ATP7A Research Articles

Polymorphic variants of genes encoding Ca(2+)-transporting sarcoplasmic reticulum proteins in the progression of chronic heart failure

Aim. To study the association between polymorphic rs1860561 variants of Ca(2+)-ATPase SERCA2a (ATP2A2) gene and rs3766871 of ryanodine receptor (RYR2) gene and the severity of chronic heart failure (CHF).Material and methods. We determined rs1860561 and rs3766871 variants of the ATP2A2 and RYR2 genes, respectively, in 168 patients with coronary artery disease (CAD) and CHF using real-time polymerase chain reaction.Results. A statistically significant (p=0,046) decrease in the left ventricular ejection fraction in AA homozygotes of the ATP2A2 gene compared to carriers of the G allele was shown. But among GG homozygotes, patients with FC II CHF prevailed and participants with FC I CHF were less common than among patients with genotype GA (p=0,041).Conclusion. The association of the AA genotype carriage for the rs1860561 variant of the ATP2A2 gene encoding Ca(2+)-ATPase SERCA2a, with a decrease in the left ventricle ejection fraction in patients with CHF and CAD was revealed. At the same time, among the GG homozygotes, FC I CHF was the least prevalent. There was no association of the rY3766871 variant of the RYR2 gene with CHF severity.

Enhanced Thalamocortical Synaptic Transmission and Dysregulation of the Excitatory-Inhibitory Balance at the Thalamocortical Feedforward Inhibitory Microcircuit in a Genetic Mouse Model of Migraine.

Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feedforward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in CaV2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain of function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feedforward inhibitory microcircuit was altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance toward excitation and the widening of the integration time window were both smaller in FHM1 compared with WT mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed toward inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.SIGNIFICANCE STATEMENT Migraine is a complex brain disorder, characterized by attacks of unilateral headache and by global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. Here we provide insights into these mechanisms by investigating thalamocortical (TC) synaptic transmission and the function of the TC feedforward inhibitory microcircuit in a mouse model of a rare monogenic migraine. This microcircuit is critical for gating information flow to cortex and for sensory processing. We reveal increased TC transmission and dysregulation of the cortical excitatory-inhibitory balance set by the TC feedforward inhibitory microcircuit, whereby the balance is relatively skewed toward inhibition during repetitive thalamic activity. These alterations may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.

An association analysis for 14 candidate genes mapping to meat quality quantitative trait loci in a Duroc pig population reveals that the ATP1A2 genotype is highly associated with muscle electric conductivity.

In previous GWAS carried out in a Duroc commercial line (Lipgen population), we detected on pig chromosomes 3, 4 and 14 several QTL for gluteus medius muscle redness (GM a*), electric conductivity in the longissimus dorsi muscle (LD CE) and vaccenic acid content in the LD muscle (LD C18:1 n-7), respectively. We have genotyped, in the Lipgen population, 19 SNPs mapping to 14 genes located within these QTL. Subsequently, association analyses have been performed. After correction for multiple testing, two SNPs in the TGFBRAP1 (rs321173745) and SELENOI (rs330820437) genes were associated with GM a*, whereas ACADSB (rs81449951) and GPR26 (rs343087568) genotypes displayed significant associations with LD vaccenic content. Moreover, the polymorphisms located at the ATP1A2 (rs344748241), ATP8B2 (rs81382410) and CREB3L4 (rs321278469 and rs330133789) genes showed significant associations with LD CE. We made a second round of association analyses including the SNPs mentioned above as well as other SNPs located in the chromosomes to which they map. After performing a correction for multiple testing, the only association that remained significant at the chromosome-wide level was that between the ATP1A2 genotype and LD CE. From a functional point of view, this association is meaningful because this locus encodes a subunit of the Na+ /K+ -ATPase responsible for maintaining an electrochemical gradient across the plasma membrane.

First Attack and Clinical Presentation of Hemiplegic Migraine in Pediatric Age: A Multicenter Retrospective Study and Literature Review.

