Hypophosphatasia and neuropathic pain: related to vitamin B6 metabolism?

Hypophosphatasia (HPP) is caused by pathogenic variant(s) of the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Diminished enzyme activity results in elevated serum concentrations of pyridoxal 5'-phosphate (PLP), the main circulating form of vitamin B6. Neuropathy has been associated with HPP, but the prevalence, pathogenesis, and symptoms remain inadequately understood. Here, we describe 5 adult HPP patients with symptoms suggestive of neuropathic pain, and speculate about potential mechanisms, related to the vitamin B6 metabolism. They reported burning pain sensations, primarily in their lower extremities. One patient was diagnosed with nociceptive pain, but he also experienced numbness and tingling sensations in his hands and feet. All patients exhibited reduced serum ALP levels along with elevated levels of serum vitamin B6 and urine phosphoethanolamine, aligning with the diagnosis of HPP. Regarding treatment, one patient received asfotase alfa which had a remarkable effect with her pain significantly decreasing already within 3 wk of starting the therapy. Another patient received nortriptyline and participated in a rehabilitation program, leading to a reduction in pain within 10 mo. Gabapentin appeared to reduce the pain in one patient, although her symptoms did not fully disappear. Mechanistically, TNSALP is essential for the transformation of PLP, the active form of vitamin B6, into pyridoxal, which is required for crossing the cell membrane and the blood-brain barrier. The deficient catalytic activity of TNSALP could lead to PLP excess extracellularly or deficiency intracellularly. Lack of PLP in the brain may result in changes to metabolites, such as adenosine, which is involved in myelin synthesis. We hypothesize that neuropathic pain could be caused by defective myelination. Alternatively, several cases of polyneuropathy linked to vitamin B6 supplementation have been reported, with a mechanism that may resemble the excess of PLP extracellularly, although the exact mechanism remains unclear.