Hiperfosfatazya mental retardasyon sendromu düşünülen olgularda tüm ekzom sekanslama ile moleküler etiyolojinin belirlenmesi
Küçük Resim Yok
Tarih
2022
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
AMAÇ: Bu çalışmanın amacı, global gelişim geriliği ve serum alkalen fosfataz (ALP) düzeyi yaşa göre normal aralığın üzerinde olan henüz tanı almamış olan, Hiperfosfatazya Mental Retardasyon Sendromu (HPMRS) düşünülen olgularda moleküler tanının araştırılmasıdır. GEREÇ ve YÖNTEM: Ege Üniversitesi Tıp Fakültesi Hastanesi Biyokimya Laboratuvarı'nda Ocak 2017- Aralık 2020 tarihleri arasında çalışılan ve ALP değeri 500 U/L ve üzerinde olan 0-18 yaş arasındaki tüm hastalar retrospektif olarak incelendi. Bu inceleme sonucunda, daha önceki ALP değeri yaşa göre normal aralıkta olan olgular, HPMRS dışında ALP yüksekliğine neden olan ek hastalığı olan olgular ve gelişimsel gerilik saptanmayan olgular çalışma listesine dahil edilmedi. Listeye dahil edilen olguların klinik bulguları, anamnezleri, öz ve soy geçmişleri HPMRS ile uyumlu olan 8 olgu çalışmaya alındı. Oluşturulan listedeki hastalar Elektronik Hasta Dosyası'ndaki kayıtlı telefon numaraları ile aranarak ayrıntılı öykü, özgeçmiş, soy geçmiş ve fizik bakılarının değerlendirilmesi için muayeneye çağrıldı. Çalışmaya alınan 8 olguya HPMRS açısından tüm ekzom dizileme (WES: Whole Exome Sequencing) yapıldı. BULGULAR: Çalışmaya alınan 8 olgunun 3'ü kız 5'i erkekti. Olguların ortalama yaşı 6,55'ti (minimum 1,63 yaş, maksimum yaş 13,5 yaş). Olguların bakılan ALP ortanca değeri 925,5 U/L'ydi (minimum:527 U/L, maximum:1657 U/L). Yapılan WES sonucunda 2 hastada PGAP3 (Post-Gpi Attachment To Proteins 3) geninde, 1 olguda da glikozilfosfatidilinozitol (GPI) ankor biyosentez yolağında yer alan bir gen olan PIGB'de (Phosphatidylinositol Glycan Anchor Biosynthesis Class B Protein) varyantlar saptandı. İlk olguda homozigot c.715_717delTGG (p.Trp239del) varyantı, ikinci olguda ise homozigot c.827C>T (p.Pro267LEu) varyantı saptandı. Global gelişim geriliği ve alkalen fosfataz yüksekliği olan diğer bir olguda da PIGB geninde homozigot c1447T>C (pTrp483Arg) varyantı saptandı. Diğer 5 olguda PGAP (Post-Gpi Attachment To Proteins) ve PIG (Phosphatidylinositol Glycan) genleri ile ilişkili bir varyant saptanmadı. Ancak WES yapılan 4 olguda, kliniklerini açıklayabilecek farklı genlerde varyantlar saptandı. Bu dört olgudan birincisinde Konjenital Glikozilasyon Defekti Tip 2F'den sorumlu olan SLC35A1 (Solute Carrier Family 35 Member 1) geninde, homozigot c.673G>T (p.Val225Phe) ve Repenning Sendromuna neden olan PQBP1 (Polyglutamine-Binding Protein 1) geninde homozigot c641G>A (p.Arg214Gln) varyantları görüldü. İkincisinde ise GM1 Ganliozidoz'dan sorumlu GLB1 (Galactosidase, Beta-1) geninde homozigot c.569G>A (p.Gly190Asp) varyantı saptandı. Kliniği nörodejeneratif olarak ilerleyen üçüncü olguda ise Herediter Spastik Paraplejiye neden olan DDHD2 (Domain-Containing Protein 2) geninde homozigot c.1078delA (p.Ile360fs) ve Sanfilippo Tip B'den sorumlu NAGLU (N-Acetylglucosaminidase, Alpha) geninde homozigot c509G>T ( pGly170Val) varyantları görüldü. Dördüncü olgunun WES analizinde ise OXA1L (Oxidase, Cytochrome C, Assembly 1-Like) geninde homozigot c.569_571delGAG (p.Gly190del) varyantı görüldü. Bir olgunun WES sonucunda ise klinik tablosunu açıklayabilecek ve HPMRS ilişkili bir varyant saptanmadı. PGAP3 ve PIGB ilişkili varyant saptanan olguların ise ALP ortanca değeri 1104 U/L (minimum: 747 U/L, maksimum: 1314U/L) olarak saptandı. PGAP3'te varyant saptanan iki olguda da ALP yüksekliğinin yanı sıra global gelişim geriliği, intelektüel gerilik ve hipotoni vardı. Fenotipik olarak incelediğimizde ikisinde de geniş burun kökü ve köprüsü, uzun filtrum, çadır ince üst dudak ve yarık damak olduğu görüldü. Olgulardan ilkinde ek olarak mikrosefali, yukarı eğimli palpebral fissürler, büyük-etli kulaklar olduğu görüldü. İkinci olguda ise makrosefali, geniş palpebral fissürler gibi fenotipik bulgular ve ataksik yürüyüş saptandı. Olguların dosyaları incelendiğinde ise birinci olgunun kranial manyetik rezonans (MR) görüntülemesinde serebral atrofi olduğu görüldü. PIGB geninde homozigot missense varyant saptanan olguda serum ALP düzeyinde yükseklik yanında global gelişim geriliği