Biochemical phenotype of hypophosphatasia in asymptomatic individuals carrying ALPL variants

Hypophosphatasia (HPP) is the rare metabolic disorder caused by variants in the ALPL gene, resulting in deficient activity of tissue-nonspecific alkaline phosphatase (ALP). This leads to accumulation of substrates contributing to impaired bone mineralization. Hypophosphatasia manifests with a broad clinical spectrum; however, an increasing number of individuals with ALPL variants have been identified presenting the hallmark biochemical feature of HPP of low serum ALP activity, with or without elevated serum pyridoxal-5-phosphate (PLP) or urine phosphoethanolamine (PEA), while remaining asymptomatic. These ALPL carriers may represent a distinct subgroup within the HPP continuum, prompting the need for clearer classification. Using data from the Global ALPL Gene Variant Database, we identified 43 subjects who fulfilled the following criteria: low ALP (adjusted for age/sex), at least one ALPL variant, and no overt or reported HPP-related symptoms. Their median age was 29 yr (range 0-64); 23 were female. Serum ALP activity was reduced in all cases, with 76% of subjects showing levels less than 50% below the lower limit of normal. In 19 of 43 individuals, PLP or PEA was also elevated. Thirty distinct genotypes were observed; 79% of subjects were heterozygous, while 21% harbored homozygous or compound heterozygous variants. The identified variants were largely missense (77%), mostly affecting regions without a specific domain (38%). Five variants showed a dominant-negative effect in vitro, yet produced no clinical manifestations. Some identified genotypes were also linked to adult, childhood, or odontohypophosphatasia phenotypes, underscoring significant genotype-phenotype variability. These findings refine our understanding of the HPP spectrum, identifying a cohort of asymptomatic ALPL carriers with biochemical phenotype of HPP. Recognizing this group is important for improving diagnostic criteria and preventing overdiagnosis and unnecessary treatment. Longitudinal studies are needed to clarify follow-up strategies and determine whether these individuals develop clinical manifestations later in life or remain asymptomatic.

Duke Scholars

Author Priya Sunil Kishnani Pediatrics, Medical Genetics