Background: Data on clinical presentation of Hemiplegic Migraine (HM) are quite limited in the literature, particularly in the pediatric age. The aim of the present study is to describe in detail the phenotypic features at onset and during the first years of disease of sporadic (SHM) and familial (FHM) pediatric hemiplegic migraine and to review the pertinent literature.Results: Retrospective study of a cohort of children and adolescents diagnosed with hemiplegic migraine, recruited from 11 Italian specialized Juvenile Headache Centers. Forty-six cases (24 females) were collected and divided in two subgroups: 32 SHM (16 females), 14 FHM (8 females). Mean age at onset was 10.5 ± 3.8 y (range: 2–16 y). Mean duration of motor aura was 3.5 h (range: 5 min−48 h). SHM cases experienced more prolonged attacks than FHM cases, with significantly longer duration of both motor aura and of total HM attack. Sensory (65%) and basilar-type auras (63%) were frequently associated to the motor aura, without significant differences between SHM and FHM. At follow-up (mean duration 4.4 years) the mean frequency of attacks was 2.2 per year in the first year after disease onset, higher in FHM than in SHM cases (3.9 vs. 1.5 per year, respectively). A literature review retrieved seven studies, all but one were based on mixed adults and children cohorts.Conclusions: This study represents the first Italian pediatric series of HM ever reported, including both FHM and SHM patients. Our cohort highlights that in the pediatric HM has an heterogeneous clinical onset. Children present fewer non-motor auras as compared to adults and in some cases the first attack is preceded by transient neurological signs and symptoms in early childhood. In SHM cases, attacks were less frequent but more severe and prolonged, while FHM patients had less intense but more frequent attacks and a longer phase of active disease. Differently from previous studies, the majority of our cases, even with early onset and severe attacks, had a favorable clinical evolution.

P.100Pseudo-increment at repetitive nerve stimulation (Arzel's sign): a new tool for Brody myopathy diagnosis

Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induced impaired muscle relaxation on exercise. Diagnosis relies on electroneuromyography (ENMG), showing electrical silence during muscle stiffness, decreased SERCA activity on muscle biopsy and genetic analysis of ATP2A1 gene. ENMG functional analyses are very useful in the diagnosis of channelopathies. Therefore, we hypothesized that they might be impaired in BM. We performed exercise tests and repetitive nerve stimulations (RNS) in 11 patients with BM. They all showed incremental response at 3 Hz RNS. Indeed there was an increase value of the compound motor action potential (CMAP), especially in the ulnar nerve (+30.2 ± 7.1 %, p<0.001), and decreased CMAP duration (-30.3 ± 2.8 %, p < 0.001). Interestingly, this sign, referred to as the Arzel's sign, was useful in the diagnostic procedure of patients with Brody disease, even for those with atypical phenotype. The Arzel's sign is easily accessible, and could prove to be a very useful tool in diagnosis BM and broadening its phenotype.

Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology.

Migraine, an extremely disabling neurological disorder, has a strong genetic component. Since monogenic mi-graines (resulting from mutations or changes in a single gene) may help researchers discover migraine pathophysiology, transgenic mice models harboring gene mutations identified in Familial Hemiplegic Migraine (FHM) patients have been gen-erated. Studies in these FHM mutant mice models have shed light on the mechanisms of migraine and may aid in the identifi-cation of novel targets for treatment. More specifically, the studies shed light on how gene mutations, hormones, and other factors impact the pathophysiology of migraine. The models may also be of relevance to researchers outside the field of mi-graine as some of their aspects are relevant to pain in general. Additionally, because of the comorbidities associated with mi-graine, they share similarities with the mutant mouse models of epilepsy, stroke, and perhaps depression. Here, we review the experimental data obtained from these mutant mice and focus on how they can be used to investigate the pathophysiology of migraine, including synaptic plasticity, neuroinflammation, metabolite alterations, and molecular and behavioral mecha-nisms of pain.

Report of a novel ATP7A mutation causing distal motor neuropathy

We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients’ blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.

ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease.

Intermediate Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using whole-exome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families. Further functional analysis revealed that these mutations led to the loss function of the ATP1A1 protein. The two mutations did not affect the levels of messenger RNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation. Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT.

Differential expression and characterization of ATP1A1 exon17 gene by high resolution melting analysis and RT-PCR in Indian goats.

