ABSTRACT
BACKGROUND: To summarize the clinical and genetic characteristics of patients with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency. METHODS: Clinical and genetic data of the patients were collected and analyzed. RESULTS: Eighteen patients from 17 families with variants in PNPO were collected, and 15 cases survived to date. The age of onset ranged from 1 day to 5 months (median age 6.5 days) and seven of them presented with seizures <24 h. About 7/18 (39%) of patients showed seizure-free with pyridoxine (PN) or pyridoxal-5'-phosphate treatment. Two patients showed surprised therapeutic responses to antiseizure medications therapy: one could be controlled for up to 1 year and 5 months, and the other showed seizure-free for >8 years. The neurodevelopment was normal in one patient, mild delay in four, in whom responded well to PN. Severe delay could be seen in the remaining 10 surviving patients. Genetic analysis revealed 14 variants of PNPO, seven of which were novel. Five pairs of unrelated patients were observed to carry the same variants, respectively, and had similar developmental status and onset age of seizures in some degree in each pair, whereas also had differences. CONCLUSIONS: The clinical characteristics, including age of onset, treatment response and prognosis, were variable and difficult to classify into different types clearly. Patients with PNPO deficiency who used PN as their main treatment and being able to control seizures seemed to be associated with better outcomes. Patients with the same genotype tended to show the correlation of phenotype-genotype.
Subject(s)
Brain Diseases, Metabolic , Hypoxia-Ischemia, Brain , Metabolic Diseases , Pyridoxaminephosphate Oxidase , Humans , Brain Diseases, Metabolic/genetics , Hypoxia-Ischemia, Brain/genetics , Oxidoreductases , Phosphates/therapeutic use , Pyridoxal Phosphate/therapeutic use , Pyridoxaminephosphate Oxidase/deficiency , Pyridoxaminephosphate Oxidase/genetics , Pyridoxine , Seizures/drug therapy , Seizures/geneticsABSTRACT
BACKGROUND: A rare subset of vitamin B6 responsive seizure disorders does not respond to pyridoxine, and requires the active form of vitamin B6, pyridoxal-5'-phosphate (PLP), to maintain seizure control. Patients with PLP-responsive seizures are dependent on chronic PLP treatment, yet no licensed PLP product is available. PLP food supplements, a product category regulated less stringently than medication, may prove of insufficient effectiveness and safety. Here we describe and discuss three patient scenarios which illustrate this conundrum. METHODS: Medical and laboratory records were reviewed with retrospective extraction for three unrelated patients who suffered complications during treatment with PLP food supplements. RESULTS: - Two cases of PNPO deficiency and one case of PLP-dependent epileptic encephalopathy without a (genetic) diagnosis are reported. These patients are critically dependent on PLP for seizure control and have suffered complications due to insufficient quality of these food supplements during the course of treatment. Complications include the occurrence of seizures following the administration of suspected low quality PLP, inactive PLP due to light exposure, a PLP intoxication, resisting administration and post-administration vomiting as a result of the ingestion of large amounts of capsules per day. CONCLUSION: - This case series illustrates that the reliance on food supplements as anti-seizure therapy is not without risk. The treatment of PLP-dependent seizures exemplifies that PLP is administered as medication, thus there is a clear need for licensed vitamin products of pharmaceutical quality.
Subject(s)
Pyridoxal Phosphate , Vitamin A , Humans , Phosphates , Pyridoxal Phosphate/therapeutic use , Pyridoxine/therapeutic use , Retrospective Studies , Vitamin B 6/therapeutic useABSTRACT
AIM: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. METHOD: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20-30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20-30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. RESULTS: Seven participants (one female, six males; age range 5-23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. INTERPRETATION: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. WHAT THIS PAPER ADDS: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy.