ve nöbet aktivitesi saptandı. Ayrıca olgunun fizik bakısında; dar alın, frontal bombeleşme, kepçe ve büyük kulaklar, uçları kalkık kulak memeleri, dolgun yanaklar, silik filtrum, ince-çadır üst dudak, el ve ayak tırnaklarında hipoplazi, ellerde brakidaktili, kısa distal falankslar saptandı. SONUÇ: Çalışmamızda ALP yüksekliği ve gelişim geriliği olan 8 olguya yapılan WES sonucunda 2 olguda PGAP3 ve 1 olguda da PIGB geni ile ilişkili varyantlar saptandı. Hiperfosfatazya sendromlarında ortak olarak mental gerilik ve ALP yüksekliğinin yanında çok çeşitli dismorfik bulgular ve konjenital anomaliler görülmektedir. Oldukça nadir görülen ancak son yıllarda yapılan çalışmalarla kliniklerine dair önemli bulgular saptanan bu sendromlar gelişme geriliği ve ALP yüksekliği olan tüm olgularda akla gelmelidir.
Aım: The aim of this study is to investigate the molecular diagnosis in cases with global developmental delay and serum alkaline phosphatase (ALP) levels above the normal range for age, undiagnosed, and suspected Hyperphosphatasia Mental Retardation Syndrome (HPMRS). Materıals and Method: All patients aged 0-18 years, who were studied in the Biochemistry Laboratory of the Ege University Medical Faculty Hospital between January 2017 and December 2020 and whose ALP value was 500 U/L and above, were retrospectively analyzed. As a result of this examination, cases with previous ALP values in the normal range for age, cases with additional disease causing ALP elevation other than HPMRS, and cases without developmental delay were not included in the study list. Eight cases whose clinical findings, anamnesis, personal and family histories were compatible with HPMRS were included in the study. The patients in the created list were called with the phone numbers registered in the Electronic Patient File and were invited for examination to evaluate their detailed history, history, family history and physical examination. Whole Exome Sequencing (WES) was performed in 8 cases included in the study in terms of HPMRS. Results: Of the 8 patients included in the study, 3 were female and 5 were male. The mean age of the cases was 6.55 years (minimum 1.63 years, maximum age 13.5 years). The median ALP value of the cases was 925.5 U/L (minimum: 527 U/L, maximum: 1657 U/L). As a result of WES, variants were detected in the PGAP3 (Post-Gpi Attachment To Proteins 3) gene in 2 patients and in PIGB (Phosphatidylinositol Glycan Anchor Biosynthesis Class B Protein), a gene involved in the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway in 1 patient. Homozygous c.715_717delTGG (p.Trp239del) variant was found in the first case, and homozygous c.827C>T (p.Pro267LEu) variant was found in the second case. Homozygous c1447T>C (pTrp483Arg) variant was detected in the PIGB gene in another patient with global developmental delay and elevated alkaline phosphatase. No variant associated with PGAP (Post-Gpi Attachment To Proteins) and PIG (Phosphatidylinositol Glycan) genes was detected in the other 5 cases. However, variants in different genes were detected in 3 patients who underwent WES, which could explain their clinics. In the first of these three cases, homozygous for SLC35A1 (Solute Carrier Family 35 Member 1) gene responsible for Congenital Glycolization Defect Type 2F, homozygous for c.673G>T (p.Val225Phe) and PQBP1 (Polyglutamine-Binding Protein 1) gene causing Repenning Syndrome. Variants of c641G>A (p.Arg214Gln) were seen. In the second, homozygous c.569G>A (p.Gly190Asp) variant was detected in the GLB1 (Galactosidase, Beta-1) gene responsible for GM1 Ganliosidosis. In the third case whose clinical progress was neurodegenerative, homozygous c.1078delA (p.Ile360fs) in the DDHD2 (Domain-Containing Protein 2) gene that causes Hereditary Spastic Paraplegia and homozygous c509G in the NAGLU (N-Acetylglucosaminidase, Alpha) gene responsible for Sanfilippo Type B> (pGly170Val) variants were seen. In the WES analysis of the fourth case, homozygous c.569_571delGAG (p.Gly190del) variant was found in the OXA1L gene. As a result of WES, a HPMRS-related variant that could explain the clinical picture was not detected in one case. In the cases with PGAP3 and PIGB-related variants, the median ALP value was found to be 