Familial case of rapid-onset dystonia-parkinsonism (DYT/PARK-ATP1A3, DYT12)

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Introduction

Dystonia is the third most common movement disorder, occurring worldwide and manifesting at any age — from infancy to old age [1]. Genetic factors play a significant role in dystonia, particularly in its early-onset forms [2]. The identification of various variants in more than two dozen dystonia genes currently known is, in many cases, the key to accurate and timely diagnosis [2–4].

ATP1A3-associated disorders constitute a heterogeneous spectrum of neurological syndromes, one of which is rapid-onset dystonia-parkinsonism (RDP). Variants in this gene are inherited in an autosomal dominant pattern or arise de novo [5]. Penetrance and expressivity are variable, with wide intra- and interfamilial variability observed among carriers of the same variant [6]. Symptom onset may occur at any age [7]. Due to the rarity of this group of disorders, reliable epidemiological data are currently lacking, and prevalence estimates are based on the most common phenotype — alternating hemiplegia of childhood (AHC) — with an approximate frequency of 1:1,000,000 [8].

Molecular mechanisms of the disease

The ATP1A3 gene is located on the long arm of chromosome 19, encodes the α3 subunit of the transmembrane Na⁺/K⁺-ATPase ion pump, and is expressed predominantly in excitable cells — neurons and, to a lesser extent, cardiomyocytes [9]. The primary function of this protein is the rapid restoration of the electrochemical gradient by extruding sodium ions from cells after multiple repetitive action potentials, even at low ATP concentrations [5, 10]. Its expression in brain neurons (including the basal ganglia, cerebellum, frontal cortex, oculomotor nuclei, hippocampus, amygdala, cingulate gyrus, hypothalamus, and pituitary gland), as well as in retinal neurons, spiral ganglion cells, and the organ of Corti, accounts for the broad spectrum and high variability of clinical symptoms [5]. It is also suggested that the α3 subunit is involved in neurotransmitter reuptake [11, 12], which may partially explain the frequent occurrence of affective disorders in this group of diseases.

Phenotypic spectrum of ATP1A3-associated disorders

With increasing accessibility of massively parallel sequencing technologies, a growing number of patients with pathogenic variants in the ATP1A3 gene are being identified, and the spectrum of known clinical manifestations of this group of disorders is steadily expanding. The first phenotypes associated with ATP1A3 variants were RDP, AHC, and CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) [10]. To date, approximately 14 phenotypes of ATP1A3-associated disorders have been described [5, 7, 13, 14]; the characteristics of the most common ones are summarized in Table 1. Despite the abundance of described syndromes, in most cases the symptomatology does not fit neatly into any single one, and these disorders are increasingly viewed as a spectrum rather than a group of distinct, well-defined phenotypes [15, 16]. Transition from one phenotype to another over time (e.g., AHC to RDP or CAPOS syndrome) is possible [13, 17]. Extraneural manifestations in ATP1A3-associated disorders are rare; however, in certain phenotypes, cardiac rhythm and conduction disturbances, as well as endocrine abnormalities (growth hormone deficiency with short stature, precocious puberty), may occur [18, 19].

 

Table 1. Phenotypic spectrum of ATP1A3-associated disorders [5, 7, 9, 10, 15]

