Phasic Knee Bending Dystonic and Parkinsonian Gait: A Characteristic Finding in X‐Linked Dystonia Parkinsonism

ABSTRACT

Background

X‐linked dystonia parkinsonism (XDP) is a rare disorder characterized by adult‐onset, progressive dystonia that, over time, is combined with or replaced by features of parkinsonism. Gait impairment is common.

Methods

Case series of 4 XDP patients with a unique gait disorder.

Results

The patients displayed a characteristic gait disorder with combined dystonic and parkinsonian gait features, with phasic knee bending. Of these patients, all had parkinsonism and three‐quarters had prominent dystonic features, but 1 had predominant parkinsonism and subtle dystonic features.

Conclusion

Although XDP is a classic form of dystonia parkinsonism, some cases can mimic idiopathic Parkinson's disease. We describe a gait disorder which appears unique to XDP, involving phasic dystonic knee bending superimposed on parkinsonian shuffling, and may help clinically differentiate one of our parkinsonian‐predominant patients from more‐common forms of parkinsonism. The gait is distinct from other complex dystonic disorders with gait involvement.

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312929-sup-v001_1.htm

Introduction

X‐linked dystonia parkinsonism (XDP) is a rare neurogenetic movement disorder, found in individuals of Filipino ancestry and particularly from Panay Island.1 XDP is characterized by adult‐onset, progressive dystonia that, over time, is combined with or replaced by features of parkinsonism.1, 2 On the island of Panay, where XDP is endemic, the reported disease prevalence is approximately 5.74 cases per 100,000 persons, with the highest rate of 18.9 cases per 100,000 in the province of Capiz.1 Recently, our group identified that the genetic cause is a hexameric repeat expansion within the SINE‐VNTR‐Alu (SVA) intronic region of the TATA‐box binding protein associated factor 1 (TAF‐1) gene on the X‐chromosome, with a larger repeat length correlating with an earlier age at onset.3 Typically, disease onset is in the third or fourth decades in men and is heralded by focal dystonia that generalizes over time. The dystonia then recedes and is replaced by features of parkinsonism. Parkinsonian features, in some patients, may be clinically indistinguishable from idiopathic Parkinson's disease (PD), with classical resting tremor, rigidity, and bradykinesia.4

Gait impairment is common in XDP, with parkinsonian features, including shuffling gait, festination, and freezing, and dystonic features including frequent truncal involvement, with often early dystonic lower‐extremity involvement.5 Although dystonia parkinsonism in XDP is well recognized, we highlight an unusual, dystonic knee bending gait, which has been alluded to in previous publications as a phasic knee bending gait and appears unique to XDP.2, 5

Subjects and Methods

This research was performed in accordance with the Declaration of Helsinki and with approval of the ethics board of the Massachusetts General Hospital (MGH) and the local Philippines Jose Reyes Memorial Medical Center Institutional Review Board/Research Ethics Committee. Patients were assessed in the Philippines at the XDP Clinic Centrum, Roxas City, Capiz, locally in their homes, or at the Jose Reyes Memorial Medical Center, Manila, and provided written consent for their videos to be published. The cases described were part of 52 consecutively enrolled XDP patients who are part of our ongoing research program in North America and the Philippines, who were assessed by a standardized video examination protocol. All videos included in the case series were reviewed by movement disorders specialist neurologists (C.S., C.G., and N.S.). All patients had genetic confirmation testing at MGH and were found to carry the SVA insertion in the TAF‐1 gene.

Case Series

In our series of 52 consecutive XDP patients, 9 patients had only features of parkinsonism, which could be indistinguishable clinically from PD or other commoner causes of parkinsonism, and 1 patient had only dystonia on assessment. Of 9 patients with parkinsonian and dystonic features involving gait, we noted an unusual knee bending dystonic gait in 4 patients. None of the 4 cases described have undergone deep brain stimulation. This gait appears to have a combination of dystonic knee bending superimposed on parkinsonian shuffling and has been previously described by Evidente et al. as “phasic dystonic knee bending,” causing the knees to bend and fold.2 This dystonic knee bending gait during straight walking in the below cases is shown in Figure 1A, and multiple frames of a single patient, illustrating the knee bending throughout the gait cycle, are shown in Figure 1B. Information regarding clinical features and TAF‐1 SVA hexameric repeat length is shown in Table 1.

Figure 1.

(A) Characteristic gait with dystonic knee flexion during straight walking in patients with XDP (patient 1, left to patient 3, right). (B) Multiple stills depicting the phasic knee bending dystonic gait in a single patient.

Table 1.

