A novel missense mutation in the ATPase, Na+/K+ transporting, alpha 3 polypeptide (ATP1A3) gene has been identified in a family affected by two distinctly different neurodegenerative conditions — alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP), according to a new study presented here June 21 at the International Congress of Parkinson's Disease and Movement Disorders.
Sergio A. Rodríguez-Quiroga, MD, of the neurogenetics unit and movement disorders section of the University Centre of Neurology in the JM Ramos Mejia Hospital, and his colleagues described the clinical and molecular features in 13 members of a family whose genetic history came to light after a 19-year-old was first diagnosed with RDP.
Clinical histories and the sequencing of the ATP1A3 gene in dozens of family members revealed that 12 others shared the symptoms of both conditions. Many of them also had a diagnosis of epilepsy.
The scientists identified a novel missense mutation in ATP1A3 that was present only in the affected members of this family. This mutation has not been reported in RDP or AHC before.
"We believe that AHC and RDP represent a phenotypic continuum of ATP1A3-related disorders," said Dr. Rodríguez-Quiroga. While in the original case, the young man, now 22, had classic symptoms of RDP — anarthria, mild dysphagia, hypotonia, and severe bradykinesia in four limbs with a rostrocaudal gradient of involvement — other family members with the mutation had hemiplegia, epilepsy, and cognitive impairment.
"The family history was consistent with an autosomal dominant inheritance," he said. The phenotypes range from seizures only, cognitive impairment, and development delay, to hemiplegia, dystonia, parkinsonism, and bulbar impairment.
"Our study highlights the variability in the neurological spectrum of symptoms that subjects with ATP1A3 mutations could have," both in severity and age of onset, he said.
"Variants in other genes or other triggers could influence the symptom severity and age of onset," Dr. Rodríguez-Quiroga added. Identifying these triggers could lead to the development of prevention strategies and treatments. The researchers are evaluating other affected members of the family for a more precise description of the distinct phenotypes.
That these conditions fall on a continuum "is not a surprise," said Kenneth Silver, MD, associate professor of pediatrics and neurology at the University of Chicago, who has consulted on a few hundred cases of AHC and was not involved with the study. "As we expand the spectrum, there will be cases that share many of the features of these conditions."
"Now, we need to figure out what is wrong with the gene to produce these symptoms," he added. "The findings from this case study suggest that this is a spectrum of disorders that appear in one family. It's the same genetic mutation, but it is expressed differently."
"This new finding lends support to the idea of an intermediate phenotype and intrafamilial variability," said Suzanne D. DeBrosse, MD, clinical assistant professor of genetics and genome sciences, pediatrics, and neurology at Case Western Reserve University, who was not involved with the study. "This could make a valuable contribution to our understanding of the variability of ATP1A3-related disorders within families."
S.A. Rodríguez-Quiroga, D. González-Moron, S.A. Vishnopolska, G.L. Vigo, M. Cordoba, N. Medina, T. Arakaki, N.S. Garretto, M.A. Kauffman. Expanding the spectrum of ATP1A3 related disorders: Continuum from alternating hemiplegia of childhood to rapid-onset dystonia parkinsonism? [abstract]. Mov Disord. 2016; 31 (suppl 2).