Subject(s)
Drug Resistant Epilepsy , Epilepsy , Cohort Studies , Drug Resistant Epilepsy/drug therapy , Epilepsy/complications , Epilepsy/drug therapy , Epilepsy/genetics , Female , Glycosylphosphatidylinositols/deficiency , Glycosylphosphatidylinositols/therapeutic use , Humans , Infant , Male , Phosphates/therapeutic use , Prospective Studies , Pyridoxal Phosphate/therapeutic use , Pyridoxine/therapeutic use , Seizures/drug therapy , Seizures/etiologyABSTRACT
To investigate the effect of P2 receptor on microglia and its inhibitor PPADS on choroidal neovascularization. Forty CX3CR1GFP/+ mice were randomly divided into 8 groups. In addition to the normal group, the rest of groups were receiving laser treatment. The retina and choroid from the second, third, fourth and fifth group of mice were taken in the 1, 4, 7, 14 days after laser treatment. The mice in the sixth and seventh group received intravitreal injection of 2 µl PPADS or PBS respectively immediately after laser treatment. The mice in the eighth group received topical application of PPADS once per day of three days. The mice in sixth, seventh and eighth group received AF and FFA examination on the fourth day after laser treatment. Immunofluorescence histochemical staining and real-time quantitative PCR were used to evaluate P2 expression and its effect on choroidal neovascularization. After laser treatment, activated microglia can express P2 receptors (P2X4, P2X7, P2Y2 and P2Y12). The expression of P2 increased on the first day after laser damage, peaked on the fourth day (tP2X4 = 6.05, tP2X7 = 2.95, tP2Y2 = 3.67, tP2Y12 = 5.98, all P < 0.01), and then decreased. After PPADS inhibition, compared with the PBS injection group, the mRNA of P2X4, P2X7, P2Y2 and P2Y12 were decreased significantly in the PPADS injection group (tP2X4 = 5.54, tP2X7 = 9.82, tP2Y2 = 3.86, tP2Y12 = 7.91, all P < 0.01) and the PPADS topical application group (tP2X4 = 3.24, tP2X7 = 5.89, tP2Y2 = 6.75, tP2Y12 = 4.97, all P < 0.01). Compared with the PBS injection group, not only the activity of microglia cells but also the leakage of CNV decreased significantly (P < 0.01) in the PPADS injection group and the PPADS topical application group. But between two PPADS groups, the leakage of CNV had no difference (P = 0.864). After laser induced CNV, activated microglia can express P2 receptors. The P2 receptor inhibitor, PPADS, can significantly affect the function of microglia and inhibit the formation of choroidal neovascularization.
Subject(s)
Choroidal Neovascularization/metabolism , Microglia/metabolism , Receptors, Purinergic P2/metabolism , Animals , Choroidal Neovascularization/drug therapy , Choroidal Neovascularization/etiology , Lasers/adverse effects , Mice , Microglia/drug effects , Purinergic P2 Receptor Antagonists/pharmacology , Purinergic P2 Receptor Antagonists/therapeutic use , Pyridoxal Phosphate/analogs & derivatives , Pyridoxal Phosphate/pharmacology , Pyridoxal Phosphate/therapeutic use , Receptors, Purinergic P2/geneticsABSTRACT
BACKGROUND: Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of choice. However, despite the use of acetylcysteine, some patients who ingest very large doses of paracetamol or who reach hospital late in the course of their poisoning, develop acute liver failure. Some will develop metabolic acidosis indicating mitochondrial toxicity. OBJECTIVE: We review the experimental and clinical data reported with the use of cimetidine, fomepizole, and calmangafodipir in the treatment of paracetamol toxicity to determine if these treatments alone or in combination with acetylcysteine might be of benefit. METHODS: We searched Ovid Medline 1946-2020, Embase 1947-2020, Scopus 2004-2020, Cochrane Databases of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov 1997-2020 for records including the concepts of paracetamol poisoning and cimetidine, fomepizole, calmangafodipir, and