Clinical features of the XDP gait disorder cases

	Demographics and Diagnosis							Dystonia Features											Parkinsonism Features
Case	Sex, dx	Age Assess, yr	Age Onset, yr	Phenotype	TAF‐1 SVA Repeat Length	Dystonia	BFM	Cerv	OM	Speech	Larynx	Bleph	Trunk	UE	LE	Gait	Park	UPDRS	Hypomim	Hypoph	Bradyk	Trem	Gait	Freezing	Post inst
1	M, XDP	42	39	DP	42	Y	10		+				+			++	Y	27	++	+	++		++
2	M, XDP	40	37	DP	43	Y	20.5	+++		+++	+++					++	Y	38	+	+	+++		++
3	M, XDP	53	47	DP	47	Y	43.5	+	+++	+			+	++	++	+++	Y	46	++	+	++	+	+++		+++
4	M, XDP	54	51	DP	39	Y	15	+++	++	+++			+			+	Y	39	+	++	++		++

Severity is designated by + denoting mild, ++ moderate, and +++ severe. Details regarding the TAF‐1 SVA hexameric expansion are also shown.

dx, diagnosis; Age assess, age at assessment; Age onset, age at onset of symptoms; M, male; F, female; y, years; XDP, X‐linked dystonia parkinsonism; DP, dystonia parkinsonism; SVA, sine‐VNTR‐Alu—short interspersed nuclear element, variable number of tandem repeats, and Alu composite; Y, yes; N, no; BFM: Burke‐Fahn‐Marsden Dystonia Rating Scale score; Cerv, cervical dystonia; OM, oromandibular dystonia; Bleph, blepharospasm; UE, upper‐extremity dystonia; LE, lower‐extremity dystonia; Parkin, parkinsonism; UPDRS, MDS‐UPDRS Part 3 motor score; Hypomim, hypomimia; Hypoph, hypophonia; Bradyk, bradykinesia; Trem, presence of resting tremor; Post Inst, postural instability.

Case 1

The patient was examined at age 42. He noted symptom onset at age 39, with initial difficulties with his right leg, and as the disease progressed, he had motor difficulties and slowness with his right upper extremity and had occasional dysphagia. He developed gait difficulties by age 41, which, over time, involved knee bending. He subsequently noted difficulties with jaw closing and the predominant feature being progressive parkinsonism, with slowness of movement spreading to the left side and worsening gait with some unsteadiness. His gait, with prominent knee bending is shown in Video 1. Medications include carbidopa/levodopa, the anticholinergic, biperiden, and, subsequently, clonazepam. Botulinum toxin injections were trialed at age 42 and were stopped because of lack of efficacy. The gait has not responded to pharmacological treatment.

Case 2

The patient was examined at age 40. Symptom onset was at age 37 with eyelid twitching, which resolved, and the subsequent development of a generalized dystonia, involving severe cervical dystonia and prominent spasmodic dysphonia, later developing dysphagia and laryngeal involvement with stridor. Mild parkinsonism developed later, including a clearly abnormal, knee bending gait by age 39 (Video 2). He has been treated with clonazepam, biperiden, and botulinum toxin injections for his cervical dystonia and spasmodic dysphonia/laryngeal dystonia. The gait has not responded to medication.

Case 3

The patient was examined at age 53. He noted the onset at age 47 of involuntary neck movement with tilting to the right, compatible with cervical dystonia, which was followed the development of jaw opening dystonia. He subsequently developed progressive symptoms of parkinsonism, including a parkinsonian right‐hand resting tremor. He was later noted to have a progressive knee bending gait disorder, requiring assistance, and resulting in substantial postural instability, with the severity of progressive knee bending during ambulation causing the patient to almost fall onto his knees (Video 3). Medications include biperiden, clonazepam, and botulinum toxin injections for his cervical dystonia. His gait has not responded to treatment.

Case 4

The patient was examined at age 54. He described the onset at age 51 of abnormal neck movements, with signs of cervical dystonia, involving retrocollis. He subsequently developed a more generalized dystonia, involving oromandibular dystonia with jaw opening, spasmodic dysphonia, and truncal bending, with less prominent parkinsonian features. He had a very mild version of the dystonic gait, with episodic knee bending (video not shown). Medications include biperiden, clonazepam, and more recently botulinum toxin injections for treatment of his dystonia. His relatively mild gait difficulties have not responded to treatment.

Discussion

XDP is a rare disorder that generally has the appearance of dystonia parkinsonism, but can change in phenomenology over the disease course, and there are cases with pure parkinsonism, which may be indistinguishable from PD. We describe 4 cases of an unusual dystonic and parkinsonian gait disorder, consistent with phasic dystonic knee bending on a background of parkinsonian shuffling, which appears to be a unique, albeit uncommon, feature of XDP.2, 5 In Filipino regions, where XDP is more prevalent, the presence of this dystonic phasic knee bending gait in the setting of an otherwise parkinsonian presentation may serve as a “red flag” for the presence of XDP, as opposed to PD (as per case 1), particularly in the setting of a family history of parkinsonism. The particular gait shown in our cases is associated with a mixed dystonia parkinsonism presentation, does not appear to be an early feature (came on within ≥2 years after symptom onset), and the progressive knee bending can contribute to worsening postural instability and increase the risk for falls, particularly illustrated by case 3.