The investigation was carried out to analyse the genetic polymorphism and gene expression of ATP1A1 gene in four different Indian goat breeds by using high resolution melting (HRM) and real time-PCR. ATPase is electro-genic ion pump which is maintains the balance of sodium and potassium ions in animal cells. The transport of Na+& K+ is variable at cellular level during extreme hot period. Therefore, susceptible and tolerant animals were selected based on the physiological responses during hot period. Blood samples were collected from individuals, DNA was isolated. The 300bp fragment of ATP1A1 gene was amplified by PCR and HRM genotyping was performed. The melting curves were analysed, differential temperature-shift plot showed three different genotypes in all the analysed samples. Out of the 135 samples, the distribution percentages were 55.56% (AA/blue), 33.33% (AC/red) and 11.11% (CC/green). The sequence variation revealed a SNP at 143rd position (A>C). The nucleotide diversity was 0.695 ± 0.403, 0.732 ± 0.424, 0.662 ± 0.433 and 0.687 ± 0.398 in Barbari, Jamunapari, Jakharna and Sirohi, respectively. The respiration rate (RR) was significantly different (P < 0.05) between AA and AC (t = 1.875, df = 38) genotype and heart rate (HR) was significantly different (P < 0.05) between AA and CC genotype. The relative expression pattern of ATP1A1 in SNP variants and non-variants animal tissues showed 19.09 and 6.93 fold higher than control (non-variant), respectively. Jamunapari showed higher fold value of ATP1A1 gene in comparison to Barbari, Jakharna and Sirohi. However, the heat stress-susceptible phenotype had significantly higher gene expression than stress-tolerant in all the breeds. The variation may be used as a marker for selection on the basis of physiological parameters and expression of ATP1A1 gene in goats indicating the specificity of expression in each tissue.

Detection and analysis of an ATP2A2 mutation in a family with Darier-White disease

To explore the molecular basis for a pedigree affected with Darier-White disease. Genomic DNA was isolated from 3 patients and 1 unaffected member from the pedigree, as well as 80 healthy controls. Targeted sequence capture and next-generation sequencing were used to screen mutations of skin disease-related genes. Candidate mutations were verified by Sanger sequencing, and co-segregation analysis was carried out to confirm the pathogenicity of mutation. Conservation analysis and protein structure and function were also predicted with Bioinformatic tools. A heterozygous mutation c.2246G>T (p.G749V) was identified in exon 15 of ATP2A2 gene in all 3 patients from the pedigree, but not in the unaffected member or 80 healthy controls. The corresponding amino acid was highly conserved, and mutation of which can lead to structural and functional changes of the protein. The c.2246G>T missense mutation of the ATP2A2 gene probably underlies the Darier-White disease in this pedigree by causing damages to the structure and function of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2).

Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans.

Mutations in pre-synaptic voltage-gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic and decreased GABAergic transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin-dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.

Revising rapid-onset dystonia-parkinsonism: Broadening indications for ATP1A3 testing.

Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

Upregulation of IL-1 Receptor Antagonist in a Mouse Model of Migraine.

Migraine is a disorder characterized by attacks of monolateral headaches, often accompanied by nausea, vomiting, and photophobia. Around 30% of patients also report aura symptoms. The cause of the aura is believed to be related to the cortical spreading depression (CSD), a wave of neuronal and glial depolarization originating in the occipital cortex, followed by temporary neuronal silencing. During a migraine attack, increased expression of inflammatory mediators, along with a decrease in the expression of anti-inflammatory genes, have been observed. The aim of this study was to evaluate the expression of inflammatory genes, in particular that of IL-1 receptor antagonist (IL-1RN), following CSD in a mouse model of familial hemiplegic migraine type 1 (FHM-1). We show here that the expression of IL-1RN was upregulated after the CSD, suggesting a possible attempt to modulate the inflammatory response. This study allows researchers to better understand the development of the disease and aids in the search for new therapeutic strategies in migraine.

