#semialdehyde

[jcrmhscasereports]

 HEREDITARY FORM OF EPILEPSY ASSOCIATED WITH PYRIDOXAMINE 5'-PHOSPHATE OXIDASE DEFICIENCY IN A CHILD by Plotnikova I.A in Journal of Clinical Case Reports Medical Images and Health Sciences

SUMMARY

The article presents a clinical case of focal epilepsy with a status course of seizures associated with a genetic mutation in exon 1 of the PNPO gene, which led to pyridoxamine-5'-phosphate oxidase deficiency. The diagnosis was made late due to the misinterpretation of symptoms, which complicated the course of the disease. Despite the fact that the first symptoms in the form of seizures appeared at the age of 1 month, only at the age of 5 the diagnosis was verified by doing targeted DNA sequencing. At the moment, the patient is receiving substitution therapy in the form of pyridoxal phosphate 300 mg/day, which enabled unstable clinical remission. Right now, it is impossible to achieve complete control over the convulsive syndrome without a strict diet: dairy-free, meat-free, egg-free and low-protein fat-free food. Currently, further search for treatment methods continues to improve the patient's quality of life and ensure stable remission. A detailed analysis was given for further genetic verification based on the amino acid profile of the patient, and the rehabilitation potential was determined based on topical neuropsychological diagnostics performed on a non-verbal child.

Key words: focal epilepsy; Pyridoxal 5′-phosphate; vitamin B6; PNPO; vitamin B6-dependent epilepsy, neuropsychological diagnostics.

INTRODUCTION

Vitamin B6-dependent epilepsies are aheterogeneous group of autosomal recessive diseases that are caused by mutations of five different genes involved in vitamin B6 metabolism [1]. Vitamin B6 is present in many forms in the human diet, but only pyridoxal-5 -phosphate (PLP) plays a vital role in the metabolism of a number of neurotransmitters, especially the inhibitory mediator gamma-aminobutyric acid. Code errors leading to a lack of pyridoxal-5'-phosphate manifest as B6-dependent epilepsy, including pyridoxamine-5-phosphate oxidase (PNPO) deficiency, which affects the synthesis and recycling of pyridoxal-5'-phosphate [2,3]. Neonatal manifestation in the form of acute encephalopathy with biphasic epileptic seizures (or status epilepticus) is the main symptom of the disease. The first phase (early attacks) is accompanied by fever and a temporary recovery of consciousness and the development; the second phase is a global cognitive dysfunction (late attacks).

Resistance to traditional antiepileptic therapy requires patient's lifelong treatment by pharmacological doses of vitamin B6 in the form of pyridoxine (PN) or a biologically active form of pyridoxal-5’-phosphate [1,4].

Case reports of PLP deficiency, verified not only clinically, but also by exome sequencing, are quite rare as well as the methods for studying molecular markers of alpha-aminoadipic semialdehyde and pipecolic acid in body fluids [5–7]. The complexity of diagnosis is caused by multiple disorders in newborns, especially in case of a slow and incomplete response to pyridoxine [8].

Recent studies have shown that the main enzyme defect in pyridoxine-dependent epilepsy is caused by alpha-aminoadipic acid semialdehyde dehydrogenase in the pathway of cerebral lysine degradation. The accumulating compound, alpha-aminoadipine semialdehyde (alpha-AASA), is in equilibrium with delta-1-piperidine-6-carboxylate (P6C). P6C inactivates pyridoxal-5’-phosphate, causing severe cerebral insufficiency. Although treatment of pyridoxal 5'-phosphate deficiency can successfully control seizures, most patients develop some degree of disability, regardless of early diagnosis and treatment. Very few patients with normal intelligence have been reported [7].

Objective: to analyze the course of epilepsy with pyridoxamin-5’-phosphate oxidase deficiency in an 8-year-old patient with diagnosis verification by clinical exome sequencing.

MATERIALS AND METHODS OF RESEARCH.

The analysis of primary medical documentation from 2013 to 2021 of a patient born in 2013 was performed. We reviewed the materials on the topic using PubMed search engines for the period 2014-2021, correlation of literature data with a specific clinical case.

RESEARCH RESULTS AND THEIR DISCUSSION.

A clinical case

Girl, 8 years old, was born from IV pregnancy of a woman with a burdened obstetric history. At the age of 1 month, tonic-clonic convulsions were first noted during sleep: gaze adversion to the left, lasting 30 seconds - 1 minute; afterwards there was up to 4 seizures per day, daily. At the age of 1 year, she was hospitalized 4 times on an emergency basis for convulsive seizures. The child was observed by a neurologist-epileptologist with a diagnosis of perinatal damage to the central nervous system, recovery period. Valproic acid was prescribed at a dosage of 50 mg/kg per day, oxcarbazepine 300 mg/day, without an effect of therapy. At the age of 2 years, she was hospitalized three times in the intensive care unit due to the status course of an epileptic seizure with a rise in temperature to febrile numbers. Neurological diagnosis at that time was: symptomatic epilepsy with complex partial seizures, status course of generalized convulsive seizures. On electroencephalography (EEG): moderate diffuse changes in the bioelectric activity (BEA) of the brain in a disorganized type. The patient's condition worsened. At the age of 3 years, she was observed in the State Autonomous Healthcare Institution of the Sverdlovsk Region "Children's City Clinical Hospital No. 9, Yekaterinburg" with the same diagnosis; the dose of oxcarbazepine was increased to 500 mg/day, valproic acid to 300 mg/day with no significant clinical effect. At the age of 4 years, she was hospitalized three times in the intensive care unit about epileptic seizures, without the effect of anticonvulsant therapy. Concomitant diseases at age 4 were: severe osteoporosis of the visible parts of the skeleton; pathological compression fracture of the body Th11; hepatomegaly; moderate expansion of the common hepatic, common bile ducts; enlargement of the gallbladder; a pronounced increase in the size of the kidneys, pancreas; diffuse changes in the parenchyma of the kidneys, a single cyst of the right kidney; unspecified form of caries; chronic gingivitis. Computed tomography of the abdominal aorta and its branches showed no evidence of hepatic artery stenosis. Autonomic dysfunction of the sinus node was noted: sinus arrhythmia with episodes of bradycardia. There were also small anomalies in the development of the heart: a functioning foramen ovale, additional chords of the cavity of the left ventricle.