acetylcysteine. We included basic science studies in animals and all available study types in humans. We reviewed the reference lists of included articles to search for references missed in the original search. We registered the protocol in PROSPERO. RESULTS: We completed all search strategies on 20 August 2019, 27 January 2020, and 15 June 2020. These produced 6,826 citations. We identified and deleted 2,843 duplicate resulting in a total of 3,856 unique citations. After applying inclusion and exclusion criteria, 89 studies remained. The largest numbers of studies described the past use of cimetidine, and the more recent use of fomepizole.Cimetidine: There is good animal evidence that cimetidine blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. Early case reports were inconclusive regarding the benefit to humans in paracetamol poisoning. Two comparative trials found no benefit of cimetidine in paracetamol poisoning, but few patients had severe poisoning.Fomepizole: There is good animal evidence that fomepizole blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. There are no comparative trials of fomepizole for acute paracetamol poisoning. Case reports are inconclusive due to multiple other interventions including the use of acetylcysteine in all cases. The benefit of fomepizole as adjunct treatment has not been demonstrated.Calmangafodipir: Calmangafodipir, a drug mimicking superoxide dismutase, has emerged as a potential treatment for severe paracetamol toxicity because the formation of superoxide free radicals appears to explain part of the mitochondrial toxicity of extremely large paracetamol overdoses. Calmangafodipir has reached Phase I/II trial of safety in humans with acute paracetamol overdose. Planning for a Phase III study of efficacy is currently underway. CONCLUSIONS: The vast majority of patients with acute paracetamol overdose enjoy excellent outcomes with acetylcysteine alone. Although cimetidine and fomepizole inhibit CYP 2E1 in animals, there is insufficient evidence to recommend their use either as a primary treatment or adjunct therapy in paracetamol poisoning. Calmangafodipir remains investigational.
Subject(s)
Acetaminophen/poisoning , Antidotes/therapeutic use , Drug Overdose/drug therapy , Mitochondria/drug effects , Acetylcysteine/therapeutic use , Acidosis/chemically induced , Animals , Cimetidine/therapeutic use , Edetic Acid/analogs & derivatives , Edetic Acid/therapeutic use , Fomepizole , Humans , Pyridoxal Phosphate/analogs & derivatives , Pyridoxal Phosphate/therapeutic useABSTRACT
PDXK encodes for a pyridoxal kinase, which converts inactive B6 vitamers to the active cofactor pyridoxal 5'-phosphate (PLP). Recently, biallelic pathogenic variants in PDXK were shown to cause axonal Charcot-Marie-Tooth disease with optic atrophy that responds to PLP supplementation. We present two affected siblings carrying a novel biallelic missense PDXK variant with a similar phenotype with earlier onset. After detection of a novel PDXK variant using Whole Exome Sequencing, we confirmed pathogenicity through in silico protein structure analysis, determination of pyridoxal kinase activity using liquid chromatography-tandem mass spectrometry, and measurement of plasma PLP concentrations using high performance liquid chromatography. Our in silico analysis shows a potential effect on PDXK dimer stability, as well as a putative effect on posttranslational ubiquitination that is predicted to lead to increased protein degradation. We demonstrate that the variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels. Our patients' early diagnosis and prompt PLP replacement restored the PLP plasma levels, enabling long-term monitoring of clinical outcomes. We recommend that patients presenting with similar phenotype should be screened for PDXK mutations, as this is a rare opportunity for treatment.