Phenotype	Age at onset	Course	Acute phase / paroxysmal episodes	Subsequent course
RDP	9 months – > 60 years	Acute/subacute onset, subsequent stabilization, possible recurrent episodes of deterioration	Multifocal/generalized dystonia; parkinsonism (without rest tremor, levodopa-resistant); pronounced bulbar symptoms; rostrocaudal gradient of symptom spread; epileptic seizures are common at onset	Persistence of acute phase symptoms; cognitive impairment; psychiatric manifestations (anxiety, depression, psychotic episodes); headache; less commonly — epilepsy, oculogyric crises, ataxia, chorea, myoclonus, hyporeflexia, pyramidal signs
AHC	0–18 months	Paroxysmal course; Episode duration from minutes to weeks	Paroxysmal episodes of hemiplegia/quadriplegia; paroxysmal episodes manifesting as dystonia, oculomotor disturbances, autonomic dysfunction, decreased consciousness; alternating laterality of manifestations; multiple seizure types, often evolving into one another within a single episode; improvement after sleep; respiratory failure; bulbar symptoms; epileptic seizures	Psychomotor developmental delay; ataxia, dystonia, choreoathetosis, parkinsonism; oculomotor apraxia, strabismus; bulbar symptoms; behavioral disturbances (aggressiveness, irritability, impulsivity); intraventricular conduction disturbances; hypothalamic-pituitary dysfunction: short stature, impaired thermoregulation; gastrointestinal pathology: constipation/diarrhea, vomiting, abdominal pain
CAPOS syndrome	6 months – 5 years	Paroxysmal course with gradual background progression	Cerebellar ataxia; hypotonia; nystagmus, strabismus; dysarthria; decreased consciousness	Hypotonia, hypo-/areflexia, pes cavus; progressive visual and hearing loss; dystonia, choreiform hyperkinesia; epileptic seizures; bulbar symptoms; cognitive impairment; behavioral/psychiatric manifestations
Recurrent encephalopathy with cerebellar ataxia; fever-induced paroxysmal weakness with encephalopathy	Infancy – early adulthood	Paroxysmal course (possible background progression)	Cerebellar ataxia; generalized weakness, hypotonia; choreiform hyperkinesia; bulbar symptoms; mutism; decreased consciousness (from drowsiness to coma); possible brief dystonic/oculomotor paroxysms	Cerebellar ataxia; dystonia; dysarthria; areflexia; mild cognitive impairment
Early-onset epilepsy, including with polymicrogyria	First months of life	Paroxysmal course with background progression	Drug-resistant epilepsy with status epilepticus; focal/regional/multiregional/generalized epileptiform activity on EEG; apnea episodes (minutes to hours)	Persistence of epileptic seizures; severe psychomotor developmental delay; microcephaly; brain MRI: cerebral atrophy, possible polymicrogyria

 

Despite the wide clinical variability, a number of features common to most patients with ATP1A3-associated disorders can be identified: acute or subacute onset with paroxysmal episodes, triggering factors (fever, infections, physical exertion, emotional stress, sleep deprivation, childbirth, head trauma, alcohol abuse, hypothermia or hyperthermia); in many cases, dystonia, bulbar symptoms, cerebellar ataxia, and cognitive impairment of varying severity are observed.

Rapid-onset dystonia-parkinsonism

RDP is one of the classic and best-known phenotypes of ATP1A3-associated disorders, characterized by acute or subacute onset of dystonia, parkinsonism, and bulbar symptoms with a rostrocaudal gradient of symptom spread and severity. Symptom onset is typically preceded by one of the triggering factors described above. The disease most often manifests in adolescence or early adulthood, although the age at onset can vary widely [6]. Approximately half of all RDP cases are caused by de novo pathogenic variants in the ATP1A3 gene [9]. The most common variants in this phenotype are p.Thr613Met and p.Ile759Ser, which together account for approximately 42% of RDP cases [6].

Previously, different forms of hereditary dystonia were assigned ordinal numbers according to their chronological order of discovery. Under this system, RDP corresponded to the designation DYT12. In 2016, the International Parkinson and Movement Disorder Society issued updated the nomenclature of genetically determined movement disorders, according to which the name of each defined form should consist of two parts: the first — the most characteristic phenotype or combination of phenotypes for the disease, the second — the involved gene. According to this nomenclature, RDP is defined as DYT/PARK-ATP1A3 (DYT and PARK indicate the predominance of dystonia and parkinsonism in this phenotype) [20].

In 2007, A. Brashear et al. first proposed diagnostic criteria for RDP [21]:

1. acute or subacute onset of dystonia with parkinsonian features (minutes to 30 days);
2. a clear rostrocaudal gradient of symptom spread (face > arm > leg);
3. pronounced bulbar symptoms.

A clinical diagnosis requires all three criteria. In 2014, the international working group on ATP1A3-associated disorders developed expanded diagnostic criteria for RDP (Table 2); however, the required number of categories for establishing a clinical diagnosis was not specified [17].