DNA sequencing was carried out in 2017. Genetic mutations that were identified are described in patients with epilepsy associated with pyridoxamine 5'-phosphate oxidase deficiency and, based on the totality of information, regarded as pathogenic - a mutation in exon 1 of the PNPO gene (chr17: 46019139A> T, rs370243877), leading to amino acid replacement at position 33 of the protein (p.Asp33Val, NM-018129.3, mutation frequency in the ExAC control sample 0.0235%); as probably pathogenic - a previously undescribed heterozygous mutation in intron 3 of the PNPO gene (chr17:46022086G>A, rs766037058), leading to disruption of the splicing site and synthesis of the full-length protein (c.363+5G>A, NM_018129.3, OMIM: 610090, the value of the algorithm for predicting its influence on the function of AdaBoost splicing sites is 1.000).

A heterozygous mutation was also found in exon 4 of the EARS2 gene (chr16:23546678A>T), leading to a premature translation termination site at codon 163 (p.Tyr163Ter, NM_001083614.1). Such mutations have been described in patients with combined oxidative phosphorylation deficiency type 12 (OMIM: 614924). In this case (when no second mutation in the gene is detected), the result is regarded as an option with uncertain clinical significance, however, the mutation may be related to the phenotype. The parents did not undergo a genetic examination.

Prescribed treatment was: pyridoxine hydrochloride intramuscularly, then - pyridoxal phosphate at the rate of 10-50 mg / kg /day. On the 7th day after the start of treatment, the patient's consciousness was assessed as clear, she was able to sit up independently and stand with support. Her seizures stopped, appetite improved, during rehabilitation positive dynamics in neuropsychic development was noted with an expansion of the range of motor activity, the appearance of gaming activity, emotions and attempts to pronounce individual sounds.

At the age of 5 years 1 month there was a new epileptic seizure. The dose of pyridoxal phosphate was increased to 600 mg/day, convulsive attacks stopped. Concomitant diseases at age 5 were perianal dermatitis, vulvitis, continuously recurrent leukocyturia. Subsequent courses of medical rehabilitation was prescribed with positive dynamics.

In 2019, hyperkinesis (blinking), tremor, restlessness reappeared; in the summer were tonic-clonic seizures with vocalization, lasting 15-20 minutes and the status course of an attack, operculations, loss of appetite. By the end of the year, there was constant nausea and a gag reflex at the sight of food, vomiting with yellow mucus and a sour smell once every 5-7 days, accompanied by febrile fever, the smell of "rotten cheese" from the scalp and excrements during attacks. Motor clonic seizures appeared with a frequency of once every 1-2 months, symmetrical chill-like tremor - up to 3-5 times a day. Periodic episodes of psychomotor agitation, stereotyped movements were also noted.

Neurological status. There are bradypsychia, delayed psycho-motor development, coordination disorder. Patient does not pronounce words, speech is active only during the game-vocalisms, self-service skills are not formed. Autism spectrum disorders with general speech underdevelopment of level 1, psychomotor alalia were noted. Cerebral, meningeal symptoms are negative. The gait is uncertain. Cerebellar tests are negative. Cranial nerves: palpebral fissures D=S, pupils D=S, pupil reaction to light: direct D=S, consensual D=S. The volume of movement of the eyeballs is complete D=S, there is no nystagmus. The face is symmetrical D=S. There is no language deviation. Swallowing, phonation are not disturbed. Muscle tone: arms - reduced D=S, legs - normal D=S. Tendon reflexes: from the arms and legs increased D=S. There are no pathological foot signs, pelvic functions are preserved. Patient shows signs of slightly asymmetrical (with an accent on the left) motor awkwardness, reduced nutrition (Body weight 21,5 kg).

Results of instrumental and laboratory studies. The following disorders were detected on the EEG prior to the start of etiological therapy: Epileptiform activity in the form of "peak-wave" complexes in the frontal and central-temporal leads, more on the right; slowing down of activity in the temporal zone.

In the biochemical analysis of blood the level of amino acids (µmol/l) is low: alanine 119.30; glutamic acid 72.00; glycine 86.50; ornithine 22.10; proline 87.00. Activity of alanine aminotransferase is 24.9 U/l (reference values 0-29 U/l), aspartate aminotransferase - 26.4 U/l (reference values 0-48 U/l).

