Pediatric Paroxysmal Exercise-Induced Neurological Symptoms: Clinical Spectrum and Diagnostic Algorithm

Abstract

Paroxysmal exercise-induced neurological symptoms (PENS) encompass a wide spectrum of clinical phenomena commonly presenting during childhood and characteristically elicited by physical exercise. Interestingly, few shared pathogenetic mechanisms have been identified beyond the well-known entity of paroxysmal exercise-induced dyskinesia, PENS could be part of more complex phenotypes including neuromuscular, neurodegenerative, and neurometabolic disease, epilepsies, and psychogenetic disorders. The wide and partially overlapping phenotypes and the genetic heterogeneity make the differential diagnosis frequently difficult and delayed; however, since some of these disorders may be treatable, a prompt diagnosis is mandatory. Therefore, an accurate characterization of these symptoms is pivotal for orienting more targeted biochemical, radiological, neurophysiological, and genetic investigations and finally treatment. In this article, we review the clinical, genetic, pathophysiologic, and therapeutic landscape of paroxysmal exercise induced neurological symptoms, focusing on phenomenology and differential diagnosis.

Pearls & Oy‐sters: Paroxysmal Exercise-Induced Dyskinesias Due to Pyruvate Dehydrogenase Deficiency

“…Typical attack duration may range from 5-30 minutes; however, this can be quite variable. 3 Pathogenic heterozygous mutations in the SLC2A1 gene, encoding for the GLUT-1 transporter and causative of GLUT1-DS, are the main cause of PED. 3,4 Nevertheless, the differential diagnosis includes several other conditions.…”

“…3 Pathogenic heterozygous mutations in the SLC2A1 gene, encoding for the GLUT-1 transporter and causative of GLUT1-DS, are the main cause of PED. 3,4 Nevertheless, the differential diagnosis includes several other conditions. Of particular relevance to this case are disorders involving brain energy metabolism such as pyruvate dehydrogenase deficiency and mitochondrial dysfunction.…”

“…The latter can occur either because of pathogenic mutations in nuclear genes relevant for mitochondrial function (such as ECHS1, HIBCH, and PRKN) or mtDNA mutations leading to respiratory chain defects. 3,[5][6][7] In addition, pathogenic variants in genes associated with other paroxysmal dyskinesia subtypes (e.g., PRRT2, MR1, ADCY5, and TBC1D24) or dopaminergic deficits (e.g., GCH1) can also present with PED, often with additional phenomenology.…”

Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene

“…The mitochondrial dysfunction was previously described for Duchenne muscular dystrophy ( 15 ) or RYR1-associated myopathies ( 16 ). Also, the highly variable clinical picture is distinctive for ion channelopathy ( 17 , 18 ).…”

Genotype–phenotype relations for episodic ataxia genes: MDSGene systematic review

“…To allow comparison with our work, we examined reviews published between January 1993 and June 15, 2022, where at least two EA genes were discussed in detail to enable comparison between genes (n = 38, Table S5) [8,35,[37][38][39][40][41][42][43][44][45][46][47][48][49][50] Twenty-four of the 38 reviews were dedicated solely to PxMD-KCNA1 and PxMD-CACNA1A (Table S5).…”