 

Table 2. Diagnostic criteria for RDP (translated and adapted from H. Rosewich et al. [17])

Major criteria	Onset of symptoms over a period ranging from several minutes to 30 days, with dystonia and parkinsonism; clear rostrocaudal gradient of symptom spread/severity (face > arm > leg); pronounced bulbar symptoms; resistance to levodopa at adequate doses; family history suggestive of autosomal dominant inheritance (however, de novo mutations are not uncommon)
Supportive criteria	Absence or mild tremor at disease onset; mild limb dystonia prior to abrupt symptoms onset; evidence of triggering factors at disease onset; recurrent episodes of acute deterioration are possible but rare; stabilization of symptoms within one month; minimal improvement after the acute attack
Atypical features	Onset after age 60 years; epileptic seizures after the appearance of motor symptoms; rapid-onset ataxia with signs of cerebellar atrophy on neuroimaging

 

Given the growing number of RDP descriptions, the proposed criteria are now being re-evaluated by many authors. For example, I.U. Haq et al., analyzing the clinical manifestations of 44 carriers of pathogenic ATP1A3 variants with the RDP phenotype and 44 of their family members without mutations, found that the major criteria were not present in all carriers [9]. In 20.5% of carriers, symptom progression lasted more than 30 days. Among patients with dystonia, a rostrocaudal gradient of symptom severity was observed in only 7%. Bulbar symptoms was found to occur in the majority of cases but was not the first or most severe manifestation in the clinical pattern. Triggering factors prior to symptom onset were identified in 77% of patients. In probands, 56% of mutations arose de novo. The authors concluded that rostrocaudal gradient of symptom spread and severity is not common among carriers of pathogenic ATP1A3 variants, and that RDP should be included in the differential diagnosis of all patients with dystonia and bulbar manifestations [9].

General principles of diagnosis and treatment

The diagnosis of ATP1A3-associated disorders is based on a thorough history and clinical evaluation, which allow identification of characteristic manifestations and determination of the optimal scope for molecular genetic testing. Since most pathogenic variants described in ATP1A3 are located in the coding region of the gene, targeted panel sequencing or whole-exome sequencing is typically performed when an ATP1A3-associated disorder is suspected [7].

Laboratory and instrumental investigations are of limited utility in establishing the diagnosis. Brain MRI generally shows no abnormal changes. In some phenotypes, cerebellar atrophy or hypoplasia (predominantly of the vermis), cerebral hemispheric atrophy, polymicrogyria, hippocampal sclerosis, and thinning of the corpus callosum may be observed [5, 10, 22, 23]. Patients with a history of paroxysmal events should undergo standard electroencephalography (EEG) and overnight video-EEG monitoring, which may reveal focal or generalized epileptiform activity or slowing of cortical rhythms [24]. Nerve conduction study and needle electromyography (EMG) show no abnormalities [5].

Despite relatively high expression of the gene in cardiomyocytes, cardiac rhythm and conduction disturbances are rare. Nevertheless, to exclude cardiac abnormalities, all patients with ATP1A3-associated disorders are recommended to undergo standard 12-lead electrocardiography (ECG), Holter ECG monitoring, and echocardiography [18].

Treatment of these conditions is primarily symptomatic. In the AHC phenotype, flunarizine, topiramate, and the ketogenic diet may be prescribed to reduce the frequency and severity of hemiplegic episodes [7]. Isolated cases of flunarizine efficacy in the RDP phenotype have also been reported [25]. For dystonia management, anticholinergic drugs, benzodiazepines, and botulinum toxin therapy may be used. Levodopa therapy is generally ineffective. Deep brain stimulation with electrodes placed in the globus pallidus internus, subthalamic nucleus, or posterior ventral oral thalamic nucleus has also shown inefficacy in dystonia correction [26]; however, K.L. Wang et al. described a single case of successful deep brain stimulation targeting the centromedian-parafascicular complex of the thalamic nuclei in a patient with RDP [27]. In the presence of epileptic seizures, psychotic and affective disorders, treatment strategy does not differ from that in the general population. Rehabilitation measures play a major role: therapeutic exercise with a physical therapist to prevent contractures, improve mobility and stability; speech therapy and nutritional correction for bulbar symptoms; and psychological support and adequate psychotropic therapy for affective disorders. In addition, patients should, where possible, avoid common triggering factors: excessive or unusual physical exertion, emotional stress, fasting, sleep deprivation, alcohol consumption, exposure to extreme temperatures, and infections [7].

