Early‐Onset Hyperkinetic Movement Disorders Define the Most Severe Presentation of the ATP8A2‐Related Phenotypic Spectrum

ABSTRACT

Variants in ATP8A2 gene have been traditionally associated with cerebellar ataxia, mental retardation and disequilibrium syndrome type 4 (CAMRQ4). However, this nomenclature fails to capture the predominantly extrapyramidal and encephalopathic nature of the most severe presentation of the ATP8A2‐related phenotypic spectrum.

We report two siblings with a novel homozygous ATP8A2 frameshift variant (p.Ser839Glyfs*21) presenting with a complex neurodevelopmental encephalopathy. Their phenotype was characterized by very early‐onset hyperkinetic movement disorders, including chorea, dystonia and myoclonus, accompanied by optic atrophy and sensorineural hearing loss. A critical literature review suggests that the profound neuromotor impairment in these patients often precludes an accurate assessment of ataxia, while hyperkinetic movements predominate. The multisystem involvement (ophthalmoplegia, ptosis and sensory loss) frequently mimics mitochondrial disorders, further complicating the diagnostic path. We argue that the current OMIM classification is restrictive and clinically misleading.

We therefore propose formally revising the clinical definition of ATP8A2‐related disorders to emphasize early‐onset complex encephalopathy with movement disorders, rather than ataxia, as the hallmark of severe cases. Integrating ATP8A2 into next‐generation sequencing (NGS) panels for early‐onset hyperkinesia is essential to ensure prompt diagnosis and resolve the diagnostic odyssey.

Our short communication establishes that the most severe, early‐onset presentation of ATP8A2 deficiency is a congenital encephalopathy hallmarked by prominent, nonprogressive hyperkinetic movement disorders. Moving beyond the historical CAMRQ4 ataxia classification is essential for the accurate diagnosis of this profound extrapyramidal phenotype.

1. Short Communication

ATP8A2 encodes the ATPase aminophospholipid transporter class I, type 8A, Member 2, a crucial P‐type ATPase that maintains cellular lipid homeostasis. This enzyme catalyses the active translocation of specific aminophospholipids, primarily phosphatidylserine and phosphatidylethanolamine, from the exoplasmic to the cytoplasmic leaflet of the membrane. This process is essential for generating and maintaining the membrane lipid asymmetry that underlies fundamental cellular functions, including vesicle trafficking and signalling (Flannery et al. 2024).

Consistent with other P‐type ATPases, the ATP8A2 transporter possesses three highly conserved cytoplasmic catalytic domains: the kinase‐acting N domain, the phosphatase‐acting A (actuator) domain and the P (phosphorylation) domain, which contains the critical Asp428 residue. The phosphorylation of this residue, mediated by the N and A domains, drives the conformational change necessary to flip the phospholipids across the plasma membrane. Variants in ATP8A2, particularly missense mutations affecting these catalytic domains, are a known cause of neurological disorders (Flannery et al. 2024).

In fact, pathogenic variants in ATP8A2 have been associated with a broad spectrum of phenotypes, described as isolated cerebellar ataxia or severe early‐onset encephalopathy (Narishige et al. 2022). The latter is characterized by hyperkinetic movement disorders (MDs), reported as chorea/choreoathetosis, severe intellectual disability, tetraplegia, axial hypotonia, significant oculomotor disturbances (ophthalmoplegia and ptosis), optic atrophy and hearing impairment, someway mimicking a mitochondrial encephalopathy (Alves Corazza et al. 2023).

These diverse neurological manifestations reflect the wide expression profile of the ATP8A2 transporter throughout the central nervous system, including the cerebrum, cerebellum, spinal cord and retina. While functional studies consistently link these variants to a loss of function through altered protein expression, mislocalization or impaired ATPase activity, the observed genotype–phenotype correlations in ATP8A2‐related disorders remain complex and heterogeneous (Heidari et al. 2021).

