Neurological disorder related to ATP1A3: importance of diagnosis

Case presentation: JRCS, female, started, at 15 years old, dysphagia initially for solids, progressing to liquids, hand dystonia and anarthria after isolated fever. At the time she was admitted to another pediatric center for diagnostic investigation, with normal brain MRI, EEG and ENMG. History of mother with undiagnosed psychiatric disorder and progressive gait dysfunction. At age 16 she was hospitalized for malnutrition associated with worsening abnormal movements. Neurological examination evidenced: preserved cognition, motor aphasia, hypomimia, dysphagia, sialorrhea, absence of vomiting reflex; reduced tongue motricity with preserved sensitivity, no myofasciculations; generalized hypotrophy, left worsening upper limb rigidity, strength grade 4+, normal deep reflexes and indifferent plantar cutaneous reflex, asymmetric hand and foot dystonic posture (worse left), bradykinesia, distal muscle atrophy, no ataxia or dysmetria; preserved sensitivity. On admission the previous tests were repeated, in addition to echocardiogram, abdominal and pelvic ultrasound, chest X-ray, cervical spine MRI, and nasopharyngolaryngoscopy, all normal. The dystonia gene panel identified a mutation in the ATP1A3 gene.

Discussion: The ATP1A3 gene encodes the α-3 catalytic subunit of the transmembrane Na⁺/K (+)-ATPase ion pump and is expressed exclusively in CNS neurons. ATP1A3-related neurological disorders of autosomal dominant inheritance have 4 described phenotypes: Rapid Onset Dystonia-Parkinsonism; Alternating Hemiplegia of Childhood; Cerebellar Ataxia, Areflexia, pes cavus, Optic Atrophy and Sensory Hearing Loss (CAPOS); and Developmental Encephalopathy and Epilepsy. The patient had the Rapid Onset Dystonia-Parkinsonism phenotype (or dystonia 12) characterized by asymmetric dystonia of acute or subacute onset associated with features of parkinsonism that evolve in hours to days stabilizing within a month. Usually, the symptoms are triggered by fever, stress, trauma, physical exercise, alcohol intake, and others. The age of onset ranges from 9 months to 55 years. The symptoms do not improve with Levodopa.

Final comments: The genetic study has enabled case outcome and appropriate treatment, as well as providing the family with genetic counseling through maternal investigation. Molecular genetic research has become a fundamental tool for elucidating cases previously without a definitive diagnosis.

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Artikel online veröffentlicht:
18. September 2023