Case reports

Only isolated cases of ATP1A3-associated disorders have been described in the Russian literature: 6 patients with AHC [28–32], 2 patients with RDP [33, 34], and 1 patient with CAPOS syndrome [35]. We present our observation of two cases from a single family with a phenotype most consistent with RDP.

Clinical case 1

Patient M., a 19-year-old female, was admitted to the Research Center of Neurology and Neurosciences (RCNN) with complaints of involuntary posturing of the right arm and distal part of the right leg, pain in the right arm and legs, gait disturbance, slurred speech, choking during meals, drooling, episodes of tonic upward eye deviation, episodes of pressing headache in the parieto-occipital region, emotional lability, sleep disturbance (difficulty falling asleep, frequent nocturnal awakenings), and episodes of urinary incontinence.

Early motor development was unremarkable. In childhood, she had gait disturbances (waddling gait) and hip pain. At 3 years and 8 months, she underwent three surgical procedures on the right hip joint (the extent of the procedures is unknown, and medical records were not provided). After surgery, a partial regression in psychomotor development was noted. She started school at age 7 but was later transferred to home schooling. She completed 9 grades and is currently studying at a college under an adapted program.

At age 12, she suddenly developed an episode of systemic vertigo and diffuse severe headache. On the third day, according to the patient's mother, upon waking and getting out of bed, she fell, lost consciousness, developed seizures (described as bilateral tonic-clonic) with involuntary urination, and the patient had no memory for the episode. Following the seizure, she acutely developed facial asymmetry, slurred speech, and weakness and numbness in the right arm and leg. Over the following days, involuntary posturing of the right arm and leg, rightward trunk deviation, limb pain, excessive sweating of the feet and hands, bowel and bladder dysfunction, choking during meals, drooling, and hearing loss developed. Subsequently, the disease course was relatively stable. To manage dystonic hyperkinesia and pain, baclofen, levodopa, and duloxetine were prescribed, and botulinum toxin therapy was administered on multiple occasions — with minimal positive effect. From age 18, paroxysmal episodes began to occur, manifesting as tonic upward deviation of the eyeballs with involuntary mouth opening and drooling; duration — up to 2 minutes, frequency — 1–2 times per day. During episodes, the patient is conscious and able to answer questions, and she does not lose memory for the episodes afterward. Lamotrigine was initiated with gradual dose titration to 100 mg/day — with no effect on seizure frequency.

The patient has two healthy siblings (a 20-year-old sister and an 18-year-old brother). The mother has similar symptoms (see below); the father is healthy.

