Saturday, January 1, 2022

Lisdexamfetamine therapy in paroxysmal non-kinesigenic dyskinesia associated with the KCNMA1-N999S Variant

Keros, S., Heim, J., Hakami, W., Zohar-Dayan, E., Ben-Zeev, B., Grinspan, Z., Kruer, M.C. and Meredith, A.L. (2022), Lisdexamfetamine Therapy in Paroxysmal Non-kinesigenic Dyskinesia Associated with the KCNMA1-N999S Variant. Mov Disord Clin Pract. 



KCNMA1-linked channelopathy is a rare movement disorder first reported in 2005. Paroxysmal non-kinesigenic dyskinesia (PNKD) in KCNMA1-linked channelopathy is the most common symptom in patients harboring the KCNMA1-N999S mutation. PNKD episodes occur up to hundreds of times daily with significant morbidity and limited treatment options, often in the context of epilepsy.


We report 6 cases with the KCNMA1-N999S variant treated with lisdexamfetamine (0.7–1.25 mg/kg/day), a pro-drug of dextroamphetamine. Data were collected retrospectively from interviews and chart review. Parent-reported daily PNKD episode counts were reduced under treatment, ranging from a 10-fold decrease to complete resolution.


Our findings suggest that lisdexamfetamine is an effective therapy for PNKD3 (KCNMA1-associated PNKD). Treatment produced dramatic reductions in debilitating dyskinesia episodes, without provocation or exacerbation of other KCNMA1-associated symptoms such as seizures.

See:  My patient is one of the 6 cases reported here.  It appears that more the one pediatric neurologist was involved in her care, unbeknownst to one another.

Miller JP, Moldenhauer HJ, Keros S, Meredith AL. An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy. Channels (Austin). 2021 Dec;15(1):447-464. doi: 10.1080/19336950.2021.1938852. PMID: 34224328; PMCID: PMC8259716.


KCNMA1-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 encodes the BK K+ channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations. In this review, we summarize 37 KCNMA1 alleles from 69 patients currently defining the channelopathy and assess key diagnostic and clinical hallmarks. At present, 3 variants are classified as gain-of-function with respect to BK channel activity, 14 loss-of-function, 15 variants of uncertain significance, and putative benign/VUS. Symptoms associated with these variants were curated from patient-provided information and prior publications to define the spectrum of clinical phenotypes. In this newly expanded cohort, seizures showed no differential distribution between patients harboring GOF and LOF variants, while movement disorders segregated by mutation type. Paroxysmal non-kinesigenic dyskinesia was predominantly observed among patients with GOF alleles of the BK channel, although not exclusively so, while additional movement disorders were observed in patients with LOF variants. Neurodevelopmental and structural brain abnormalities were prevalent in patients with LOF mutations. In contrast to mutations, disease-associated KCNMA1 single nucleotide polymorphisms were not predominantly related to neurological phenotypes but covered a wider set of peripheral physiological functions. Together, this review provides additional evidence exploring the genetic and biochemical basis for KCNMA1-linked channelopathy and summarizes the clinical repository of patient symptoms across multiple types of KCNMA1 gene variants.


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