 Control visit. After the diagnosis was verified by exome sequencing, the patient was prescribed etiotropic therapy: pyridoxal phosphate 300 mg/day. The pre-elevated (1070 nmol/l) plasma concentration of vitamin B6 (pyridoxal-5-phosphate) normalized. EEG data - video monitoring showed moderately severe violations of BEA of the brain; the main rhythm is formed by age; registered regional slowing of the rhythm in the right central-parietal region. Epileptiform activity, clinical paroxysms, EEG patterns of epileptic seizures were not registered.

Final diagnosis: Genetic focal epilepsy due to a mutation in the PNPO gene (chr17: 46019139A> T, rs370243877). The type of attack is focal with impaired consciousness. PNPO developmental and epileptic encephalopathy. Cognitive impairment. Alalia. Motor awkwardness.

Psychological status. Diagnostics of cognitive activity showed that the girl is accessible to contact; she does not speak and comprehension of the speech is shown only in the form of understanding simple commands and simple instructions for the task. The child's object-sensory activity is carried out 100% through visual perception and shape perception, the perception of size is developed by 50%, spatial perception - 12%, color perception is completely absent. The insufficiency of these afferentations is a consequence of the decrease in the “zone of actual development”, which may be attributed to pedagogical neglect. In the motor sphere, gross motor skills are fully formed, fine motor skills are developed by 54%, objective activity is formed by 9%, taking into account the skills of game and constructive praxis, speech function is developed by 25%, self-service skills - by 60%, socialization – by 40%. Psychological diagnostics of the state of higher mental functions was carried out by depicting the structural and functional features of the brain, as a result of which topical insufficiency of brain areas was revealed. Figure 1 shows the level of formation of brain zones.

Figure 1: The degree of formation of brain departments that implement sensory and motor skills.

Despite the pronounced cognitive deficit in the child, the implementation of the program of psychological rehabilitation may expand the "zone of actual development" in the structure of the sensory, subject and pedagogical profile (since there are preserved components of cognitive activity)

DISCUSSION

Patient’s clinical diagnosis was established only at the age of 5 years, based on clinical manifestations and exome sequencing. The primal reduction of the dose of pyridoxal-5'-phosphate provoked a relapse of status epilepticus and a regression of acquired cognitive skills. A subsequent increase of treatment in combination with dietary therapy provided an unstable clinical remission without further improvement in the patient's condition. Such a response to the therapy has also been demonstrated in other studies [6,7].

Although in patients with a typical course of the disease, there is a several-fold increase in the level of glycine and glutamic acid in the blood plasma [1,5–7,9], in our case there is a decrease in glycine to 86,50 µmol/l (norm: 100-400 µmol /l) and other amino acids. Hypoglycinemia is an extremely rare condition, it occurs only in severe hereditary aminoacidopathy, but in our patient, tandem mass spectrometry was performed twice (including against the background of an attack) in 2016 and did not show any data of hereditary aminoacidopathy, organic aciduria, defects β-oxidation of fatty acids. The girl has a positive reaction to the oral intake of amino acid complexes and glycine separately, therefore, additional genetic analysis can be performed for 3-phosphoglycerate dehydrogenase deficiency, the clinical manifestations of which may be encephalopathy and seizures unresponsive to anticonvulsants [10]. Symptoms of this disease can be stopped by joint intake of serine and glycine so this diet may be developed for our patient. The study of vitamin B6 metabolites in de novo serine biosynthesis by Ramos et al (2017) had one group of rats which received a pyridoxine-deficient diet, while the diet of the control group of rats contained a normal amount of pyridoxine. This study has demonstrated a decrease in serine biosynthesis in Neuro-2a cells in vitamin B6 deficient rats. The pyridoxal-5'-phosphate-dependent enzyme phosphoserine aminotransferase (PSAT, EC 2.6.1.52) cannot function fully in conditions of vitamin B6 deficiency, and likely reduces the synthesis of phosphoserine and serine in animals on a pyridoxine-deficient diet. The production of glycine depends on the availability of serine and on the pyridoxal-5'-phosphate-dependent enzyme SHMT, which catalyzes part of the transformation of glycine, and the simultaneous deficiency of serine and pyridoxal-5'-phosphate can reduce its activity and lead to a decrease in the content of glycine in blood plasma [9].

Some authors reported EEG changes in patients with pyridoxine-dependent epilepsy [11]. In our patient, no clear epileptiform activity was registered either before or after the start of treatment with pyridoxal-5'-phosphate; this variant of EEG was also described by other researchers [5,6]. Changes in the brain during magnetic resonance imaging in patients with pyridoxine-dependent epilepsy may vary from normal to diffuse atrophy of the gray and white matter of the hemispheres [2]; in our case no changes were detected.