We describe the case of two siblings of Egyptian origin (aged 12 and 8 years), born to consanguineous parents (first cousins) with no relevant family history of neuropsychiatric disorders. In both cases, pregnancy was uneventful, and the neonatal period was regular, except for staturoponderal growth restriction. The clinical presentation of the older brother was characterized by early evidence of severe psychomotor developmental delay, leading to the first neurological consultation at the age of 30 months. At that time, neurological examination revealed an a‐postural dystonic–dyskinetic tetraparesis associated with rigidity and absent patellar reflexes. Head control was poor, and he had not acquired trunk control. Reaching was possible, although difficult, and was performed without dysmetria or intentional tremor; however, it was parasitized by generalized movement disorders. The child could point and vocalize with communicative intent but never developed effective expressive or receptive language. The associated features included bilateral ptosis, ophthalmoplegia, visual and hearing impairment, together with minor facial dysmorphisms. MDs predominantly included chorea, dystonic postures and dystonic–dyskinetic movements, facial grimaces and orobuccal dyskinesias; occasionally, more rapid, proximal movements occurred, consistent with myoclonus (Video S1). The disease course remained nonprogressive, and MDs slightly improved with oral tetrabenazine (up to 25 mg/day), coupled with the implementation of physical, occupational and speech therapies. At the most recent neurological follow‐up, his functional status was assessed using several standardized scales: Gross Motor Function Classification System (GMFCS) Class 5, Manual Ability Classification System (MACS) Level 5, Eating and Drinking Ability Classification System (EDACS) Level 4 and Communication Function Classification System (CFCS) Level 5. Additionally, he scored 23 out of 264 (8.7%) on the 88‐item Gross Motor Function Measure (GMFM‐88) and 26 out of 32 on the Barry–Albright Dystonia (BAD) scale. Brain magnetic resonance imaging (MRI) performed at the ages of 30 months, 6 years and 10 years revealed stable findings, including thinning of the optic nerves up to the chiasm, mild and non‐specific reduction of the frontal and occipital white matter, enlarged lateral ventricles with squared frontal horns and a slightly thinned corpus callosum (Figure 1). Electrophysiological studies showed poor organization, low voltage and an excess of diffuse rhythmic activity in early sleep phases on EEG; normal EMG/NCS results; normal electroretinogram (ERG) with markedly hypovolted Visual Evoked Potential (VEP) tracing, consistent with optic nerve atrophy; and bilateral sensorineural hearing loss confirmed by brainstem auditory evoked potentials (BAEP). The younger brother presented with a qualitatively similar clinical history to his older sibling's, although he was functionally less affected. His presentation was characterized by early global developmental delay, with the achievement of only partial head control prompting his first neurological consultation at 8 months of age. Like his sibling, he developed an early‐onset movement disorder; however, its milder clinical presentation resulted in a better preserved neuromotor functional profile. This milder presentation allowed for greater purposeful use of the upper limbs. Furthermore, he demonstrated better head control. From a language‐communicative and sociorelational perspective, the patient displayed clinical and functional characteristics that overlapped with those of the older brother. Interestingly, standardized assessments at his most recent neurological follow‐up did not fully reflect this observed functional advantage. His classification remained severe across most domains: GMFCS Class 5, MACS Level 5, CFCS Level 5 and EDACS Level 3. Furthermore, he scored 9/264 (3.4%) on the GMFM‐88. However, the slightly reduced severity of his movement disorder, compared to his brother, was captured by the BAD scale, on which he scored 21/32. Brain MRI performed at the ages of 9 months, 2 years and 5 years, 11 months revealed the same, stable findings as his older brother (Figure 1). Similarly, the younger brother's disease course remained nonprogressive, with his movement disorders showing slight improvement following the administration of oral tetrabenazine (up to 25 mg/day) and rehabilitation therapies. Differential diagnosis focused on congenital/early‐onset encephalopathies with predominant extrapyramidal involvement. Laboratory testing, including thyroid hormones, copper, ceruloplasmin, uric acid, plasma lactate and pyruvate, urinary organic acids, plasma amino acids, transferrin isoelectric focusing (IEF), lysosomal enzymes and CSF analysis (chemical/physical, lactate/pyruvate, biogenic amines and 5‐MTHFR), was all normal. Array‐CGH and targeted next‐generation sequencing (NGS) of genes associated with congenital extrapyramidal encephalopathy were negative. Trio whole‐genome sequencing (WGS) identified a likely pathogenic homozygous variant in ATP8A2 gene (c.2515_2518del; p.Ser839Glyfs*21); segregation analysis confirmed both parents as heterozygous carriers (Figure S1). Written informed consent was obtained from the patients' parents prior to data acquisition.

