Long‐Term Outcomes of Deep Brain Stimulation in Woodhouse–Sakati Syndrome

Abstract

Background

Woodhouse–Sakati syndrome (WSS) is a rare autosomal recessive disease with distinctive neuroendocrine manifestations, with dystonia being the most common. No clear guidelines are available for the treatment of dystonia in WSS.

Objective

The aim was to analyze the impact of deep brain stimulation (DBS) on WSS‐associated dystonia.

Methods

Patients with genetically confirmed WSS who underwent globus pallidus internus (GPi) DBS for dystonia were analyzed retrospectively. The participants were assessed using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) and were videotaped pre‐ and post‐surgery at multiple follow‐up points. The primary outcome was the BFMDRS score at 1 year post‐surgery, compared with baseline. The primary outcome was correlated with preoperative factors, including age at onset, disease duration at surgery, proportion of life lived with dystonia, and severity rate.

Results

Five patients with severe progressive generalized dystonia secondary to clinically and genetically confirmed WSS underwent bilateral GPi DBS from February 2011 through September 2023. The mean age at disease onset and at the time of DBS was 11.3 and 18.6, respectively. All patients' BFMDRS total scores improved from baseline to 12 months post‐DBS. The mean pre‐DBS BFMDRS score was 71.1, and the mean post‐DBS BFMDRS score was 43.6. The percentage improvement in the BFMDRS mean score from pre‐ to post‐DBS was approximately 39%.

Conclusions

Our case series showed clinical improvement in patients who underwent bilateral GPi DBS as an advanced therapy for generalized dystonia secondary to WSS. We recommend further research on DBS in a larger sample of WSS patients to obtain significant results. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Woodhouse and Sakati first described the rare autosomal recessive Woodhouse–Sakati syndrome (WSS) in 1983. WSS is distinguished by several multisystemic features, including a wide range of neurological manifestations that are typically progressive. ¹ Alopecia, hypogonadism, diabetes mellitus, intellectual disability, sensorineural hearing loss, and movement disorders are the cardinal traits of WSS. Other signs include seizures, brain white matter anomalies, polyneuropathy, thyroid dysfunction, keratoconus, and syndactyly of the hands or feet. ² More than 50% of reported patients exhibit movement disorders, which include dystonia, cogwheel rigidity, tremor, choreoathetosis, and ataxia. ² , ³

One of the most common symptoms of WSS is dystonia. ³ , ⁴ , ⁵ Dystonia is defined as sustained or intermittent abnormal movements, postures, or both. Dystonia is classified by body distribution as focal, segmental, multifocal, hemidystonia, or generalized dystonia. ⁶ WSS patients are more likely to experience dystonic spasms combined with dystonic posturing. The first neurologic manifestation is dystonia, which begins subtly in childhood or early adolescence. Dystonia progresses and becomes generalized and disabling in most patients. ⁷

The age at onset, specific symptoms, and symptom intensity vary greatly across individuals with WSS, even those within the same family. Such phenotypic variability might delay diagnosis or lead to misdiagnosis. ⁵ , ⁷ WSS predominantly affects the Middle Eastern population, although the illness has been observed in people of other ethnicities, including those in Europe and Asia. Homozygous pathogenic mutations in the DCAF17 gene (formerly known as C2orf37) on chromosome 2q31 are the primary cause of WSS. To date, over 11 genetic variants have been linked to WSS. Those with the same Saudi Arabian progenitor DCAF17 pathogenic mutation exhibited a wide range of phenotypic variations. ⁵

Several brain imaging modalities have been used to assess WSS characteristics. The most common brain MR abnormalities in WSS include a small pituitary gland, iron accumulation in the globus pallidus, and nonenhancing frontoparietal/periventricular white matter alterations. WSS can be distinguished from other neurodegenerative illnesses by white matter abnormalities and pituitary involvement. ⁴

Deep brain stimulation (DBS) is regarded as the cornerstone of treatment for many medication‐refractory movement disorders. There is convincing evidence that globus pallidus internus (GPi) DBS can be used to treat isolated dystonia (either generalized or segmental). Limited data are available on this treatment, and little is known about how DBS affects dystonia resulting from uncommon genetic factors. GPi DBS efficacy in WSS is unknown. ⁸

Treatment for WSS is symptomatic and must be conducted by a multidisciplinary team; regarding dystonia, treatment frequently starts with an oral medication trial followed by a botulinum toxin injection in some individuals and, finally, DBS. ³

In this study, we investigated the effects of DBS surgery in a cohort of genetically confirmed WSS patients, focusing on functional status and overall life satisfaction. We also outlined the distinctive intraoperative gross anatomical characteristics of WSS patients.