As the gait involves, in essence, the phasic development of a squatting position during straight walking, a complex combination of agonist and antagonist muscles are involved. However, given that the dystonia involves the abnormal downward component, with dystonic knee bending and abnormal lowering into this posture, the hip flexors (primarily iliopsoas and rectus femoris) and hamstrings appear most prominently involved. In the 4 patients discussed, this particular gait has not responded to pharmacological treatment. Targeting the muscles driving the abnormal gait with botulinum toxin injections would be problematic, Given the widespread, large, and powerful muscles involved, these would require very high doses, and excess weakness would likely greatly contribute to gait difficulties, as these muscles are essential in maintaining standing posture.

This gait can be differentiated from other complex dystonic disorders where there is gait involvement. Although there is a somewhat similar knee bending element, in the “hobby horse” gait in DYT4, the gait we describe in XDP is much slower, with larger steps and less distal leg dystonic involvement of the feet and toes, does not involve walking on the toes, and without widening of the base or other more clearly cerebellar qualities.6 It is also interesting to note that there are several similarities in the presentation of certain DYT4 and XDP patients, which were alluded to in the article by Wilcox et al.7 Similarly, it is also distinct from the “cock‐walk gait” of manganese toxicity, whether acquired or genetic, in which prominent lower‐limb dystonia results in patients walking on their tiptoes on the metatarsal joints and presents with a wide‐based and very unstable gait.8 The gait also can be distinguished from the postural lapses in the knees, with episodes of knee buckling, as part of the “rubbery gait” of chorea‐acanthocytosis, which is often associated with head drops.9

Larger, ongoing natural history studies will help better ascertain the prevalence of what appears to be a characteristic gait abnormality in XDP. Quantitative study of the gait disorder in XDP is required to better characterize the broad range of gait abnormalities present in this complex, mixed movement disorder.

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 of the First Draft, B. Review and Critique.

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

C.G.: 1B, 3B

P.A.: 1B, 3B

N.S.: 1B, 1C, 3B

Disclosures

Ethical Compliance Statement

This research was performed with approval of the ethics board of the Massachusetts General Hospital and the local Philippines Jose Reyes Memorial Medical Center Institutional Review Board/Research Ethics Committee. The patients have given written and informed consent for online publication of their videos and images. 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

This work was supported by The Collaborative Center for X‐Linked Dystonia Parkinsonism at Massachusetts General Hospital and National Institutes of Health grant 5P01NS087997. The authors report no conflicts of interest.

Financial Disclosures for previous 12 months

C.D.S. has sat on a scientific advisory board for Xenon Pharmaceuticals and received research funding from Sanofi‐Genzyme for a study in late‐onset GM2 gangliosidosis. He has received financial support from Sanofi‐Genzyme, Biogen, and Biohaven for the conduct of clinical trials. N.S. has received honoraria for serving as Editor‐In‐Chief of Brain and Behavior, a journal published by John Wiley & Sons.

Supporting information

Video 1. The video shows patient 1 and displays slight dystonic jaw closure mouth movements and truncal involvement. There are clear signs of symmetric parkinsonism, including hypomimia, mainly upper‐extremity bradykinesia, and there is no resting tremor, no postural tremor, and slight kinetic tremor. There is a combined, parkinsonian, and dystonic gait, with shuffling and dystonic phasic knee bending, which appears hobby‐horse like. There is no postural instability.

Video 2. The video shows patient 2 and displays considerable dystonic features with substantial cervical dystonia with retrocollis, in addition to severe spasmodic dysphonia, with laryngeal dystonia causing stridulous breathing. There is additional parkinsonism, with hypomimia, considerable bradykinesia, which is more prominent in the upper extremities and slightly worse on the right, and there is no resting, postural, or action tremor. This shows another example of the combined parkinsonian and dystonic gait, with shuffling and superimposed phasic dystonic knee bending, with a slow hobby‐horse–like quality and without postural instability.

Video 3. The video shows patient 3 and displays clear dystonic features, including mild cervical dystonia with considerable jaw‐opening dystonia and left greater than right arm and leg dystonia and truncal involvement. There are additional signs of parkinsonism, including hypomimia, hypophonia, considerable, left greater than right upper extremity predominant bradykinesia, and a typical right‐hand parkinsonian resting tremor. There is also the most severe example of the hobby‐horse–like dystonic phasic knee bending gait, with considerable combined dystonic and parkinsonian gait disorder, involving shuffling and superimposed, progressive knee bending, resulting in substantial postural instability and, by the end of the segment, shows the patient almost falling to his knees as he approaches the chair.