Atypical presentation of rapid-onset dystonia–parkinsonism in a toddler with a novel mutation in the ATP1A3 gene

Abstract

ATP1A3 gene mutations can result in a spectrum of diseases with diverse neurological manifestations. One such disorder linked to this mutation is rapid-onset dystonia–parkinsonism (RDP), which manifests as dystonia with features of parkinsonism, such as tremors, rigidity, muscle spasms, and bulbar symptoms. Affected patients are typically adolescents or young adults, with symptoms occurring in a rostrocaudal pattern. We report a unique case of a 2-year-old child with an early onset, atypical presentation of RDP. In addition to motor developmental delay, he presented with muscle rigidity and mild asymmetric dystonia of the limbs, with the lower limbs being more affected than the upper limbs. Genetic sequencing of the child revealed a novel heterozygous autosomal dominant mutation of ATP1A3 gene c.173A>G (p. Tyr58Cys). This report highlights that RDP can present with atypical presentations in the paediatric population and adds to existing medical literature on the clinical spectrum of ATP1A3 genetic channelopathy.

Background

Pathogenic ATP1A3 gene mutations result in a myriad of clinical neurological manifestations. Classical phenotypes commonly linked with ATP1A3 gene mutations include rapid-onset dystonia–parkinsonism (RDP or primary dystonia type 12),¹ alternating hemiplegia of childhood (AHC)² and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome.³

The ATP1A3 gene, located on chromosome 19, encodes for the alpha-3-subunit of the sodium–potassium pump (Na⁺/K⁺-ATPase) channel of the nervous system. This channel plays a significant role in regulating cell membrane excitability and neurotransmitter function, thus affecting the cerebral and cerebellar neuronal function.^{4 5}

RDP (dystonia type 12 or DYT12) is a syndrome characterised by the abrupt manifestation of dystonia and parkinsonism, typically spreading in a rostrocaudal pattern (face >arms> legs). These symptoms are often precipitated by specific triggers, with onset commonly reported in adolescence or early adulthood.⁶

However, atypical symptoms and intermediate phenotypes that do not conform to the classical presentations of ATP1A3 gene mutations and RDP have been reported.^{7 8} This warrants the consideration of the above-mentioned syndromes as part of a spectrum of ATP1A3-related disorders instead of as distinct entities.⁹ Rare instances of RDP in infants have presented with motor development delay and ataxia.¹⁰

Given these diverse phenotypes, detection of ATP1A3 mutations is often delayed, with diagnosis typically occurring as one of exclusion.¹¹ The genotype–phenotype relationship needs to be better understood, to allow for quicker pathways towards diagnosis, counselling and targeted management.

Case presentation

We report the case of a 2-year-old boy, who is the third-born child of healthy, non-consanguineous parents, with two developmentally normal siblings. The antenatal history was insignificant, and the boy was born at term via emergency caesarean section in view of breech position and meconium-stained amniotic fluid. He was non-vigorous at birth, but spontaneous resuscitation was achieved after a cycle of bag-mask ventilation. He was admitted for observation in the neonatal intensive care unit. After an uneventful hospital stay, he was discharged on day 7 of life.

The parents observed their son having progressive stiffness of both lower limbs and right upper limb from 1 year of age. Thereupon, they initiated physiotherapy for the child and brought him to the child development clinic for further evaluation.

A detailed history was elicited, which revealed that the child had a delay in attaining all motor milestones from an early age. He could lift his head up and roll over only at 5 months of age. He was able to crawl, sit upright with assistance or unassisted in ‘tripod’ position, and grasp objects with left-hand preference at 8 months. (figure 1) At 10 months of age, he was noted to be able to transfer objects from the left hand to the right, but not vice versa. He began to walk with assistance only from 10 months of age. At the time of consultation, he could not sit upright or walk without support. Language and social milestones were achieved within the age-appropriate ranges. The child had no history of seizures, intellectual disability or bulbar symptoms. No diurnal variation in symptoms was noticed, and the family history was unremarkable.

Figure 1.

Child sitting in the ‘tripod’ position unassisted (head and back bent forward, arms in front for balance), displaying left-hand preference.

A neurological examination revealed hypertonia (rigidity) of all four limbs and hips, with lower limbs being affected more than the upper limbs and the right upper limb more affected than the left. Deep tendon reflexes were brisk with a bilateral extensor plantar (‘Babinski’) reflex and ill-sustained clonus of the lower limbs. He could walk only with support and he exhibited a scissoring gait. (figure 2). He also had a movement disorder in the form of dystonia, predominantly involving the hands and feet. No facial dysmorphism, cranial nerve abnormalities or neurocutaneous markers were noted. The parental neurological examination was unremarkable.

Figure 2.

Child lying down with attitude showing apparent spasticity of both lower limbs and the right upper limb.

The Developmental Assessment Scale for Indian Infants, a standardised Indian development assessment tool, was employed. He scored a 35 on the motor quotient and 146 on the mental quotient. The Oral Peripheral Mechanism Examination test indicated that all structures and articulators related to speech production were normal. Speech and language assessments carried out in the patient’s spoken language found him to have age-adequate language skills.