Relief Following Chronic Stress Augments Spreading Depolarization Susceptibility in Familial Hemiplegic Migraine Mice

Cortical spreading depolarization (CSD) is the electrophysiological substrate of migraine aura, and a putative trigger of trigeminovascular activation and migraine headache. Many migraineurs report stress or relief after a stress triggers an attack. We tested whether various stress conditions might modulate CSD susceptibility and whether this is dependent on genetic factors. Male and female wild type and familial hemiplegic migraine type1 (FHM1) knock-in mice heterozygous for the S218L missense mutation were subjected to acute or chronic stress, or chronic stress followed by relief (36 h). Acute stress was induced by restraint and exposure to bright light and white noise (3 h). Chronic stress was induced for 28 days by two cycles of repeated exposure of mice to a rat (7 days), physical restraint (3 days), and forced swimming (3 days). Electrical CSD threshold and KCl-induced (300 mM) CSD frequency were determined in occipital cortex in vivo at the end of each protocol. Relief after chronic stress reduced the electrical CSD threshold and increased the frequency of KCl-induced CSDs in FHM1 mutants only. Acute or chronic stress without relief did not affect CSD susceptibility in either strain. Stress status did not affect CSD propagation speed, duration or amplitude. In summary, relief after chronic stress, but not acute or chronic stress alone, augments CSD in genetically susceptible mice. Therefore, enhanced CSD susceptibility may explain why, in certain patients, migraine attacks typically occur during a period of stress relief such as weekends or holidays.

Phenotypic and genotypic characteristics of fever-induced paroxysmal weakness and encephalopathy caused by ATP1A3 pathogenic variants

Objective: To characterize fever-induced paroxysmal weakness and encephalopathy (FIPWE) caused by ATP1A3 gene pathogenic variant. Methods: Phenotypic and genotypic characteristics of 4 FIPWE patients (3 boys and 1 girl), who were ascertained from October 2016 to March 2018 in Beijing Children's Hospital due to ATP1A3 heterozygous variants, were retrospectively analyzed. The whole exsome sequencing was used for genetic testing. Results: The onset ages of 4 patients were 2 years and 9 months, 2 years and 4 months, 8 months, 2 years and 5 months respectively. The episode ranged from 1 to 3 times, and at 3 months to 2 years and 10 months intervals. All 4 patients had symptoms of limb weakness and encephalopathy, accompanied with mild to severe ataxia or athetosis. The tendon reflex was absent in all patients, and the Babinski's sign was positive. Three patients had dysphagia and 3 patients had slurred speech. Three patients had abnormal eye movements, including strabismus and opsoclonus. None of the 4 patients exhibited visual impairment, auditory impairment or talipes cavus. The duration of acute phase ranged from 1 week to 3 months. In 3 relapsing patients, symptoms became progressively worse, with relapses occurring frequently and recovery being more difficult, and various sequelae were found after the last relapse. All patients carried heterozygous variant in ATP1A3 gene. The missense variants result in the substitution of an arginine residue at position 756. Three variants were identified, including C. 2267G > T (p. R756L) (1 case), C. 2266C > T (p. R756C) (2 cases), and C. 2267G > A (p. R756H) (1 case). Three were de novo and one inherited from his father, but the grandparents did not carry the variant. All variants were reported as pathogenic. Conclusions: FIPWE is one of new clinical phenotypes of ATP1A3 spectrum disease and most cases are sporadic. The missense variants result in the substitution of an arginine residue at position 756. This report provided insights into the phenotype-genotype association in patients with FIPWE caused by pathogenic variants of ATP1A3.

Basal astrocyte and microglia activation in the central nervous system of Familial Hemiplegic Migraine Type I mice.

Gain-of-function missense mutations in the α1A subunit of neuronal CaV2.1 channels, which define Familial Hemiplegic Migraine Type 1 (FHM1), result in enhanced cortical glutamatergic transmission and a higher susceptibility to cortical spreading depolarization. It is now well established that neurons signal to surrounding glial cells, namely astrocytes and microglia, in the central nervous system, which in turn become activated and in pathological conditions can sustain neuroinflammation. We and others previously demonstrated an increased activation of pro-algogenic pathways, paralleled by augmented macrophage infiltration, in both isolated trigeminal ganglia and mixed trigeminal ganglion neuron-satellite glial cell cultures of FHM1 mutant mice. Hence, we hypothesize that astrocyte and microglia activation may occur in parallel in the central nervous system. We have evaluated signs of reactive glia in brains from naïve FHM1 mutant mice in comparison with wild type animals by immunohistochemistry and Western blotting. Here we show for the first time signs of reactive astrogliosis and microglia activation in the naïve FHM1 mutant mouse brain. Our data reinforce the involvement of glial cells in migraine, and suggest that modulating such activation may represent an innovative approach to reduce pathology.

