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 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.

Atypical presentation of rapid-onset dystonia–parkinsonism in a toddler with a novel mutation in the ATP1A3 gene

2021 ◽  
Vol 14 (8) ◽  
pp. e244152
Author(s):  
Aishwarya Ganesh ◽  
Samyuktha Sivakumar ◽  
RanjithKumar Manokaran ◽  
Udayakumar Narasimhan
Keyword(s):  
Novel Mutation ◽  
Gene Mutations ◽  
Paediatric Population ◽  
Rapid Onset ◽  
Lower Limbs ◽  
Muscle Rigidity ◽  
Atypical Presentation ◽  
Genetic Sequencing ◽  
Atypical Presentations ◽  
Atp1a3 Gene

ATP1A3 gene mutations can result in a spectrum of diseases with diverse neurological manifestations. One such disorder linked to this mutation is rapid-onset dystonia–parkinsonism (RDP), which manifests as dystonia with features of parkinsonism, such as tremors, rigidity, muscle spasms, and bulbar symptoms. Affected patients are typically adolescents or young adults, with symptoms occurring in a rostrocaudal pattern. We report a unique case of a 2-year-old child with an early onset, atypical presentation of RDP. In addition to motor developmental delay, he presented with muscle rigidity and mild asymmetric dystonia of the limbs, with the lower limbs being more affected than the upper limbs. Genetic sequencing of the child revealed a novel heterozygous autosomal dominant mutation of ATP1A3 gene c.173A>G (p. Tyr58Cys). This report highlights that RDP can present with atypical presentations in the paediatric population and adds to existing medical literature on the clinical spectrum of ATP1A3 genetic channelopathy.

scholarly journals Plasmapheresis-induced Clinical Improvement in a Patient with Steroid-Resistant Nephrotic Syndrome Due to Podocin (NPHS2) Gene Station

2010 ◽  
Vol 53 (3) ◽  
pp. 157-159 ◽  
Author(s):  
Sylva Skálová ◽  
Miroslav Podhola ◽  
Karel Vondrák ◽  
Gil Chernin
Keyword(s):  
Nephrotic Syndrome ◽  
Clinical Improvement ◽  
Combined Therapy ◽  
Immunosuppressive Agents ◽  
Gene Mutations ◽  
First Year ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Heterozygous Form ◽  
First Year Of Life

Podocin mutations (NPHS2 gene) are mostly responsible for steroid-resistant nephrotic syndrome (SRNS) of childhood onset. Patients with NPHS2 gene mutations do not respond to corticoids and other immunosuppressive agents; partial remission can be rarely induced by cyclosporin A. We present a boy, where SRNS was diagnosed within first year of life. By the age of 15 years, proteinuria reached 9000 mg/24 h, cholesterolemia 15 mmol/L, albuminemia 19.6 g/L, in spite of combined therapy with cyclosporine A, methylprednisolone, enalapril and losartan. At that time a combined heterozygous form of two NPHS2 gene mutations (p.R138Q and p.V290M) was diagnosed, methylprednisolone was discontinued and patient underwent ten plasmapheresis procedures. This resulted in clinical improvement (proteinuria 3000 mg/24 h, S-cholesterol 6 mmol/L, albumin 30g/L) lasting for three years. In conclusion, plasmapheresis can result in clinical improvement and stabilization of SRNS caused by podocine mutation, before renal replacement therapy is initiated.

scholarly journals Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

2021 ◽  
Vol 12 ◽  
Author(s):  
Gianluca Piccolo ◽  
Giuseppe d'Annunzio ◽  
Elisabetta Amadori ◽  
Antonella Riva ◽  
Paola Borgia ◽  
...  
Keyword(s):  
Genetic Basis ◽  
First Year ◽  
Arthrogryposis Multiplex Congenita ◽  
Neurodevelopmental Delay ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Distal Muscle ◽  
Neurodevelopmental Impairment ◽  
First Year Of Life

