pramipexole, and subsequently with rotigotin, in addition to levodopa. The symptoms initially responded to l‐dopa treatment, and after 5 years of rapid progression, he was prescribed duodenal l‐dopa infusion instead. Upon examination, 8 years after disease onset, his upper extremities were bilaterally severely affected by painful dystonia, frequent freezing, severe rigidity, and general bradykinesia. He experienced rapid motor fluctuations, with UPDRS‐III scores that varied from 43 to 61, despite continuous l‐dopa infusion. A mild peak‐dose dyskinesia was noted in his right foot. There were no signs of tremor. H & Y stage was 4. He reported severe fatigue and depression, for which venlafaxine was prescribed. Despite treatment, his Montgomery‐Åsberg Depression Rating Scale (MADRS‐S) was 14 of 56, Beck Depression Inventory‐II (BDI‐II) was 20 of 63, and Hospital Anxiety and Depression Scale (HADS) was 18 of 42, indicating persisting symptomatology. His Montreal Cognitive Assessment (MoCA) score was 25/30, with difficulties in visualspatial/executive and delayed recall functions. Orthostatic blood pressure measurements did not indicate significant autonomic dysfunction. Loss of smell was quantified using 40‐item University of Pennsylvania Smell Identification Test (UPSIT), which showed severe hypoosmia (18/40 p). Previous constipation was ameliorated after initiation of infusion therapy. He denies symptoms of rapid eye movement sleep behavioral disorder (RBD) on specific questions. NMS scales (Non‐Motor Symptoms Questionnaire [NMS‐Quest] and mental fatigue), as well as life‐quality scales (39‐item Parkinson's Disease Questionnaire [PDQ‐39], EuroQoL [EQ‐5D]), indicated difficulties in several aspects of daily life (Table 1).

Case 2 (II:5)

At 47 years of age, the half‐brother of the aforementioned case, a previous painter exposed to chemicals, noted impaired coordination and rigidity in his left hand and leg. Two years later, he was diagnosed with PD. He received the monoamine oxidase B inhibitor, selegiline, which was complemented with the dopamine D2 receptor agonist, ropinirole, with satisfying alleviation of symptoms. Six years after disease onset, he experienced relatively mild motor symptoms, but several NMS. Motor symptoms reported included unilateral impairment of alternating hand movements, mild general bradykinesia, impaired gait, and left hand tremor. Upon examination, mild rigidity was observed bilaterally in the upper extremities, and a bilateral postural tremor was identified. No signs of resting tremor were noted. His UPDRS‐III was 17. He did not experience significant motor fluctuations or dyskinesias. H & Y stage was 2. Regarding NMS, mild depression‐like symptoms were reported, most disabling. However, his MADRS‐S was 4, BDI‐II 9, and HADS 10, confirming a limited extent of symptoms. His MoCA was 25 with deficits in visualspatial/executive functions and delayed recall. He recalled losing his sense of smell several years before the onset of motor symptoms, confirmed by an UPSIT demonstrating severe hypoosmia (22/40 p). From an early age, he had lively dreams and dream‐enacting behavior reminiscent of RBD. He also reported symptoms of intermittent orthostatic hypotension, which could not be confirmed. Other NMS included mild constipation and erectile dysfunction. Scales for NMS and quality of life confirm that case 2 is less affected than case 1. Lumbar puncture showed a slight increase in NFL (1,090 ng/L; reference, <890 ng/L), but no increase in Tau or β‐amyloid. No signs of inflammation were evident in the CSF. His MRI is normal, but the DaTSCAN shows a reduced dopamine uptake bilaterally with a more pronounced decrease on the right side.

None of the other family members showed any signs or symptoms of neurological disorders. In particular, their 82‐year‐old mother (I:4) showed no signs of parkinsonism or reported any NMS, including depression, RBD, smell loss, or constipation.

Genetic Results

Both half‐brothers, and their mother and cousins, were found to be heterozygous for the GBA mutation S107L (Fig. 1). Case III:1, a child previously diagnosed with GD, carried GBA mutation N370S on the second allele. No other GBA mutations were detected in the patients or controls.

