J Poon, CK Chow, LY Hung, T Tsui

Abstract

An 11-month-old girl presented to us with recurrent episodes of hemiplegia affecting either side of the body, which were associated with febrile illnesses. Extensive workup in efforts to rule out other causes including vascular, metabolic or neuromuscular causes were unremarkable. Clinical diagnosis of alternating hemiplegia of childhood (AHC) was made and was later confirmed with genetic analysis. This report aims to enlighten clinicians on the complex presentation of AHC and to highlight that epileptic seizure, although a different disease entity, may be common in the presentation of AHC.

Case Report

Our case was born full term with uneventful antenatal and postnatal course. Her family history was unremarkable and her parents were non-consanguineous. She enjoyed good past health except known beta thalassemia trait.

She was initially known to us for onset of seizures at three months of age, presenting with loss of consciousness, staring eyes, increased four limb tone with no tonic-clonic convulsion. Seizure episodes lasted for a few minutes each with postictal drowsiness. She was started on phenobarbitone for seizure control and had one episode of breakthrough seizure at seven months of age.

Physical examination showed no dysmorphism or neurocutaneous stigmata. Her neurological exam was normal and development appropriate to her age at presentation. Wood's lamp showed no fluorescent skin lesions. Neuroimaging upon initial seizure presentation showed no abnormality. Electroencephalogram done at five months old was normal.

At nine months of age, she was admitted for two days of right-sided weakness associated with febrile illness. Her parents subsequently volunteered six months' history of alternating unilateral weakness lasting around two to three day and occurring once every one to two months. Muscle weakness was most prominent with fine motor movement, with gross motor function relatively spared. There was also associated involuntary eye deviation to the hemiplegic side but no alteration in sensorium or consciousness.

In view of the newly reported hemiplegic symptoms, evaluation to exclude other structural, vascular and metabolic disorders was performed. Magnetic resonance imaging of the brain with angiography was done to rule out structural lesions with no abnormality detected. Metabolic workup (including plasma lactate and

ammonia; urine organic acids; plasma amino acids; serum free carnitine, acylcarnitine, transferrin isoforms, biotinidase and very long chain fatty acids) was unremarkable. Clinical diagnosis of alternating hemiplegia with recurrent episode of unilateral weakness was made. Genetic analysis for ATP1A3 was performed by polymerase chain reaction followed by Sanger sequencing of genomic DNA extracted from EDTA blood samples of the proband and her parents, and confirmed a de novo heterozygous missense variant NM_152296.4(ATP1A3):c.2401G>A, p.(Asp801Asn) in the proband, which was a known pathogenic variant.¹ (Figure 1) The diagnosis of alternating hemiplegia of childhood (AHC) was confirmed and the patient was subsequently started on a trial of flunarizine at 2.5 mg daily dosing.

At 11 months of age, she was noted to have delayed development by about three months over the gross motor aspect. She was unable to pull to stand and had decreased ability to sit unsupported. She was referred for formal development assessment and training. Since then, her developmental milestone had shown gradual improvement especially over the gross motor aspect with no regression noted all along.

There were nine further episodes of hemiplegic attacks after presentation. Some of the episodes were associated with febrile illness and all had similar semiology of unilateral weakness with eye deviation to affected side, resolving spontaneously after two days. However, the attacks were reported to be milder in severity and duration. Flunarizine was stepped up to 5 mg daily to optimise control of the attacks.

In addition, there was an episode of breakthrough seizure at 17 months of age with increased tone over four limbs and starring gaze lasting a few minutes, features were

different to those seen in her hemiplegic attacks. Phenobarbitone was gradually weaned off while anticonvulsant was being switched to sodium valproate at 13 months old. Later topiramate was added on for control of seizure andecurrent hemiplegic attack. Since the addition of topiramate there was no recurrence of hemiplegic episodes or breakthrough seizures. Her developmental milestone had caught up and was appropriate to age. The current management plan was to continue with flunarizine at 5 mg daily andtep up topiramate as additional prophylaxis, while tailing off valproate gradually.

(A)	(B)
Figure 1 Electropherogram of (A) heterozygous pathogenic ATP1A3 variant, c.2401 G>A p.(Asp801Asn), detected in the proband and (B) wildtype sequence detected in the parents. The affected nucleotide is marked by an arrow.

Discussion

AHC is a rare early-onset neurological disorder with estimated incidence of 1 in 1,000,000 births.² The major pathognomonic features include paroxysmal attacks of hemiplegia or hemidystonia affecting either side of body, or generalised fluctuating dystonia, quadriplegia or quadriparesis with onset within six months of age. Other accompanying non-paroxysmal features may range from global developmental delay, variable intellectual disability, pyramidal tract signs, and epilepsy. Some patients may have atypical presentation including predominantly dystonic rather than hemiplegic paroxysmal episodes.³ This disease was first characterised as a distinct syndrome in 1971, but the causative gene ATP1A3 was identified only in 2012.^3,4

ATP1A3 encodes for the alpha-3 isoform of the catalytic subunit of the Na⁺/K⁺-ATPase transmembrane ion pump. This isoform is exclusively expressed in neurons and is crucial in maintaining the neuronal excitability.¹

Pathogenic variants in ATP1A3 may account for up to 74% of patients with sporadic, typical AHC.⁴ To date, at least 34 unique variants in ATP1A3 clustering near the transmembrane domains have been identified, including two recurrent variants p.Asp801Asn and p.Glu815Lys. Functional studies showed the p.Asp801Asn variant, which was found in the proband, had decreased binding to potassium ions and reduced ATPase catalytic activity.⁵ The variant was found to be associated with a milder phenotypic expression.⁶