Subject(s)
Optic Atrophy/drug therapy , Phosphotransferases (Alcohol Group Acceptor)/genetics , Polyneuropathies/drug therapy , Pyridoxal Phosphate/therapeutic use , Vitamin B 6/metabolism , Adolescent , Female , Humans , Male , Mutation , Pyridoxal Kinase/metabolismABSTRACT
BACKGROUND: Parkinsonism is a neurodegenerative disorder with a heavy disease burden, despite the discovery and application of drugs. Current research is beginning to suggest the possible crucial roles of micronutrients such as pyridoxal phosphate in the prevention or management of neurodegenerative disorders. OBJECTIVE: We investigated the possible protective effects of supplemental pyridoxal phosphate in Chlorpromazine (CPZ)-induced Parkinsonism-like changes in mice. METHODS: Mice were assigned to eight groups of 30 mice each. Groups included Vehicle control (fed standard diet (SD), and administered intraperitoneal {ip} injection of saline and saline per orem), levodopa-carbidopa (LD) group (SD, saline ip and LD per orem), two groups fed pyridoxal phosphate-supplemented diet (at 100 and 200 mg/kg of feed), and administered saline both ip and orally, CPZ group (SD, CPZ ip and saline per orem), CPZ/LD group (SD, CPZ ip and LD per orem) and finally two groups fed pyridoxal phosphate -supplemented diet (at 100 and 200 mg/kg of feed) and administered CPZ ip plus saline per orem. Treatments were administered daily for a period of 21 days to allow for the induction of Parkinsonism features. Body weight and food intake were measured weekly while neurobehavioural and biochemical tests were assessed at the end of the experimental period. RESULTS: Pyridoxal phosphate supplementation was associated with a reduction in CPZ-induced suppression of open-field horizontal locomotion and rearing; and a significant increase in grooming activity. Administration of pyridoxal phosphate-supplemented diet was also associated with improvements in working-memory in CPZ-treated mice; and there was reduction in the index of anxiety and catalepsy score. CONCLUSION: Pyridoxal phosphate supplementation was associated with significant benefits in CPZ-induced Parkinsonism-like changes in mice.
Subject(s)
Antipsychotic Agents , Chlorpromazine , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/drug therapy , Pyridoxal Phosphate/therapeutic use , Animals , Antioxidants/metabolism , Antiparkinson Agents/therapeutic use , Behavior, Animal/drug effects , Body Weight/drug effects , Carbidopa , Diet , Drug Combinations , Eating/drug effects , Grooming/drug effects , Levodopa , Lipid Peroxidation/drug effects , Mice , Motor Activity/drug effectsABSTRACT
Inborn errors of metabolism cause disease because of accumulation of a metabolite before the blocked step or deficiency of an essential metabolite downstream of the block. Treatments can be directed at reducing the levels of a toxic metabolite or correcting a metabolite deficiency. Many disorders have been treated successfully first in a single patient because we can measure the metabolites and adjust treatment to get them as close as possible to the normal range. Examples are drawn from Komrower's description of treatment of homocystinuria and the author's trials of treatment in bile acid synthesis disorders (3ß-hydroxy-Δ5 -C27 -steroid dehydrogenase deficiency and Δ4 -3-oxosteroid 5ß-reductase deficiency), neurotransmitter amine disorders (aromatic L-amino acid decarboxylase [AADC] and tyrosine hydroxylase deficiencies), and vitamin B6 disorders (pyridox(am)ine phosphate oxidase deficiency and pyridoxine-dependent epilepsy [ALDH7A1 deficiency]). Sometimes follow-up shows there are milder and more severe forms of the disease and even variable clinical manifestations but by measuring the metabolites we can adjust the treatment to get the metabolites into the normal range. Biochemical measurements are not subject to placebo effects and will also show if the disorder is improving spontaneously. The hypothesis that can then be tested for clinical outcome is whether getting metabolite(s) into a target range leads to an improvement in an outcome parameter such as abnormal liver function tests, hypokinesia, epilepsy control etc. The metabolite-guided approach to treatment is an example of personalized medicine and is a better way of determining efficacy for disorders of variable severity than a randomized controlled clinical trial.