Discussion

Here, we present, for the first time, the clinical features of PD in heterozygote S107L GBA mutation carriers. To our knowledge, only 5 cases with this specific GBA mutation have been published previously.7, 8, 9, 10, 11 All, except one, of these cases had neuronopathic GD and died at a young age. Mutations in the first exons of GBA are much less common than in exons 8 to 11,14 and many studies therefore only sequence the last exons of GBA. Prevalence of the S107L GBA mutation therefore may be underestimated. However, in three multicenter studies, the entire coding region of GBA was sequenced in a total of 4,100 PD or Lewy body dementia patients,1, 15, 16 and S107L was not detected in any case.

Our observation of relatively early disease onset in both cases, and, in the first case, a rapid disease progression of motor symptoms, is in accord with a severe phenotype of S107L GBA. Interestingly, neither of the cases exhibited the PD cardinal sign, resting tremor. GBA mutation carriers have previously been found to have a lower frequency of resting tremor compared to noncarriers.17 Studies claim that GBA mutation status increases the prevalence of motor complications. Here, case 1 experienced both severe motor fluctuations and mild dyskinesia, whereas case 2 exhibited neither. Jesús et al. reported a higher progression rate of treatment‐associated motor complications in GBA‐PD, but their patients had a longer disease duration (11.4 ± 5.3 years) than our cases.17

NMS are reported to be more frequent in GBA‐PD than in iPD.18 Olfaction has been reported as the most common NMS in GBA‐PD,19 which is in line with our present observations. Likewise, autonomic dysfunction, self‐reported by our cases, has previously been reported to be more common in GBA‐PD compared to iPD.18 RBD has previously been linked to GBA‐PD and has been suggested as a marker for prodromal PD to identify individuals at risk.20 Case 2 showed symptoms of classic RBD since an early age. However, neither case 1 nor the other carriers in the family have RBD. On the other hand, none of the present cases or mutation carriers have marked cognitive decline, which is often associated with GBA mutations. Recent data suggest that the risk of developing dementia increases with the severity of the GBA mutation.6 A cautionary note is that the cases reported here have experienced a relatively short disease duration and both show minor deficits in visualspatial/executive functions and delayed recall, the same domains as reported impaired in GBA carriers with early‐onset PD.3

Conclusion

The strong association between GBA mutations and an increased risk of PD is well established, but genotype‐phenotype correlations remain to be better understood. The clinical phenotype of PD related to the GBA mutation, S107L, appears to be a relatively early onset of motor symptoms of PD in combination with a variety of NMS. However, as reported here, even within a family the clinical course of GBA‐PD varies considerably. This highlights the need for further studies investigating genetic and environmental modifiers. Stringent clinical descriptions are the first step in deciphering the phenotypic variations, and will enhance our understanding of the underlying disease mechanisms.

Author Roles

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

E.H.: 1A, 1B, 1C, 3A

M.T.: 3B

B.H.: 3B

M.M.: 3B

E.S.: 1B, 3B

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

Disclosures

Ethical Compliance Statement: This study was approved by the Local Research Ethics committee (Regionala Etikprövningsnämnden Stockholm, 2016/19‐31/2). Participants provided oral and written informed consent. 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.

Funding Sources and Conflicts of Interest: Ellen Hertz is funded by a PhD collaboration program between Karolinska Institute, Wallenberg Clinical Scholar and PhD collaboration program and the National Institutes of Health. Ellen Sidransky was supported by the intramural research program of the National Human Genome Research Institute and of the National Institutes of Health. Maciej Machaczka and Per Svenningsson are supported by ALF funding from Stockholm City Council and Parkinsonfonden. Per Svenningsson is a Wallenberg Clinical Scholars. The authors report no conflicts of interest.

Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.

Supporting information

Methods S1. Detailed information on materials and methods.

Appendix S1. Primers. Primers used to Sanger sequence GBA.