Paroxysmal Asymmetric Dystonic Arm Posturing—A Less Recognized but Characteristic Manifestation of ATP1A3‐related disease

ABSTRACT

Background

ATP1A3 mutations cause a wide clinical spectrum, and are one of the “commoner rare diseases”.

Methods

Case series of four patients with ATP1A3 mutations.

Results

The patients displayed characteristic episodes of dystonic arm posturing, involving a dystonic, flexed arm held in front of the body or close to the body, but with the hand raised upwards. Other attacks manifested with arm extension, either beside the body or reaching upwards. Dystonic posturing occurred paroxysmally, with no neurological signs between attacks, or combined with other signs like chorea, ataxia, and hypotonia.

Conclusions

While previous diagnostic criteria have not included paroxysmal or episodic dystonia, recent expert consensus has proposed to include alternating or paroxysmal dystonia as major feature calling for ATP1A3 genetic testing. Attacks of marked arm flexion posturing, either paroxysmal or as episodic exacerbation of mild pre‐existent dystonia, are a characteristic clue to ATP1A3‐related disease.

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Introduction

ATP1A3 mutations were initially described as the cause of rapid‐onset dystonia parkinsonism (RDP),1 but have since been found to cause alternating hemiplegia of childhood (AHC).2, 3

Subsequently, a series of publications have suggested that ATP1A3 mutations are associated with a wide clinical spectrum, and that they are one of the “commoner rare diseases”.4, 5, 6 A diagnosis of ATP1A3‐related disease has specific management implications, including avoidance of triggers and pharmacological prophylaxis of attacks.7 Routine blood tests and brain MRI are typically normal; hence, recognition of the disorder on clinical grounds is of utmost importance. For example, monocular nystagmus has been recognized as a distinct feature of the disease.4

We have observed that patients with ATP1A3 mutations tend to have characteristic episodes of paroxysmal dystonic arm posturing, mostly manifesting as one arm extending or flexing. This might be an important red flag which, to the best of our knowledge, has not been highlighted to date.

Case Series

Case One

This seven‐year‐old boy suffered from paroxysmal events since age four. These consisted of painful, abnormal arm posturing (Fig. 1; Video 1), which was either unilateral, or very asymmetric if bilateral, sometimes associated with retrocollis and speech difficulties. They were typically precipitated by swimming, playing in the sun, or fatigue, abated with sleep and could last 30 minutes up to three days. In between attacks, he was normal (Video 1). Genetic testing revealed a pathogenic variant in the ATP1A3 gene (c.1838C > T), and treatment with flunarizine and topiramate lead to improvement.

Figure 1.

Characteristic paroxysmal unilateral or asymmetric arm posturing in patients with ATP1A3 mutations.

Case Two

Four days after a fall, this eight‐year‐old boy developed posturing of the left arm (Fig. 1; Video 2), and subsequently also posturing of the left leg. He had walking difficulties with frequent falls, and was eventually unable to walk independently. He was reported to have had an episode of dancing‐like movements of all limbs without loss of consciousness, and one tonic‐clonic seizure. After three months, the movement disorder progressed to involve the right side and face. Examination revealed prominent dystonic posturing of the left arm more than the left leg, mild generalized chorea, and mild dysarthria. There were no weakness, cerebellar signs, or sensory dysfunction. Targeted sequencing revealed a heterozygous missense variant in exon 21 of the ATP1A3 gene (c.2878G > A).

Case Three

This patient had first symptoms at six months of age, when he had staring spells and clustered episodes of hemiparesis lasting for hours, followed by full recovery after all but one episode that showed only partial improvement. Other episodes consisted mainly of asymmetric dystonic posturing of the arms, the main feature being arm flexion, but also with dystonic hand posturing (Fig. 1; Video 3). Attacks were sometimes combined with cerebellar signs (particularly in recent years), axial hypotonia, or chorea. He had some developmental delay with walking only at age five. At age 21, he developed focal and secondarily generalized seizures. At age 36, examination revealed intellectual disability and constant but mobile dystonic posturing affecting predominantly the left arm. Cerebellar signs included gaze‐evoked nystagmus on lateral gaze, dysarthria, limb dysmetria, and a wide‐based gait with intermittent veering. Pyramidal signs consisted of left‐sided hyperreflexia with ankle clonus and extensor plantar response. Genetic testing revealed a pathogenic variant in the ATP1A3 gene (c.2401G > A).