Investigations

Diagnostic workup included a thyroid profile test, which revealed high free T4 (fT4) of 2.29 ng/dL (biological reference range=0.93–1.7 ng/dL) and thyroid-stimulating hormone of 1.826 mIU/mL (biological reference range=0.7–6.6 mIU/mL). Serum prolactin levels were found to be elevated at 24.57 ng/mL (biological reference range=4.04–15.2 ng/mL). Serum homocysteine levels, uric acid and complete blood count were found to be normal.

MRI of the brain as well as magnetic resonance angiography and magnetic resonance venography of the intracranial vessels revealed no significant structural abnormalities. Fundoscopic examination and metabolic syndrome workup were unremarkable.

Genetic sequencing of the proband identified a novel heterozygous missense variant in exon 3 of the ATP1A3 gene (Chr19:g.42492489T>C;c.173A>G;p.Tyr58Cys). This variant has not been reported in the 1000 Genomes Project or Genome Aggregation (gnomAD) databases. Genetic testing of the parents by Next Generation Sequencing revealed the same mutation in his asymptomatic father with reduced penetrance (figure 3A). His mother did not carry any similar mutations (figure 3B). These results were further validated by Sanger sequencing.

Figure 3.

Sequence chromatogram and alignment to the reference sequence showing the variation in exon 3 of the ATP1A3 gene (chr19:g.42492489T>C; c.173A>G; p.Tyr58Cys). This variation was detected in the heterozygous condition in the father of the index patient (figure 3A), but not in his mother (figure 3B).

Differential diagnosis

A diagnosis of dopa-responsive dystonia was initially considered owing to the elevated serum prolactin levels. However, it was ruled out when a trial of levodopa therapy yielded no significant improvements in his symptoms.

Outcome and follow-up

The child showed a modest improvement in hypertonia after the initiation of baclofen treatment (10 mg/day) and physiotherapy. However, given the constraints on the parents due to the COVID-19 pandemic, physiotherapy could not be continued although baclofen was taken regularly. During the 6-month follow-up visit, the condition of the child was found to be stable, although improvement was minimal. No regression of milestones or worsening of symptoms was noted.

Discussion

The purpose of this report is to describe the case of a child with atypical, early-onset symptoms owing to a novel mutation of the ATP1A3 gene. The ATP1A3 gene has been only recently linked to the clinical neurological syndromes of RDP, dystonia 12 or DYT12 in 2004,¹ AHC in 2012² and CAPOS syndrome in 2014,³ as well as other emerging phenotypes.^{12 13}

A 2014 international task force on ATP1A3-related disorders formulated diagnostic criteria with additional observed features to help guide physicians toward their diagnoses.⁶ A comparison between the RDP diagnostic criteria and the proband, listed in table 1, highlights the atypical nature of the latter’s clinical presentation.

Table 1.

RDP diagnostic criteria*⁶ compared with the atypical presentation of the proband.

Major criteria for diagnosis of RDP	Proband
1. Onset of symptoms (dystonia–parkinsonism) over a few minutes to days	Uncertain, owing to onset since infancy
2. Clear rostrocaudal gradient (face>arms>legs)	No (lower limb dystonia appeared first and was more severe than upper limb dystonia)
3. Prominent bulbar findings	No
4. Absence of response to an adequate trial of L-dopa therapy (eg, carbidopa/levodopa 25/100 mg, 1 pill three times/day)	Yes
5. Family history consistent with autosomal dominant inheritance or de novo mutations	Yes (autosomal dominant inheritance, with father carrying similar heterozygous missense mutation with reduced penetrance)

*This article was published in Neurology: Genetics, Vol. 3,2, e139, by Rosewich et al, ‘Research conference summary from the 2014 International Task Force on ATP1A3-Related Disorders’, Copyright: The Author(s), published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology (2017).

RDP, rapid-onset dystonia–parkinsonism.

A variety of physical, physiological and psychological triggers have been implicated in the onset of RDP.⁷ However, a careful analysis of the proband’s history revealed no such specific triggers. Furthermore, he exhibited a bilateral extensor plantar reflex (‘Babinski Sign’), which has only been noted in one other case reported by Liu et al.¹⁴

An important aspect to be considered is the child’s young age, and the possibility of his current symptoms of mild limb dystonia being a precursor for more severe, classical RDP later in life. Brashear et al described two cases of infantile-onset RDP, where both cases suffered from motor developmental delay and episodes of mild-to-moderate dystonic spasms before a triggering episode incited the onset of long-lasting motor disability and bulbar symptoms.¹⁰ This biphasic pattern of disease progression has commonly been reported in adults as well.⁶ Close follow-up of the child’s condition may demonstrate how infantile-onset RDP progresses with age.

