Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management

Huggins, Erin; Ong, Ricardo C.; Rockman‐Greenberg, Cheryl; Flueckinger, Lauren B.; Dahir, Kathryn; Kishnani, Priya S.

doi:10.1016/j.ymgmr.2020.100661

Cited by 12 publications

(9 citation statements)

References 30 publications

(17 reference statements)

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“…Irrespective of the age of onset, the variable clinical presentation of HPP in adults often leads to misdiagnosis, substantial delays in diagnosis, delays in treatment and multidisciplinary supportive care (e.g., genetic counseling, physical therapy, pain management, occupational therapy, and dental care), or exposure to potential harmful treatment, such as bisphosphonates [ 8 – 10 ]. To better inform disease management, this study aimed to understand the clinical profiles of adults with HPP.…”

Section: Introductionmentioning

confidence: 99%

Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry

Dahir

Seefried

Kishnani

et al. 2022

Orphanet J Rare Dis

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Background The clinical signs and symptoms of hypophosphatasia (HPP) can manifest during any stage of life. The age at which a patient’s symptoms are reported can impact access to targeted treatment with enzyme replacement therapy (asfotase alfa), as this treatment is indicated for patients with pediatric-onset HPP in most countries. As such, many patients reported to have adult-onset HPP typically do not receive treatment. Comparison of the disease in treated and untreated adult patients is confounded by the approved indication. To avoid this confounding factor, a comparison between baseline disease manifestations prominent among treated versus untreated adult patients was limited to those with pediatric-onset HPP using data collected from the Global HPP Registry. The hypothesis was that treated adults will have a greater disease burden at baseline than untreated adults. The analysis of disease manifestations in adults with adult-onset HPP was conducted separately. Results A total of 398 adults with HPP were included; 213 with pediatric-onset (114 treated, 99 untreated) and 141 with adult-onset HPP (2 treated and 139 untreated). The treated, pediatric-onset patients were more likely to have a history of pain (prevalence ratio [PR]: 1.3, 95% confidence interval [CI] 1.1, 1.4), skeletal (PR: 1.3, 95% CI 1.1, 1.6), constitutional/metabolic (PR: 1.7, 95% CI 1.3, 2.0), muscular (PR: 1.8, 95% CI 1.4, 2.1) and neurological (PR: 1.7, 95% CI 1.1, 2.3) manifestations of HPP, and also had poorer measures for health-related quality of life, pain, and disability compared with untreated pediatric-onset patients. In patients with adult-onset HPP, the most frequent signs and symptoms were chronic bone pain (52.5%), dental manifestations (42.6%), fatigue (23.4%), recurrent fractures or pseudofractures (22.0%), and generalized body pain (22.0%). Conclusions Along with the more classical skeletal signs and symptoms, pain, muscular, and constitutional/metabolic manifestations are common in adults with HPP, regardless of age of disease onset, highlighting a full spectrum of HPP manifestations.

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Section: Introductionmentioning

confidence: 99%

Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry

Dahir

Seefried

Kishnani

et al. 2022

Orphanet J Rare Dis

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“…Most importantly, information must be given during pregnancy focusing on the genotyping of prenatal HPP cases in an attempt to differentiate between lethal and benign HPP cases and also to detect cases who will benefit from prompt enzyme replacement therapy during the perinatal period [ 113 ].…”

Section: Managementmentioning

confidence: 99%

Hypophosphatasia

Tournis

Yavropoulou

Polyzos

et al. 2021

JCM

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Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5΄-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

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“…One example was reported in a family with two affected daughters with the same ALPL mutation, where one girl developed a severe and the other a mild HPP onset [22]. These variable genotype-phenotype correlations pose difficulties for genetic counseling and an optimized disease management in HPP [25]. The majority of reported mutations in the human ALPL gene are missense mutations that are resulting in amino acid changes (https://www.ncbi.nlm.nih.gov/clinvar/?term=alpl%5Bgene%5D, accessed on 11 December 2020).…”

Section: Structure Function and Substrates Of Tnapmentioning

confidence: 99%

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

Graser

Liedtke

Jakob

2021

IJMS

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This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.

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Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management

Cited by 12 publications

References 30 publications

Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry

Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry

Hypophosphatasia

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

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