ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA.

The aim of this research is to study the phenotype, genotype, treatment strategies, and short-term prognosis of Chinese children with ATP1A3 (Na+/K+-ATPase alpha 3 gene)-related disorders in Southwest China. Patients with pathogenic ATP1A3 variants identified using next-generation sequencing were registered at the Children's Hospital of Chongqing Medical University from December 2015 to May 2019. We followed them as a cohort and analyzed their clinical data. Eleven patients were identified with de novo pathogenic ATP1A3 heterozygous variants. One (c.2542 + 1G > T, splicing) has not been reported. Eight patients with alternating hemiplegia of childhood (AHC), one with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), and two with relapsing encephalopathy with cerebellar ataxia (RECA) were included. The initial manifestations of AHC included hemiplegia, oculomotor abnormalities, and seizures, and the most common trigger was an upper respiratory tract infection without fever. All patients had paroxysmal hemiplegic attacks during their disease course. The brain MRI showed no abnormalities. Six out of eight AHC cases reached a stable disease state after treatment. The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria, and the brain MRI indicated mild cerebellar atrophy. No fluctuation was noted after using Acetazolamide. The initial manifestations of the two RECA cases were dystonia and encephalopathy, respectively. One manifested a rapid-onset course of dystonia triggered by a fever followed by dysarthria and action tremors, and independent walking was impossible. The brain MRI image was normal. The other one presented with disturbance of consciousness, seizures, sleep disturbance, tremor, and dyskinesias. The EEG revealed a slow background (δ activity), and the brain MRI result was normal. No response to Flunarizine was noted for them, and it took 61 and 60 months for them to reach a stable disease state, respectively. CONCLUSION: Pathogenic ATP1A3 variants play an essential role in the pathogenesis of Sodium-Potassium pump disorders, and AHC is the most common phenotype. The treatment strategies and prognosis depend on the phenotype categories caused by different variation sites and types. The correlation between the genotype and phenotype requires further exploration. WHAT IS KNOWN: • Pathogenic heterozygous ATP1A3 variants cause a spectrum of neurological phenotypes, and ATP1A3-disorders are viewed as a phenotypic continuum presenting with atypical and overlapping features. • The genotype-phenotype correlation of ATP1A3-disorders remains unclear. WHAT IS NEW: • In this study, the genotypes and phenotypes of ATP1A3-related disorders from Southwest of China were described. The splice-site variation c.2542+1G>T was detected for the first time in ATP1A3-related disorders. • The prognosis of twins with AHC p. Gly947Arg was more serious than AHC cases with other variants, which was inconsistent with previous reports. The phenomenon indicated the diversity of the correlation between the genotype and phenotype.

Management of children with glucose-6-phosphate dehydrogenase deficiency presenting with acute haemolytic crisis during the SARs-COV-2 pandemic.

BACKGROUND AND OBJECTIVES: Shortage of blood during the severe acute respiratory syndrome-COV-2 (SARs-COV-2) pandemic impacted transfusion practice. The primary aim of the study is to assess management of acute haemolytic crisis (AHC) in glucose-6-phosphate dehydrogenase(G6PD)- deficient children during SARs-COV-2 pandemic, and then to assess blood donation situation and the role of telemedicine in management. METHODS: Assessment of G6PD-deficient children attending the Emergency Department (ER) with AHC from 1 March 2020 for 5 months in comparison to same period in the previous 2 years, in three paediatric haematology centres. AHC cases presenting with infection were tested for SARs-COV-2 using RT-PCR. Children with Hb (50-65 g/L) and who were not transfused, were followed up using telemedicine with Hb re-checked in 24 h. RESULTS: A 45% drop in ER visits due to G6PD deficiency-related AHC during SARs-COV-2 pandemic in comparison to the previous 2 years was observed. 10% of patients presented with fever and all tested negative for COVID-19 by RT-PCR. 33% of patients had Hb < 50 g/L and were all transfused. 50% had Hb between 50 and 65 g/L, half of them (n = 49) did not receive transfusion and only two patients (4%) required transfusion upon follow up. A restrictive transfusion strategy was adopted and one of the reasons was a 39% drop in blood donation in participating centres. CONCLUSION: Fewer G6PD-deficient children with AHC visited the ER during SARs-COV-2 and most tolerated lower Hb levels. Telemedicine was an efficient tool to support their families. A restrictive transfusion strategy was clear in this study.