Physical examination: height — 143 cm, weight — 43 kg, BMI — 21 kg/m². The skin of the palms and soles was moist. Heart sounds were clear and regular. Blood pressure 100/70 mmHg, heart rate 81 bpm. Pollakiuria, imperative urges to urinate, and episodes of urinary incontinence were noted. Neurological examination revealed facial asymmetry due to tension of the oromandibular muscle group on the right. Hearing was subjectively reduced, but no impairment was detected on screening assessment. Mild dysphagia and moderate dysarthria were observed. The tongue deviated to the right on protrusion. Tetraparesis: muscle strength was reduced in the right arm (proximally and distally) to 3/5, in the left arm proximally to 4/5, in the right hip flexors to 2.5–3/5, and in the left hip flexors to 3/5. Muscle tone was increased in a mixed (plastic and spastic) pattern in the arms and legs; paratonia was present in the arms and legs. Deep tendon reflexes were diffusely brisk, S>D. The Babinski sign was present bilaterally, more pronounced on the right. Generalized dystonia: adduction of the right arm at the shoulder joint, flexion at the elbow, flexion and pronation at the wrist, and, at rest, clenching of the right fingers into a fist. When extending the arms forward, she uses compensatory maneuvers to extend the right arm at the elbow and open the fingers, after which the right hand shows extension at the metacarpophalangeal and proximal interphalangeal joints of the 3rd–5th fingers, flexion at the metacarpophalangeal joints of the 1st and 2nd fingers, and flexion at the proximal interphalangeal joint of the 1st finger; on the left — extension and abduction at the metacarpophalangeal joints of the 2nd–4th fingers, flexion at the proximal interphalangeal joint of the 5th finger (Figures 1, 2). In the right leg at rest — extension and adduction at the ankle joint, extension at the 1st metatarsophalangeal joint. During walking, the right foot is placed on the toes, the foot is externally rotated, the 2nd–4th toes are flexed at the proximal interphalangeal joints, and trunk tilt and pelvic deviation to the right are observed. Performance of motor tests in the right arm and leg is not possible due to the severity of dystonia; in the left limbs, mild bradykinesia is present. The patient is unsteady in the Romberg test. She mobilizes with assistance or in a wheelchair. No coordination impairment was found in the left arm and leg; assessment in the right limbs was difficult.

 

Fig. 1. Dystonic posturing of the fingers and hands.

 

Fig. 2. Oromandibular dystonia, dystonic posturing of the right arm at rest.

 

Neuropsychological assessment revealed moderate visuospatial agnosia, moderate impairment of auditory-verbal memory (under interference conditions), and elements of dynamic apraxia. Speech showed dysarthria and elements of motor difficulties. Montreal Cognitive Assessment (MoCA) score: 22/30 (visuospatial/executive — 3/5, attention — 3/6, language — 2/3, delayed recall — 3 out of 5 words). Hospital Anxiety and Depression Scale (HADS): anxiety — 16 points (clinically significant anxiety), depression — 4 points (normal).

Additional investigations:

• Complete blood count and biochemistry (glucose, AST, ALT, total bilirubin, total protein, creatinine, urea, lipid profile, creatine kinase, total and ionized calcium, phosphorus, alkaline phosphatase, magnesium, potassium, sodium) revealed no clinically significant abnormalities;
• ECG, echocardiography, abdominal ultrasound, renal and bladder ultrasound, nerve conduction studies, overnight video-EEG monitoring, and brain MRI were unremarkable;
• Needle electromyography (EMG) revealed a mild myogenic pattern without signs of active abnormal process;
• Auditory brainstem evoked potentials showed mild peripheral hearing impairment on the left;
• Whole-genome sequencing revealed a heterozygous c.2974G>A (p.Asp992Asn) variant in the ATP1A3 gene, validated by Sanger sequencing.

Clinical case 2

Patient S., a 45-year-old female, mother of patient M., was admitted to the RCNN with complaints of unsteadiness and instability during walking, gait disturbance, pressing headache of the right-sided hemicrania type, leg weakness, tension in the leg muscles (predominantly in the posterior aspect), hand tremor, episodes of hand numbness, sensation of numbness in the legs, episodes of speech disturbance (numbness of the lips and tongue, slurred speech, stuttering), episodes of systemic vertigo leading to falls, reportedly with brief loss of consciousness and tonic body tension, and urinary incontinence.

She grew and developed normally. She has considered herself ill since age 43, when, suddenly with elevated blood pressure up to 250/110 mmHg, she developed systemic vertigo, intense headache, unsteadiness, coordination impairment, and weakness in the right limbs. Brain CT showed no evidence of acute cerebrovascular accident. Subsequently, mild right-sided hemiparesis and gait unsteadiness persisted, and involuntary posturing of the right foot appeared. From that time, she began using a unilateral support for walking. From age 44, episodes of tonic tension in the trunk muscles with elevation of the right shoulder and breathing difficulty began to appear, along with frequent episodes of lip and tongue numbness with speech disturbance (slurring, stuttering). Baclofen, gabapentin, and duloxetine were prescribed for dystonic hyperkinesia and pain, with moderate positive effect. Over the past year, she has experienced episodes with impaired consciousness at a frequency of approximately once per month, all occurring during wakefulness: she notes weakness in the legs ("jelly legs"), falls backward, then develops seizures with tongue biting and involuntary urination; after the seizure — disorientation, headache, and lethargy. According to her daughter, prior to loss of consciousness, the patient exhibited rotation around her own axis and laughter. Levetiracetam was initiated with dose titration to 1000 mg/day, with a positive effect in reducing seizure frequency.