According to Plecko B. Et al., with late diagnosis stable remission after the appointment of pyridoxal-5'-phosphate is observed only in a few patients [1]. Early treatment is critical to prevent irreversible damage to the central nervous system and shows positive results [1,5,6]. Patients with pyridoxine-dependent epilepsy require lifelong supplementation with pyridoxal-5'-phosphate. Therapeutic doses of the drug vary from 15 to 30 mg/kg/day [1]. The daily requirement for vitamin B6 in infancy is 0.1–0.3 mg. Pyridoxal-5'-phosphate doses up to 500 mg/day are considered safe in children with classical vitamin B6 deficiency, but higher doses may cause reversible sensory and rare motor neuropathy [1], so total daily doses of pyridoxal-5'-phosphate, should not exceed 200-300 mg. There are no data on the optimal dose of the vitamin for long-term treatment. In experimental animals, doses of pyridoxal 5'-phosphate >50mg/kg/d induce ataxia, peripheral neuropathy, and muscle weakness; histological examination demonstrates neuronal damage with loss of myelin and degeneration of sensory fibers in peripheral nerves, dorsal columns of the spinal cord, and descending tract of the trigeminal nerve. In most cases of peripheral neuropathy, the total dose of pyridoxal 5'-phosphate is >1000 mg/day. Some children who take high concentrations of pyridoxal-5'-phosphate develop a persistent increase in transaminases with progression to cirrhosis and hepatocellular carcinoma [3]. To avoid side effects, a fixed effective dose should be used. However, studies showed that daily doses up to 1100 mg/day and 50 mg/kg/day to achieve a state without epileptic seizures did not cause any side effects when they were divided into 4–5 doses per day [12]. In our case the doses of pyridoxal-5'-phosphate less than 600 mg/day induces epileptic seizures and cognitive disfunction. Some mutations in the genes encoding of pyridoxamine-5-phosphate oxidase may require the combined treatment with pyridoxal-5'-phosphate and pyridoxine [12,13]. It is possible that such treatment will have a positive response in our patient as well.

Another interesting feature of this clinical case is an intolerance of the patient to many products: remission occurs only on a low-protein, low-fat diet with the exclusion of dairy, meat products and eggs. Similar dietary restrictions are observed in ALDH7A1 deficiency (antiquitin deficiency), which often accompanies PNPO gene mutation. In our case ALDH7A1 deficiency was excluded by exome sequencing [13,14]. However, a lysine-restricted diet can also be effective for homozygous mutations in the PNPO gene in some patients [14]. As an example of a diet, the recommendations of Koelker and Ross on glutaric aciduria type I can be used [15].

The patient also has a high content of vitamin B6 in plasma (775.0 nmol/l), which is typical response to an intake of pyridoxal-5'-phosphate (described levels of vitamin B6 in plasma: 400 nmol/l, 1060 nmol /l and 624 nmol/l) [12,18]. It is not known why some patients continue to have seizures even when taking high doses of pyridoxal-5'-phosphate, while others grow almost normally [1,7,19]. The long-term prognosis for this patient remains unclear. For our patient a clarifying genetic study with modification of pharmacological treatment and diet is required, considering that the girl does not tolerate protein hydrolysates and an unstable clinical remission only on a low-protein low-fat diet with the exclusion of dairy, meat products and eggs.

CONCLUSIONS

DNA diagnostics using the method of sequencing of exome regions of the genome is a key method for early verification of the diagnosis of epilepsy in newborns and young children, which in combination with the therapy can improve the prognosis.

The presence of heterozygous mutations in this clinical case suggests other metabolic deficits, which complicates the selection of treatment and requires additional examination of the exome.

To ensure stable remission, nutritional correction is required to compensate for deficient conditions during severe elimination measures, as well as the selection of the minimum sufficient dosage of pyridoxal-5'-phosphate in combination with pyridoxine hydrochloride.

Topical neuropsychological diagnostics and psychological correction based on intact higher mental functions makes the recovery of the patient possible.

Conflict of Interest: The authors of this article have confirmed that there are no conflicts of interest or financial support to report.

For more information: https://jmedcasereportsimages.org/about-us/

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[whats-in-a-sentence]

Initially, the enzyme glycolate dehydrogenase (see Table 8.3, reaction 13) converts photorespiratory glycolate into glyoxylate [glycolate + NAD+ → glyoxylate + NADH + H+]. Next, two enzymes catalyze the conversion of glyoxylate into glycerate:

Tartronic semialdehyde synthase [glyoxylate → tartronate semialdehyde + CO2] (see Table 8.3, reaction 14)

Tartronic semialdehyde reductase [tartronate semialdehyde + NADH + H+ → glycerate + NAD+] (see Table 8.3, reaction 15)

Finally, cyanobacterial glycerate kinase phosphorylates glycerate, yielding 3-phosphoglycerate that reenters the Calvin-Benson cycle [glycerate + ATP → 3-phosphoglycerate + ADP] (see Table 8.3, reaction 10). As in land plants, the alternative photorespiratory cycle of cyanobacteria releases one carbon atom (see Table 8.3, reaction 14) and incorporates a three-carbon skeleton back into the Calvin-Benson cycle (see Table 8.3, reaction 10). (...) Chloroplasts of these transgenic plants have an entirely functional photorespiratory cycle while additionally accommodating the bacterial enzymes glycolate dehydrogenase, tartronic semialdehyde synthase, and tartronic semialdehyde reductase (see Table 8.3, reactions 13, 14, and 15).

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[rollicomp]

