LOSS OF MOTOR CONTROL
Breda Genetics panel testing recommended for this condition (EXOME PANEL):
Clinical variability
Episodic ataxia (EA) is an inherited disease that leads to occasional loss of motor control (i.e. poor coordination and balance: ataxia) in combination with variable other symptoms such as vertigo, migraine and myokymia.
More than one gene
Episodic ataxia is a genetically heterogeneous disorder. Besides EA1 (KCNA1 gene mutation) and EA2 (CACNA1A), other forms for which the gene was identified are: EA5, caused by mutation in the CACNB4 gene, and EA6, caused by mutation in the SLC1A3 gene. Isolated myokymia 2 is associated with mutation in the KCNQ2 gene. For EA3, EA7, EA8 and EA9 the gene has not been identified yet.
Episodic ataxia 1 (EA1)
Episodic ataxia type 1 (EA1) is a potassium (K+) channelopathy. Affected patients may experience constant myokymia (muscle cramping, stiffness, and twitching) and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. Dizziness (vertigo) is also frequent and may be associated with blurred or double vision, nausea, headache, slurred speech, excessive sweating, clumsiness, stiffening of the body, difficulty in breathing, and ringing in the ears (tinnitus). Anxiety, emotional stress, fatigue, caffeine, alcohol, certain medications, physical activity, illness or sudden postural changes may trigger the attacks, during which hemiplegia may also occur. Interestingly, EA1 may present with or without ataxia (cataplexy and nonataxic presentations), as the clinical spectrum is variable. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. The frequency of the attacks is highly variable (from many a day to one or two per year).
Episodic ataxia 2 (EA2)
Eye movement disorders (nystagmus and pursuit and saccade alterations) are an early manifestation of CACNA1A mutations (EA2) in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling, and appropriate emergency management. Of note, CANCA1A mutations may also cause the allelic disorders familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6).
A form of later onset episodic ataxia may be part of a convergent clinical phenotype which includes neonatal seizures and is caused by gain-of-function mutations in the SNC2A gene.
Acetazolamide has been found to be effective in reducing frequency and severity of vertigo and headache attacks.
Differential diagnosis
Episodic ataxia can occur sporadically or in a number of hereditary disorders, like for instance in pyruvate carboxylase deficiency (PC gene) and pyruvate dehydrogenase deficiency (PDHA1 gene). In addition, mutations in the OTC gene, which may be evident as partial deficiency in females and complete deficiency in males, can cause episodic extreme irritability, episodic vomiting and lethargy, protein avoidance, ataxia, stage II coma, delayed growth, developmental delay, and seizures. Hyperammonemias caused by deficiencies of urea cycle enzymes (CPS1, ASS1, ASL, ARG1 gene mutations) are characterized by intermittent ataxia, dysarthria, vomiting, headache, ptosis, involuntary movements, seizures, and confusion. Aminoacidurias may also be a significant part of the differential diagnosis of episodic ataxias: Hartnup disease (SLC6A19 gene mutations), maple syrup urine disease (MSUD, caused by BCKDHA, BCKDH, DBT, or DLD gene mutation), and isovaleric acidemia (IVD gene mutation). Finally, the following can be considered: familial paroxysmal kinesigenic dyskinesia, familial paroxysmal nonkinesigenic dyskinesia (PNKD gene mutation), and Isaacs syndrome.
Breda Genetics panel testing recommended for this condition (EXOME PANEL):
References:
A Disease Mutation Causing Episodic Ataxia Type I in the S1 Links Directly to the Voltage Sensor and the Selectivity Filter in Kv Channels. Petitjean D, Kalstrup T, Zhao J, Blunck R. J Neurosci. 2015 Sep 2;35(35):12198-206. PMID: 26338330
Episodic Ataxia Type 1. Hasan SM, D’Adamo MC. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2010 Feb 9 [updated 2018 Nov 1]. PMID: 20301785
Episodic Ataxia Type 2. Spacey S. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2003 Feb 24 [updated 2015 Oct 15]. PMID: 20301674
Eye movement disorders are an early manifestation of CACNA1A mutations in children. Tantsis EM, Gill D, Griffiths L, Gupta S, Lawson J, Maksemous N, Ouvrier R, Riant F, Smith R, Troedson C, Webster R, Menezes MP. Dev Med Child Neurol. 2016 Jun;58(6):639-44. PMID: 26814174
Acetazolamide in vestibular migraine prophylaxis: a retrospective study. Çelebisoy N, Gökçay F, Karahan C, Bilgen C, Kirazlı T, Karapolat H, Köse T. Eur Arch Otorhinolaryngol. 2016 Oct;273(10):2947-51. PMID: 26728486
Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia. Schwarz N, Hahn A, Bast T, Müller S, Löffler H, Maljevic S, Gaily E, Prehl I, Biskup S, Joensuu T, Lehesjoki AE, Neubauer BA, Lerche H, Hedrich UBS. J Neurol. 2016 Feb;263(2):334-343. PMID: 26645390
Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations. Brownstein CA, Beggs AH, Rodan L, Shi J, Towne MC, Pelletier R,4, Cao S, Rosenberg PA, Urion DK, Picker J, Tan WH, Agrawal PB. Neurogenetics. 2016 Jan;17(1):11-6. PMID: 26395884
New insights into the pathogenesis and therapeutics of episodic ataxia type 1. D’Adamo MC, Hasan S, Guglielmi L, Servettini I, Cenciarini M, Catacuzzeno L, Franciolini F. Front Cell Neurosci. 2015 Aug 19;9:317. PMID: 26347608
