Pyridoxal 5′-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy

Akiyama, Tomoyuki; Kubota, Takuo; Ozono, Keiichi; Michigami, Toshimi; Kobayashi, Daisuke; Takeyari, Shinji; Sugiyama, Yasuo; Noda, Masahiro; Harada, Daisuke; Namba, Noriyuki; Suzuki, Atsushi; Utoyama, Maiko; Kitanaka, Susumu; Uematsu, Mitsugu; Mitani, Yusuke; Matsunami, Kunihiro; Takishima, Shigeru; Ogawa, Erika; Kobayashi, Katsuhiro

doi:10.1016/j.ymgme.2018.07.006

Cited by 19 publications

(16 citation statements)

References 15 publications

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“…A low ALP activity leads to elevated levels of the tissue non-specific alkaline phosphatase (TNSALP) substrates PPi (inorganic pyrophosphate), PLP (pyridoxal 5'-phosphate), and PEA (phosphoethanolamine), which are generally high in HPP patients and used in the next step of the diagnostic procedure (3). Serum PLP is a specific marker for HPP (9) and also indicates the effects of enzyme replacement therapy for HPP, as an elevated PLP means that all TNSALP isoforms are deficient (13). The serum PLP level of the patient after asfotase alfa therapy was 87.8 nmol/L (normal range: 20.5-151 U/L).…”

Section: Discussionmentioning

confidence: 99%

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels

et al. 2020

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A 40-year-old Japanese woman presented to our hospital with general fatigue and muscle weakness. She had a history of premature loss of deciduous teeth at 4 years old, her serum alkaline phosphatase (ALP) activity was as low as 91 U/L, and radiologic studies revealed thoracic deformity and sacroiliac calcification. Genetic sequencing revealed a heterozygous c.1559delT mutation in the tissue non-specific alkaline phosphatase gene (ALPL). Based on these findings, she was diagnosed with hypophosphatasia (HPP), and treatment with asfotase alfa, a recombinant human tissue-nonspecific alkaline phosphatase (TNSALP), was initiated. After six months of treatment with asfotase alfa, improvements were observed in the SF-36 score, sixminute walk distance, and grasping power. Although the overdiagnosis needs to be avoided, HPP should be considered in patients with undiagnosed musculoskeletal symptoms and a low serum ALP activity.

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Section: Discussionmentioning

confidence: 99%

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels

et al. 2020

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“…Urinary phosphoethanolamine is elevated. Plasma PLP and PLP/pyridoxal ratio are elevated (even prior to pyridoxine supplementation) . There may be biochemical evidence of intracellular PLP deficiency, for example, increased excretion of vanillactate …”

Section: Congenital Hypophosphatasia Due To Alpl Mutationsmentioning

confidence: 99%

“…Recently enzyme replacement therapy (ERT) that treats the bone disease has become available . ERT reduces the plasma PLP concentration to a normal or mildly elevated level and the PLP‐to‐PL ratio to mildly reduced or low‐normal levels …”

Section: Congenital Hypophosphatasia Due To Alpl Mutationsmentioning

confidence: 99%

“…Plasma PLP and PLP/pyridoxal ratio are elevated (even prior to pyridoxine supplementation). 102 There may be biochemical evidence of intracellular PLP deficiency, for example, increased excretion of vanillactate. 101 In some neonates with CHP, seizures are antiepileptic drug-resistant and respond dramatically to pyridoxine.…”

Section: Deficiency Of Aldh7a1mentioning

confidence: 99%

“…105 ERT reduces the plasma PLP concentration to a normal or mildly elevated level and the PLP-to-PL ratio to mildly reduced or low-normal levels. 102 There are several reports of subacute brainstem degeneration in patients with CHP both on and off pyridoxine treatment. One hypothesis is that this is due to toxicity of very high extracellular PLP levels.…”

Section: Deficiency Of Aldh7a1mentioning

confidence: 99%

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Disorders affecting vitamin B₆ metabolism

Wilson¹,

Plecko²,

Mills³

et al. 2019

J of Inher Metab Disea

169

186

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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.

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LC‐MS/MS method for the differential diagnosis of treatable early onset inherited metabolic epilepsies

Mathis

Beese

Rüegg

et al. 2020

J of Inher Metab Disea

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Rapid diagnosis and early specific treatment of metabolic epilepsies due to inborn errors of metabolism (IEMs) is crucial to avoid irreversible sequalae. Nowadays, besides the profile analysis of amino‐ and organic acids, a range of additional targeted assays is used for the selective screening of those diseases. This strategy can lead to long turn‐around times, repeated sampling and diagnostic delays. To replace those individual targeted assays, we developed a new liquid chromatography mass spectrometry method (LC‐MS/MS) for the differential diagnosis of inherited metabolic epilepsies that are potentially treatable. The method was developed to simultaneously quantify 12 metabolites (sulfocysteine, guanidinoacetate, creatine, pipecolic acid, Δ1‐piperideine‐6‐carboxylate (P6C), proline, Δ1‐pyrroline‐5‐carboxylate (P5C), and the B6‐vitamers) enabling the diagnosis of nine different treatable IEMs presenting primarily with early‐onset epilepsy. Plasma and urine samples were mixed with internal standards, precipitated and the supernatants were analyzed by LC‐MS/MS. In comparison with previous assays, no derivatization of the metabolites is necessary for analysis. This LC‐MS method was validated for quantitative results for all metabolites except P6C and P5C for which semiquantitative results were obtained due to the absence of commercially available standards. Coefficients of variation for all analytes were below 15% and recovery rates range between 80% and 120%. Analysis of patient samples with known IEMs demonstrated the diagnostic value of the method. The presented assay covers a selected panel of biochemical markers, improves the efficiency in the laboratory, and potentially leads to faster diagnoses and earlier treatment avoiding irreversible damage in patients affected with IEMs.

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Pyridoxal 5′-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy

Abstract: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.

Cited by 19 publications

References 15 publications

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels

Disorders affecting vitamin B₆ metabolism

LC‐MS/MS method for the differential diagnosis of treatable early onset inherited metabolic epilepsies

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Pyridoxal 5′-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy

Abstract: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.

Cited by 19 publications

References 15 publications

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels

Disorders affecting vitamin B6 metabolism

LC‐MS/MS method for the differential diagnosis of treatable early onset inherited metabolic epilepsies

Contact Info

Product

Resources

About

Disorders affecting vitamin B₆ metabolism