Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes

Abstract

Paroxysmal movement disorders encompass varied motor phenomena. Less recognized features and wide phenotypic and genotypic heterogeneity are impediments to straightforward molecular diagnosis. We describe a family with episodic ataxia type 1, initially mis-characterized as paroxysmal dystonia to illustrate this diagnostic challenge. We summarize clinical features in affected individuals to highlight underappreciated aspects and provide comprehensive phenotypic description of the rare familial KCNA1 mutation. Delayed diagnosis in this family is emblematic of the broader challenge of diagnosing other paroxysmal motor disorders. We summarize genotypic and phenotypic overlap and provide a suggested diagnostic algorithm for approaching patients with these conditions.

Figure 1

Family Pedigree. Dark Symbols – Symptomatic; Light Symbols – Asymptomatic; “+” – KCNA1 c.748_750delTTC; “‐” – KCNA1 wild type; “*” – Phenotypically positive per report, individuals not examined. A single noncarrier (V9) reported multiple symptoms (Vertigo, Muscle cramp, muscle twitch, weakness, headache, nausea, blurred vision, light sensitivity, dyspnea, hypothermia, altered mental status, chest pain, irregular heartbeat). This individual most likely represents a negative phenocopy but false negative genetic testing cannot be excluded.

Figure 2

Characteristic Hand Posture. Typical hand posture of adducted thumb and extended fifth finger present in mother (D) and daughter (C). These postures are similar to those pictured in the original description of EA1 in Van Dyke et al., 1975 (A, B). (Reprinted with permission).

Figure 3

Paroxysmal motor disorder diagnostic algorithm. I. Seizures should be considered in any patient with a paroxysmal motor disorder; II. Age of onset, family history, examination and imaging findings may guide diagnosis. Abnormal neurologic examination or imaging findings may occur with secondary and metabolic etiologies. Care should be taken to exclude treatable metabolic causes (Table 3). Developmental delay, if present should be evaluated independent of the movement disorder. Benign paroxysmal motor disorders may be considered if phenotype is consistent. Evolution of motor findings over time may provide clues to diagnoses that are not immediately apparent; III. Identifying the predominant character of the spells is the first step in categorization; IV. Distinguishing features including triggers or other characteristic aspects may enable accurate phenotypic classification; V. Phenotypic characterization limits the genes to consider. Most commonly associated gene/s in bold with less commonly associated genes in plain type. Where phenotype is classic, targeted gene testing or small gene panel may be considered first. If phenotype is not well defined or varies then multi‐gene panel or exome is a preferred initial step;1Paroxysmal epileptic events may result from mutations in PRRT2, SCN1A, KCNA1, ATP1A3, CACNA1A, KCNMA1, etc.;2Only genes with seizure as a typical feature are listed. See Table 2 for other genes associated with epileptic events;3Secondary causes may include trauma, stroke, demyelinating event, electrolyte disturbance, etc.;4See Table 3, 5; Paroxysmal Benign/Developmental Disorders most commonly include tic disorders but may also include stereotypies, shuddering spells, benign myoclonus of early infancy, benign neonatal sleep myoclonus and infantile gratification. Paroxysmal torticollis during infancy is also typically considered benign as symptoms typically resolve over months to years. However, patients should be monitored as there may be later development of various migrainous symptoms including paroxysmal vertigo and hemiplegic migraine and there may be associated developmental issues. Mutations in CACNA1A and PRRT2 may be found;6Consider classification as “ataxia” if patient complains of vertigo, dysarthria, headache, nausea, or visual disturbances without specific complaint or examination finding of ataxia;7Nonkinesigenic triggers include alcohol, fatigue, caffeine, stress, menses, and excitement;8BCKDc = BCKD complex,9Other genes associated with dyskinesia and nonkinesigenic trigger include: SLC16A2, SCN8A, PDHA1, PDHX, DLAT, ECHS1, SCN1A, and ALDH5A1;10Also consider genes associated with EA1, EA2, EA6, EA6, and EA8; FHx, family history; PND, paroxysmal nocturnal dyskinesia; AHC, alternating hemiplegia of childhood; FHM, familial hemiplegic migraine; PKD, paroxysmal kinesigenic dyskinesia; PED, Paroxysmal exercise‐induced dyskinesia; PNKD, Paroxysmal nonkinesigenic dyskinesia; EA, episodic ataxia