504P Myonuclear abnormalities in hypokalemic periodic paralysis due to ATP1A2 variant

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.637
• Main Authors: Yae, Y., Ogasawara, M., Nonaka, I., Hayashi, S., Iida, A., Okamura-Oho, Y., Noguchi, S., Nishino, I.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.646

Hypokalemic periodic paralysis (HPP) is a rare neuromuscular disease characterized by periodic attacks of acute muscle weakness concomitant with low serum potassium. To date, only one variant in the ATP1A2, which encodes the α2 subunit of the Na+/K+ ATPase and is abundantly expressed in skeletal muscle and brain astrocytes, has been reported to cause primary HPP along with intellectual disability. The previous case did not present distinct pathological abnormalities. In this report, we describe a case of HPP in a child, highlighting unique pathological findings. Case presentation: The case is a 3-year-old girl. She had weak sucking ability and poor weight gain after birth. She had mild hypotonia, motor developmental delay and intellectual disability. The proximal muscles of her extremities showed atrophy and mild weakness, and Gowers' sign and gait disturbance were observed. She had no facial muscle involvement or joint contractures. From the age of 2 years and 2 months, she started to experience flaccid paralytic attacks every 4-5 days. The laboratory examination revealed hypokalemia during the attacks. Non-ictal potassium was normal and creatinine kinase was elevated at 200-600 U/L. Genetic analysis revealed a heterozygous variant c.2336G>A (p.S779N) of ATP1A2, which is the same variant previously reported to cause HPP with intellectual disability. Muscle biopsy showed marked fiber size variation, scattered necrotic and regenerating fibers, increased internal nuclei and vacuoles. Interestingly, tubular aggregate like deposits were seen at the margins of the myofibers. Additionally, electron microscopy revealed severely fragmented nuclei with condensed chromatin, collapsed nuclear membrane, and nucleophagy. This case is the second report of ATP1A2 variant in HPP. The pathological findings, in particular nuclear abnormalities are remarkable, expanding the clinicopathological phenotype associated with ATP1A2 variant.