Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients

Michigami, Toshimi; Tachikawa, Kanako; Yamazaki, Miwa; Kawai, Masanobu; Kubota, Takuo; Ozono, Keiichi

doi:10.1007/s00223-019-00626-w

Cited by 27 publications

(27 citation statements)

References 33 publications

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“…Adult HPP was diagnosed, if ALP or BAP activity was repeatedly below the reference range or around the lower limit value together with elevated PLP, bone complications and at least one further complication concerning teeth, muscle, central nervous and mental system supported by at least one rare ALPL variant (ACMG class 4 or higher) the clinical findings thus support the presence of adult HPP. A similar frameshift mutation c.1559delT has been described for patients with different HPP forms [37], whereas the perinatal severe form was only observed in homozygous c.1559delT patients. The complete absence of TNSALP expression on the cell surface was accounted for perinatal HPP [38].…”

Section: Discussionsupporting

confidence: 62%

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

et al. 2020

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Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

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Section: Discussionsupporting

confidence: 62%

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

et al. 2020

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“…Our study included only two patients with perinatal lethal HPP, and no patient was documented as perinatal benign HPP, which indicated the low rate of perinatal HPP in China. In contrast to our results, Michigami et al analyzed 98 unrelated Japanese HPP patients found that perinatal lethal was the most frequent form of HPP in Japan, followed by the perinatal benign form [9]. Diagnostic delay is common among patients with HPP [13].…”

Section: Discussioncontrasting

confidence: 99%

“…It is worth noting that our study found obvious differences in the spectrum of ALPL mutations between Chinese individuals and other countries. For example, p.Leu520ArgfsX86 and p.Asp378Val were the most common mutations in Japan [9] and the USA [16], respectively, while no report has been found in the Chinese HPP patients. p.Glu191Lys was known to occur with a high frequency (up to 55%) in HPP patients with European ancestry [27].…”

Section: Discussionmentioning

confidence: 94%

“…Additionally, the great variety of ALPL mutations produces numerous combinations of compound heterozygous mutations, which further promotes the diversity of the clinical manifestations. Previously, Michigami et al analyzed 98 unrelated Japanese HPP patients found that p.Leu520ArgfsX86 (c.1559delT) and p.Phe327Leu (c.979T > C) were the two most common mutations and were usually associated with the perinatal severe and perinatal benign forms of HPP, respectively [9]. The mutation p.Glu191Lys (c.571G > A) was the most frequent mutations in Caucasian HPP patients and was commonly associated with mild forms of HPP [10].…”

Section: Introductionmentioning

confidence: 99%

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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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“…Ведение международных регистров позволяет накопить информацию как о естественном течении гипофосфатазии, так и особенностях течения гипофосфатазии у пациентов, получающих ферментозаместительную терапию асфотазой альфа [18,26]. Исходя из личного опыта авторов и данных клинического случая, целесообразно повышать информированность врачей первичного звена о гипофосфатазии.…”

Section: Discussionunclassified

Infantile Hypophosphatasia: Clinical Case

Габрусская

Панютина

Revnova

et al. 2020

Vopr. sovr. pediatr.

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Обоснование. Гипофосфатазия-редкое наследственное заболевание, вызванное дефицитом изофермента тканенеспецифичной щелочной фосфатазы, проявляется нарушением минерализации костей и зубов, электролитными и дыхательными нарушениями, судорожным синдромом, задержкой физического развития, нефрокальцинозом. Редкость заболевания, полиморфизм клинических проявлений, неспецифичность жалоб являются причиной поздней диагностики гипофосфатазии. Для лечения тяжелых форм заболевания применяется ферментозаместительная терапия рекомбинантной щелочной фосфатазой-асфотазой альфа. Описание клинического случая. Девочка, возраст 1 год 4 мес, госпитализирована в плановом порядке с жалобами на задержку физического и психомоторного развития, деформацию нижних конечностей, грудной клетки, нарушение походки, выпадение зубов, с диагнозом «белково-калорийная недостаточность». Отмечены рахитоподобные изменения скелета, миопатический синдром, раннее выпадение неизмененных зубов, гепатомегалия. Выявлена сниженная активность щелочной фосфатазы в сыворотке крови (33 Ед/л; норма 156-369 Ед/л). Диагностирована инфантильная форма гипофосфатазии. При молекулярногенетическом исследовании в гене ALPL обнаружены патогенные варианты c.526G>A (p.Ala176Thr) и c.1375G>A (p/Val459Met) в компаунд-гетерозиготном состоянии, подтвердившие диагноз. В возрасте 1 года 10 мес была начата терапия асфотазой альфа в дозировке 2 мг/кг массы тела подкожно 3 раза в неделю. За 6 мес терапии наблюдали значительное увеличение активности щелочной фосфатазы (максимально 4400 Ед/л), массы тела (+2 кг), роста (+6 см), уменьшение выраженности костных деформаций, восстановление мышечного тонуса, нормализацию походки, повышение толерантности к физическим нагрузкам. Введение препарата переносила удовлетворительно. Редко в месте инъекции отмечали появление гиперемии до 4 см в диаметре с умеренным уплотнением, которая самостоятельно разрешалась в течение 2-3 сут. Заключение. Пациентам с рахитоподобными заболеваниями с низкой активностью щелочной фосфатазы необходима генетическая диагностика для подтверждения гипофосфатазии. Своевременная диагностика и назначение ферментозаместительной терапии может существенно улучшить качество жизни детей с гипофосфатазией. Ключевые слова: дети, гипофосфатазия, рахитоподобные заболевания, щелочная фосфатаза, асфотаза альфа, ген ALPL.

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Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients

Cited by 27 publications

References 33 publications

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Children

Infantile Hypophosphatasia: Clinical Case

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