Patients and Methods

Patient Selection and Surgical Procedure

Patients of any age diagnosed with WSS based on clinical characteristics and genetic testing who underwent surgery at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia, up to September 2023 were included. Patients with a high suspicion of WSS without genetic confirmation or managed medical management, including supportive therapy, were excluded. All patients with severe dystonia were deemed refractory to multiple oral medications because of insufficient clinical benefit before DBS was considered (Table 1). Programming was performed based on the standard practice of Toronto Western Hospital algorithms (DBS parameters are similar to Parkinson's disease programming; a detailed description is provided in reference). ⁹ DBS amplitude and pulse widths were gradually increased as tolerated without side effects. Multiple contacts and frequencies were tested when the response was suboptimal.

TABLE 1.

Demographics, DBS parameters, and outcomes of study subjects

Subject	Age at diagnosis (yr)	Genetic test results	Family history	Age at surgery (yr)	Disease duration at surgery (yr)	DBS target	Last stimulation parameters				Dystonia distribution	Additional clinical features beyond dystonia	Medications failed before DBS	Medication used after DBS	Additional clinical improvement beyond dystonia		Surgical complications/battery replacement
							Contact	Amplitude	Frequency (Hz)	PW (μs)					Pre‐DBS BMI	Post‐DBS BMI
1	14	DCAF17	None	24	11	BL GPi	R C+ (−2 –3) L C+ (−2 –3)	4 4	190 190	120 120	Generalized	Dysarthria	C/L 300 daily Tetrabenazine 50 mg daily Trihexyphenidyl 7.5 mg daily BTX injection	Baclofen 45 mg daily Tetrabenazine 75 daily Trihexyphenidyl 10 mg daily BTX injection	18.5	21	None/2019 and 2021
2	10	DCAF17	None	20	10	BL GPi	R C+ −9 –10 L C+ (−1)	2.5 2.3	130 130	60 60	Generalized	Dysarthria	C/L 750 daily Baclofen 40 mg daily	C/L 500 mg daily Baclofen 30 mg daily	19.7	23	None/2021
3	17	DCAF17	Brother with WSS and neurological complications	20	3	BL GPi	R C+ −1 −2 L C+ (−1 –2)	3.6 3.6	150 150	120 120	Generalized	Dysarthria and dysphagia	Baclofen 45 mg daily C/L 450 daily Clonazepam 2 mg daily Trihexyphenidyl 6 mg daily	None	26	27.5	None/2021
4	14	DCAF17	Sister with WSS and neurological complications	19	4	BL GPi	R C+ (−1) L C+ (−8)	4 4	200 200	90 90	Generalized	Dysarthria and dysphagia	C/L 200 daily Trihexyphenidyl 6 mg daily BTX injection for jaw muscles	C/L 200 mg daily Trihexyphenidyl 5 mg daily	14	20	None/2015, 2017, 2020
5	1.5	DCAF17	Sister with WSS without neurological complications	10	9	BL GPi	R C+ (−2) L C+ (−2 –3)	4 3	130 130	60 60	Generalized	Dysarthria and dysphagia	C/L 500 daily Trihexyphenidyl 3 mg daily Baclofen 30 mg daily	Baclofen 30 mg daily	10	11.4	None/none

Abbreviations: DBS, deep brain stimulation; BMI, body mass index; DCAF17, DDB1‐ and CUL4‐associated factor 17; PW, pulse width; BL, bilateral; GPi, globus pallidus internus; R, right; C, case; L, left; C/L, carbidopa/levodopa; BTX, bottonium toxin; WSS, Woodhouse–Sakati syndrome.

Statistical Analysis and Ethical Considerations

All patients were assessed using the Burke–Fahn–Mardsen Dystonia Rating Scale (BFMDRS) and videotaped before and after surgery at different follow‐up points. ¹⁰ Two patients were not assessed using the BFMDRS prior to surgery; the BFMDRS was retrospectively applied to the videos recorded at baseline and different follow‐up points. Our primary outcome was the BFMDRS score difference from baseline (before surgery) at 1 year post‐DBS surgery. The differences in patients' disability scores at baseline and 1 year post‐DBS, changes in medication, and encountered adverse events were the secondary outcomes. Variables were summarized and reported using descriptive statistics. Interval variables, such as the age at diagnosis and time of DBS surgery, were summarized and reported as means and standard deviations. Categorical variables, such as symptoms at onset, were summarized and reported as frequency distribution. All categorical and interval variables were compared statistically across the study using χ² and t tests, respectively. Finalized data are presented as the minimum, maximum, mean, and standard deviation. The median and interquartile range were assessed for nonnormally distributed factors.