Apart from AHC, the spectrum of ATP1A3-related disorders encompasses two other clinical phenotypes: rapid-onset dystonia-parkinsonism (RDP) and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). Presence of atypical phenotypes and the findings of different phenotypes among patients carrying the same pathogenic variant suggest that the three phenotypes may represent a continuum of neurological disorder.⁷ Before the discovery of the causative gene in 2012, the diagnosis of AHC was based on expert-consensus clinical criteria (Table 1).⁸ A new diagnostic approach that advocates referral for ATP1A3 molecular analysis based on neurologic symptoms or signs broadly supporting an association with ATP1A3-related disease instead of specific syndromes has been proposed at the 2014 International Task Force meeting on ATP1A3-related disorders.⁹ With this case-finding approach, there may be expansion of the phenotypic spectrum and improved understanding of the pathophysiology behind these disorders.

Due to the disease's complexity and variability in phenotypes, its diagnosis and subsequent multidisciplinary management is often difficult and delayed.² Most children with AHC will have some degree of long term disability and other medical problems, with majority of them having developmental delay and 50% of them having epilepsy.³ The prognosis of patients with AHC are often poor due to associated developmental delay and stepwise deterioration after severe attacks.

The mainstay of treatment is by prophylactic medication and acute management of hemiplegic attacks. Lifestyle measures such as avoidance of precipitating factors including psychological stress, fatigue and early induction of sleep is recommended as part of the management strategy. Early recognition of febrile illnesses and vaccinations are also recommended to patients with AHC. There is no curative treatment but various medications including steroids, coenzyme Q10, acetazolamide have been recommended. However, current evidence for the above medications is inconclusive with their clinical efficacy evaluated mostly in case reports or case series. A case report in our locality achieved remission while being treated with corticosteroids, possibly through direct induction of the Na⁺/K⁺-ATPase activity.¹⁰ Topiramate, an anticonvulsant, may improve the frequency and severity of non-epileptic paroxysmal symptoms and seizure-like episodes.^11,12 However, patients treated with topiramate are at risk of anhidrosis and hyperthermia, thus care-takers should be educated to monitor these side effects and avoid overheating. Increasing evidence has shown flunarizine, a calcium channel blocker to be effective in reducing the frequency and severity of the hemiplegic attacks.^3,13,14 The efficacy of flunarizine is based on its use in hundreds of patients, albeit in open-label experience, whereas reports for the other agents were either single case reports or case series of a small number of patients.¹⁵ As in our case, the combination of the above drugs including flunarizine and topiramate had led to improved outcome in terms of the hemiplegic attack and seizure control.

In summary, ATP1A3 is the major pathogenic gene of AHC patients and is associated with multiple neurological phenotypes. Lower threshold for genetic analysis of the ATP1A3 gene is recommended, once clinical symptoms fulfil the diagnostic criteria and also for those with atypical presentation. Correct and timely diagnosis can help to avoid delayed management and unnecessary treatments while more evidence is needed in evaluating the effectiveness of different treatment modalities.

Declaration of Interest

The authors declare that there is no conflict of interest.

References

1. Rosewich H, Thiele H, Ohlenbusch A, et al. Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol 2012;11:764-73.

2. Neville BGR, Ninan M. The treatment and management of alternating hemiplegia of childhood. Dev Med Child Neurol 2007;49:777-80.

3. Mikati MA, Kramer U, Zupanc ML, Shanahan RJ. Alternating hemiplegia of childhood: clinical manifestations and long-term outcome. Pediatr Neurol 2000;23:134-41.

4. Heinzen El, Swoboda KJ, Hitomi Y, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 2012;44:1030-4.

5. Weigand KM, Messchaert M, Swarts HGP, Russel FGM, Koenderink JB. Alternating Hemiplegia of Childhood mutations have

a differential effect on Na⁺/K⁺-ATPase activity and ouabain binding. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2014;1842:1010-6.

6. Panagiotakaki E, De Grandis E, Stagnaro M, et al. Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood - a study of 155 patients. Orphanet J Rare Dis 2015;10:123.

7. Termsarasab P, Yang AC, Frucht SJ. Intermediate Phenotypes of ATP1A3 Mutations: Phenotype-Genotype Correlations; Tremor Other Hyperkinet Mov (NY) 2015;5:336.

8. Bourgeois M, Aicardi J, Gouti鋨es F. Alternating hemiplegia of childhood. J Pediatr 1993;122:673-9.

9. Rosewich H, Sweney M, DeBrosse S, et al. Research conference summary from the 2014 International Task Force onATP1A3-Related Disorders. Neurol Genet 2017;3:e139.

10. Wong VCN, Kwong AKY. ATP1A3 mutation in a Chinese girl with alternating hemiplegia of childhood-Potential target of treatment. Brain Dev 2015;37:907-10.

11. Jiang WJ, Chi ZF, Ma L, et al. Topiramate: a new agent for patients with alternating hemiplegia of childhood. Neuropediatrics 2006;37:229-33.

12. Aishworiya R, Low PS, Tay SKH. Alternating hemiplegia of childhood: successful treatment with topiramate and flunarizine, a case report. Ann Trop Paediatr 2011;31:149-52.

13. Pisciotta L, Gherzi M, Stagnaro M, et al. Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients. Brain Dev 2017;39:521-8.

14. Sasaki M, Sakuragawa N, Osawa M. Long-term effect of flunarizine on patients with alternating hemiplegia of childhood in Japan. Brain Dev 2001;23:303-5.

15. Samanta D. Management of Alternating Hemiplegia of Childhood: A Review. Pediatr Neurol 2020;103:12-20.