Research progress in Menkes disease

Menkes Disease(MD)is a multisystemic disorder of impaired copper metabolism with an X-linked recessive inheritance, which is caused by defects in ATP7A gene encoding a copper-transporting ATPase.It is characterized by infantile onset, peculiar curls and facial changes, mental retardation with progressive neurodegeneration, as well as hypotonia and connective tissue abnormalities.Many intermediate phenotypes have been found in recent years, the mildest form of which is occipital horn syndrome(OHS). Its clinical variants show a broad spectrum from chromosome abnormalities to single-nucleotide mutation.Early copper-histidine supplementation is still the most crucial treatment at present, and L-DOPS combination therapy may benefit some patients clinically.This article reviews the pathogenesis, clinical features and the progress of diagnosis and treatment of MD. Key words: Menkes disease; ATP7A gene; Copper transport; Copper metabolism

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

BackgroundAlthough many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.MethodsIn this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants.ResultsWe identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in SPG11, two (p.T55 M, p.S308 T) in AP5Z1, one (p.S242 N) in ALDH18A1, one (p.D597fs) in GBA2, and one (p.Q486X) in ATP13A2 in 8 index patients and their family members. Mutations in ALDH18A1, AP5Z1, CAPN1 and ATP13A2 genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in ALDH18A1 decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in AP5Z1 induced lysosomal dysfunction.ConclusionOur results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

Successful treatment of psychosis in a patient with Kufor-Rakeb syndrome with low dose aripiprazole: a case report

ABSTRACTWe present a case of a 32-year-old male with Kufor-Rakeb syndrome (KRS), a form of juvenile parkinsonism due to mutations of the ATP13A2 gene at PARK9 locus. The patient was seen for daily behavioral outbursts and psychotic symptoms. At first assessment, CGI scale was estimated at 5; “Markedly ill”. Aripiprazole was started at 2 mg and then increased to 3 mg. Two years later, psychotic symptoms were judged to be “much improved” (CGI-C = 2). This significant improvement without drug-induced motor side effects suggests that aripiprazole at low doses (2–5 mg) is effective and tolerated in patients with KRS.

The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid homeostasis

Mutations in the ATP13A2 gene (PARK9, CLN12, OMIM 610513) were initially associated with a form of Parkinson's Disease (PD) known as Kufor Rakeb Syndrome (KRS). However, the genetic spectrum of ATP13A2-associated disorders was expanded in the last years, because it has been found to underlay variants of neuronal ceroid-lipofuscinoses (NCLs) and hereditary spastic paraplegia. As ATP13A2 seems to be a key component of the endo-lysosome pathway, the fact that these pathologies are commonly characterized by endo-lysosomal dysfunction is not surprising.Here we report that increasing the level of functional ATP13A2 in a stable SH-SY5Y cell line disrupts lipid homeostasis. ATP13A2 overexpression increases the fluorescence intensity of the fluorescent analog phosphatidylethanolamine (NBD-PE) and the formation of multilamellar bodies, resembling the so-called “drug-induced phospholipidosis”. We also found that expression of ATP13A2 reduces the ceramide-fluorescence intensity and the content of bis(monoacylglyceryl)phosphate (BMP). BMP is required for lipid degradation and exosome biogenesis inside acidic compartments, so this result suggests that ATP13A2 may be modifying the lipid digestion capacity and/or the redistribution of lipids in these subcellular organelles. In addition, ATP13A2-overexpression decreased the total content of triglycerides (TGs), cholesterol and lipid droplets. As TGs are necessary for the synthesis of new membranes, this observation suggests that increasing the function of ATP13A2 switches the endo-lysosomal system towards vesicle secretion.