Expanding Phenotype of ATP1A3 Mutation

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Sir, ATP1A3 gene mutations are associated with alternating hemiplegia of childhood (AHC);[1] rapid-onset dystonia–parkinsonism (RDP);[2] and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS).[3] Rapid-onset dystonia–parkinsonism (RDP) is characterized by an abrupt onset of dystonia usually accompanied by signs of parkinsonism.[2] AHC is characterized by transient episodes of alternating hemiplegia, dystonic attacks, paroxysmal abnormal ocular movements, seizures, episodes of autonomic dysfunction, and intellectual disability.[1] AHC, RDP, and CAPOS syndrome are autosomal dominant disorders with reduced penetrance and variable expressivity.[1,2]ATP1A3 mutations are now known to cause a relapsing encephalopathy with cerebellar ataxia (RECA)[4] and an early infantile epileptic encephalopathy,[5] suggesting the broadening phenotypic spectrum. ATP1A3-related neurological disorder purely confined to the cortical grey matter for decades as epilepsy and subnormal cognition without the involvement of other parts of the neuraxis has not been reported. A 26-year-old woman, single child born of nonconsanguineous parentage, with a history of mental retardation in the mother presented with worsening seizures in her third decade. Her antenatal and immediate postnatal history was normal. However, she had a poor intellect, was unable to read and write, and had a score of 70 on the Wechsler adult intelligence and performance scale. She had habitual generalized seizures since infancy. Since then till 26 years of age, she has had a combination of focal seizures with impaired awareness, secondary generalized tonic-clonic seizures, and generalized tonic seizures with occasional clustering in the perimenstrual period. At presentation, she had a clustering of seizures following an infection, which led to decreased food intake and gradual deterioration of functional status worsened by drug noncompliance. She required ventilatory support from which she was slowly weaned off and on recovery attained a functional status that was below her premorbid deterioration. She was thin built; her fundus, deep tendon reflexes, and sensory examination were normal bilaterally. Routine blood counts, renal, liver, thyroid function test, serum lactate levels, magnetic resonance imaging (MRI) brain were normal. Nerve conduction study (NCS) showed motor predominant axonopathic neuropathy. Cardiac evaluation including electrocardiography and echocardiography were normal. Electroencephalogram (EEG) showed diffuse slowing of the background activity without any interictal epileptiform discharges. Suspecting a mitochondrial cytopathy in view of positive maternal history of mental subnormality, a clinical exome sequencing was done, which showed a heterozygous pathogenic mutation in exon 16 of ATP1A3 gene (c. 2155G > A; p.Gly719Arg). She was optimized on a combination of sodium valproate, phenobarbitone, and clobazam. Our case broadens the clinical spectrum of ATP1A3-related disorders from the classical RDP, AHC, and CAPOS [Figure 1], adding a new phenotype to it, confined exclusively to the cortical grey matter for a long time, as epilepsy and subnormal cognition without involvement of other parts of the neuraxis. The positive maternal history of mental subnormality prompted us to search for a genetic etiology affecting mitochondria, which revealed a heterozygous mutation in the ATP1A3 gene. The observed variation lies in the haloacid dehalogenase-like hydrolase domain of the ATP1A3 protein and has previously been reported (as p.Gly706Arg) in a patient affected with alternating hemiplegia in childhood.[6] The variant has also been reported as pathogenic in the ClinVar database.[7]Figure 1: Schematic representation of the phenotypic spectrum in ATP1A3 mutations. Orange circles represent well-defined phenotypes with definite criteria and blue circles represent phenotypes recently reported. Asterix denotes the phenotype of the current case. (CAPOS-Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; RECA-relapsing encephalopathy with cerebellar ataxia; EIEE- early-onset infantile epileptic encephalopathy; FIPWE- fever-induced paroxysmal weakness and encephalopathy)ATP1A3 gene encodes the α3 subunit of Na+/K+-ATPase, which is predominantly expressed in neurons in the thalamus, hippocampus, and dendritic spines. It controls the size and speed of the small depolarizations caused by fluctuations of intracellular sodium that occur during the activation of ion-gating neurotransmitter receptors. These α3 subunits have approximately fourfold-reduced sodium affinity compared to α1 and are specifically required for rapid restoration of large transient increases in sodium. Two children—one with catastrophic early life epilepsy and reduced survival, and another with epilepsy, postnatal microcephaly, episodic prolonged apnea, and severe developmental disability—have been reported[5] with heterozygous mutations in the ATP1A3 gene. Intractable neonatal seizures, early-onset epilepsy, and status epilepticus have been reported in children with AHC,[1] and an association has been shown with p.Glu815Lys mutations in ATP1A3 and neonatal-onset seizures.[8] Phenotypic overlap of AHC and CAPOS syndrome has been documented.[9]ATP1A3 mutations also cause a wide spectrum of nonmotor features such as psychosis, anxiety, mood disorders, and substance abuse/dependence. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset and can be considered as yet another phenotypic expression of the ATP1A3 gene mutation.[10] Patients with ATP1A3 R756H have disease onset in childhood characterized by fever triggered paroxysms of encephalopathy and weakness, which incompletely improve, leaving persistent deficits. Motor weakness is mostly generalized, and long-term sequelae include persistent bulbar, oculomotor problems, cognitive deficits, motor apraxia, and inability to walk because of ataxia. This phenotype of ATP1A3 mutation has been labeled as fever-induced paroxysmal weakness and encephalopathy (FIPWE) syndrome.[11] These FIPWE patients improved but recovery was below the premorbid baseline status as in our case. Our patient has some overlap with FIPWE in that she had a sudden worsening associated with infection with a less than optimal outcome though this happened in adulthood and not in childhood. The above-reported cases including ours emphasize the fact that ATP1A3 is no longer exclusively the gene for certain compartmentalized syndromes alone. Epilepsy as the exclusive or dominant clinical presentation needs to be included in the phenotype description. The fact that she had an axonal neuropathy may suggest an overlap with CAPOS where pes cavus is a feature. There can be a spectrum of manifestations that can be caused by ATP1A3 mutation and insidious presentation confined to the cortical grey matter for more than two decades as epilepsy and subnormal cognition without the involvement of other parts of the neuraxis may be considered as one [Figure 1]. Rather than watertight compartmentalized phenotypes, one may see an array of phenotypic presentations as next-generation sequencing studies become more easily available. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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