Data access was limited to the involved study authors. Strict confidentiality was maintained during data collection and analysis. The principal investigator was in charge of data storage and backup. Access to data was limited. All participants or their caregivers provided informed consent to use their records in this study. Video recording of patients was permitted for publication purposes and medical tracking. Ethics approval was obtained from the institution (study approval number RAC 2221122).

Results

Five patients with severe progressive generalized dystonia secondary to clinically and genetically confirmed WSS underwent bilateral GPi DBS as an advanced therapy for medication‐refractory dystonia from February 2011 through September 2023 (Table 1). The mean age at disease onset was 11.3, and that at DBS surgery was 18.6. The oldest and youngest patients who underwent DBS were 24 and 10, respectively. The mean duration from disease onset to DBS surgery was 7.4 years, with the shortest period being 3 years. All patients tried and failed to obtain benefits from at least two first‐ and second‐line dystonia treatments before undergoing DBS surgery (Table 1). All patients' BFMDRS total scores improved from baseline to 12 months post‐DBS (Fig. 1). The mean pre‐DBS BFMDRS score was 71.1, and the mean post‐DBS BFMDRS score was 43.6. The percentage improvement in the BFMDRS mean scores from before to after DBS was ~39. All dystonia regions assessed using the BFMDRS improved in all patients (Fig. 1). The neck and trunk regions demonstrated the most significant improvement as assessed using the BFMDRS, followed by the arms and legs. Regarding the mouth, the speech and swallowing regions exhibited mean score improvements from 5.3 to 3.8 and 12.4 to 10, respectively. Patient mean body mass index (BMI) scores increased from 17.64 at baseline to 20.58 12 months after surgery. Further details of the BFMDRS score of each category with mean scores and percentage improvement are presented in Appendixes 1 and 2. All patients underwent bilateral GPi DBS for severe generalized genetic combined dystonia; 4 had omnidirectional leads, and 1 had directional leads. Most patients required high DBS parameter settings, with amplitudes ranging from 2.3 to 4 V or milliamperes, depending on the DBS manufacturer device, pulse widths ranging from 60 to 120, and frequencies ranging from 130 to 200.

FIG. 1.

BFMDRS mean scores pre‐DBS and post‐DBS. BFMDRS, Burke–Fahn–Marsden Dystonia Rating Scale; DBS, deep brain stimulation. [Color figure can be viewed at wileyonlinelibrary.com]

Discussion

DBS targeting the GPi has been established as a highly effective method for improving the quality of life and the BFMDRS scores of individuals with isolated generalized and segmental dystonia. Moreover, these benefits have been shown to persist over 5 years, indicating the long‐term efficacy of this treatment approach. ¹¹ , ¹² , ¹³ This study reports the clinical outcome of patients with genetically confirmed WSS who underwent DBS as an advanced therapy. All patients had generalized dystonia as the prominent neurological complication. The BFMDRS was used as the assessment instrument to measure dystonia severity at the 12‐month follow‐up. All patients underwent bilateral GPi DBS for generalized dystonia. All patients demonstrated improved BFMDRS scores, and the percentages of clinical improvement varied, averaging 39%. All patients exhibited meaningful axial improvement in the BFMDRS at 1 year post‐DBS. A literature search revealed 2 patients with WSS who underwent bilateral GPi DBS for generalized dystonia. ¹ , ² One patient with generalized dystonia secondary to WSS who underwent bilateral GPi DBS demonstrated improved BFMDRS scores (from 50 to 27) at the 12‐month follow‐up. ⁸ The study has several limitations. The small sample size limits statistical power and generalizability of the findings. The nonblinded design and the absence of a control group constitute additional limitations. For 2 patients, DBS surgery was performed more than 10 years ago, and BFMDRS scores were obtained retrospectively from preoperative video recordings. The follow‐up period was limited to 1 year, with no objective data on the durability of therapeutic effects beyond this time frame. Due to the progressive nature of WSS, longer‐term studies are necessary to fully assess the sustained efficacy and long‐term safety of DBS.

Despite the use of high DBS settings, all but 1 patient still required multiple medications to manage severe dystonia. BFMDRS scores beyond 12 months are not reported here; however, our patients continued to benefit from GPi DBS beyond the first year post‐DBS, and most patients required implanted pulse generator (IPG) battery changes every 2 years. GP DBS should be considered a part of severe generalized dystonia management in WSS, along with medications to alleviate symptoms and improve quality of life.

