X‐Linked Dystonia‐Parkinsonism in a Manifesting Female: First Case Report of Deep Brain Stimulation

X‐linked dystonia‐parkinsonism (XDP), affecting mostly male Filipinos from Panay, results in progressive neostriatal neuronal loss, causing severe dystonia and later parkinsonism. ¹ , ² Despite variable clinical courses, it usually manifests with severe, progressive dystonia, followed by parkinsonism in later years of life. ³ It has a prevalence rate of 0.31 per 100,000 in the Philippines. ⁴ There are currently >1200 men diagnosed with XDP compared with only 15 cases of symptomatic women. ⁵ Women who present primarily with hyperkinetic symptoms have on average a younger age at onset (44 years) compared to those who present with dominant parkinsonian symptoms (66 years). ⁵ Deep brain stimulation (DBS) in the globus pallidus internus (GPi) has shown efficacy in XDP treatment but faces cost barriers. ⁶ This case report explores a rare female XDP patient's significant improvement 1 month and 1 year post‐DBS.

The patient is a 43‐year‐old Filipino woman who first presented with blepharospasm at 39 years of age. Initially diagnosed with myasthenia gravis, she was later referred to a neurologist. Within 4 years, her symptoms progressed rapidly from blepharospasm to dysphonia, forceful involuntary mouth opening, dystonic movements of the tongue and jaw, predominantly triggered by attempts to speak and chew, and generalized dystonia characterized by sustained and intermittent involuntary muscle contractions involving the neck, trunk, arms and legs (Video 1). Baseline Burke‐Fahn‐Marsden Dystonia Rating Movement Scale (BFMDRS) was 77 (Severe).

Video 1.

This is a video of the patient before DBS.

Coming from an XDP endemic region in the Philippines, the patient's two brothers and mother were diagnosed with XDP (Fig. S1, Table S1; Supplementary Results). Genetic testing in the available patients confirmed the XDP‐causing mutation in the TAF1 gene (Fig. S2; Supplementary Results). Both the index patient and her mother exhibited imbalanced X‐chromosome inactivation (skewed towards preferential expression of the mutated allele in blood: proband: 2:98, proband's mother: 10:90), most likely explaining their disease manifestation. Out of the patient's four sons, three were free of the XDP haplotype, and one was not tested (Fig. S1).

Treatment with a combination of levodopa and carbidopa, clonazepam, biperiden, zolpidem, and Botulinum toxin A provided minimal resolution. Consequently, a multidisciplinary group recommended bilateral GPi DBS, which was performed as described in the Supplementary Methods (Table S2, Fig. S3).

Two weeks post‐surgery, full programming resulted in significant improvement, with generalized dystonia notably reduced. One month post‐DBS, the patient exhibited remarkable progress, including improved speech intelligibility, absence of dystonia and parkinsonism, and independence in daily activities. She had a Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) score of 1. One year post‐DBS, optimal parameters for left and right GPi were determined, resulting in a BFMDRS score of 4.5 with stimulation alone at 12 months. Blepharospasm, and cervical, arm, and trunk dystonia were completely resolved, with mouth closure improving and swallowing normalized. There was still dysarthria and minimal bradykinesia and rigidity. Mobility and gait returned to normal, and no new parkinsonian symptoms were observed (Fig. 1).

Figure 1.

Burke Fahn Marsden Dystonia Rating Scale (BFMDRS): Movement Scale.

Currently, the patient is undergoing physical and speech therapy, showcasing the efficacy of GPi DBS in ameliorating XDP symptoms.

