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Two novel mutations in the ALPL gene of unrelated Chinese children with Hypophosphatasia: case reports and literature review.

ABSTRACT: OBJECTIVE:Hypophosphatasia (HPP) is an inherited disorder of defective skeletal mineralization caused by mutations in the ALPL gene that encodes the Tissue Non-specific Alkaline Phosphatase (TNSALP). It is subdivided into six forms depending on the age of onset: perinatal lethal, prenatal benign, infantile, childhood, adult, and odonto HPP. Among these, infantile HPP is characterized by early onset and high frequency of lethal outcome. Few studies have reported the phenotype and genetic characteristics of HPP in Chinese children. CASE PRESENTATION:Three forms of HPP were identified in four unrelated patients from four different Chinese families, including one lethal infantile (patient 1), two childhood (patient 2 and 3) and one odonto HPP (patient 4). Six variants in the ALPL gene were identified, including five missense mutations and one frameshift mutation. Of which, none were reported previously in the Chinese population, and two were novel (c.359G?>?C: p.G120A and c.1017dupG: p.H340AfsX3). Patient 1 carrying a novel homozygous (c.359G?>?C) mutation showed respiratory distress and pneumonia at first day of his life. He presented nearly negligible level of serum ALP activity, overall skeletal hypominaralization and died at 3?months old. Patient 2, 3 and 4 were compound heterozygotes with decreased serum ALP activity. Patient 2 and 3 presented premature loss of deciduous teeth, muscle weakness and bone pain, whereas patient 4 had early loss of deciduous teeth only. All four pedigrees exhibited autosomal recessive pattern of inheritance. CONCLUSIONS:In this study, six mutations in the ALPL gene were found in four Chinese HPP patients, two of which were novel: c.359G?>?C in exon 5 and c.1017dupG in exon 10. Our results strongly indicated that the novel mutation c.359G?>?C might be disease-causing and associated with severe infantile form of HPP.

SUBMITTER: Mao X

PROVIDER: S-EPMC6876108 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Two novel mutations in the ALPL gene of unrelated Chinese children with Hypophosphatasia: case reports and literature review.

Mao Xiaojian X Liu Sichi S Lin Yunting Y Chen Zhen Z Shao Yongxian Y Yu Qiaoli Q Liu Haiying H Lu Zhikun Z Sheng Huiyin H Lu Xinshuo X Huang Yonglan Y Liu Li L Zeng Chunhua C

BMC pediatrics 20191125 1

<h4>Objective</h4>Hypophosphatasia (HPP) is an inherited disorder of defective skeletal mineralization caused by mutations in the ALPL gene that encodes the Tissue Non-specific Alkaline Phosphatase (TNSALP). It is subdivided into six forms depending on the age of onset: perinatal lethal, prenatal benign, infantile, childhood, adult, and odonto HPP. Among these, infantile HPP is characterized by early onset and high frequency of lethal outcome. Few studies have reported the phenotype and genetic ...[more]

PMID: 31760938

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Project description:BackgroundHypophosphatasia (HPP) is a rare hereditary disorder characterized by defective bone and tooth mineralization caused by mutations in the alkaline phosphatase (ALPL) gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Here we performed clinical and molecular studies on 5 HPP children to investigate the pathogenic mechanisms of the ALPL gene variants.MethodsClinical and genetic analyses were performed on 5 HPP children, and the loci where ALPL variants were identified. Plasmids containing the relevant loci were constructed. The molecular and cellular mechanisms of the pathogenic ALPL variants were investigated by cellular immunofluorescence, enzyme activity assay, and protein expression assay.ResultsA total of 6 ALPL variants were identified in 5 HPP children: proband 1: c.346G>A (p.A116T); proband 2: c.346G>A (p.A116T)/deletions from c.1097 to c.1099 CCT (p.T366_S367deli) compound heterozygous variant; proband 3: insertion of G from c.1014 to c.1015 (p.H338fs)/c.1446C>A (p.H482Q) compound heterozygous variant; proband 4: c.920C>T (p.P307L); and proband 5: c.883A>G (p.M295V). Twenty-four hours after the HEK-293T was transfected with different variant plasmids, its alkaline phosphatase activity and enzyme protein content were reduced compared with the wild type, and there were differences among different variants. Except for 1014-G-1015+C1446A, the degree of reduction in enzyme activity was negatively correlated with the severity of clinical manifestations. Immunofluorescence revealed that the variants (especially c.883A>G and c.920C>T) caused a decrease in alkaline phosphatase expression in the cellular membrane.ConclusionsIn total, 3 novel variants were identified in these 5 HPP children, the discovery of which will enrich the human ALPL gene mutation database. Different variants in the ALPL gene can downregulate the activity of TNSALP enzyme (and thus affect its function) by affecting protein expression and translational modifications. The same variant may cause clinical manifestations of different severities in different individuals due to the presence of dominant negative effects, alterations in noncoding sequences, blind area of intron regulatory region sequencing, and variations in environmental and individual factors. The molecular mechanisms via which the ALPL gene exerts its expression effect in vivo are highly variable and warrant further investigation.