Subject(s)
3-Hydroxysteroid Dehydrogenases/deficiency , Bile Acids and Salts/blood , Epilepsy/etiology , Vitamin B 6/metabolism , Administration, Oral , Bile Acids and Salts/biosynthesis , Epilepsy/drug therapy , Epilepsy/metabolism , Humans , Metabolic Diseases/drug therapy , Metabolic Diseases/physiopathology , Pyridoxal Phosphate/therapeutic use , Pyridoxaminephosphate Oxidase/deficiency , Pyridoxine/therapeutic use , Randomized Controlled Trials as Topic , Vitamin B 6 Deficiency/complicationsABSTRACT
A cat was referred because of diffuse parenchymal lung disease. Close examinations revealed a swollen abdominal lymph node and multiple nodules of the liver. Mycobacterium avium subspecies hominissuis infection was confirmed by culture and single nucleotide polymorphism analysis of samples recovered from the liver and bronchoalveolar lavage. After administration of combination antibiotics for 6 months, culture results were negative. Though atonic seizures were observed during the treatment, it disappeared after isoniazid discontinuation and pyridoxal phosphate administration. On day 771 of illness, no clinical signs, lung diseases, or obvious swelling of lymph nodes was observed. This is the first report to confirm Mycobacterium avium subspecies hominissuis infection in cats through gene analysis and to completely cure it with combination antibiotics.
Subject(s)
Cat Diseases/microbiology , Lung Diseases/veterinary , Mycobacterium avium/isolation & purification , Tuberculosis/veterinary , Animals , Anti-Bacterial Agents/therapeutic use , Cats , Drug Therapy, Combination , Isoniazid/adverse effects , Isoniazid/therapeutic use , Liver/microbiology , Lung Diseases/drug therapy , Lung Diseases/microbiology , Male , Mycobacterium avium/genetics , Polymorphism, Single Nucleotide , Pyridoxal Phosphate/therapeutic use , Seizures/chemically induced , Seizures/veterinary , Tuberculosis/drug therapy , Tuberculosis/microbiologyABSTRACT
Vitamin B6 (VB6) deficiency contributes to oncogenesis and tumor progression in certain cancers, and is prevalent in cancer patients in general. VB6 is also an essential element of heme synthesis, and deficiency can lead to anemia. Primary myelofibrosis (PMF) and secondary myelofibrosis (sMF) are myeloproliferative neoplasms often presenting with anemia along with other cytopenias. We performed a prospective study to determine whether PMF and sMF patients suffer from VB6 deficiency, and whether VB6-deficient patients show improvement of anemias with VB6 supplementation. Twelve PMF patients and 11 sMF patients were analyzed. A total of 16 of 23 patients (69.6%) were found to have VB6 deficiency, but VB6 supplementation with pyridoxal phosphate hydrate did not elevate hemoglobin levels in deficient patients. None of the patients presented with vitamin B12, iron, or copper deficiencies. Four patients showed serum folate levels below the lower limit of normal and eight patients showed serum zinc levels below the lower limit of normal; however, these deficiencies were marginal and unlikely to contribute to anemia. Compared to VB6-sufficient patients, VB6-deficient patients showed significantly lower serum folate levels and higher serum copper levels. Studies elucidating the relationship of VB6 deficiency and etiology of PMF/sMF are warranted.
Subject(s)
Primary Myelofibrosis/blood , Vitamin B 6 Deficiency/blood , Adult , Anemia , Copper/blood , Female , Folic Acid/blood , Humans , Male , Middle Aged , Prevalence , Primary Myelofibrosis/etiology , Prospective Studies , Pyridoxal Phosphate/therapeutic use , Vitamin B 6 Deficiency/drug therapyABSTRACT
BACKGROUND: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. METHODS: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24â¯h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (nâ¯=â¯6) or NAC alone (nâ¯=â¯2). Calmangafodipir doses were 2, 5, or 10⯵mol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). FINDINGS: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NACâ¯+â¯calmangafodipir (2⯵mol/kg), 4/6; NACâ¯+â¯calmangafodipir (5 µmol/kg), 2/6; NACâ¯+â¯calmangafodipir (10⯵mol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALTâ¯>â¯100â¯U/L; with NACâ¯+â¯calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20â¯h fold change, NACâ¯+â¯calmangafodipir (5⯵mol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. INTERPRETATION: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.
