Eveline Lefever1, Peter Witters2, Evelien Gielen3, Annick Vanclooster4, Wouter Meersseman4, Eva Morava5, David Cassiman6, Michaël R Laurent7. 1. Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium. 2. Centre for Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium. 3. Center for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium. 4. Centre for Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium. 5. Centre for Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium; Hayward Genetics Center, Tulane University Medical School, New Orleans, LA, USA; Clinical Genomics Department, Mayo Clinic, Rochester, MN, USA. 6. Centre for Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium. 7. Center for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium. Electronic address: michael.laurent@uzleuven.be.
Abstract
BACKGROUND: Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium. METHODOLOGY: Adults with HPP were identified through medical record review. Inclusion criteria were: (1) age ≥ 16 yr; (2) consecutively low ALP levels not explained by secondary causes; (3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation. RESULTS: Nineteen patients met our inclusion criteria (n = 2 infantile, n = 6 childhood, n = 10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n = 7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N = 7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p = 0.013) and significantly higher pyridoxal-5'-phosphate (p = 0.0018) and urinary phosphoethanolamine (p = 0.0001) concentrations. CONCLUSIONS: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.
BACKGROUND:Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium. METHODOLOGY: Adults with HPP were identified through medical record review. Inclusion criteria were: (1) age ≥ 16 yr; (2) consecutively low ALP levels not explained by secondary causes; (3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation. RESULTS: Nineteen patients met our inclusion criteria (n = 2 infantile, n = 6 childhood, n = 10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n = 7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N = 7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p = 0.013) and significantly higher pyridoxal-5'-phosphate (p = 0.0018) and urinary phosphoethanolamine (p = 0.0001) concentrations. CONCLUSIONS: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.
Authors: Wei Zhou; Jeroen G J van Rooij; Peter R Ebeling; Annemieke J M H Verkerk; M Carola Zillikens Journal: Curr Osteoporos Rep Date: 2021-02-15 Impact factor: 5.096
Authors: Juan Miguel Villa-Suárez; Cristina García-Fontana; Francisco Andújar-Vera; Sheila González-Salvatierra; Tomás de Haro-Muñoz; Victoria Contreras-Bolívar; Beatriz García-Fontana; Manuel Muñoz-Torres Journal: Int J Mol Sci Date: 2021-04-21 Impact factor: 5.923
Authors: Nico Maximilian Jandl; Tobias Schmidt; Tim Rolvien; Julian Stürznickel; Konstantin Chrysostomou; Emil von Vopelius; Alexander E Volk; Thorsten Schinke; Christian Kubisch; Michael Amling; Florian Barvencik Journal: Calcif Tissue Int Date: 2020-11-15 Impact factor: 4.333