Bilateral GPi DBS has proven effective in reducing dystonic symptoms in XDP. Targeting GPi addresses abnormal neuronal firing patterns, inducing excitatory and inhibitory effects that modulate the basal ganglia thalamocortical network. ⁷ Studies often show immediate, striking results, with a 34%–95% improvement in dystonia symptoms. The presented case of a female XDP patient revealed a remarkable 97% improvement at 1 month post‐DBS and an 83% improvement after 1 year based on the BFMDRS. It is theorized that XDP females, having less striatal degeneration, may experience even higher improvement rates. ⁸ However, parkinsonism symptoms, including residual dysarthria, gait problems, and bradykinesia, may be less responsive independent of the underlying sex. ⁹

The patient's candidacy for DBS stemmed from significant disability due to dystonia, being unresponsive to medical management, a rapidly progressive symptom onset, and confirmation of XDP on genetic testing, which supports the likelihood of a favorable response to DBS. Baseline scores for the Unified Parkinson Disease Rating Scale, XDP‐Movement Disorder Society of the Philippines, and BFMDRS were taken before the GPi DBS procedure, which led to an immediate and substantial improvement in symptoms, especially dystonia resolution (Tables S3 and S4; Video 2). One year post‐DBS, while the BFMDRS score increased slightly, the improvement remained considerable albeit with some progression in dysarthria and gait problems. Considering the progressive nature of the disorder, it is not surprising to see these results 1 year post‐DBS. The patient continued her engagement in physical and speech therapy, along with regular multidisciplinary follow‐ups for DBS reprogramming and medication adjustments. The successful outcome highlights the importance of multidisciplinary collaboration and personalized treatment approaches for complex neurological disorders.

Video 2.

(Left) This is a video of the patient 1 month post‐DBS and (Right) 1 year post‐DBS

The presented case marks the first symptomatic female XDP patient undergoing DBS with remarkable improvement. While GPi DBS is still relatively rare for XDP in the Philippines, it proves effective for symptomatic dystonia‐predominant females, offering comparable benefits to male counterparts. Immediate and significant improvement in the patient's quality of life was observed up to 1 year post‐DBS. However, a slight decline in improvement from baseline after 1 year is noted. Considering XDP's progressive nature, the long‐term efficacy of DBS remains uncertain. Nevertheless, GPi DBS stands as a valuable modality post suboptimal pharmacologic and supportive management.

Author Roles

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

A.N. B: 1A, B, C, 2A.

R.L.R: 1A, B, C, 2A, 2B.

C.E.D: 2A.

J.Q.O: 2A.

A.W: 1B, 1C, 2B.

N.B: 1B, 1C, 2B.

C.K: 2B.

Disclosures

Ethical Compliance Statement: The authors confirm that this case report was approved by the Research Ethics Committee of the University of Santo Tomas Hospital, Manila, Philippines. Written informed consent was obtained and documented through having the patient and one witness (blood relative) sign the informed consent form. The authors confirm that they 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 Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: A.W. and C.K. serve as advisors to CENTOGENE GmbH. C.K. is also an advisor to Retromer Therapeutics and Takeda and has received speaking honoraria from Desitin and Bial, and royalties from Oxford University Press. N.B. Dr. Brüggemann received honoraria from Abbott, Abbvie, Biogen, Biomarin, Bridgebio, Centogene, Esteve, Ipsen, Merz, Zambon. The remaining authors declare that there are no additional disclosures to report.

Supporting information

Figure S1. Index patient's pedigree.

Figure S2. Index patient's blood RNA‐derived cDNA sequence of the XDP‐specific single‐nucleotide change 3 (DSC3) showing that the patient preferentially expresses the mutated (T) allele (arrow, upper figure).

Figure S3. Pre‐operative (DBS) cranial MRI, B. Post‐operative cranial radiography showing bilateral pallidal stimulation of DBS.

Table S1. Detailed genetic testing of index patient and two family members (mother, one brother).

Table S2. DBS Settings immediately post‐operatively, 4 months post‐operatively, 6 months post‐operatively, and 1 year post‐operatively.

Table S3. XDP–Movement Disorder Society of the Philippines (MDSP) Scale.

Table S4. Unified Parkinson's Disease Rating Scale (UPDRS).