Subject(s)
Acetaminophen/administration & dosage , Acetaminophen/adverse effects , Acetylcysteine/therapeutic use , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/etiology , Edetic Acid/analogs & derivatives , Protective Agents/therapeutic use , Pyridoxal Phosphate/analogs & derivatives , Adult , Biomarkers , Chemical and Drug Induced Liver Injury/metabolism , Drug Interactions , Drug Overdose , Edetic Acid/therapeutic use , Female , Humans , Male , Pyridoxal Phosphate/therapeutic use , Time Factors , Young AdultABSTRACT
Complementary and alternative treatment modalities are commonly utilized by patients for neuropathy and neuropathic pain due to perceived lack of benefit from conventional medical treatment. As the association between metabolic syndrome and neuropathy is increasingly recognized, diet and lifestyle interventions are becoming important components in the management of neuropathy. Progress in the understanding of the gut-immune interaction highlights the role the gut microbiome and inflammation plays in the modulation of neuropathy and neuropathic pain. Evidence for nutritional interventions, exercise, supplements, acupuncture, and mindfulness-based practices in the treatment of neuropathic pain is encouraging. This article reviews the available evidence to support the safe use of complementary and alternative treatments for commonly encountered conditions associated with neuropathy and neuropathic pain. Muscle Nerve 60: 124-136, 2019.
Subject(s)
Diet Therapy , Dietary Supplements , Exercise Therapy , Life Style , Neuralgia/therapy , Peripheral Nervous System Diseases/therapy , Vitamin B Complex/therapeutic use , Acetylcarnitine/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Curcumin/therapeutic use , Diet , Dysbiosis/metabolism , Exercise , Fatty Acids, Omega-3/therapeutic use , Folic Acid/analogs & derivatives , Folic Acid/therapeutic use , Gastrointestinal Microbiome , Humans , Integrative Medicine , Metabolic Syndrome/metabolism , Neuralgia/metabolism , Peripheral Nervous System Diseases/metabolism , Pyridoxal Phosphate/therapeutic use , Thioctic Acid/therapeutic use , Vitamin B 12/analogs & derivatives , Vitamin B 12/therapeutic use , Vitamin B Complex/metabolism , Vitamin B Deficiency , Vitamin D/therapeutic useABSTRACT
Hypophosphatasia (HPP) is a rare disorder caused by low serum tissue non-specific alkaline phosphatase (ALP) activity due to hypomorphic mutations in the ALPL gene. HPP is characterized by defective bone mineralization. It frequently accompanies pyridoxine-responsive seizures. Because alkaline phosphatase change pyridoxal 5' phosphate (PLP) into pyridoxal (PL), which can cross the blood brain barrier and regulates inhibitory neurotransmitter gamma-aminobutyric acid. The female patient was born at a gestational age of 37â¯weeks 2â¯days. She presented severe respiratory disorder due to extreme thoracic hypoplasia. With the extremely low serum ALP value (14â¯IU/L), she was clinically diagnosed as HPP. The diagnosis was confirmed with genetic testing. On day1, the subclinical seizures were detected by aEEG. Together with enzyme replacement therapy by asfotase alfa, pyridoxine hydrochloride was administered, then the seizures were rapidly controlled. While confirming that there was no seizure by aEEG monitoring, pyridoxine hydrochloride was gradually discontinued after 1â¯month. Before administration of pyridoxine hydrochloride, PL was extremely low (4.7â¯nM) and PLP was increased (1083â¯nM). After the withdrawal, PL was increased to 84.9â¯nM only by enzyme replacement. Monitoring with aEEG enabled early intervention for pyridoxine responsive seizures. Confirming increased serum PL concentration is a prudent step in determining when to reduce or discontinue pyridoxine hydrochloride during enzyme replacement therapy.
