Paroxysmal tonic upgaze: A heterogeneous clinical condition responsive to carbonic anhydrase inhibition

Quade, Annegret; Thiel, Anne; Kurth, Ingo; Holtgrewe, Manuel; Elbracht, Miriam; Beule, Dieter; Eggermann, Katja; Scholl, Ute I.; Häusler, Martin

doi:10.1016/j.ejpn.2019.11.002

Cited by 13 publications

(13 citation statements)

References 23 publications

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“…This eye movement disorder sometimes occurs as a transient benign phenomenon in healthy infants, but it has also been reported in disorders of neurotransmitter depletion and genetic disorders. It is of particular interest that the few gene mutations with which this finding has been associated ( CACNA1A, GRID2 , and SEPSECS ) involve proteins related to normal cerebellar function, and ataxia typically accompanies the paroxysmal tonic upgaze, similar to the probands in this study (Agamy et al, 2010; Blumkin et al, 2015; Hills et al, 2013; Makrythanasis et al, 2014; Quade et al, 2020). The pathomechanism of this eye movement finding is unclear, but these genetic associations raise the possibility that it may originate from cerebellar dysfunction and may be related to the normal cerebellar flocculus inhibition of upward eye movements and firing bias toward downward eye movements that underly downbeat nystagmus (Baloh & Spooner, 1981; Marti et al, 2005; Zee et al, 1981).…”

Section: Discussionsupporting

confidence: 62%

“…To the best of our knowledge, this is the first report of pathogenic variants in POU4F1 causing disease in humans. the probands in this study (Agamy et al, 2010;Blumkin et al, 2015;Hills et al, 2013;Makrythanasis et al, 2014;Quade et al, 2020). The pathomechanism of this eye movement finding is unclear, but these genetic associations raise the possibility that it may originate from cerebellar dysfunction and may be related to the normal cerebellar flocculus inhibition of upward eye movements and firing bias toward downward eye movements that underly downbeat nystagmus (Baloh & Spooner, 1981;Marti et al, 2005;Zee et al, 1981).…”

Section: Discussionmentioning

confidence: 74%

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Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

et al. 2021

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De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-offunction variants in POU4F1 are causative of a novel ataxia syndrome.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 74%

Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

et al. 2021

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“…In cryptogenic cases, neurophysiological, laboratory, and neuroimaging investigations are normal. Genetic studies have shown that PTU is a common early feature of CACNA1A-related disease [74,[81][82][83]. In addition, PTU has been documented in patients with GRID2 mutations [84] and in association with genetic or acquired structural brain lesions, including white-matter disease, perinatal injury, hydrocephalus, brain tumors, or brain malformations [5,73].…”

Section: Developmental Paroxysmal Movement Disordersmentioning

confidence: 99%

“…In a few cases, response to l-DOPA has been reported [79,85], raising the issue of distinction between PTU and oculogyric crisis (OGC), observed in biogenic amines synthesis defects [73]. In other cases, carbonic anhydrase inhibitors proved to be effective [74,81]. In conclusion, the exact nosological boundaries and etiology of PTU remain to be elucidated.…”

Section: Developmental Paroxysmal Movement Disordersmentioning

confidence: 99%

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

Garone

Capuano

Travaglini

et al. 2020

IJMS

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Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.

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“…To date, mutations in CACNA1A, GRID2, and SEPSECS genes have been identified to be associated with PTU (4)(5)(6). Mutations in ADAMTS2, CACNA1A, CDK13, SIM1, and ZNF331 have also been reported as PTU-associated in the Human Gene Mutation Database (HGMD) (7), while only two mutations in CACNA1A are clearly classified as disease-causing (5).…”

Section: Introductionmentioning

confidence: 99%

Identification of Two de novo Variants of CACNA1A in Pediatric Chinese Patients With Paroxysmal Tonic Upgaze

Zhang

Wang

2021

Front. Pediatr.

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Objective: Investigate the clinical manifestations and genotypes of paroxysmal tonic upgaze (PTU) in Chinese children.Patients and Methods: We report the clinical manifestations and genetic test results of four pediatric PTU patients in China. Recent articles on PTU cases are also summarized and analyzed.Results: The onset age of all four cases was at early infancy, and they presented as episodic binocular upward gaze with mild growth retardation. Two patients each carried a novel de novo variant in the CACNA1A gene, c.4046C>T (p.R1349X), and c.4415C>T (p.S1472L).Conclusion: Patients with infantile-onset paroxysmal binocular upward gaze should be considered to diagnose as PTU.

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Paroxysmal tonic upgaze: A heterogeneous clinical condition responsive to carbonic anhydrase inhibition

Cited by 13 publications

References 23 publications

Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

Identification of Two de novo Variants of CACNA1A in Pediatric Chinese Patients With Paroxysmal Tonic Upgaze

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