Cataplexy definition

In addition, if short-term use of an opioid (eg, post- or perioperative) is required, interruption of treatment with XYREM should be considered.Īfter first initiating treatment and until certain that XYREM does not affect them adversely (eg, impair judgment, thinking, or motor skills), caution patients against hazardous activities requiring complete mental alertness or motor coordination such as operating hazardous machinery, including automobiles or airplanes. If use of these CNS depressants in combination with XYREM is required, dose reduction or discontinuation of one or more CNS depressants (including XYREM) should be considered. The concurrent use of XYREM with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. WARNINGS AND PRECAUTIONS Central Nervous System Depression patients with succinic semialdehyde dehydrogenase deficiency.combination with sedative hypnotics or alcohol.1ĬONTRAINDICATIONS XYREM is contraindicated for use in: Nocturnal sleep polysomnography (PSG) showing rapid eye movement (REM) sleep latency of 15 minutes or less, or a multiple sleep latency test (MSLT) showing a mean sleep latency of 8 minutes or less and more than 2 sleep onset rapid eye movement periods (SOREMPs).Hypocretin deficiency, as measured by cerebrospinal fluid (CSF) hypocretin-1 immunoreactivity values of one-third or less of those obtained in healthy subjects using the same assay, or 110 pg/mL or less.In children or in individuals within 6 months of onset, spontaneous grimaces or jaw-opening episodes with tongue thrusting or global hypotonia, without any obvious emotional triggers.In individuals with long-standing disease, brief (sec to min) episodes of sudden, bilateral loss of muscle tone with maintained consciousness that are precipitated by laughter or joking.Episodes of cataplexy, occurring at least a few times per month, and as defined by either:.The presence of at least one of the following:.These must have been occurring at least 3 times per week over the past 3 months. Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day.All of the following DSM-5 criteria should be met for narcolepsy patients. How narcolepsy is diagnosed according to the American Psychiatric Association (APA) DSM-5 criteria.

[moleculardepot]

Human ALDH6A1 Protein

Human ALDH6A1 Protein Catalog number: B2011579 Lot number: Batch Dependent Expiration Date: Batch dependent Amount: 20 µg Molecular Weight or Concentration: 250 µg/mL Supplied as: Solution Applications: molecular tool for various biochemical applications Storage: -20 °C Keywords: ALDH6A1 protein, Human ALDH6A1 protein, Recombinant ALDH6A1 protein, Methylmalonate-semialdehyde dehydrogenase…

[siglerprescriptiondrugcards]

Valproate Sodium

Common Brand Names: Depacon

Therapeutic Class: Anticonvulsant

Common Injectable Dosage Forms:

Injection: Valproate sodium injection equivalent to 100 mg of valproic acid per mL in 5 mL single-dose vials

Dosage Ranges:

For use as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur in isolation or in association with other types of seizures: The usual initial dose is 10-15 mg/kg/day. Dosage increases 5-10 mg/kg may be made weekly to reach optimal clinical response.

For use as monotherapy and adjunctive therapy in the treatment of patients with simple and complex absence seizures: The usual initial dose is 15 mg/kg/day. Dosage increases of 5-10 mg/kg may be made weekly to reach optimal clinical response. The maximum daily dose is 60 mg/kg.

Administration and Stability: Depacon should be administered as a 60-minute infusion (no more than 20 mg/minute), using plasma concentration (50-100 µg/mL) monitoring as a guideline. Patients should be switched to oral valproate as soon as possible. When switching to or from oral valproate, the equivalent total daily dose of injectable valproate sodium should be given. Vials should be stored at room temperature. Compatible for 24 hours at room temperature when diluted in Dextrose (5%) Injection, USP, Sodium Chloride (0.9%) Injection, USP, and Lactated Ringer’s Injection, USP. pH 7.6

Pharmacology/Pharmacokinetics: Valproate’s mechanism of action is unknown although it is thought to be related to increased brain levels of gamma-aminobutyric acid (GABA). This increase in GABA levels may be due to an inhibition of GABA transaminase or succinic semialdehyde dehydrogenase or by inhibition of reuptake by glial cells and nerve endings. Equivalent doses of IV valproate (when given as a 60-minute infusion) and oral valproate are expected to result in equivalent Cmax and Cmin. Valproate is highly bound (90%) to plasma proteins. Metabolism occurs in the liver, primarily by glucuronidation. IV administered valproate has a mean terminal elimination half-life of approximately 16 hours.

Drug and Lab Interactions: Aspirin may displace valproate from protein binding sites and inhibit its metabolism, thereby increasing free fraction of valproate. Felbamate may increase plasma levels of valproate. Rifampin may decrease the plasma levels of valproate. Valproate may increase the plasma levels or unbound fraction of amitriptyline, nortriptyline, ethosuximide, lamotrigine, phenobarbital, warfarin, and zidovudine. Valproate may decrease the serum levels of carbamazepine. Use with clonazepam may cause absence seizures.

Contraindications/Precautions: Contraindicated in patients with hepatic disease or significant hepatic dysfunction and in patients with known hypersensitivity to valproate sodium. Hepatic failure has occurred during therapy; therefore, monitor symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. Cases of life-threatening pancreatitis have been reported in patients receiving valproate. Symptoms such as abdominal pain, nausea, vomiting, and/or anorexia require prompt medical attention.  

Monitoring Parameters: Liver enzymes, CBC, PT, serum ammonia, serum valproate acid

Adverse Effects: Adverse effects are dose-related and include dizziness (5.2%), headache (4.3%), nausea (3.2%), injection site pain (2.6%), taste perversion (1.9%), chest pain (1.7%), somnolence (1.7%), and vomiting (1.3%). Effects such as abdominal pain, nausea, vomiting, and/or anorexia may be a sign of pancreatitis and require medical attention. Effects such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting may be a sign of hepatic failure and require medical attention.

Common Clinical Applications: Valproate sodium injection is indicated as an alternative in patients for whom oral administration of valproate is temporarily not feasible. It is useful in the treatment of complex partial seizures and simple and complex absence seizures.

[neurosciencenews]

Novel Genetic Mutation Discovered in Parkinson's Disease Patient

Mutations in the human genome may be responsible for many diseases. In the case of Parkinson's disease (PD), five locations have been the subject of recent attention. Variants of one of these locations, ACMSD (aminocarboxymuconate semialdehyde decarboxylase), may be implicated in PD, but until now, no mutations in ACMSD have been found in any PD patients.