Different phenotypes of neurological diseases, including alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism, caused by de novo ATP1A3 mutation in a family.

BACKGROUND: The spectrum of neurological diseases related to ATP1A3 gene mutations is highly heterogeneous and exhibits different phenotypes. Phenotype overlaps, including alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy, and rapid-onset dystonia-parkinsonism (RDP), can also occur at extremely low incidences. Currently, over 90 types of pathogenic mutations have been identified in ATP1A3. PATIENTS AND METHODS: The family of a 2-year-11-month-old proband with AHC was recruited for this clinical investigation. The proband was screened for candidate mutation gene sites using next-generation sequencing and target-region capture technology. Sanger sequencing was used to identify carriers among family members. RESULTS: The mother of the proband with AHC was diagnosed with dystonia (later diagnosed as RDP). The biochemical and immune indices of the proband and the mother were not abnormal. Moreover, brain imaging of the proband revealed no significant abnormalities. However, the electroencephalogram of the mother was mildly abnormal, with no spike wave discharge. Brain MRI revealed slight cerebellar atrophy. Electromyography revealed neurogenic damage, with a decrease in the conduction velocity of the left ulnar and radial nerves. Based on the sequencing data, both the proband and her mother carried c.823G > C p. (Ala275Pro) heterozygotes; other family members were not identified as carriers. With a PolyPhen-2 score of 0.997 and SIFT score of 0.001, this mutation can be considered damaging. CONCLUSION: Family genotype-phenotype correlation analysis revealed that the phenotype and gene mutation were co-segregated, suggesting that it may be a pathogenic mutation.

Derivatives of Cinnamic Acid Esters and Terpenic Diversity in Volatiles of Thirty-Six Sand Ginger (Kaempferia galanga L.) Accessions of Eastern India Revealing Quality Chemovars.

The essential oil of Kaempferia galanga L. commonly known as sand ginger has increased its demand in national and international market for decades. Cinnamic acid esters like ethyl-p-methoxy cinnamate (EPMC) and ethyl cinnamate (EC) are major constituents in its essential oil. In spite of the high demand for the plant as raw material, identification of quality chemovars having high essential oil (EO) yield and constituents is still at an infant stage. With this in mind, we have evaluated the EO yield of 36 accessions from three provinces of Eastern India, which varied within a range of 0.41 ± 0.01 to 2.63 ± 0.03 v/w. Further, a total of 65 compounds were detected by gas chromatography and mass spectrometry (GC-MS) with area percentages varying from 76.16 to 97.3%. EPMC was found to be the major component in 14 accessions with area percentages varying from 10.7% to 41.1%, whereas other 22 accessions showed EC as the major constituent, varying from 16% to 29.1%. Further, a diversity study among accessions was performed by agglomerative hierarchical clustering (AHC) and principal component analysis (PCA) analysis based on the abundance of identified constituents, which categorized all 36 accessions into three clusters. Thus, the present study helps to identify quality chemovar K.g16 and K.g14 with respect to oil yield and constituents, respectively, which could be used to guide commercial cultivation and further improvement of the taxa.

How the Outliers Influence the Quality of Clustering?

In this article, we evaluate the efficiency and performance of two clustering algorithms: AHC (Agglomerative Hierarchical Clustering) and K-Means. We are aware that there are various linkage options and distance measures that influence the clustering results. We assess the quality of clustering using the Davies-Bouldin and Dunn cluster validity indexes. The main contribution of this research is to verify whether the quality of clusters without outliers is higher than those with outliers in the data. To do this, we compare and analyze outlier detection algorithms depending on the applied clustering algorithm. In our research, we use and compare the LOF (Local Outlier Factor) and COF (Connectivity-based Outlier Factor) algorithms for detecting outliers before and after removing 1%, 5%, and 10% of outliers. Next, we analyze how the quality of clustering has improved. In the experiments, three real data sets were used with a different number of instances.

Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity.

Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (α3) of Na+/K+-ATPase, are the primary genetic cause for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), early infantile epileptic encephalopathy (EIEE), childhood rapid onset ataxia (CROA) and relapsing encephalopathy with rapid onset ataxia (RECA) extend the clinical spectrum of ATP1A3 related disorders. AHC and RDP demonstrate distinct clinical features, with AHC symptoms being generally more severe compared to RDP. Currently, it is largely unknown what determines the disease severity, and whether severity is linked to the degree of functional impairment of the α3 subunit. Here we compared the effect of twelve different RDP and AHC specific mutations on the expression and function of the α3 Na+/K+-ATPase in transfected HEK cells and oocytes. All studied mutations led to functional impairment of the pump, as reflected by lower survival rate and reduced pump current. No difference in the extent of impairment, nor in the expression level, was found between the two phenotypes, suggesting that these measures of pump dysfunction do not exclusively determine the disease severity.

Spontaneous fertility and variable spectrum of reproductive phenotype in a family with adult-onset X-linked adrenal insufficiency harboring a novel DAX-1/NR0B1 mutation.

BACKGROUND: Adrenal hypoplasia congenita (AHC) is an X-linked disorder that affects the adrenal cortex and hypothalamus-pituitary-gonadal axis (HPG), leading to primary adrenocortical insufficiency (PAI) and hypogonadotropic hypogonadism. AHC is caused by a mutation in the DAX-1 gene (NR0B1). More commonly, this disease is characterized by early-onset PAI, with symptoms in the first months of life. However, a less severe phenotype termed late-onset AHC has been described, as PAI signs and symptoms may begin in adolescence and adulthood. Here we describe a family report of a novel mutation within NR0B1 gene and variable reproductive phenotypes, including spontaneous fertility, in a very late-onset X-linked AHC kindred. CASE PRESENTATION: Three affected maternal male relatives had confirmed PAI diagnosis between 30 y and at late 64 y. The X-linked pattern has made the endocrinology team to AHC suspicion. Regarding the HPG axis, all males presented a distinct degree of testosterone deficiency and fertility phenotypes, varying from a variable degree of hypogonadism, oligoasthenoteratozoospermia to spontaneous fertility. Interestingly, the other five maternal male relatives unexpectedly died during early adulthood, most likely due to undiagnosed PAI/adrenal crisis as the probable cause of their premature deaths. Sequencing analysis of the NR0B1 gene has shown a novel NR0B1 mutation (p.Tyr378Cys) that segregated in three AHC family members. CONCLUSIONS: NR0B1 p.Tyr378Cys segregates in an AHC family with a variable degree of adrenal and gonadal phenotypes, and its hemizygous trait explains the disease in affected family members. We recommend that NR0B1 mutation carriers, even those that are allegedly asymptomatic, be carefully monitored while reinforcing education to prevent PAI and consider early sperm banking when spermatogenesis still viable.

Inverse national trends of laser interstitial thermal therapy and open surgical procedures for refractory epilepsy: a Nationwide Inpatient Sample-based propensity score matching analysis.

OBJECTIVE: Surgery for medically refractory epilepsy (RE) is an underutilized treatment modality, despite its efficacy. Laser interstitial thermal therapy (LITT), which is minimally invasive, is increasingly being utilized for a variety of brain lesions and offers comparable seizure outcomes. The aim of this study was to report the national trends of open surgical procedures for RE with the advent of LITT. METHODS: Data were extracted using the ICD-9/10 codes from the Nationwide Inpatient Sample (NIS, 2012-2016) in this retrospective study. Patients with a primary diagnosis of RE who underwent either open surgeries (lobectomy, partial lobectomy, and amygdalohippocampectomy) or LITT were included. Patient demographics, complications, hospital length of stay (LOS), discharge disposition, and index hospitalization costs were analyzed. Propensity score matching (PSM) was used to analyze outcomes. RESULTS: A cohort of 128,525 in-hospital patients with RE was included and 5.5% (n = 7045) of these patients underwent either open surgical procedures (94.3%) or LITT (5.7%). LITT is increasingly being performed at a rate of 1.09 per 1000 epilepsy admissions/year, while open surgical procedures are decreasing at a rate of 10.4/1000 cases/year. The majority of procedures were elective (92%) and were performed at large-bed-size hospitals (86%). All LITT procedures were performed at teaching facilities and the majority were performed in the South (37%) and West (30%) regions. The median LOS was 1 day for the LITT cohort and 4 days for the open cohort. Index hospitalization charges were significantly lower following LITT compared to open procedures ($108,332 for LITT vs $124,012 for open surgery, p < 0.0001). LITT was associated with shorter median LOS, high likelihood of discharge home, and lower median index hospitalization charges compared to open procedures for RE on PSM analysis. CONCLUSIONS: LITT is increasingly being performed in favor of open surgical procedures. LITT is associated with a shorter LOS, a higher likelihood of being discharged home, and lower index hospitalization charges compared to open procedures. LITT is a safe treatment modality in carefully selected patients with RE and offers an opportunity to increase the utilization of surgical treatment in patients who may be opposed to open surgery or have contraindications that preclude open surgery.