The increasing number of atypical presentations and intermediate phenotypes of RDP warrant the expansion of existing diagnostic criteria.^{7 15} Of note, a cohort study by Haq et al challenged the supposed significance of a rostro-caudal severity gradient. Although bulbar symptoms remained a likely finding, 62% of the study’s participants initially presented with limb dystonia.¹⁶

The ATP1A3 gene codes for an essential channel called the Na⁺ - K⁺ - ATPase pump in neurons. It has been postulated that this pump is majorly expressed only in certain structures of the brain, including the basal ganglia, thalamic nuclei, cerebellum and pons.¹⁷ Moreover, the pump is vital for maintaining an electrochemical gradient prior to depolarisation.¹⁸

RDP occurs because of a mutation in the alpha-3 subunit of the ATP1A3 gene, wherein there exists a dysfunction of electron exchange and transmission of electrical impulses across the neuronal membrane. Pathogenic mutations have been found to decrease protein levels of ATPase and the pump’s activity.^{1 4}

Experimental models have demonstrated that mutations cause a selective reduction in the pump’s affinity to sodium ions (Na⁺) and lower rates of pump current.^{4 19} Increased intracellular Na⁺ causes increased calcium ions (Ca⁺⁺) influx. This impairs the uptake of dopamine and other neurotransmitters, leading to parkinsonism and dystonia, respectively.²⁰

Interestingly, there is no evidence of structural damage to the substantia nigra in patients with RDP.²¹ The MRI of our patient was unremarkable. The Na⁺-K⁺-ATPase pump is highly expressed in the basal ganglia, which may explain why mutations result in dystonia and parkinsonism.²²

A novel heterozygous missense variation in exon 3 of the ATP1A3 gene (Chr19:g.42492489T>C;c.173A>G;p.Tyr58Cys) was identified in our patient. The in-silico predictions of the variant were predicted by PolyPhen-2 (Polymorphism Phenotyping v2), SIFT (Sorting Intolerant From Tolerant), LRT (Likelihood Ratio Test) and MutationTaster2 programmes to be damaging. The reference codon was also found to be conserved across species. A limitation of this report is our inability to perform functional studies or detailed segregation analysis to further establish the genotype–phenotype relationship associated with this mutation, owing to financial constraints on the family. The atypical features presented by the child may be attributed to the fact that different variants of the mutation have been reported to cause distinct types of damage to the pump, resulting in different clinical manifestations.²³ However, the mutation and reduction in the pump activity cannot account for the variety of phenotypes expressed; thus, the onus can be placed on genetic, epigenetic and environmental factors.²⁴ The proband’s father was asymptomatic, but his genetic test revealed an identical heterozygous mutation with reduced penetrance. This reduced penetrance could explain the asymptomatic nature of the disease, which is in line with previous reports of younger children with autosomal dominant ATP1A3 gene mutations having asymptomatic carrier parents.⁵

Close follow-up of the patient will be required to assess the progression of his condition with his current line of treatment using baclofen and physiotherapy for his dystonia and spasticity.^{25 26} His cognitive development and mental well-being will also require attention, as these aspects have often been reported to be affected in patients with ATP1A3-related disorders.^{5 27}

Parental perspective.

My son did not cry immediately after he was born. He was shifted to the neonatal intensive care unit and was fortunately discharged soon after. We noticed that he did not attain his developmental milestones at the appropriate age. He was an active boy until six months of age when we noticed tightness in his legs and right arm. We were quite concerned and decided to consult a developmental paediatrician. He advised us to start physiotherapy and referred us to a paediatric neurologist. The doctors took a detailed history, examined our child, and ordered blood tests and imaging scans. The doctor told us that he suspected a condition called dopa-sensitive dystonia and prescribed a medicine called levodopa for one month. However, we did not notice any improvements in our son upon administering the medicine. During a follow-up visit, the doctors advised us to undergo genetic testing. A diagnosis of a rare genetic disorder was made, and the doctors explained to us that it was causing his symptoms. While we were initially shocked by this, we understood that physiotherapy and a medicine called baclofen were essential for our son. We know that there is currently no treatment to cure his condition, but if gene therapy for such rare disorders was available, that would be life-changing for our family. At present, our son is unable to attend physiotherapy sessions due to the COVID-19 pandemic, but his condition has not deteriorated. We are anxious for our son to resume physiotherapy so that his condition improves. I feel privileged to write this perspective about my child’s health, and I sincerely hope that other physicians can understand this condition better and find better treatment options.

Learning points.

• Initial presentation of rapid-onset dystonia–parkinsonism (RDP) in infants may manifest as motor development delay.

• The absence of specific ‘hallmark’ characteristics of RDP should not eliminate the diagnosis from consideration while approaching a case suggestive of the condition.

• Patients with dystonia unresponsive to levodopa therapy must undergo genetic testing to rule out RDP.

• RDP is commonly inherited in an autosomal dominant manner, but the carrier parents may not always exhibit symptoms.

• As more atypical presentations of RDP are reported, the genotype–phenotype correlation should be examined further to help achieve broader diagnostic criteria for RDP and other ATP1A3-related disorders.

Ethics statements

Patient consent for publication

Parents/Guardians consent obtained.