Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene

García-Fontana, Cristina; Villa-Suárez, Juan Miguel; Andújar-Vera, Francisco; González-Salvatierra, Sheila; Martínez-Navajas, Gonzalo; Real, Pedro J.; Vida, José María Gómez; Haro, Tomás de; García-Fontana, Beatriz; Muñóz-Torres, Manuel

doi:10.1038/s41598-019-46004-2

Cited by 29 publications

(35 citation statements)

References 36 publications

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“…By Sanger sequencing approximately 95% of all mutations in ALPL can be detected ( Mornet, 2000 ; Taillandier et al, 2015 ). Compared to previous studies ( García-Fontana et al, 2019 ; Maman et al, 2016 ; Riancho-Zarrabeitia et al, 2016 ; Tornero et al, 2020 ), we also included MPLA for detection of deletions and duplications and found one patient with a large deletion of exon 2, indicating that MLPA should be considered in patients with signs of HPP and normal Sanger sequencing.…”

Section: Discussionmentioning

confidence: 99%

Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark

et al. 2021

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Background Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. Methods A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (≤ 35 ± 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. Results Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported ( n = 9). The variant c. 571G > A; p.(Glu191Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP ( p = 0.059), the bone specific alkaline phosphatase (BALP) ( p = 0.056) and pyridoxal-5′-phosphate (PLP) ( p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls ( p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treated with bisphosphonates and did not show complications due to the treatment. Conclusions Pathogenic variants in ALPL are common among patients with endocrinological diagnoses and low ALP. Regarding diagnostics, genetic testing is necessary to identify mild HPP due to fluctuating biochemical findings. Antiresorptive treatment is a frequent reason for hypophosphatasaemia and effects of these agents in adults with a variant in ALPL and osteoporosis remain unclear and require further studies.

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Section: Discussionmentioning

confidence: 99%

Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark

et al. 2021

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“…Thus, the greater parental concern about short stature in sons versus daughters may be one of the explanations for the higher proportion of males in pediatric HPP patients. It is worth noting that contrary to the pediatric HPP, a higher proportion of females than males was observed in adult HPP [ 14 , 19 – 21 ]. Considering the small number of pediatric HPP patients diagnosed in our country, the sex differences observed in the current study still need to be verified in further studies.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics of hypophosphatasia in Chinese children

Liu

Liang

et al. 2021

Orphanet J Rare Dis

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Background Hypophosphatasia (HPP) is a rare inherited disorder, which is caused by loss-of-function mutations in the ALPL gene. HPP is a heterogeneous disease that has a wide spectrum of phenotypes. Few studies were carried out in the Chinese population with HPP, especially in children. Methods The clinical and genetic characteristics of 10 Chinese children with HPP who were referred to the Beijing Children’s Hospital were described. Previously reported HPP cases of children in China were also reviewed. Results A total of 33 cases were identified, which included 2 perinatal lethal HPP, 10 infantile HPP, 10 childhood HPP, and 11 odonto HPP. The male-to-female ratio was 24:9. The average age at onset was 0.69 years (ranged from 2 h after birth to 14 years), while the average age at clinical diagnosis was 3.87 years (ranged from 2 h after birth to 19 years). Serum alkaline phosphatase (ALP) levels were significantly decreased in patients with perinatal lethal/infantile HPP when compared with those with the mild forms of HPP childhood/odonto HPP (P < 0.01). Although serum phosphate levels were not different (P > 0.05), serum calcium levels were elevated, and serum intact parathyroid hormone levels were decreased in patients with perinatal lethal/infantile HPP in comparison with those with the childhood/odonto HPP (P all < 0.01). Genetic analyses identified 40 mutations in 31 HPP cases, including 28 missense mutations, 9 frameshift mutations, 2 splice junction alterations, and 1 regulatory mutation. Of which, 5 novel mutations were identified in our present study: 2 frameshift mutations (p.Arg138GlyfsTer27, p.Leu511Profs*272); 2 missense mutations (p.Ala176Val, p.Phe268Leu), and 1 splice junction alteration (c.297+5G>A). Compound heterozygous mutations accounted for 80.6% of all variants. No mutational “hot-spot” was found. Most mutations of ALPL were located in exons 5, 7, 10, and 3. Notably, subjects that carrying single heterozygous mutations showed milder phenotypes of HPP, while subjects with nonsense mutations were associated with a severer phenotype. Conclusions HPP is a rare disease with often delayed diagnosis, and the incidence of HPP in China may be seriously underestimated. The present study expands the phenotypic and genotypic spectrum and the understanding of HPP in Chinese children. These findings will be useful for clinical assessment and shorten the diagnosis time for pediatric HPP in China.

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“…Thus, the greater parental concern about short stature in sons versus daughters may be one of the explanations for the higher proportion of males in pediatric HPP patients. It is worth noting that contrary to the pediatric HPP, a higher proportion of females than males was observed in adults diagnosed with HPP [13,[18][19][20]. Considering the small number of pediatric HPP patients diagnosed in our country, the sex differences observed in the current study still need to be veri ed in further studies.…”

Section: Discussionmentioning

confidence: 67%

Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Children

Liu

Liang

et al. 2020

Preprint

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Background: Hypophosphatasia (HPP) is a rare inherited disorder, which is caused by loss-of-function mutations in the ALPL gene. HPP is a heterogeneous disease that has a wide spectrum of phenotypes. Few studies were carried out in the Chinese population with HPP, especially in children. Methods: The clinical and genetic characteristics of 10 Chinese children with HPP who were referred to the Beijing Children’s Hospital were described. We also reviewed previously reported HPP cases of children in China.Results: A total of 33 cases were identified, which included 2 perinatal lethal, 10 infantile, 10 childhood, and 11 odonto types of HPP. The male to female ratio was 24:9. The average age at onset was 0.69 years (ranged from 2 hours after birth to 14 years), while the average age at clinical diagnosis was 3.87 years (ranged from 2 hours after birth to 19 years). Serum alkaline phosphatase (ALP) levels were significantly decreased in patients with severe forms of HPP (perinatal lethal/infantile HPP) when compared with those with the mild forms of HPP (childhood/odonto HPP, P<0.01). Although serum phosphate levels were not significantly different (P>0.05), serum calcium levels were elevated, and serum intact parathyroid hormone (i-PTH) levels were decreased in patients with severe forms of HPP in comparison with those with the mild forms of HPP (P all <0.01). Genetic analyses identified 40 mutations in 31 HPP cases, including 28 missense mutations, 9 frameshift mutations, 2 splice junction alterations, and 1 regulatory mutation. Of which, 5 novel mutations were identified in our present study: 2 frameshift mutation (p.Arg138GlyfsTer27, p.Leu511Profs*272); 2 missense mutations (p.Ala176Val, p.Phe268Leu), and 1 splice junction alterations (c.297+5G>A). Compound heterozygous mutations accounted for 89.29% of all variants. No mutational “hot-spot” was found. Most mutations of ALPL were located in exons 5, 7, 10 and 3. Notably, subjects that carrying single heterozygous mutations showed milder phenotypes of HPP, while subjects with nonsense mutations were associated with a severe phenotype.Conclusions: HPP is a rare disease with often delayed diagnosis, and the incidence of HPP in China may be seriously underestimated. The present study expands the phenotypic and genotypic spectrum and our understanding of HPP in Chinese children.These findings will be useful for clinical assessment and shorten the diagnostics of pediatric HPP in China.

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Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene

Cited by 29 publications

References 36 publications

Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark

Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark

Clinical and genetic characteristics of hypophosphatasia in Chinese children

Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Children

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