Expanding the Allelic spectrum in ATP1A3-related disorders with 3 novel mutations and clinic features

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Figure 1
-brain MRI showing atrophy of corpus callosum (Patient 6).

Table 1

- Summary of phenotypes associated with ATP1A3 gene mutation.

Classical distinct phenotypes			Emerging new phenotypes
AHC	RDP	CAPOS	EIEE	RECA/FIPWE	Intermediate phenotypes
6–18 months	Childhood to adulthood	6 months–5 years	Neonatal period	Childhood	Childhood
Paroxysmal episodes of hemiplegia, bilateral hemiplegia, or quadriplegia Abnormal eye movements, monocular nystagmus, dystonia, autonomic disturbance	Abrupt onset dystonia with prominent dysarthria and dysphagia postural instability bradykinesia Rostro-caudal gradient	Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss	Early-onset epileptic encephalopathy, catastrophic epilepsy, refractory	Abrupt-onset ataxia after febrile illness, resembling encephalitis, relapsing course and then stable Evolution can be a mixed phenotype ataxia-dystonia	Paroxysmal episodes of weakness, strabismus resembling AHC spells; ataxia, dystonia with rostro-caudal gradient as in RDP
E801N, E815K, G947R, S811P	T613M, D903N	E818K	G358C, G358V, I363N, E815K	R756, E818K	R756

AHC - alternating hemiplegia of childhood, RDP - rapid-onset dystonia parkinsonism, CAPOS - cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss, EIEE - early infantile epilepsy and encephalopathy, RECA - relapsing encephalopathy with cerebellar ataxia Adapted from A. Capuano et al (The Cerebellum 2018)²

Table 2

- Patients with AHC phenotype

Patient	Sex	Age of onset	Phenotype	Presenting symptoms
				AHC			Dystonia	Cognition and Behavior	Seizures	Other
				Onset	Offset	Duration
1	F	3 years	c.998T>A: p.Val333Asp de novo Pathogenic (PS2;PP3;PM1;PM2;PP5)	3 years	7 years controlled by carbamazepine	last for hours		Impaired speech mild intellectual disability	none
2	F	2 years	c.2435A>T: p.D812Val de novo Pathogenic (PM1;PS2;PM5;PP3;PM2)	2 years	11 years	hours to days		Global developmental delay + Autistic features	At 2 years, intractable, Atonic and Generalized Tonic/Clonic
3	M	15 months	c.1198G>A: p.Glu400Lys de novo Likely Pathogenic (PS2;PM2;PP5)	15 months	3 years	hours to days		Global Developmental Delay	At 34 months Focal seizure	Nystagmus
4	M	3 years	c.2284G>T: p.Gly762Cys de novo Pathogenic (PM2;PS2;PM5;PP3;PM5)	3 years	6 years	15-30 mins		Aggressive and hyperactive	At 8 years Focal secondarily generalized. Controlled on Topamax.
5	F	2 months	c.2434G>A: p.D812N de novo Pathogenic (PM1;PS2;PS3;;PM5; PP3;PM5;PM2)	2 months	1-2 months triggered by emotional stress treated by flunarizine and currently by carbamazepine	hours to days	Mild dystonia	Global Developmental Delay, aggressive and hyperactive	At 2 months Focal with secondarily generalized	Spasticity L>R

Mean=24 months age of onset, Group 1 participants 60% female and 40% male; mean age=24 months. AHC-alternating hemiplegia of childhood, L-left, R-right

Table 3

- Group 2 patients without AHC phenotype.

Compatible Phenotype	Patient	Sex	Age of onset	Phenotype	Presenting symptoms
Compatible Phenotype	Patient	Sex	Age of onset	Phenotype	Cognition and Behavior	Seizures	Other
EIEE	6	F	at birth	c.2440G>A: p.G814S de novo	Severe Global Developmental Delay. Died at 17 months	At 6 weeks Generalized Tonic + Cyanosis	Nystagmus, Axial Hypotonia and perpendicular hypertonia, decelerated head circumference
RECA/FIPWE	7	F	2 years	c.2300G>A: p.R767H de novo Episodic encephalopathy, ataxia, movement disorder	Mild intellectual disability	At 1 year focal motor with impaired awareness	Features of cerebellar involvement

Mean= 10.25 months, All Group 2 patients female; mean age=12 months. AHC - alternating hemiplegia of childhood, EIEE - early infantile epilepsy and encephalopathy, RECA - relapsing encephalopathy with cerebellar ataxia, FIPWE - fever-induced paroxysmal weakness and encephalopathy