Wieacker-Wolff syndrome (WWS) is an X-linked Arthrogryposis Multiplex Congenita (AMC) disorder associated with broad neurodevelopmental impairment. The genetic basis of WWS lies in hemizygous pathogenic variants in ZC4H2, encoding a C4H2 type zinc-finger nuclear factor abundantly expressed in the developing human brain. The main clinical features described in WWS families carrying ZC4H2 pathogenic variants encompass having a short stature, microcephaly, birth respiratory distress, arthrogryposis, hypotonia, distal muscle weakness, and broad neurodevelopmental delay. We hereby report a Sicilian family with a boy clinically diagnosed with WWS and genetically investigated with exome sequencing (ES), leading to the identification of a c.593G>A (p. R198Q) hemizygous pathogenic variant in the ZC4H2 gene. During the first year of life, the onset of central hypoadrenalism led to recurrent hypoglycemic events, which likely contributed to seizure susceptibility. Also, muscle biopsy studies confirmed a pathology of the muscle tissue and revealed peculiar abnormalities of the neuromuscular junction. In conclusion, we expand the phenotypic spectrum of the WWS-related neurodevelopmental disorders and discuss the role of ZC4H2 in the context of the potential neuroendocrinological and neuromuscular features associated with this condition.

scholarly journals Incidental Finding of MEGDEL Syndrome Based on Neuroimaging: Case Report

2021 ◽  
pp. 429-433
Author(s):  
Salma A. Alshammari ◽  
Fouad A. Alghamdi ◽  
Rami Alhazmi ◽  
Shaikhah Aldossary
Keyword(s):  
Incidental Finding ◽  
Molecular Genetic ◽  
Cerebellar Atrophy ◽  
Failure To Thrive ◽  
Autosomal Recessive Disorder ◽  
Disease Diagnosis ◽  
First Year ◽  
Pathogenic Variants ◽  
Clinical Presentations ◽  
First Year Of Life

MEGDEL 3-methylglutaconic (MG) aciduria, deafness, encephalopathy, Leigh-like syndrome is an autosomal recessive disorder associated with infantile hypoglycemia, progressive psychomotor developmental delay, cerebellar atrophy with lesions in the basal ganglia, spasticity, dystonia, deafness, and transient liver problems, which typically occur in the first year of life. Other clinical presentations include failure to thrive, epilepsy, and optic nerve atrophy. The serine active site-containing 1 (SERAC1) mutation is localized at the mitochondria-associated membranes, which are responsible for encoding a phosphatidylglycerol remodeler essential for both mitochondrial function and intracellular cholesterol trafficking and is thus responsible for the disease. Diagnosis is confirmed by the elevation of and concentrations of 3-MG acid and 3-methylglutaric acid in the urine or by identification of bi-allelic SERAC1 pathogenic variants on molecular genetic testing. Different pathological variants of SERAC1 have been identified in MEGDEL syndrome to date. Here, we report a case of a child with MEGDEL syndrome due to SERAC1 mutation. The child presented with accidental finding by CT showing hypodensity on bilateral symmetric anterior putamen and caudate abnormal. Neurological examination was unremarkable. This report presents a new neuroimaging finding by CT of MEGDEL syndrome.

scholarly journals Epilepsy combined with Wolf-Hirschhorn syndrome: a literature review and description of clinical cases

2019 ◽  
Vol 10 (4) ◽  
pp. 39-52
Author(s):  
M. B. Mironov ◽  
N. V. Chebanenko ◽  
S. O. Ayvazyan ◽  
S. A. Vladimirova ◽  
K. V. Osipova ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Epileptic Seizures ◽  
Febrile Seizures ◽  
First Year ◽  
Eeg Activity ◽  
Epileptic Spasms ◽  
High Incidence ◽  
Clonic Seizures ◽  
First Year Of Life ◽  
Patients With Epilepsy