Analysis of Cattle Social Transitional Behaviour: Attraction and Repulsion.

Understanding social interactions in livestock groups could improve management practices, but this can be difficult and time-consuming using traditional methods of live observations and video recordings. Sensor technologies and machine learning techniques could provide insight not previously possible. In this study, based on the animals' location information acquired by a new cooperative wireless localisation system, unsupervised machine learning approaches were performed to identify the social structure of a small group of cattle yearlings (n=10) and the social behaviour of an individual. The paper first defined the affinity between an animal pair based on the ranks of their distance. Unsupervised clustering algorithms were then performed, including K-means clustering and agglomerative hierarchical clustering. In particular, K-means clustering was applied based on logical and physical distance. By comparing the clustering result based on logical distance and physical distance, the leader animals and the influence of an individual in a herd of cattle were identified, which provides valuable information for studying the behaviour of animal herds. Improvements in device robustness and replication of this work would confirm the practical application of this technology and analysis methodologies.

Exploration of Outliers in If-Then Rule-Based Knowledge Bases.

The article presents both methods of clustering and outlier detection in complex data, such as rule-based knowledge bases. What distinguishes this work from others is, first, the application of clustering algorithms to rules in domain knowledge bases, and secondly, the use of outlier detection algorithms to detect unusual rules in knowledge bases. The aim of the paper is the analysis of using four algorithms for outlier detection in rule-based knowledge bases: Local Outlier Factor (LOF), Connectivity-based Outlier Factor (COF), K-MEANS, and SMALLCLUSTERS. The subject of outlier mining is very important nowadays. Outliers in rules If-Then mean unusual rules, which are rare in comparing to others and should be explored by the domain expert as soon as possible. In the research, the authors use the outlier detection methods to find a given number of outliers in rules (1%, 5%, 10%), while in small groups, the number of outliers covers no more than 5% of the rule cluster. Subsequently, the authors analyze which of seven various quality indices, which they use for all rules and after removing selected outliers, improve the quality of rule clusters. In the experimental stage, the authors use six different knowledge bases. The best results (the most often the clusters quality was improved) are achieved for two outlier detection algorithms LOF and COF.

Chemometric approach based characterization and selection of mid-early cauliflower for bioactive compounds and antioxidant activity.

The present study was aimed to analyse bioactive compounds (total phenolics, ascorbic acid and sinigrin) and antioxidant activity in 14 mid-early cauliflower genotypes. Significant differences (pb 0.05) were observed among the genotypes for all bioactive compounds and antioxidant activity. Total phenolics content of curd were ranged from 20.36 to 48.93 mg gallic acid equivalent (GAE) 100 g-1 fresh weight (FW) which showed 2.5 times variation. The ascorbic acid content was maximum in DC522 (88.53 mg 100 g-1 FW) followed by Pusa Sharad (65.64 mg 100 g-1 FW) while minimum in DC310 (39.62 65.64 mg 100 g-1 FW). Wide variation was observed for cupric reducing antioxidant capacity and ferric reducing antioxidant power ranging from 9.04 to 20.83 mg GAE 100 g-1 FW and 13.11 to 26.31 mg GAE 100 g-1 FW, respectively. Sinigrin was found to be highest in DC306 (39.50 µmol 100 g-1 FW) for leaf and in DC326 (36.93 µmol 100 g-1 FW) for curd sample. The cauliflower genotypes were classified based on chemometric approaches namely principal component analysis (PCA) and agglomerative hierarchical clustering (AHC). The first two principal components (PC1 and PC2) explained 50.62% and 23.28% of total variance, respectively. The AHC as revealed by heat map classified cauliflower genotypes into four main groups based on measured traits. The information is useful for developing varieties and/or hybrids rich in bioactive compounds and antioxidant activity.

