Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Peripheral neuropathy attributed to elevated B6 as the first presentation of adult onset hypophosphatasia: highly uncommon or highly unrecognised? (#396)

Bella Halim 1 2 , Michael Thompson 1 2
  1. Department of Endocrinology, Royal Hobart Hospital , Hobart, TAS , Australia
  2. Menzies Institute of Medical Research, University of Tasmania, Hobart, TAS, Australia

Case presentation:

A 42-year-old female presented with a seven-year history of acral paraesthesia and neuropathic pain. Past medical and medication history was unremarkable.  Neurological examination suggested a small fibre neuropathy. Investigations revealed vitamin B6 level (PLP) of 770 nmol/L, alkaline phosphatase (ALP) level of 17 U/L and urine phosphoethanolamine(PEA) of 18 μmol/mmol (Table 1).She was diagnosed with vitamin B6-induced neuropathy from hypophosphatasia (HPP).

There was no history of musculoskeletal or dental issues. Other investigations for low ALP were unremarkable (Table 1).X-rays showed no fracture or pseudofracture (Figure 1).Bone mineral density demonstrated osteopenia (Figure 2).C-telopeptide and P1NP were 120 ng/L and 19 μg/L respectively (Table 1).Genetic testing revealed a missense variant on her ALPL gene (c.931G>A,p.(Glu311Lys)).

Discussion:

HPP is an inborn error of metabolism due to tissue non-specific ALP (TNSALP) deficiency caused by loss-of-function mutation(s) in ALPL gene. TNSALP hydrolyses inorganic pyrophosphate to inorganic phosphate, that binds with Ca2+ to form hydroxyapatite crystals (1).Inorganic pyrophosphate interferes with hydroxyapatite formation causing skeletal fragility. TNSALP also dephosphorylates PLP, the principal circulating B6 vitamer, to pyridoxal, the intracellular B6 vitamer (1).Historically treatment was supportive.  Recently administration of recombinant human TNSALP has demonstrated disease modifying activity with substantial improvements in musculoskeletal outcomes(1).

Our case demonstrates a mild skeletal phenotype with severe neurological phenotype with elevated PLP as the sole explanation. Although neurological features have been reported (2),vitamin B6-induced neuropathy has not been described despite elevated PLP. As the mechanism of vitamin B6-induced neuropathy is unclear (3),this suggests either the excessive PLP in HPP is not toxic or vitamin B6-induced neuropathy is underrecognized in HPP. This case highlights potential association between HPP and B6-induced neuropathy possibly mediated by excess extracellular B6 vitamers. Further assessments are required to determine the prevalence of neuropathy in HPP cohorts and provide insights into the mechanism of vitamin B6-induced neuropathy.

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  1. Whyte MP. Hypophosphatasia—aetiology, nosology, pathogenesis, diagnosis and treatment. Nature Reviews Endocrinology. 2016;12(4):233-246.
  2. Colazo J, Hu J, Dahir K, Simmons J. Neurological symptoms in hypophosphatasia. Osteoporosis International. 2019;30:469-480.
  3. Hadtstein F, Vrolijk M. Vitamin B-6-induced neuropathy: exploring the mechanisms of pyridoxine toxicity. Advances in Nutrition. 2021;12(5):1911-1929.