ATP1A3 mutations

Abu Libdeh A, Talman L, Chambers C, Dhamija R. Clinical Reasoning: A 13-year-old boy with chronic ataxia and developmental delay. Neurology. 2017 Mar 28;88(13):e116-e121.

A 13-year-old boy presented to the neurology clinic for evaluation of ataxia and intellectual disability. He was born at term via vaginal delivery after an uncomplicated pregnancy with no perinatal complications. Newborn screening (Virginia, 2012) was normal. He was first noted to be ataxic at age 6 months (when he began to sit with support) and his symptoms gradually worsened over time. He had global developmental delay. He began to sit at 14 months of age and walked at 20 months. He had his first words around age 2 and received physical and speech therapy early on. He had acute worsening of his symptoms at age 8 months in the setting of a flu-like illness and was admitted to a local hospital. Workup at the time was reportedly unrevealing and included a normal CT and a normal brain MRI with contrast. His ataxia remained fairly stable over time without regression. He had several episodes of acute worsening with febrile illnesses. He continued to have learning problems at school.

His general examination at the time of initial clinic visit was unremarkable. On neurologic examination, he was alert and cooperative. He had dysarthria. He had normal tone and strength with exaggerated muscle stretch reflexes, most notable in the legs. He was observed to have choreoathetoid movements of the face, arms, and legs. He had bilateral dysmetria and dysdiadochokinesia. His gait was unsteady and wide-based…

A detailed family history is critical when considering a genetic disorder. Further history obtained for this child revealed that the patient's mother also had ataxia. She initially developed ataxia at age 3 during a febrile illness then had full recovery. The ataxia recurred at age 20 when she was pregnant with her second child (the patient); her symptoms had been slowly progressive since then. She eventually became wheelchair-bound. She was evaluated in the adult neurology clinic, where her examination showed severe truncal and appendicular ataxia, spastic dysarthria, and bilateral dysmetria...

Given continued concern for an inherited/genetic disorder, a chromosomal microarray was ordered for our patient and was normal. Whole exome sequencing (WES) was subsequently ordered and showed an ATP1A3 variant, c.2267G>A, p.R756H (NM_152296), which was maternally inherited. No other variants were noted.

The ATP1A3 gene is located on chromosome 19q13.2 and encodes the [alpha]3 subunit of the Na+/K+ transporting ATPase. ATP1A3 pathogenic variants have been previously associated with rapid-onset dystonia parkinsonism; alternating hemiplegia of childhood; and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. More recently, it has been linked to early-onset epileptic encephalopathy and episodic prolonged apnea and to relapsing encephalopathy with cerebellar ataxia. All of these variable phenotypes associated with ATP1A3 pathogenic variants can occur sporadically as a result of a de novo mutation or can be inherited. Inheritance is autosomal dominant.

The c.2267G>A, p.R756H (NM_152296) variant is located in exon 17 of ATP1A3. This alteration results from a G to A substitution at nucleotide position 2267, causing the arginine (A) at the amino acid position 756 to be replaced by a histidine (H). This amino acid change has been observed in affected individuals, including a father and his daughter with rapid-onset dystonia parkinsonism, and a 34-year-old woman with relapsing cerebellar ataxia, generalized dystonia, pyramidal signs, and anger outbursts. Nearby alterations have been reported in patients with alternating hemiplegia of childhood.  The alteration cosegregated with disease in the family described here, as it is present in heterozygous form in the patient's mother but not in his father. The altered amino acid is conserved throughout evolution. The alteration is not observed in healthy individuals and is predicted to be deleterious by in silico models. The mutation was therefore determined to be likely pathogenic. The patient's brother was not found to have the same alteration. His epilepsy is likely related to a different etiology.

This case demonstrates 2 genetic phenomena: variable expressivity and pleiotropy. Variable expressivity measures the extent to which a genotype exhibits its phenotypic expression. The patient and his mother both have ataxia but have differing degrees of severity.

Pleiotropy describes the varying phenotypic traits that can manifest from a single gene mutation.8 In this case, the same ATP1A3 gene mutation manifests as ataxia, chorea, and athetosis in the patient and as ataxia in his mother.

Courtesy of Doximity

See:  http://childnervoussystem.blogspot.com/2016/06/variable-manifestations-of-atp1a3.html