FIGURE 1.

Brain MRI of the two siblings. The first row displays the 10‐year‐old sibling, showing mild enlargement of the lateral ventricles with squared frontal horns, a bilateral reduction in hemispheric white matter (a,b), and thinning of the corpus callosum (c), optic nerves (d) and chiasm (e). The second row, representing the 15‐year‐old sibling, shows nearly identical findings: mild ventricular enlargement and reduced white matter (f,g), alongside thinning of the corpus callosum (h), optic nerves (i) and chiasm (l).

Narishige et al. (2022) reviewed cases of ATP8A2‐related disorders reported up to that time. The review focused on the classic CAMRQ4 syndrome (cerebellar ataxia, mental retardation and disequilibrium syndrome Type 4), the original acronym used to describe the clinical phenotype before the spectrum was recognized to be broader. The analysis aggregated 33 patients, revealing a consistent presentation marked by profound intellectual disability and severe neuromotor dysfunction. Clinically, 80%–90% of patients exhibited a nonambulatory status, hypotonia, feeding difficulties and involuntary movements (choreoathetosis/dystonia). Ocular and auditory abnormalities were also prominent, with optic atrophy, ophthalmoplegia and other visual impairments observed in around 50% of patients. Crucially, while most patients were reported to have ataxia, including astasia and abasia, the vast majority were non‐ambulatory (88% of 33 cases) and lacked sitting or head control (73%). This severe clinical picture makes it difficult to determine whether these impairments were solely attributable to ataxia.

The examination of the reported clinical summaries for these 33 patients, focusing on signs of cerebellar dysfunction (including titubation, ataxic gait/astasia/abasia, dysarthria, tremor and nystagmus), warrants reflection. Although the analysis is intrinsically limited by numerous missing or inadequately described data points, due to the constraints of a literature review, all reported patients presented with severe global developmental delay. Moreover, it is noteworthy that there was a low reporting of other classically associated cerebellar signs, such as nystagmus and titubation, which were often not described in the original papers. Although 89% of patients suffered from dysarthria, this neurological sign may not exclusively reflect cerebellar pathology, especially considering that only a minority of patients achieved basic language milestones (e.g., a few words). Strikingly, 30 patients with available brain MRI data did not exhibit either mild cerebellar atrophy or other significant cerebellar abnormalities. These observations suggest the likelihood of underlying extracerebellar dysfunction or subtle functional network dysfunction, or at least the co‐occurrence of pathogenic mechanisms.

The observed neurological complexity, particularly the co‐occurrence of ataxia (cerebellar pathology) and choreoathetoid movements (basal ganglia pathology), is supported by known reciprocal connections between these subcortical structures. Furthermore, neuropathological evidence supports a functional circuit impairment rather than a primary structural defect. This is characterized by distal axonal degeneration rather than neuronal cell body loss, consistent with neuroimaging showing preserved trophism in the basal ganglia and cerebellum. Indeed, the absence of cell death in ATP8A2‐mutant mice supports an axonal‐defect mechanism, potentially explaining the inconsistent findings of cerebellar atrophy in human patients (Zhu et al. 2012).

For all these reasons, Alves Corazza et al. (2023) proposed revising the CAMRQ4 classification. Aligning with the earlier observations of McMillan et al. (2018), they suggested moving beyond the strict definition of cerebellar ataxia toward a distinct, more severe phenotype primarily associated with biallelic loss‐of‐function variants in ATP8A2. These latter authors suggested that the presentation of early‐onset movement disorder associated with hypotonia and developmental delay should drive clinicians to exclude this genetic condition from the many other causes of cognitive impairment.