Case Four

This patient had first symptoms at 14 months of age, when he was diagnosed with “encephalitis.” At 18 months, he developed an episode of abnormal posturing following surgery (double hernia operation). He was then noted to have developmental delay. At age nine, he had another severe episode of dystonia with painful spasms, after which dystonia of his hands and dysarthric speech persisted. No clear trigger was identified. At age 12, he developed chorea. Subsequently, he progressively deteriorated and had frequent dystonic spasms. At age 36, after an episode of gastroenteritis, he developed a worsening of dysarthria and frequent, debilitating dystonic spasms. Examination (Fig. 1; Video 4) revealed generalized chorea and severe dysarthria. During a typical dystonic episode, he developed right elbow flexion and right leg extension dystonic posturing, with right arm weakness. Subsequently, dystonic posturing became less pronounced on the right, affecting predominantly the left side, with the left arm being flexed at the elbow and raised to the height of the head. He had no formal diagnosis until age 38, when genetic testing revealed a pathogenic variant in the ATP1A3 gene (c.2357A > G).

Detailed information about the mutations in ATP1A3 of all cases is listed in Supporting Table 1.

Discussion

Here we present four patients with ATP1A3 mutations who display characteristic episodes of dystonic arm posturing.

While paroxysmal dystonic posturing, or episodic worsening of a movement disorder is seen with various aetiologies—for example in PRRT2, GCH1, GLUT1, or ADCY5‐related disease, and various mitochondrial and metabolic diseases including glutaric aciduria8—the episodic dystonic posturing in ATP1A3‐related disease highlighted here seems to be a distinct sign.

This might involve a dystonic, flexed arm that may be held in front of the body, or more often and distinct, held close to the body with the hand up at the height of the head (Fig. 1). During other episodes, the arm might be extended (but often with hand flexion) and be held beside the body, or reaching upwards.

There are additional features worth pointing out here, such as the very focal involvement of (predominantly) one arm. This is typically not seen in the majority of the above disorders, where dystonia is typically more generalized. Exercise‐induced dystonia, as seen with GCH1 or GLUT1 mutations, manifests most typically in the legs after prolonged exercise.8, 9 Rarely, it can involve the hands after their prolonged use, but dystonic posturing of one arm would be very unusual. Lastly, of course, the trigger (exercise) would be readily identifiable. Similarly, sudden movements are the trigger in PRRT2‐related paroxysmal kinesigenic dyskinesia.9 Apart from the trigger, the other difference is the duration of attacks: the dystonic arm posturing in ATP1A3 often lasts for hours to days, which is very different from the shorter episodes of exercise‐induced dystonia with GCH1 or GLUT1 mutations and the very brief dystonic episodes (lasting seconds) associated with PRRT2 mutations.9

Some patients are distressed and complain of pain during these episodes. While painful paroxysmal dyskinesias are typically seen in the tonic spasms of demyelinating disease (neuromyelitis optica, multiple sclerosis), again, it is their short duration (seconds to minutes), which can be used as a handle to differentiate them from the ATP1A3‐related paroxysmal dyskinesias.

“Dystonic fits” or dystonic episodes have been mentioned in case descriptions of ATP1A3‐related disease.6, 10, 11 Some of these sound like oculogyric crises,12 others are described as “typical for AHC” without much detail. However, because of its name, the attacks widely considered typical for AHC are the hemiplegic attacks. The distinct phenomenology of the dystonic arm posturing has not been highlighted to date, but it is important particularly for adult neurologists less familiar with AHC, who may see these cases due to the clinical spectrum encompassing milder phenotypes with late and mono‐symptomatic onset. Therefore, with this case series, we aimed to emphasize the distinct, asymmetric dystonic arm posturing as a red flag for ATP1A3‐related disease.