Novel frameshift mutation of the NR0B1(DAX1) in two tall adult brothers.

NR0B1 (nuclear receptor subfamily 0, group B, member 1) is a transcription factor encoded by DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) responsible for the development and maintenance of the steroidogenic tissues. In humans the DAX1 mutations cause congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism (HHG) in boys. Here we report two brothers who were assessed by endocrinologist at the age of 51 and 43 because of their serious osteoporosis. They had been substituted with prednisolone since the age of 4 and 9 years because of their primary adrenal insufficiency (PAI). Due to their late puberty caused by HHG at the age of 16 and 17 years their heights were - 3.1 and - 3.3 SD, but then they had a significant growth during their adulthood and reached the + 1.85 SD and + 3.78 SD respectively. During this period, they received glucocorticoid supplementation, but the treatment of their HHG was inadequate. At the age of 51 and 43 years insulin tolerance test (ITT) and gonadotropin releasing hormone (GnRH) test confirmed their PAI and HHG. Genetic test performed at this time revealed a novel, four nucleotides deletion (del.586-571c.GGGC or 572-575c.GGGC) of DAX1 gene. The two brothers with AHC and HHG caused by a novel DAX1 mutation, reached tall final heights, despite of the disadvantageous prednisolone treatment during their childhood. We assume that the long-term lack of the sexual hormone substitution was a significant reason of their above average height as well as their serious osteoporosis.

Headspace Solid Phase Microextraction Coupled to GC/MS for the Analysis of Volatiles of Honeys from Arid and Mediterranean Areas of Algeria.

The volatile composition of seven honey samples collected from various regions of Algeria and feeding on different plants have been determined. The Headspace Solid-Phase MicroExtraction (HS-SPME) coupled with Gas Chromatography-Mass Spectrometry (GC/MS) was used to achieve the purpose. In this work, different parameters of the HS-SPME analytical method were investigated in order to reach maximal sensitivity, and thus to obtain maximum information about the volatile profile of Algerian honey. These parameters include saline medium, HS extraction temperature, and the nature of the fiber used. The results showed a great diversity in the chemical composition, in total 124 compounds from different chemical classes were identified, including compounds found for the first time in honey. The Ascending Hierarchical Classification (AHC) demonstrated the importance of choosing SPME extraction conditions to find volatile compounds, which could be as specific markers of the floral or geographical origin of honey, the latter was optimized in the parameter PDMS-55 °C.

Aromatic Plants from Plateau des Cataractes: Occurrence of the Citronella Chemotype of Cymbopogon flexuosus (Nees ex Steud.) W.Watson Acclimatized in Congo-Brazzaville.

Cymbopogon flexuosus var. flexuosus (citral chemotype) was introduced in a local plantation in 2006 at Plateau des Cataractes, Congo-Brazzaville to remedy the difficult adaptation and low production of essential oil of C. citratus, a source of citral. After some 10 years of acclimatization, C. flexuosus had adapted perfectly with a very high biomass and essential oil production. A citronella chemotype (Cymbopogon flexuosus var. albescens) was unexpectedly identified among lemongrass in the field, grown in a local experimental citronella plot covering 0.25 ha. Its essential oil was extracted by hydrodistillation and analyzed by GC and GC/MS to determine its chemotype. The citronella chemotype indicated by the chemical profile found was confirmed by descriptive statistics (radar plot) and by principal component analysis (PCA) and ascending hierarchical clustering (AHC).

Volatiles Profiling, Allelopathic Activity, and Antioxidant Potentiality of Xanthium Strumarium Leaves Essential Oil from Egypt: Evidence from Chemometrics Analysis.