Subject(s)
Enzyme Replacement Therapy/methods , Hypophosphatasia/drug therapy , Alkaline Phosphatase/deficiency , Alkaline Phosphatase/genetics , Alkaline Phosphatase/therapeutic use , Electroencephalography , Female , Humans , Hypophosphatasia/physiopathology , Immunoglobulin G/therapeutic use , Infant, Newborn , Pyridoxal Phosphate/therapeutic use , Pyridoxine/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Seizures/drug therapy , Vitamin B 6/analysis , Vitamin B 6/blood , Vitamin B 6/metabolismABSTRACT
Vitamin B6 is present in our diet in many forms, however, only pyridoxal 5'-phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs nonphosphorylated B6 vitamers, which are converted by specific enzymes to the active PLP form. The role of PLP is enabled by its reactive aldehyde group. Pathways reliant on PLP include amino acid and neurotransmitter metabolism, folate and 1-carbon metabolism, protein and polyamine synthesis, carbohydrate and lipid metabolism, mitochondrial function and erythropoiesis. Besides the role of PLP as a cofactor B6 vitamers also play other cellular roles, for example, as antioxidants, modifying expression and action of steroid hormone receptors, affecting immune function, as chaperones and as an antagonist of Adenosine-5'-triphosphate (ATP) at P2 purinoceptors. Because of the vital role of PLP in neurotransmitter metabolism, particularly synthesis of the inhibitory transmitter γ-aminobutyric acid, it is not surprising that various inborn errors leading to PLP deficiency manifest as B6 -responsive epilepsy, usually of early onset. This includes pyridox(am)ine phosphate oxidase deficiency (a disorder affecting PLP synthesis and recycling), disorders affecting PLP import into the brain (hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects), a disorder of an intracellular PLP-binding protein (PLPBP, previously named PROSC) and disorders where metabolites accumulate that inactivate PLP, for example, ALDH7A1 deficiency and hyperprolinaemia type II. Patients with these disorders can show rapid control of seizures in response to either pyridoxine and/or PLP with a lifelong dependency on supraphysiological vitamin B6 supply. The clinical and biochemical features of disorders leading to B6 -responsive seizures and the treatment of these disorders are described in this review.
Subject(s)
Epilepsy/etiology , Vitamin B 6 Deficiency/complications , Vitamin B 6/metabolism , Epilepsy/drug therapy , Epilepsy/metabolism , Humans , Metabolism, Inborn Errors/metabolism , Proline/blood , Pyridoxal Phosphate/therapeutic use , Pyridoxaminephosphate Oxidase/deficiency , Pyridoxine/therapeutic useABSTRACT
Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.
Subject(s)
Epilepsy/etiology , Proteins/genetics , Proteins/metabolism , Animals , Disease Models, Animal , Epilepsy/physiopathology , Female , HEK293 Cells , Humans , Male , Phenotype , Pyridoxal Phosphate/therapeutic use , Pyridoxine/deficiency , Vitamin B 6/metabolism , Vitamin B 6 Deficiency/genetics , Vitamin B 6 Deficiency/metabolism , ZebrafishABSTRACT
Mabry syndrome is the triad of seizures, hyperphosphatasia, and mental disability. It usually manifests in first year of life and has an autosomal recessive mode of inheritance. Besides the usual triad, other manifestations of Mabry syndrome include hypoplasia of distal phalanges, brachytelencepahly, gastrointestinal malformations and constipation, hypertelorism, short nose with a broad nasal bridge and dip, and thin upper lip with down turned corners of the mouth. More than 20 cases of Mabry syndrome have been reported in medical literature. Herein, we report the case of a six-month child with Mabry syndrome that presented with decreased neck holding, hypotonia and delayed motor milestones. The child also had a high-arched palate and hyperplastic malar eminences. Constipation was present but had a delayed onset, starting at 19 months of age. This is the first case of Mabry syndrome occurring in a child of South Asian descent.
