TY - JOUR
T1 - RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood
AU - Zagaglia, Sara
AU - Steel, Dora
AU - Krithika, S.
AU - Hernandez-Hernandez, Laura
AU - Custodio, Helena Martins
AU - Gorman, Kathleen M.
AU - Vezyroglou, Aikaterini
AU - Møller, Rikke S.
AU - King, Mary D.
AU - Hammer, Trine Bjørg
AU - Spaull, Robert
AU - Fazeli, Walid
AU - Bartolomaeus, Tobias
AU - Doummar, Diane
AU - Keren, Boris
AU - Mignot, Cyril
AU - Bednarek, Nathalie
AU - Cross, J. Helen
AU - Mallick, Andrew A.
AU - Sanchis-Juan, Alba
AU - Basu, Anna
AU - Raymond, F. Lucy
AU - Lynch, Bryan J.
AU - Majumdar, Anirban
AU - Stamberger, Hannah
AU - Weckhuysen, Sarah
AU - Sisodiya, Sanjay M.
AU - Kurian, Manju A.
N1 - Publisher Copyright:
© 2021 American Academy of Neurology.
Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2021/3/16
Y1 - 2021/3/16
N2 - OBJECTIVE: To explore the phenotypic spectrum of RHOBTB2-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals. METHODS: Individuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review. RESULTS: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in ATP1A3, these events were reported later only in RHOBTB2 mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients. CONCLUSION: Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.
AB - OBJECTIVE: To explore the phenotypic spectrum of RHOBTB2-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals. METHODS: Individuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review. RESULTS: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in ATP1A3, these events were reported later only in RHOBTB2 mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients. CONCLUSION: Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.
U2 - 10.1212/WNL.0000000000011543
DO - 10.1212/WNL.0000000000011543
M3 - Journal article
C2 - 33504645
AN - SCOPUS:85102964006
VL - 96
SP - e1539-e1550
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 11
ER -