Physical examination: height — 168 cm, weight — 75 kg, BMI — 26.6 kg/m². Heart sounds were muffled but regular. Blood pressure 140/90 mmHg, heart rate 80 bpm. Imperative urges to urinate and urinary incontinence were noted. Neurological examination revealed mild divergent strabismus due to the right eye, and mild left-sided facial paresis during testing of facial expression. Mild laryngeal dystonia was observed. Swallowing was not impaired. Muscle strength was reduced in the right limbs to 3.5–4.0/5. Paratonia was noted in the arms and legs. Deep tendon reflexes were brisk in the arms and legs, D = S. Coordination tests were performed with dysmetria bilaterally. She was unsteady in the Romberg test. Dystonic posturing of the right foot was observed, with extension and abduction at the ankle joint. Bradykinesia was present in the right leg. The patient is unsteady in the Romberg test. She mobilizes independently using a unilateral support.

Neuropsychological assessment revealed moderate impairment of auditory-verbal memory, mild visuospatial agnosia, mild kinesthetic apraxia, and dysarthria. Montreal Cognitive Assessment (MoCA) score: 21/30 (visuospatial/executive — 3/5, attention — 5/6, language — 2/3, delayed recall — 0 out of 5 words). Hospital Anxiety and Depression Scale (HADS): anxiety — 15 points, depression — 11 points (clinically significant anxiety and depression).

Additional investigations:

• Complete blood count showed no clinically significant abnormalities. Blood chemistry revealed mild cytolytic syndrome: ALT — 51 U/L (normal < 35 U/L), AST — 50 U/L (normal < 35 U/L), attributed to steatohepatosis;
• ECG: sinus rhythm 68 bpm. Left axis deviation. Incomplete right bundle branch block;
• Brain CT (MRI was not performed due to a metal fragment in the soft tissues of the parietal region following head trauma), nerve conduction studies, and overnight video-EEG monitoring were unremarkable;
• Needle EMG: mild myogenic pattern without signs of active abnormal process;
• Bladder ultrasound with residual urine volume measurement: no structural bladder abnormalities. Residual urine volume — 61 mL;
• Abdominal ultrasound: splenomegaly, signs of diffuse changes in the pancreas and liver (consistent with hepatic steatosis) with hepatomegaly.

Given the patient's symptoms and the identification of the ATP1A3:c.2974G>A (p.Asp992Asn) nucleotide variant in her daughter by whole-genome sequencing, Sanger sequencing of the ATP1A3 gene was performed, which revealed the same variant in the patient.

Table 3 presents a comparative summary of the two cases described.

 

Table 3. Comparative characteristics of the two patients

Sign	Patient M.	Patient S.
Age at onset, years	12	43
Triggering factor	Unknown	Emotional stress, elevated blood pressure
Dystonia	Generalized	Multifocal
Parkinsonism	+	+
Bulbar symptoms	+	–
Pyramidal signs	+	–
Paresis	+	+
Bowel and bladder dysfunction	+	+
Cerebellar signs	–	+
Affective disorders	+	+
Cognitive disorders	+	+
Paroxysmal episodes	+	+
Short stature	+	–
Headache	+	+
Neuroimaging	No focal abnormalities detected	No focal abnormalities detected
EMG	Myopathic pattern	Myopathic pattern

 

Discussion

In the presented family, a missense variant NM 152296:c.2974G>A (p.Asp992Asn) was identified in exon 22 of the ATP1A3 gene (Figure 3). The variant is not present in public population databases (gnomAD); the canonical nucleotide at this position is highly conserved (phyloP100 — 7.787) [36]. In silico prediction tools assess the variant as pathogenic: REVEL — 0.787 [37], CADD Score — 26.2 [38], AlphaMissense — 0.977 [39], SIFT — 0 [40].