Subject(s)
Abnormalities, Multiple/diagnosis , Intellectual Disability/diagnosis , Phosphorus Metabolism Disorders/diagnosis , Seizures/diagnosis , Abnormalities, Multiple/drug therapy , Abnormalities, Multiple/genetics , Brain/diagnostic imaging , Brain/physiopathology , Humans , Infant , Intellectual Disability/drug therapy , Intellectual Disability/genetics , Male , Phosphorus Metabolism Disorders/drug therapy , Phosphorus Metabolism Disorders/genetics , Pyridoxal Phosphate/analogs & derivatives , Pyridoxal Phosphate/therapeutic use , Seizures/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder characterized by rachitic bone manifestations and a low serum alkaline phosphatase (ALP) level. It is caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which encodes the tissue non-specific isozyme of ALP. HPP patients exhibit various presentations depending on their age at onset, such as infantile HPP combined with vitamin B6-responsive seizures. CASE PRESENTATION: A newborn with infantile HPP presented with tonic convulsions from day 5 after birth and received intravenous vitamin B6 (10mg/kg/day pyridoxal phosphate). Eleven days later, frequent apneic episodes occurred, and head magnetic resonance imaging (MRI) showed bilateral reticular formation lesions in the brain stem, including the medulla oblongata. After the pyridoxal phosphate dose was increased (to 40mg/kg/day), the patient's seizures and apnea resolved, and her MRI findings also improved. Genetic testing revealed that she was homozygous for the 1559delT mutation of TNSALP. CONCLUSIONS: High-dose pyridoxal phosphate is a useful treatment for HPP-induced seizures and might improve reticular formation lesions.
Subject(s)
Anticonvulsants/therapeutic use , Hypophosphatasia/drug therapy , Pyridoxal Phosphate/therapeutic use , Reticular Formation/diagnostic imaging , Seizures/drug therapy , Diagnosis, Differential , Female , Humans , Hypophosphatasia/diagnostic imaging , Hypophosphatasia/genetics , Hypophosphatasia/physiopathology , Infant, Newborn , Seizures/diagnostic imaging , Seizures/genetics , Seizures/physiopathologyABSTRACT
PURPOSE: Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC). PATIENT AND METHODS: mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m2, 5-fluorouracil bolus 400 mg/m2, oxaliplatin 85 mg/m2 and 5-fluorouracil 2400 mg/m2 continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale. RESULTS: Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1-8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups. CONCLUSIONS: Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.
Subject(s)
Antineoplastic Agents/adverse effects , Colorectal Neoplasms/drug therapy , Edetic Acid/analogs & derivatives , Organoplatinum Compounds/adverse effects , Peripheral Nervous System Diseases/prevention & control , Pyridoxal Phosphate/analogs & derivatives , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/mortality , Disease-Free Survival , Double-Blind Method , Edetic Acid/therapeutic use , Female , Fluorouracil/adverse effects , Humans , Kaplan-Meier Estimate , Leucovorin/adverse effects , Male , Middle Aged , Oxaliplatin , Peripheral Nervous System Diseases/chemically induced , Pyridoxal Phosphate/therapeutic useSubject(s)
Chlorides , Contrast Media , Edetic Acid/analogs & derivatives , Magnetic Resonance Imaging/methods , Manganese Compounds , Neurodegenerative Diseases/diagnostic imaging , Pyridoxal Phosphate/analogs & derivatives , Animals , Chlorides/administration & dosage , Chlorides/adverse effects , Contrast Media/administration & dosage , Contrast Media/adverse effects , Edetic Acid/administration & dosage , Edetic Acid/therapeutic use , Humans , Manganese Compounds/administration & dosage , Manganese Compounds/adverse effects , Mice, Transgenic , Pyridoxal Phosphate/administration & dosage , Pyridoxal Phosphate/therapeutic useABSTRACT
Mutations in KCNQ2, encoding for subunits of potassium channels, are known to cause neonatal epileptic encephalopathy (NEE). Therapeutic options for these children are often limited. Recently, there are indications that some patients with KCNQ2 NEE show seizure response to vitamin B6 (VB6) therapy. We present a young infant with severe KCNQ2 encephalopathy resulting from a novel de novo mutation (c.1023G>C; p.(Gln341His)). In our patient, VB6 responsiveness could be demonstrated clearly by remarkable seizure-response to VB6 therapy and seizure exacerbation to discontinuation of VB6 therapy. The pathophysiology of VB6 response in potassium channel mutations is not understood. Some hypothetical mechanisms are currently in discussion. To identify the group of patients who benefits from VB6 therapy, further investigations are necessary.