scholarly journals ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

2021 ◽  
Vol 12 ◽  
Author(s):  
Philippe A. Salles ◽  
Ignacio F. Mata ◽  
Tobias Brünger ◽  
Dennis Lal ◽  
Hubert H. Fernandez
Keyword(s):  
Original Description ◽  
Rapid Onset ◽  
Acute Onset ◽  
Clinical Spectrum ◽  
Pes Cavus ◽  
Sodium Potassium ◽  
Pathogenic Variants ◽  
Alternating Hemiplegia Of Childhood ◽  
The Central Nervous System ◽  
Neurological Features

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum.

Variants in the ATP1A3 Gene Mutations within Severe Apnea Starting in Early Infancy: An Observational Study of Two Cases with a Possible Relation to Epileptic Activity

2018 ◽  
Vol 49 (05) ◽  
pp. 342-346 ◽  
Author(s):  
Niklas Holze ◽  
Andreas Baalen ◽  
Ulrich Stephani ◽  
Ingo Helbig ◽  
Hiltrud Muhle
Keyword(s):  
Neurological Disorders ◽  
Gene Mutations ◽  
Epileptic Seizures ◽  
Rapid Onset ◽  
Epileptic Activity ◽  
First Year ◽  
Pathogenic Variants ◽  
Alternating Hemiplegia Of Childhood ◽  
First Year Of Life ◽  
Atp1a3 Gene

AbstractMutations in the ATP1A3 gene are known to cause alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP). Both conditions are childhood-onset neurological disorders with distinct symptoms and different times of onset. ATP1A3 has also been associated with CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss). Within the various ATP1A3-related neurological syndromes, a specific genotype–phenotype correlation is starting to emerge. Several mutations such as the relatively common p.E815K pathogenic variant have been shown to strongly correlate with AHC, while others may cause both AHC and RDP. A significant subset of patients with AHC and RDP are reported to have epileptic seizures. Even though detailed clinical descriptions of seizures in childhood are rare, seizures involving apneic events seem to be frequent in ATP1A3-related neurological disorders. Here, we describe two children with unexplained severe apnea beginning around the first year of life and pathogenic variants in ATP1A3. We hypothesize that the symptoms are early-onset autonomic seizures related to the underlying pathogenic ATP1A3 variants.

scholarly journals An 88.8-kb Novel Deletion of 19q13.2 Encompassing the ATP1A3Gene Detected by Array CGH in a Patient with Delayed Psychomotor Development, Generalized Hypotonia and Macrocephaly

2021 ◽  
pp. 1-6
Author(s):  
Elena García-Payá ◽  
María Gutiérrez-Agulló ◽  
Francisco F. García-Prieto ◽  
Jorge Francés Ferre
Keyword(s):  
Motor Coordination ◽  
Array Cgh ◽  
Phenotypic Expression ◽  
Causative Factor ◽  
Psychomotor Development ◽  
Pes Cavus ◽  
Alternating Hemiplegia Of Childhood ◽  
The Central Nervous System ◽  
Childhood Type

Many neurodevelopmental disorders are caused by the presence of CNVs. Chromosome microarray technology is widely used to accurately detect CNVs. We report the case of a male, aged 3 years, presenting with delayed psychomotor development, generalized hypotonia, encephalopathy, delayed myelination in the central nervous system, and poor motor coordination. The array CGH revealed an interstitial deletion of chromosome 19q13.2 with a size of 88.8 kb involving 3 OMIM genes: <i>RABAC1</i>, <i>ARHGEF1</i>, and <i>ATP1A3</i>. Heterozygous mutations in the <i>ATP1A3</i> gene are associated with delayed psychomotor development, alternating hemiplegia of childhood type 2 (AHC2), dystonia type 12, and cerebellarataxia-areflexia–pes cavus-optic atrophy-sensorineural hearing loss syndrome, also called CAPOS syndrome. The phenotypic expression of partial <i>ATP1A3</i> deletion is, however, poorly described in the literature. The deletion was confirmed by MLPA, and we identified a hitherto undescribed novel deletion of exons 3b–21 of the <i>ATP1A3</i> gene. Our data suggest that the deletion of the <i>ATP1A3</i> gene is a causative factor of the AHC2 phenotype in the patient.

Early Life Epilepsy and Episodic Apnea Revealing an ATP1A3 Mutation: Report of a Pediatric Case and Literature Review

2018 ◽  
Vol 49 (05) ◽  
pp. 339-341 ◽  
Author(s):  
Hanene Benrhouma ◽  
Hedia Klaa ◽  
Aida Rouissi ◽  
Myriam Chaabouni ◽  
Ichraf Kraoua ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Neurological Disorders ◽  
Early Life ◽  
Rapid Onset ◽  
Diverse Group ◽  
Pediatric Case ◽  
Pes Cavus ◽  
Alternating Hemiplegia Of Childhood ◽  
Phenotypic Spectrum

Abstract ATP1A3 mutations have now been recognized in infants, children, and adults presenting with a diverse group of neurological phenotypes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and most recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand. In this case study, we report on early life epilepsy with episodic apnea potentially secondary to ATP1A3 mutation in a Tunisian child.