 

Fig. 3. Sanger sequencing electropherogram of the ATP1A3:c.2974G>A variant; the variant is indicated by an arrow.

A — patient M.; B — patient S.

 

A similar variant was described by R. Baviera-Muñoz et al. in a 55-year-old female patient with the RDP phenotype. The disease onset occurred in adolescence with the appearance of involuntary facial movements and grimacing; at age 18, acute dystonia developed in the right arm, followed by two similar acute episodes, after which dystonic hyperkinesia spread to the right leg and trunk. Prior to the acute attacks, the patient reported triggering factors (emotional stress, alcohol consumption). Subsequently, the disease course remained stable [41].

S. Miyatake et al. performed a functional study with vector cell transfection for a deletion at the same position (p.Asp992del), demonstrating the pathogenic effect of the variant on the phenotype [22]. Substitutions to other amino acids at this position are known, with the AHC phenotype identified in all cases: p.Asp992Tyr — in three unrelated probands [42–44], and p.Asp992His — in one proband [45].

Based on the available data, the ATP1A3:c.2974G>A (p.Asp992Asn) variant meets PM2, PM5, PP1, PP3, and PP4 criteria — according to the American College of Medical Genetics (ACMG) guidelines [46], the variant may be classified as likely pathogenic.

The phenotype of Patient M., given the rapid symptom progression over a short period, adolescent onset, and generalized dystonia, parkinsonism, and bulbar symptoms, is most consistent with RDP. The acute episode with hemiparesis shares features with the characteristic attacks seen in the AHC phenotype; however, in our case, the symptoms persist. The patient's height (143 cm) is below the 3rd percentile for 19-year-old females according to WHO standards [47]. This manifestation is most likely due to hypothalamic-pituitary axis dysfunction (growth hormone deficiency) — short stature may be observed in patients with ATP1A3-associated disorders (particularly, there are descriptions of this symptom in the AHC phenotype), which is attributed to high gene expression in neuroendocrine glands [19]. Subjective hearing loss and the detection of auditory brainstem evoked potential abnormalities indicating peripheral hearing impairment may suggest partial overlap with CAPOS syndrome. In addition, the patient's clinical picture includes pyramidal signs and bowel and bladder dysfunction, which are relatively rare in ATP1A3-associated disorders and have been described in only isolated cases in the literature [14, 48].

The described paroxysmal episodes of involuntary upward eye deviation require differential diagnosis between epileptic seizures and oculogyric crises — both phenomena have been described in patients with ATP1A3-associated disorders [7, 16, 49]. During episodes, the patient is fully conscious and able to answer questions. Overnight video-EEG monitoring did not capture these episodes, and no interictal epileptiform activity was detected. Given the unclear etiology of the episodes, ex juvantibus therapy with an antiepileptic agent (lamotrigine titrated to 100 mg/day) was initiated — with no effect on seizure frequency. The combination of phenomenological and neurophysiological findings suggests a dyskinetic rather than epileptic nature of these episodes. Nevertheless, capture of one of the episodes during video-EEG monitoring is required to definitively rule out an epileptic origin.

Patient S. shows a significantly milder phenotype with late symptom onset. Given the presence of multifocal dystonia and signs of parkinsonism, the symptomatology is consistent with RDP. An atypical feature in this case is mild cerebellar ataxia, which is generally not described in patients with RDP.

Despite the considerable heterogeneity of symptoms in our cases, overlapping features are observed. In both cases, unlike the classic acute episodes in patients with ATP1A3-associated disorders, acute hemiparesis developed at disease onset without subsequent regression. The cephalgic syndrome present in both patients occurs more frequently in carriers of pathogenic ATP1A3 variants than in healthy individuals [5]. Notably, both cases showed an electromyographic pattern of primary muscle involvement. A review of the current literature revealed no descriptions of myopathy in patients with ATP1A3-associated disorders, warranting further investigations to elucidate the pathophysiological mechanisms underlying these changes.

