Rare coding variants in <i>ALPL</i> are associated with low serum alkaline phosphatase and low bone mineral density

Nielson, Carrie M.; Zmuda, Joseph M.; Carlos, Amy S.; Wagoner, Wendy; Larson, Emily A.; Orwoll, Eric; Klein, Robert F.

doi:10.1002/jbmr.527

Cited by 36 publications

(38 citation statements)

References 57 publications

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“…In France, in 2011, Mornet and colleagues (33) estimated from DNA specimens referred to their laboratory for TNSALP mutation analysis that the prevalence of severe HPP is $1/300,000. (34) with low serum ALP activity, higher blood phosphate levels, and low BMD. The authors concluded ''it is intriguing to consider the possibility that a mild genetic form of HPP.…”

Section: Discussionmentioning

confidence: 99%

“Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia

Sutton

Mumm

Coburn

et al. 2012

Journal of Bone and Mineral Research

156

126

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We report a 55-year-old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for ''osteoporosis.'' Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began. Bisphosphonate (BP) administration was stopped following the ASFFs, and the adult form of hypophosphatasia (HPP) was diagnosed from low serum alkaline phosphatase (ALP) activity, high endogenous levels of two natural substrates for the ''tissue-nonspecific'' isoenzyme of ALP (TNSALP), and a heterozygous mutation within the gene that encodes this enzyme. Experience with other HPP families showed that her mutation (Arg71His) with a second defective TNSALP allele can cause severe HPP in infancy, and when heterozygous can cause mild HPP featuring premature loss of deciduous teeth in children. Because the skeletal disease of HPP results from extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, perhaps HPP patients or carriers will have adverse effects from BPs. BPs are analogues of PPi and can suppress bone turnover but also deactivate TNSALP. Our report is the first of BP exposure preceding ASFFs in adult HPP. To explore a potential role for TNSALP deactivation in ASFFs, mutation analysis of TNSALP should be studied in a cohort of these patients. Meanwhile, clinicians must suspect HPP when clinical or laboratory clues include premature loss of primary dentition, pseudofractures or recurrent poorly healing metatarsal stress fractures, a family history suggestive of HPP, or low serum ALP activity. If HPP is documented, BP treatment might be avoided. To establish the diagnosis of HPP, assays for two natural substrates for TNSALP and TNSALP mutation analysis are available in commercial laboratories. With positive findings, radiological or bone biopsy evidence of acquired osteomalacia would indicate the adult form of this inborn-error-of-metabolism. ß

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Section: Discussionmentioning

confidence: 99%

“Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia

Sutton

Mumm

Coburn

et al. 2012

Journal of Bone and Mineral Research

156

126

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“…Moreover, the MrOS study led to the identification of some rare, non-synonymous ALPL gene mutations associated with low serum ALP activity and low BMD in elderly males [31]. Future investigations might identify some TNSALP polymorphisms as determinants of BMD variability and as predisposing genetic factors for low bone mass and osteoporosis.…”

Section: Geneticsmentioning

confidence: 98%

Hypophosphatasia: an overview of the disease and its treatment

Bianchi

2015

Osteoporos Int

100

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This review presents the current knowledge on hypophosphatasia, a rare genetic disease of very variable severity (from lethal to mild) and clinical presentation, caused by defective production of tissue-non-specific alkaline phosphatase (TNSALP). Hypophosphatasia can affect babies in utero as well as infants, children, and adults. The article first presents the genetics of TNSALP and its many known mutations underlying the disease. Then, it presents the epidemiology, classification, and clinical presentation of the six different forms of the disease (perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia) as well as the essential diagnostic clues. The last section on treatment presents a survey of the therapeutic approaches, up to the ongoing phase 2 studies of enzyme replacement therapy.

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“…ALPL gene mutations associated with low ALP and low BMD have been described in elderly men [17]. This raises the possibility of TNSALP polymorphisms not associated with HPP diseases, but being predisposing factors for low bone mass and may be osteoporosis.…”

Section: Diagnosis Of Hypophosphatasia In Adultsmentioning

confidence: 97%