scholarly journals De novo ATP1A3 variants cause polymicrogyria

2021 ◽  
Vol 7 (13) ◽  
pp. eabd2368
Author(s):  
Satoko Miyatake ◽  
Mitsuhiro Kato ◽  
Takuma Kumamoto ◽  
Tomonori Hirose ◽  
Eriko Koshimizu ◽  
...  
Keyword(s):  
De Novo ◽  
Sensorineural Deafness ◽  
Rapid Onset ◽  
Severe Form ◽  
Brain Diseases ◽  
Pes Cavus ◽  
Cortical Malformation ◽  
Alternating Hemiplegia Of Childhood ◽  
Whole Exome ◽  
Malformation Of Cortical Development

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

Alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism: Phenotypic spectrum of ATP1A3-associated disorders

2013 ◽  
Vol 44 (02) ◽  
Author(s):  
K Brockmann ◽  
H Rosewich ◽  
H Thiele ◽  
U Maschke ◽  
P Huppke ◽  
...  
Keyword(s):  
Rapid Onset ◽  
Alternating Hemiplegia Of Childhood ◽  
Phenotypic Spectrum

scholarly journals Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 2824
Author(s):  
Jan H. Döring ◽  
Julian Schröter ◽  
Jerome Jüngling ◽  
Saskia Biskup ◽  
Kerstin A. Klotz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Transmembrane Domain ◽  
Potassium Conductance ◽  
Epileptic Encephalopathy ◽  
Clinical Spectrum ◽  
The Novel ◽  
Developmental Abnormalities ◽  
Pathogenic Variants ◽  
Infantile Seizures ◽  
Early Developmental

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

scholarly journals Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1218
Author(s):  
Raffaella Brunetti-Pierri ◽  
Marianthi Karali ◽  
Francesco Testa ◽  
Gerarda Cappuccio ◽  
Maria Elena Onore ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Joubert Syndrome ◽  
Male Adult ◽  
Full Field ◽  
Pathogenic Variants ◽  
Disease Spectrum ◽  
Male Individual ◽  
The Central Nervous System

Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in MKS1 that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the ‘molar tooth sign’ and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in MKS1.

Sporadic Creutzfeldt-Jakob Disease: Diagnosing Typical and Atypical Presentations under Limited Circumstances

2021 ◽  
pp. 1-7
Author(s):  
Shazma Khan ◽  
Sara Khan
Keyword(s):  
Developing Countries ◽  
Brain Mri ◽  
Tertiary Care ◽  
Rapid Onset ◽  
Spongiform Encephalopathy ◽  
Care Hospital ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
Missed Diagnosis ◽  
Atypical Presentations

<b><i>Introduction:</i></b> Sporadic Creutzfeldt-Jakob disease (sCJD) is a transmissible disorder of the central nervous system caused by the transformation of normal prion protein into an abnormal misfolded form. The process begins spontaneously and runs a vicious cycle to cause spongiform encephalopathy, rapidly resulting in death. Amply described in the western literature, CJD is scarcely reported in Asia due to certain limitations including missed diagnosis, under-reporting, and rarity of the disease. Brain MRI, electroencephalogram, cerebrospinal fluid testing, and biopsy of the infected brain tissue support the diagnosis in cases of clinical suspicion. However, the diagnosis can still be made with limited available resources in developing countries. <b><i>Method:</i></b> A review of CJD cases evaluated in the neurology department of a tertiary care hospital in Pakistan was done from 2002 to 2018. <b><i>Results:</i></b> Eleven cases labeled as sCJD are identified based on the European MRI-CJD consortium criteria. This is the first study on CJD from Pakistan, which includes both the typical and atypical presentations. <b><i>Conclusion:</i></b> Even with limited testing available, the diagnosis of CJD can be made with confidence in the developing countries, provided the suspicion is kept high in cases of rapid onset dementia and acute behavioral changes.

Acute Bilateral Blindness in the Setting of Sudden Onset of Bilateral Proptosis and Ophthalmoplegia: A Case Report With Literature Review

2021 ◽  
pp. 10.1212/CPJ.0000000000001090
Author(s):  
sara zarei ◽  
Phuong Vo ◽  
Christian Sam ◽  
Robert W Crow ◽  
Charles Stout ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Visual Pathway ◽  
Rapid Onset ◽  
Sudden Onset ◽  
Acute Onset ◽  
Posterior Chamber ◽  
Ischemic Optic Neuropathy ◽  
Radiographic Findings ◽  
Underlying Pathophysiology ◽  
Eye Retina

ABSTRACTPurposeof review: Acute bilateral blindness has an extensive differential diagnosis that requires a careful history and physical exam to narrow down. In this paper we discuss the pathophysiology and radiographic findings of each possible diagnosis for acute bilateral blindness.Recent findings:Visual pathology with respect to bilateral blindness can be broadly broken down into three anatomic categories: media (i.e. the anterior and posterior chamber of the eye), retina, and neural visual pathway. Possible causes of rapid onset bilateral blindness include bilateral occipital infarcts, endogenous bacterial endophthalmitis, orbital cellulitis, orbital compartment syndrome, cavernous sinus thrombophlebitis, thyroid disease and bilateral non-arteritic ischemic optic neuropathy.Summary:In this case we present a patient with acute onset of bilateral blindness, in addition to bilateral ophthalmoplegia, proptosis, and orbital chemosis. We believe this rare case of acute bilateral blindness is thought provoking and aids in the understanding of the differential diagnosis and underlying pathophysiology of visual loss.

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