The research is in Journal of Parkinson's Disease. (full open access)

[severetacoartisan]

June 2021 Report on  Global Succinic Semialdehyde (Cas 692-29-5) Industry Market Size, Share, Value, and Competitive Landscape 2020-2026

Under COVID-19 outbreak globally, this report provides 360 degrees of analysis from supply chain, import and export control to regional government policy and future influence on the industry. Detailed analysis about market status (2015-2020), enterprise competition pattern, advantages and disadvantages of enterprise products, industry development trends (2020-2025), regional industrial layout characteristics and macroeconomic policies, industrial policy has also been included. From raw materials to end users of this industry are analyzed scientifically, the trends of product circulation and sales channel will be presented as well. Considering COVID-19, this report provides comprehensive and in-depth analysis on how the epidemic push this industry transformation and reform.

Also Read: http://www.marketwatch.com/story/global-wind-direction-sensor-professional-survey-market-outlook-industry-analysis-and-prospect-2021-2021-05-03

In COVID-19 outbreak, Chapter 2.2 of this report provides an analysis of the impact of COVID-19 on the global economy and the Succinic Semialdehyde (Cas 692-29-5) Industry. Chapter 3.7 covers the analysis of the impact of COVID-19 from the perspective of the industry chain. In addition, chapters 7-11 consider the impact of COVID-19 on the regional economy.

The Succinic Semialdehyde (Cas 692-29-5) Industry market can be split based on product types, major applications, and important countries as follows:

Key players in the global Succinic Semialdehyde (Cas 692-29-5) Industry market covered in Chapter 12:  MDV Group Dupont Tyvek Granwell Products, Inc. Taghleef Industries Arjobex Yupo Nan YaPlastics PPG Industries HOP Industries Avery Dennison American Profol Treofan Group

Also Read: http://www.marketwatch.com/story/global-parcel-services-industry-market-size-share-value-and-competitive-landscape-forecast-year-2021-2026-2021-05-04

In Chapter 4 and 14.1, on the basis of types, the Succinic Semialdehyde (Cas 692-29-5) Industry market from 2015 to 2025 is primarily split into: HDPE BOPP Others

In Chapter 5 and 14.2, on the basis of applications, the Succinic Semialdehyde (Cas 692-29-5) Industry market from 2015 to 2025 covers: Non-Label Label

Also Read: http://www.marketwatch.com/story/global-high-grade-anthracite-industry-market-size-share-value-and-competitive-landscape-forecast-year-2021-2026-2021-05-05

Geographically, the detailed analysis of consumption, revenue, market share and growth rate, historic and forecast (2015-2025) of the following regions are covered in Chapter 6, 7, 8, 9, 10, 11, 14: North America (Covered in Chapter 7 and 14) United States Canada Mexico Europe (Covered in Chapter 8 and 14) Germany UK France Italy Spain Russia Others Asia-Pacific (Covered in Chapter 9 and 14) China Japan South Korea Australia India Southeast Asia Others Middle East and Africa (Covered in Chapter 10 and 14) Saudi Arabia UAE Egypt Nigeria South Africa Others South America (Covered in Chapter 11 and 14) Brazil Argentina Columbia Chile Others

Years considered for this report: Historical Years: 2015-2019 Base Year: 2019 Estimated Year: 2020 Forecast Period: 2020-2025

List OF CONTENTS AND TABLES:

Table of Content

 1 Succinic Semialdehyde (Cas 692-29-5) Industry Introduction and Market Overview

1.1 Objectives of the Study

1.2 Overview of Succinic Semialdehyde (Cas 692-29-5) Industry

1.3 Scope of The Study

1.3.1 Key Market Segments

1.3.2 Players Covered

1.3.3 COVID-19's impact on the Succinic Semialdehyde (Cas 692-29-5) Industry

1.4 Methodology of The Study

1.5 Research Data Source

Also Read: http://www.marketwatch.com/story/global-digital-handwriting-industry-market-size-share-value-and-competitive-landscape-forecast-year-2021-2026-2021-05-06

2 Executive Summary

2.1 Market Overview

2.1.1 Global Succinic Semialdehyde (Cas 692-29-5) Industry Market Size, 2015 – 2020

2.1.2 Global Succinic Semialdehyde (Cas 692-29-5) Industry Market Size by Type, 2015 – 2020

2.1.3 Global Succinic Semialdehyde (Cas 692-29-5) Industry Market Size by Application, 2015 – 2020

2.1.4 Global Succinic Semialdehyde (Cas 692-29-5) Industry Market Size by Region, 2015 - 2025

2.2 Business Environment Analysis

2.2.1 Global COVID-19 Status and Economic Overview

2.2.2 Influence of COVID-19 Outbreak on Succinic Semialdehyde (Cas 692-29-5) Industry Development

Also Read: http://www.marketwatch.com/story/global-drip-irrigation-systems-market-insights-overview-analysis-and-forecast-2021-2021-05-07