Combined dystonia has unpredictable outcomes; results reported in the literature are varied, and the evidence is not as strong as that for isolated dystonia. A study of 8 patients with combined dystonia revealed a BFMDRS mean rate of improvement of 41.4%. ¹⁴ Another study revealed a 39% improvement in BFMDRS at a mean follow‐up of 29 months. ¹⁵ Bilateral GPi DBS in a patient with combined dystonia secondary to Pantothenate kinase‐associated neurodegeneration (PKAN) showed a mean BFMDRS score improvement from 76 at baseline to 54 at the 12‐month follow‐up. The result differs between classical and atypical PKAN, with atypical PKAN patients demonstrating better BFMDRS scores. ¹⁶

No correlation existed between the BFMDRS score and patient demographic factors observed in our series. The presence of other neurological impairments, such as speech and swallowing difficulties, affected the accuracy of BFMDRS scoring in our patients. Speech impairment was the least likely symptom to respond to GPi DBS in our patients. However, all patients demonstrated an increased BMI at the 12‐month follow‐up compared to pre‐DBS, potentially indicating improved swallowing. Two years after GPi DBS surgery, 1ne patient (patient D) experienced weight loss and worsened generalized dystonia according to the BFMDRS. We found that he had a depleted IPG battery.

One patient underwent DBS surgery at age 10; the remainder developed dystonia during childhood but underwent DBS surgery after age 18. The evidence for DBS in pediatric patients is limited; however, numerous positive results have been reported for isolated and combined dystonia, and isolated dystonia demonstrates a better outcome. ¹⁷ , ¹⁸ , ¹⁹

None of our patients demonstrated surgical complications from GPi DBS. One patient developed stimulation‐induced gait impairment that did not improve despite DBS parameter adjustment. However, this patient demonstrated improved BFMDRS scores.

Although not significant, the BFMDRS improvement observed in our study indicates that all patients should benefit from GPi DBS, as reflected in symptom improvement observed in our patients and their greater independence in daily living activities. WSS is a rare and complex neuroendocrine disorder, and GPi DBS can be considered a third‐line treatment to manage severe medication‐ and botulinum toxin injection‐refractory dystonia.

Author Roles

H.A. and Y.A. contributed to the design of the study, analyzed the data, drafted and revised the manuscript for intellectual content, and approved the final version for publication. S.A. and S.B. revised the manuscript for intellectual content and approved the final version for publication. A.A. and F.A. conceived and designed the study, directed the acquisition of data, analyzed the data, drafted and revised the manuscript for intellectual content, and approved the final version for publication.

Financial Disclosures and Conflicts of Interest

Author disclosures are available in the Supporting Information.

Appendix 1. Detailed BFMDRS scores of each category for all subjects.

Pre‐DBS	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Average
Eyes	0	0	0	0	0	0
Mouth	8	2	6	8	4	5.6
Speech and swallowing	12	9	9	16	12	11.6
Neck	6	2	2	8	8	5.2
Right arm	12	12	8	16	16	12.8
Left arm	8	12	8	16	16	12
Trunk	12	4	0	16	16	9.6
Right leg	12	8	4	16	16	11.2
Left leg	12	8	4	16	16	11.2
Total score	82	57	41	112	104	79.2

Post‐DBS	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Average
Eyes	0	0	0	0	0	0
Mouth	8	0	4	6	1.5	3.9
Speech and swallowing	12	9	6	12	4	8.6
Neck	4	0	2	2	0.5	1.7
Right arm	8	8	8	8	16	9.6
Left arm	8	8	8	8	4	7.2
Trunk	4	0	0	4	16	4.8
Right leg	8	4	8	8	12	8
Left leg	8	4	8	8	4	6.4
Total score	60	33	44	56	58	50.2

Abbreviations: BFMDRS, Burke–Fahn–Marsden Dystonia Rating Scale; DBS, deep brain stimulation.

Appendix 2. Mean score BFMDRS before DBS, post‐DBS, and percentage of improvement.

Subject	Mean score BFMDRS pre‐DBS	Mean score BFMDRS 1 year post‐DBS	Improvement percentage
1	9.1	6.6	27
2	6.3	3.6	42
3	4.5	4.8	–10
4	12.4	6.2	50
5	11.5	6.4	44

Abbreviations: BFMDRS, Burke–Fahn–Marsden Dystonia Rating Scale; DBS, deep brain stimulation.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author on reasonable request. The data are not publicly available due to privacy or ethical restrictions.