This article presents the anamnestic, clinical, electro-encephalographic and neuroimaging findings in 5 patients with epilepsy combined with Wolf-Hirschhorn syndrome (WHS). According to our data and the results of others, this combination has its specific characteristics. These include: a high incidence of epilepsy in patients with WHS (50-100% of cases), an early debut of seizures (mainly in the first year of life), fever-provoked seizures, and a variety of seizure types – focal paroxysms, bilateral tonic-clonic seizures, atypical febrile seizures, atypical absences and epileptic spasms. In addition, there may be frequent epileptic seizures tending toward status epilepticus, a slowing of the major EEG activity, a local EEG slowing (mainly in the posterior and bi-frontal areas), and regional / multiregional epileptiform activity. In more than 50% of cases, the diffuse peakwave activity is observed; the broad spectrum anti-epileptic drugs are highly efficient in 80% of cases. Based on this study, we propose recommendations for the management of patients with epilepsy combined with WHS.

Alternating Hemiplegia of Childhood in an Infant with Symptoms Resembling Glucose Transporter 1 Deficiency

2017 ◽  
Vol 15 (04) ◽  
pp. 180-182
Author(s):  
Mini Sreedharan ◽  
Shiji Chalipat ◽  
Kunju Mohammed ◽  
Kalpana Devadathan
Keyword(s):  
Developmental Delay ◽  
Glucose Transporter ◽  
Gene Mutations ◽  
Deficiency Syndrome ◽  
Global Developmental Delay ◽  
Glucose Transporter 1 ◽  
Alternating Hemiplegia Of Childhood ◽  
Slc2a1 Gene ◽  
Glut1 Deficiency ◽  
Atp1a3 Gene

AbstractGlucose transporter type 1 (glut1) deficiency syndrome presents with developmental delay, microcephaly, and recurrent seizures during infancy, as well as cerebrospinal fluid (CSF) hypoglycorrhachia and mutations in the SLC2A1 gene. We describe a baby with microcephaly, global developmental delay, seizures from 3 months of age, and CSF glucose in the lower limit of normal range, with heterozygous p.Glu815Lys mutation of the ATP1A3 gene and no mutation in the SLC2A1 gene. Mutations in ATP1A3 gene are associated with alternating hemiplegia of childhood (AHC). Interestingly the baby developed episodes of recurrent bouts of alternating hemiplegia from 13 months of age. The case is reported to highlight ATP1A3 mutation as a probable etiology for glut1 deficiency like syndrome and AHC. A brief review of literature emphasizing the overlapping paroxysmal and nonparoxysmal symptoms of the two conditions is also included.

scholarly journals Failure to clear developmental apoptosis contributes to the pathology of RNASET2-deficient leukoencephalopathy

2019 ◽  
Author(s):  
Noémie Hamilton ◽  
Holly A. Rutherford ◽  
Hannah M. Isles ◽  
Jessica J. Petts ◽  
Thomas Weber ◽  
...  
Keyword(s):  
Immune Response ◽  
White Matter ◽  
Neurological Disorders ◽  
Preclinical Model ◽  
First Year ◽  
Zebrafish Model ◽  
Brain Infection ◽  
White Matter Disorder ◽  
Embryonic Origin ◽  
First Year Of Life

SummaryThe contribution of microglia in neurological disorders is emerging as a leading driver rather than a consequence of pathology. RNAseT2-deficient leukoencephalopathy is a severe childhood white matter disorder affecting patients in their first year of life and mimics a cytomegalovirus brain infection. The early onset and resemblance of the symptoms to an immune response suggest an inflammatory and embryonic origin of the pathology. In this study, we identify deficient microglia as an early marker of pathology. Using the ex utero development and the optical transparency of an rnaset2-deficient zebrafish model, we found that dysfunctional microglia fail to clear apoptotic neurons during brain development. This was associated with increased number of apoptotic cells and behavioural defects lasting into adulthood. This zebrafish model recapitulates all aspect of the human disease to be used as a robust preclinical model. Using microglia-specific depletion and rescue experiments, we identified microglia as potential drivers of the pathology and highlight tissue-specific approaches as future therapeutic avenues.

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