Background/Purpose:

Different from infantile forms, adult forms of hypophosphatasia have less severe manifestations and may go unrecognized. Low serum levels of alkaline phosphatase (ALP), the enzyme encoded by the ALPL gene, are a hallmark of hypophosphatasia. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. 

Methods:

In order to clarify this issue, we performed a clinical and biochemical study of subjects with reduced serum ALP activity. The screening of the coding sequences and intron/exon boundaries of ALPL gene was performed by direct sequencing using the BrightDye Terminator cycle kit.    

Results:

Forty two adult individuals with unexplained persistently low serum ALP were studied. There was a 3:1 female:male ratio. Age range was 20-77 yr.  Although many subjects experienced minor complains, such as mild musculoskeletal pain (60%), none had major health problems. ALPL mutations were found in 21 out of 42 subjects (50%). Twenty patients carried heterozygous mutations; whereas 1 had a homozygous mutation. Eight mutations were novel and had not been previously described. Eighteen of the 21 patients with mutations (86%) had a missense mutation; in 1 case the mutation caused a splice change and there were 2 frameshift mutations. Most mutations were located in exons 5 and 6 (12 aminoacid positions were mutated in 17 patients) and were predicted to have a damaging effect on the protein activity, both according to the structure-based Polyphen webtool (13 mutations) and the evolutionary criteria proposed by Silvent (14 mutations). The presence of a mutated allele was associated with premature tooth loss (48% versus 12%; p=0.04), slightly lower levels of serum AP (30±6 vs 25±6 u/l; p=0.002) and higher levels of enzyme substrates, such as serum pyridoxal phosphate (p<0.0001) and urine phosphoetanolamine (p<0.0001), as well as mildly increased serum phosphate (p=0.03). Ten patients had pyridoxal phosphate levels above the normal range, a test frequently used when hypophosphatasia is suspected. All carried a gene mutation; predicted to be deleterious in 9 cases and of doubtful significance in one.  

Conclusion: One  half of adults with persistently low levels of total alkaline phosphatase had a mutated allele of the ALPL gene. Although clinical manifestations are usually mild, in about 50% of them enzyme activity is low enough to cause substrate accumulation and may predispose to disorders of the teeth and other calcified tissues.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-clinical-and-genetic-spectrum-of-low-alkaline-phosphatase-in-adults/