The arm posturing may be paroxysmal, with no neurological signs between attacks (e.g., case one) or occur together with other signs including chorea, ataxia, and hypotonia (cases two, three, and four). Reviewing the videos of recent reports of adult patients with ATP1A3 mutations further lent support to our belief that attacks of marked arm flexion posturing, sometimes as episodic exacerbation of mild pre‐existent dystonia, are a clue to ATP1A3‐related disease.13, 14 Indeed, while previous diagnostic criteria did not include paroxysmal or episodic dystonia, a recent expert consensus proposed alternating or paroxysmal dystonia as a major feature calling for ATP1A3 genetic testing.15

The pathophysiological mechanisms underlying the marked asymmetry and the episodic nature are intriguing. ATP1A3 encodes the α3 isoform of the catalytic subunit of the Na⁺/K⁺ pump, which is an adenosine triphosphatase (ATPase) cation transporter, crucial for maintaining electrochemical gradients for Na⁺ and K⁺ across plasma membranes. Data from rodents shows that ATP1A3 expression is restricted to certain neuronal populations, such as GABAergic neurons of the basal ganglia (striatum, globus pallidus, subthalamic nucleus, and substantia nigra), thalamus, cerebellum, red nucleus, several areas of the pons, and the hippocampus.16 There are different α isoforms; while the ubiquitously expressed α₁ isoform maintains neuronal housekeeping functions, it is thought that the α₃ isoform serves as a reserve pump that only becomes activated when the intracellular Na⁺ concentration is high (e.g., after repeated action potentials), in order to protect neurons against catastrophic elevation of intracellular Na⁺. Reduced α3 activity has also been suggested to interfere with reuptake of neurotransmitters such as glutamate, γ‐aminobutyric acid (GABA), and dopamine.17 Hence, it is conceivable that structures and neurotransmitters known to be involved in dystonia can be affected in ATP1A3 mutation carriers.18 Similar to other paroxysmal dyskinesias (e.g., those caused by PRRT2 mutations), the marked asymmetry and often alternating manifestation of signs remain a mystery.

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.

B.B.: 1C, 3A

C.D.S.: 3B

V.U.: 3B

C.S.S.: 3B

N.K.B.: 3B

A.E.L.: 3B

K.P.B.: 1A, 1B, 3B

Disclosures

Ethical Compliance Statement: We hereby confirm that the present study conforms to the ethical standards and guidelines of the journal. The patients have given written and informed consent for online publication of their videos.

Funding Sources and Conflict of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: B.B. is supported by the Robert Bosch Foundation. C.D.S., V.U., N.H.B., and C.S.S. report no relevant financial disclosures or conflicts of interest. A.E.L. has served as an advisor for Abbvie, Acorda, Biogen, Janssen, Jazz Pharma, Sun Pharma, Kallyope, Merck, Paladin, Theravance, and Corticobasal Degeneration Solutions; has received honoraria from Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion; has received grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Society Canada, and W. Garfield Weston Foundation; and has received publishing royalties from Elsevier, Saunders, Wiley‐Blackwell, Johns Hopkins Press, and Cambridge University Press. K.P.B. has received grant support from Welcome/MRC, NIHR, Parkinsons's UK and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), of Marsden's Book of Movement Disorders (Oxford University Press, 2012), and of Case Studies in Movement Disorders–Common and uncommon presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals and from the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society.

Supporting information

Supporting Table 1. Detailed genetic information about the mutations in ATP1A3 of all cases.

Video 1. Segment 1 shows Patient 1 during a severe and distressing attack. The predominant sign is a dystonic right arm held in a flexed position with the hand at the height of the head. Segment 2 shows another attack. There is also mild retrocollis and mild posturing of the right leg. Segment 3 shows the patient between attacks when he is asymptomatic.

Video 2. The video shows Patient Two during an episode. There is prominent dystonic posturing of the left arm, which is held flexed at the elbow and wrist in front of the body. He also has mild generalized chorea. Subsequently, the arm is held extended but with wrist flexion. When walking, mild leg involvement on the same side becomes apparent.

Video 3. The video shows Patient Three during an episode. He is holding his left dystonic arm flexed at the elbow with his hand at shoulder level. Less prominent features comprise mild generalized chorea, gait ataxia, and hypotonia.

Video 4. Segment 1 shows Patient Four during an episode. First, his right arm is affected by dystonic flexion of elbow and wrist, and there is also some mild leg posturing. Subsequently, dystonic posturing predominantly affects the left arm, which is flexed at elbow level and raised, while the right arm is choreic. When walking, the left arm remains flexed and up, so the hand is held at the height of the head. Segment 2 shows the patient a few minutes afterwards when the attack has resolved, with some generalized chorea and only subtle dystonic posturing.