3 Industry Chain Analysis

3.1 Upstream Raw Material Suppliers of Succinic Semialdehyde (Cas 692-29-5) Industry Analysis

3.2 Major Players of Succinic Semialdehyde (Cas 692-29-5) Industry

3.3 Succinic Semialdehyde (Cas 692-29-5) Industry Manufacturing Cost Structure Analysis

3.3.1 Production Process Analysis

3.3.2 Manufacturing Cost Structure of Succinic Semialdehyde (Cas 692-29-5) Industry

3.3.3 Labor Cost of Succinic Semialdehyde (Cas 692-29-5) Industry

3.4 Market Distributors of Succinic Semialdehyde (Cas 692-29-5) Industry

3.5 Major Downstream Buyers of Succinic Semialdehyde (Cas 692-29-5) Industry Analysis

3.6 The Impact of Covid-19 From the Perspective of Industry Chain

3.7 Regional Import and Export Controls Will Exist for a Long Time

3.8 Continued downward PMI Spreads Globally

….….continued

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[cancersfakianakis1]

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

Abstract

Background

Bioenergetic characterisation of malignant tissues revealed that different tumour cells can catabolise multiple substrates as salvage pathways, in response to metabolic stress. Altered metabolism in gliomas has received a lot of attention, especially in relation to IDH mutations, and the associated oncometabolite D-2-hydroxyglutarate (2-HG) that impact on metabolism, epigenetics and redox status. Astrocytomas and oligodendrogliomas, collectively called diffuse gliomas, are derived from astrocytes and oligodendrocytes that are in metabolic symbiosis with neurons; astrocytes can catabolise neuron-derived glutamate and gamma-aminobutyric acid (GABA) for supporting and regulating neuronal functions.

Methods

Metabolic characteristics of human glioma cell models – including mitochondrial function, glycolytic pathway and energy substrate oxidation – in relation to IDH mutation status and after 2-HG incubation were studied to understand the Janus-faced role of IDH1 mutations in the progression of gliomas/astrocytomas. The metabolic and bioenergetic features were identified in glioma cells using wild-type and genetically engineered IDH1-mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression studies and liquid chromatography-mass spectrometry.

Results

U251 glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase (SSADH) expression was correlated to GABA oxidation. GABA addition to glioma cells increased proliferation rates. Expression of mutated IDH1 and treatment with 2-HG reduced glutamine and GABA oxidation, diminished the pro-proliferative effect of GABA in SSADH expressing cells. SSADH protein overexpression was found in almost all studied human cases with no significant association between SSADH expression and clinicopathological parameters (e.g. IDH mutation).

Conclusions

Our findings demonstrate that SSADH expression may participate in the oxidation and/or consumption of GABA in gliomas, furthermore, GABA oxidation capacity may contribute to proliferation and worse prognosis of gliomas. Moreover, IDH mutation and 2-HG production inhibit GABA oxidation in glioma cells. Based on these data, GABA oxidation and SSADH activity could be additional therapeutic targets in gliomas/glioblastomas.

https://ift.tt/2RDNlSH

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/targeted-neurotechnology-restores-walking-humans-spinal-cord-injury/

Targeted neurotechnology restores walking in humans with spinal cord injury

Content introduction:

TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Targeted neurotechnology restores walking in humans with spinal cord injury

DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Shared and distinct transcriptomic cell types across neocortical areas

De novo NAD+ synthesis enhances mitochondrial function and improves health

1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.

Read more, please click https://www.nature.com/articles/s41586-018-0665-2

2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.

Read more, please click https://www.nature.com/articles/s41586-018-0649-2

3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.

Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0654-5

5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.

Read more, please click https://www.nature.com/articles/s41586-018-0645-6

[moleculardepot]

Human AASDHPPT Protein

Human AASDHPPT Protein Catalog number: B2011448 Lot number: Batch Dependent Expiration Date: Batch dependent Amount: 100 µg Molecular Weight or Concentration: 1 mg/mL Supplied as: Solution Applications: molecular tool for various biochemical applications Storage: -20 °C Keywords: AASDHPPT protein (His tag), LYS5 protein, CGI-80 protein, LYS2 protein, AASD-PPT protein, L-aminoadipate-semialdehyde…

[bioadvisers]

Bioadvisers shared on Biotech Advisers

Targeted neurotechnology restores walking in humans with spinal cord injury

Content introduction:

TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Targeted neurotechnology restores walking in humans with spinal cord injury

DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Shared and distinct transcriptomic cell types across neocortical areas

De novo NAD+ synthesis enhances mitochondrial function and improves health

1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.

Read more, please click https://www.nature.com/articles/s41586-018-0665-2

2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.

Read more, please click https://www.nature.com/articles/s41586-018-0649-2

3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.

Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0654-5

5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.

Read more, please click https://www.nature.com/articles/s41586-018-0645-6

[abbkine]

BioAdvisers said on Biotech Advisers

Targeted neurotechnology restores walking in humans with spinal cord injury

Content introduction:

TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Targeted neurotechnology restores walking in humans with spinal cord injury

DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Shared and distinct transcriptomic cell types across neocortical areas

De novo NAD+ synthesis enhances mitochondrial function and improves health

1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.

Read more, please click https://www.nature.com/articles/s41586-018-0665-2

2. Targeted neurotechnology restores walking in humans with spinal cord injury Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.

Read more, please click https://www.nature.com/articles/s41586-018-0649-2

3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.

Read more, please click https://www.nature.com/articles/s41586-018-0670-5 4. Shared and distinct transcriptomic cell types across neocortical areas The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0654-5

5. De novo NAD+ synthesis enhances mitochondrial function and improves health Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.

Read more, please click https://www.nature.com/articles/s41586-018-0645-6

[siglerprescriptiondrugcards]

Divalproex Sodium

Brand Names: Depakote and Depakote ER.