Project description:Background and Objective. Grisel's syndrome is a rare syndrome characterized by nontraumatic rotatory subluxation of the atlantoaxial joint. It usually affects children and typically presents with torticollis after ear, nose, and throat (ENT) surgery or head and neck infections. In the pediatric literature, there is only a small amount of available data; moreover, no systematic review has been previously done with focus on the pediatric population. We report our experience of two cases, and we provide a systematic review on Grisel's syndrome in children in order to offer a deeper insight about its clinical presentation, its current diagnosis, and principles of treatment. Case Reports and Review. We describe two boys of 9 and 8 years old, who developed atlantoaxial subluxation after adenoidectomy. Considering the early diagnosis, a conservative treatment was chosen, with no recurrence and no sequelae at follow-up. We identified 114 case reports, of which 90 describe children, for a total of 171 pediatric patients. Of the 154 cases in which cause was reported, 59.7% presented a head and neck infection and 35.7% had previous head and neck surgery. There is no sex prevalence (49.7% males versus 50.2% females). Mean delay in diagnosis is 33 days. Eight % of the patients had neurological impairment of the 165 cases which mentioned treatment, 96% underwent a conservative treatment, of whom the 8.8% recurred with the need of surgery. As a whole, 12% underwent surgery as a first- or second-line treatment. 3 6% of the patients whose follow-up was reported developed a sequela, minor limitation of neck movement being the most frequent. Conclusion. Grisel's syndrome should be suspected in children with painful unresponsive torticollis following ENT procedures or head and neck inflammation. CT scan with 3D reconstruction is the gold standard for diagnosis, allowing the identification of the subluxation and the classification according to the Fielding-Hawkins grading system. Surgical treatment is indicated in case of high-grade instability or failure of conservative treatment. Review of the literature shows how early diagnosis based on clinical and radiological evaluation is crucial in order to avoid surgical treatment and neurologic sequelae.

Project description:ALPL encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme expressed in bone, teeth, liver, and kidney. ALPL loss-of-function mutations cause hypophosphatasia (HPP), an inborn error-of-metabolism that produces skeletal and dental mineralization defects. Case reports describe widely varying dental phenotypes, making it unclear how HPP comparatively affects the three unique dental mineralized tissues: enamel, dentin, and cementum. We hypothesized that HPP affected all dental mineralized tissues and aimed to establish quantitative measurements of dental tissues in a subject with HPP. The female proband was diagnosed with HPP during childhood based on reduced alkaline phosphatase activity (ALP), mild rachitic skeletal effects, and premature primary tooth loss. The diagnosis was subsequently confirmed genetically by the presence of compound heterozygous ALPL mutations (exon 5: c.346G>A, p.A116T; exon 10: c.1077C>G, p.I359M). Dental defects in 8 prematurely exfoliated primary teeth were analyzed by high resolution micro-computed tomography (micro-CT) and histology. Similarities to the Alpl-/- mouse model of HPP were identified by additional analyses of murine dentoalveolar tissues. Primary teeth from the proband exhibited substantial remaining root structure compared to healthy control teeth. Enamel and dentin densities were not adversely affected in HPP vs. control teeth. However, analysis of discrete dentin regions revealed an approximate 10% reduction in the density of outer mantle dentin of HPP vs. control teeth. All 4 incisors and the molar lacked acellular cementum by micro-CT and histology, but surprisingly, 2 of 3 prematurely exfoliated canines exhibited apparently normal acellular cementum. Based on dentin findings in the proband's teeth, we examined dentoalveolar tissues in a mouse model of HPP, revealing that the delayed initiation of mineralization in the incisor mantle dentin was associated with a broader lack of circumpulpal dentin mineralization. This study describes a quantitative approach to measure effects of HPP on dental tissues. This approach has uncovered a previously unrecognized novel mantle dentin defect in HPP, as well as a surprising and variable cementum phenotype within the teeth from the same HPP subject.

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Two novel mutations in the ALPL gene of unrelated Chinese children with Hypophosphatasia: case reports and literature review.

Publications

Two novel mutations in the ALPL gene of unrelated Chinese children with Hypophosphatasia: case reports and literature review.

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