The essential oil (EO) of Xanthium strumarium L. leaves (family: Asteraceae) was extracted by hydrodistillation, and then analyzed by gas chromatography-mass spectrometry (GC-MS). Forty-three essential compounds were identified. The sesquiterpenoids represented the major constituents (72.4%), including oxygenated (61.78%) and non-oxygenated (10.62%) sesquiterpenes, followed by monoterpenes (25.19%). The diterpenoids and oxygenated hydrocarbons were determined as minor compounds. The main constituents of the EO were 1,5-dimethyltetralin (14.27%), eudesmol (10.60%), l-borneol (6.59%), ledene alcohol (6.46%), (-)-caryophyllene oxide (5.36%), isolongifolene, 7,8-dehydro-8a-hydroxy (5.06%), L-bornyl acetate (3.77%), and aristolene epoxide (3.58%). A comparative analysis was stated here between the EO of Egyptian X. strumarium and those previously reported from Pakistan, Iran, and Brazil based on chemometic tools such as principal components analysis (PCA) and agglomerative hierarchical clustering (AHC). The EO of X. strumarium showed weak 1, 1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity with IC50 321.93 µL/L-1, which was comparable to ascorbic acid as a reference. However, the EO exhibited significant allelopathic potential regarding the germination and growth of the noxious weed Bidens pilosa in a concentration-dependent manner. Therefore, further study is recommended to characterize the EO from X. strumarium as an eco-friendly green bioherbicide against weeds, as well as determine their mode of actions.

Volatile Aroma Compounds of Brandy 'Lozovaca' Produced from Muscat Table Grapevine Cultivars (Vitis vinifera L.).

Grape brandy, known as 'Lozovaca', is one of the most produced alcoholic beverages in the Republic of Serbia. Muscat cultivars are highly priced in grape brandy manufacturing. Among the numerous factors, cultivar-specific characteristics have a significant influence on its quality and aroma profile. Pectolytic enzymes play a part in increasing intensity of the prefermentative aroma by hydrolysis of terpenic glycosides, from which the compounds that contribute to the aroma of brandy are released. In this study, grape brandy samples were produced from five Muscat table grapevine cultivars (Vitis vinifera L.) namely, Early Muscat, Radmilovac Muscat, Banat Muscat, Italia Muscat, and Muscat Hamburg, with the addition of pectolytic enzyme in two different concentrations or without it (control). A total of 58 volatile aroma compounds were detected by means of combined gas chromatographic-mass spectrometric (GC/MS) method. Ethyl esters of C8-C18 fatty acids (21) and terpene (16) compounds were considerably more abundant in all grape brandy samples compared to the other volatile compounds identified. Pectolytic enzyme, positively affected terpenes content in the brandy of all studied cultivars. The similarities between brandy samples produced from Muscat Hamburg (MH) and other Muscat cultivars may be attributed to the parentage of MH to those cultivars.

Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations.

ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.

Neurological disease mutations of α3 Na+,K+-ATPase: Structural and functional perspectives and rescue of compromised function.

Na+,K+-ATPase creates transmembrane ion gradients crucial to the function of the central nervous system. The α-subunit of Na+,K+-ATPase exists as four isoforms (α1-α4). Several neurological phenotypes derive from α3 mutations. The effects of some of these mutations on Na+,K+-ATPase function have been studied in vitro. Here we discuss the α3 disease mutations as well as information derived from studies of corresponding mutations of α1 in the light of the high-resolution crystal structures of the Na+,K+-ATPase. A high proportion of the α3 disease mutations occur in the transmembrane sector and nearby regions essential to Na+ and K+ binding. In several cases the compromised function can be traced to disturbance of the Na+ specific binding site III. Recently, a secondary mutation was found to rescue the defective Na+ binding caused by a disease mutation. A perspective is that it may be possible to develop an efficient pharmaceutical mimicking the rescuing effect.

Mosaicism in ATP1A3-related disorders: not just a theoretical risk.

Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS. Here, we report on two unrelated sets of full siblings with ATP1A3 mutations, (c.2116G>A) p. Gly706Arg in the first family, and (c.2266C>T) p. Arg756Cys in the second family, presenting with familial recurrence of the disease. Both families displayed parental germline mosaicism. In the first family, the brother and sister presented with severe intellectual deficiency, early onset pharmacoresistant epilepsy, ataxia, and autistic features. In the second family, both sisters demonstrated severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with ATP1A3-related disorders.

Alternating Hemiplegia of Childhood as a New Presentation of Adenylate Cyclase 5-Mutation-Associated Disease: A Report of Two Cases.

Mutations in the adenylate cyclase 5 (ADCY5) gene recently have been identified as the cause of a childhood-onset disorder characterized by persistent or paroxysmal choreic, myoclonic, and/or dystonic movements. The 2 novel mutations we identified expand the clinical spectrum of ADCY5 mutations to include alternating hemiplegia of childhood.