Generic Available.

Common Dosage Forms:

Tablets, enteric-coated (Depakote): 125 mg, 250 mg, 500 mg.

Tablets, extended-release (Depakote ER): 250 mg and 500 mg.

Capsules, enteric-coated particles (Depakote): 125 mg.

FDA Indications/Dosages:

Treatment of simple (petit mal), complex absence, and complex partial seizures: Initial dose is 15 mg/kg/day. May be increased at one week intervals by 5-10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosages is 60 mg/kg/day.

Treatment of acute mania or mixed episodes associated with bipolar disorder, with or without psychotic features: Begin with 250 mg three times a day (Depakote) or 35 mg/kg (Depakote ER) given once daily. Increase as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect. The maximum daily dose is 60 mg/kg.

Prophylaxis of migraine headaches: Start with Depakote 250 mg twice daily or one Depakote ER tablet daily. Maximum daily dose is 1000 mg given twice daily (Depakote) or once daily (Depakote ER).

Monitor: LFT, CBC, serum valproate.

Pharmacology/Pharmacokinetics: Divalproate dissociates into valproate in the gastrointestinal tract. Its mechanism of action is unknown although it is thought to be related to increased brain levels of gamma-aminobutyric acid (GABA). This increase in GABA levels may be due to an inhibition of GABA transaminase or succinic semialdehyde dehydrogenase or by inhibition of reuptake if glial cells and nerve endings. Enteric-coated tablets produce peak serum levels of valproate in 3-4 hours with a half-life range from 6-16 hours. Extended-release tablets have a bioavailability equal to 81-89% of the enteric-coated tablets, with peak plasma levels reached in 7-14 hours. Valproate is highly bound (90%) to plasma proteins and is eliminated in the urine as the glucuronide conjugate.

Drug Interactions: Aspirin, carbamazepine, and dicumarol may alter serum levels through protein binding. May impair the renal clearance of phenobarbital. May alter the levels of phenytoin. Use with clonazepam may cause absence seizures. Use with topiramate can cause hyperammonemia and encephalopathy.

Contraindications/Precautions: Contraindicated in patients with hepatic disease. HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECIEVING VALPROIC ACID. Caution should be observed when administering to patients with prior history if hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. CASES OF LIFE-THREATENING PACREATITIS HAVE BEEN REPORTED IN PATIENTS RECIEVING VALPROATE. Patients should seek immediate medical evaluation if abdominal pain, nausea, vomiting, or anorexia occur. May cause decreased platelet aggregation. Platelet counts and coagulation tests are recommended prior to and during therapy. Antiepileptic drugs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indications. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. NEURAL TUBE DEFECTS, OTHER MALFORMATIONS, AND DECREASED IQ CAN OCCUR IF USED DURING PREGNANCY. Pregnancy Category D/X.

Adverse Effects: Nausea (31%), asthenia (20%), somnolence (17%), dyspepsia (13%), dizziness (12%), diarrhea (12%), vomiting (11%), abdominal pain (9%), tremor (9%), weight gain (8%), back pain (8%), alopecia (7%), and increased appetite (6%).

Patient Consultation:

Do not abruptly discontinue therapy without first consulting physician.

May cause drowsiness. Use caution while operating machinery or when mental alertness is required. Alcohol will increase this effect.

May take with food or milk to avoid GI upset.

Capsules may be swallowed whole of the contents sprinkled over soft food and ingested. Sprinkle the contents on a teaspoonful of the soft food and ingest without chewing.

Store in a cool, dry place away from sunlight and children.

If a dose is missed, take it as soon as possible. If it is closer to the time of your next dose than the dose you missed, skip the missed dose and return to your dosing schedule. Do not double doses.

Contact a physician if the above side effects are severe or persistent or if any of the following adverse effects are seen: facial edema, weakness, malaise, lethargy, abdominal pain, nausea, and/or anorexia.

[jaroffacts]

Glutamate-1-semialdehyde is a molecule formed from by the reduction of tRNA bound glutamate, catalyzed by glutamyl-tRNA reductase. JarofFacts.com

[robjustus]

This here is little Penny. Two of my closest friends daughter. She has an extremely rare deficiency called Succinic Semialdehyde Dehydrogenase Deficiency (SSADH). Despite this she is a happy, active, playful, sweet two year old. I drew this piece for her. She's awesome. #drawing #ssadh #illustration #happy #kidlitart #art #scbwi #littlebirdie

[neurogenpapers]

Pyridoxine-dependent epilepsy: A novel mutation in a Tunisian child.

PubMed: Related Articles Pyridoxine-dependent epilepsy: A novel mutation in a Tunisian child. Arch Pediatr. 2017 Jan 25;: Authors: Ben Younes T, Kraoua I, Benrhouma H, Nasrallah F, Ben Achour N, Klaa H, Hassen-Rouissi A, Drissi C, Benoist JF, Ben Youssef-Turki I Abstract Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive metabolic disease characterized by seizures in neonates or infants, which is unresponsive to antiepileptic drugs but controlled by pyridoxine. Without prompt treatment, continued seizures and severe encephalopathy result. Mutations in the ALDH7A1 gene encoding α-amino-adipic semialdehyde (α-AASA) dehydrogenase (antiquitin) have been identified as the cause of PDE. We report on a novel ALDH7A1 mutation in a Tunisian child with PDE. PMID: 28131559 [PubMed - as supplied by publisher] http://dlvr.it/NFy7C9