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Hypophosphatasia (HPP) is a rare disease caused by a loss-of-function mutation in the ALPL gene leading to a deficiency in the tissue-non-specific isoenzyme alkaline phosphatase (ALP) and excess of extracellular inorganic pyrophosphate (PPi) and pyridoxal 5’phosphate (PLP). Patients with HPP have a widely variable clinical phenotype, from neonatal seizures and hypomineralization to isolated dental or joint disease in adults. Patients present with ALP activity levels below their age-adjusted reference interval and elevations in PLP. This variable clinical phenotype leads to significant diagnostic challenges, particularly in those with minor disease manifestations. Biomarkers for diagnosing HPP and monitoring patients on enzyme replacement therapy (ERT) are limited. Low ALP activity is not specific for HPP; it can be low in other conditions including untreated hypothyroidism, and other skeletal dysplasias. Accurate PLP assessment is limited in patients on ERT due to hydrolysis of the substrate. Phosphoethanolamine (PEA) is a substrate hydrolyzed by TNSALP and elevated levels of PEA may be observed in HPP, supporting the diagnosis of HPP, but have been reported to be non-specific. We hypothesized that urine PEA levels could be used to diagnose HPP and as a surrogate marker for ERT compliance. We performed a retrospective analysis on 83 adult patients (63F: 20M) presenting for investigation or follow-up of HPP from 7/1/2014 to 1/7/2020. Urine was sent to the Children’s Hospital in Colorado for PEA testing. Patients were diagnosed with HPP if they had ALP levels persistently below the age-adjusted reference interval, were positive for an ALPL gene mutation/had a family history of HPP and had musculoskeletal/dental symptoms consistent with the disease. Patients were negative for HPP if ALP was not persistently low, vitamin B6 levels were normal without supplementation, negative ALPL genetic testing results (when available) and no musculoskeletal/dental symptoms. PEA levels were not considered for diagnosis. The following was collected from the EMR: PEA results, diagnosis, and ERT status. PEA levels were higher in patients with HPP not on ERT (median=117.0, N=39) vs. those negative for HPP (median=24.0, N=15, p53.5 ng/ml (sensitivity=79.5%) with an NPV of 65.2% and PPV of 100%. Initial PEA values in patients with HPP and not on ERT were higher (median 117.0, N=39) than patients on ERT (median 65.0, N=16, p=0.004). Patients who began ERT had a decline in PEA levels after treatment (mean decrease 68.1%). PEA is a specific diagnostic marker for HPP in patients undergoing investigation for HPP and may be used as a surrogate marker to monitor ERT compliance. Future studies are necessary to evaluate the association between PEA levels and functional performance.

Introduction: Hypophosphatasia (HPP) is an inborn error of metabolism due to deficiency of tissue non-specific alkaline phosphatase (TNSALP), characterized by a wide range of skeletal and neurological symptoms. Little is known about the mechanism of neurologic involvement, but it may result from inefficient hydrolysis of vitamin B6 (pyridoxal 5’-phosphate, PLP), which is involved in neurotransmitter synthesis and is markedly elevated in HPP. However, it remains unknown what PLP levels are in the cerebrospinal fluid (CSF) of patients with HPP. We report two cases: (1) one with pre- and post-treatment CSF PLP levels and (2) one with pre-treatment CSF PLP and neurotransmitter levels. Case 1: A 30-year-old woman with extensive fracture history presented with seizure-like activity. Laboratory evaluation while on no B6 supplementation was notable for low ALP (14 U/L, ref: 40-150), high plasma PLP (362 mcg/L, ref: 5-50), and high CSF PLP (16 mcg/L), with a low CSF/plasma PLP ratio (0.04, ref: 0.1-0.7[1]). Genetic testing showed a pathogenic variant of TNSALP (Het c.1133A>T, p.Asp378Val, rs 121918008). After initiation of enzyme replacement therapy (ERT), her plasma and CSF PLP levels normalized to 6.3 and 1.4 mcg/L, respectively, with a ratio of 0.23. She reported improvement in energy level and seizure-like activity after several months of ERT. Case 2: A 34-year-old man with no history of skeletal pathology presented with diffuse musculoskeletal pain, weakness, and loss of sensory function attributed to generalized peripheral neuropathy. Laboratory evaluation while on no B6 supplementation was notable for low ALP (23 U/L), high plasma PLP (496 mcg/L), and high CSF PLP (17 mcg/L) with a low CSF/plasma ratio (0.03). CSF neurotransmitter levels were also low, including 5-hydroxyindoleacetic acid (40 nmol/L, ref: 67-140) and homovanillic acid (115 nmol/L, ref: 145-324). Genetic testing showed heterozygous expression of a catastrophic frameshift mutation of TNSALP (c.662del, p.Gly221Valfs*56). ERT is being considered at this time. Conclusions: We report the novel findings that in these patients with HPP: 1. CSF PLP levels are markedly elevated, though to a much lesser extent than plasma levels. Elevated CSF/plasma ratios suggest that transport of PLP and its metabolites across the blood brain barrier may be impaired in HPP. 2. Decreased CSF neurotransmitter levels, as seen in our patient, may contribute to neurologic symptoms of HPP. 3. Enzyme replacement therapy normalized both CSF and plasma PLP in case 1. Further studies are needed to understand how these changes affect patient symptoms and prognosis. Citation: 1. Albersen, M., et al., Vitamin B-6 vitamers in human plasma and cerebrospinal fluid. Am J Clin Nutr, 2014. 100(2): p. 587-92