Numerous families with marked phenotypic polymorphism have been described in the literature: within a single family and with the same variant, RDP, AHC, epileptic, and ataxic phenotypes may co-occur [50, 51]. The factors underlying the significant intra- and interfamilial variability among patients with the same variant are currently unclear. Modifying effects of variants in other genes involved in the same molecular pathways, epigenetic factors, and environmental factors have been hypothesized [43, 52]; molecular and epidemiological studies are needed to determine the contribution of each of these factors to the symptom polymorphism in patients with ATP1A3-associated disorders.

Conclusion

There are certain challenges in diagnosing ATP1A3-associated disorders that prevent timely recognition of the adequate diagnosis. These include wide clinical variability with overlapping and atypical phenotypes, incomplete penetrance and variable expressivity (symptoms in a parent carrying the same variant may be much milder or completely absent), as well as limited awareness of this group of disorders among clinicians. Further research is needed to provide more detailed descriptions of the molecular mechanisms and to define the full phenotypic and mutational spectra of this group of disorders. To improve the detection rate of ATP1A3-associated disorders, neurologists should be educated about the key clinical features, such as sudden onset with short-term symptom progression followed by stabilization, paroxysmal hemiplegic or hyperkinetic episodes triggered by fever, emotional stress, or physical activity, and the frequent presence of dystonia, bulbar symptoms, ataxia, and epileptic seizures.

Current treatment options (both conservative and surgical) for ATP1A3-associated disorders are limited. Clinical studies evaluating response to various symptomatic and pathogenetic therapies could help reduce the severity of the most disabling manifestations and improve patients' quality of life. Furthermore, further investigation into the molecular mechanisms of the disease may open prospects for the development of targeted therapies.

About the authors

Liliya R. Zaripova

Russian Center of Neurology and Neurosciences

Author for correspondence.
Email: zaripova.l.r@neurology.ru
ORCID iD: 0009-0009-6800-0860

Postgraduate Student, 5th Neurology Department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Konstantin M. Evdokimov

Russian Center of Neurology and Neurosciences

Email: zaripova.l.r@neurology.ru
ORCID iD: 0000-0001-6217-4151

Neurologist, Functional Diagnostics Specialist, Consultative and Diagnostic Department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Ksenia A. Gromova

Russian Center of Neurology and Neurosciences

Email: zaripova.l.r@neurology.ru
ORCID iD: 0009-0008-1360-2605

Resident

Russian Federation, Moscow

Mariam A. Sadekova

Russian Center of Neurology and Neurosciences

Email: zaripova.l.r@neurology.ru
ORCID iD: 0000-0002-0159-2453

Junior Researcher, Molecular Genetics Laboratory, 5th Neurology Department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Evgenii P. Nuzhnyi

Russian Center of Neurology and Neurosciences

Email: zaripova.l.r@neurology.ru
ORCID iD: 0000-0003-3179-7668

Dr. Sci. (Med.), Senior Researcher, Neurologist, 5th Neurology Department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Nataliya Y. Abramycheva

Russian Center of Neurology and Neurosciences

Email: zaripova.l.r@neurology.ru
ORCID iD: 0000-0001-9419-1159

Cand. Sci. (Biol.), Senior Researcher, Head, Molecular Genetics Laboratory, 5th Neurology Department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Ekaterina Y. Fedotova

Russian Center of Neurology and Neurosciences

Email: zaripova.l.r@neurology.ru
ORCID iD: 0000-0001-8070-7644

Dr. Sci. (Med.), Leading Researcher, Head, 5th Neurology Department, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Sergey N. Illarioshkin

Russian Center of Neurology and Neurosciences; Russian University of Medicine

Email: zaripova.l.r@neurology.ru
ORCID iD: 0000-0002-2704-6282

Dr. Sci. (Med.), Professor, Full Member of the RAS, Director, Brain Institute, Deputy Director for Science; Head, Neurology Department

Russian Federation, Moscow; Moscow

References

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