In the paediatric population, and particularly in infants/toddlers with such a complex and early‐onset disease presentation, certain cerebellar signs, such as truncal ataxia and intentional tremor, may be confused with, or are difficult to distinguish from, hyperkinetic movement disorders like dystonia, chorea, choreoathetosis and myoclonus, especially when they are subtle or coexisting (Gana and Valente 2020; Martinez‐Ramirez et al. 2020). Furthermore, an important notion to consider is the increasing evidence and wide recognition that MDs pathophysiology does not rely solely on basal ganglia dysfunction. Instead, it involves the improper function of wider neural networks that include the basal nuclei, the thalamus, the cerebellum and other anatomical structures (Gana and Valente 2020; Schirinzi et al. 2018). Thus, the broad expression of the ATP8A2 transporter across different components of the central nervous system suggests and strengthens the hypothesis of a global network connectivity dysfunction. This dysfunction may also be responsible for the other typical signs and symptoms of this condition, reminiscent of a mitochondrial disease presentation due to the observed multisystem brain involvement, as afore mentioned (Alves Corazza et al. 2023).

Further support for the hypothesis of a static/nonprogressive encephalopathy associated with involuntary movement comes again from Narishige et al. (2022). These authors underlined the difficulty in distinguishing this condition from dyskinetic cerebral palsy, particularly in sporadic cases where symptoms do not progress in the early developmental period, as observed in our siblings. However, the authors underlined that the associated visual and hearing impairments, along with the severe developmental delay, serve as critical diagnostic clues for this distinction.

Regarding disease progression, our cases did not provide clinical findings suggestive of a progressive disorder. The overall clinical picture has remained relatively stable from diagnosis through the most recent follow‐up, and we observed a reduction in the severity of the movement disorder. Visual and BAEP showed abnormalities, but we lack follow‐up data. However, some authors have suggested that early findings such as flattening on ABR, progressive loss of head control and ophthalmoplegia, and feeding difficulties may indicate progressive brainstem dysfunction, even when neuroimaging does not reveal brainstem atrophy (Narishige et al. 2022).

Therefore, our study highlights the need to redefine the whole spectrum of ATP8A2‐related disorders. We provide further evidence supporting the existence of a distinct neurodevelopmental phenotype at the most severe end of this spectrum, characterized by congenital, nonprogressive encephalopathy with early‐onset movement disorders as a prominent feature. In stark contrast, it is noteworthy that the milder extreme of the phenotypic spectrum presents as cerebellar ataxia associated with mild intellectual disability (ID) or a normal IQ, allowing patients to remain ambulatory even after a 10‐year follow‐up (Damásio et al. 2021; Guissart et al. 2020).

In conclusion, when evaluating a patient presenting with early‐onset, static/nonprogressive encephalopathy, characterized by severe developmental delay and complex movement disorders, genetic variants in ATP8A2 should be investigated. Therefore, we also propose the gene to be included in targeted NGS gene panels for early‐onset static/nonprogressive encephalopathies with involuntary movements or at least to be considered when performing clinical exome sequencing. The co‐occurrence of ptosis, ophthalmoplegia, optic atrophy and hearing impairment could mistakenly suggest mitochondrial disease; however, the absence of biochemical and radiological features typical of these conditions should prompt consideration of ATP8A2‐related disorder as a diagnostic possibility.

Author Contributions

Fabio Bruschi: conceptualization, data curation, validation visualization, writing – original draft, writing – review and editing. Clara E. Antonello: data curation, writing – review and editing. Cecilia Parazzini: data curation, writing – review and editing. Ylenia Vaia: writing – review and editing. Maria Iascone: data curation, writing – review and editing. Davide Tonduti: conceptualization, data curation, validation visualization, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki; accordingly, written informed consent was obtained from the patient's parents for the publication of this report and any accompanying images and videos.

Conflicts of Interest

The authors have nothing to report.

Supporting information

Figure S1: Whole‐genome sequencing (WGS) read alignments for ATP8A2; representative integrative genomics viewer (IGV) tracks displaying sequencing coverage and read alignments across the ATP8A2 locus.

Video S1: Clinical features of the affected siblings include complex movement disorder characterized by chorea, dystonia, facial grimacing and orobuccal dyskinesia, with occasional proximal myoclonus. Associated signs include bilateral ptosis, ophthalmoplegia and minor facial dysmorphisms.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.