1104 U/L (minimum: 747 U/L, maximum: 1314U/L). In addition to elevated ALP, two cases with variants in PGAP3 also had global developmental delay, intellectual retardation, and hypotonia. When we examined it phenotypically, it was observed that both had wide nasal root and bridge, long filtrum, tent thin upper lip and cleft palate. In the first of the cases, additionally microcephaly, upward sloping palpebral fissures, and large fleshy ears were observed. In the second case, phenotypic findings such as macrocephaly, large palpebral fissures and ataxic gait were detected. When the files of the cases were examined, cerebral atrophy was observed in the cranial magnetic resonance (MR) imaging of the first case. In the case with homozygous missense variant in the PIGB gene, global developmental delay and seizure activity were detected, as well as high serum ALP levels. In addition, in the physical examination of the case; Narrow forehead, frontal cambering, prominent and large ears, upturned earlobes, full cheeks, faint philtrum, thin-tent upper lip, hypoplasia in finger and toenails, brachydactyly in hands, short distal phalanges were detected. Conclusıon: In our study, variants associated with the PGAP3 gene in 2 patients and the PIGB gene in 1 patient were found as a result of WES performed on 8 patients with high ALP and developmental delay. In addition to mental retardation and high ALP, various dysmorphic findings and congenital anomalies are common in hyperphosphatasia syndromes. These syndromes, which are quite rare but have been found to be clinically important in recent studies, should be considered in all cases with growth retardation and elevated ALP.
Aım: The aim of this study is to investigate the molecular diagnosis in cases with global developmental delay and serum alkaline phosphatase (ALP) levels above the normal range for age, undiagnosed, and suspected Hyperphosphatasia Mental Retardation Syndrome (HPMRS). Materıals and Method: All patients aged 0-18 years, who were studied in the Biochemistry Laboratory of the Ege University Medical Faculty Hospital between January 2017 and December 2020 and whose ALP value was 500 U/L and above, were retrospectively analyzed. As a result of this examination, cases with previous ALP values in the normal range for age, cases with additional disease causing ALP elevation other than HPMRS, and cases without developmental delay were not included in the study list. Eight cases whose clinical findings, anamnesis, personal and family histories were compatible with HPMRS were included in the study. The patients in the created list were called with the phone numbers registered in the Electronic Patient File and were invited for examination to evaluate their detailed history, history, family history and physical examination. Whole Exome Sequencing (WES) was performed in 8 cases included in the study in terms of HPMRS. Results: Of the 8 patients included in the study, 3 were female and 5 were male. The mean age of the cases was 6.55 years (minimum 1.63 years, maximum age 13.5 years). The median ALP value of the cases was 925.5 U/L (minimum: 527 U/L, maximum: 1657 U/L). As a result of WES, variants were detected in the PGAP3 (Post-Gpi Attachment To Proteins 3) gene in 2 patients and in PIGB (Phosphatidylinositol Glycan Anchor Biosynthesis Class B Protein), a gene involved in the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway in 1 patient. Homozygous c.715_717delTGG (p.Trp239del) variant was found in the first case, and homozygous c.827C>T (p.Pro267LEu) variant was found in the second case. Homozygous c1447T>C (pTrp483Arg) variant was detected in the PIGB gene in another patient with global developmental delay and elevated alkaline phosphatase. No variant associated with PGAP (Post-Gpi Attachment To Proteins) and PIG (Phosphatidylinositol Glycan) genes was detected in the other 5 cases. However, variants in different genes were detected in 3 patients who underwent WES, which could explain their clinics. In the first of these three cases, homozygous for SLC35A1 (Solute Carrier Family 35 Member 1) gene responsible for Congenital Glycolization Defect Type 2F, homozygous for c.673G>T (p.Val225Phe) and PQBP1 (Polyglutamine-Binding Protein 1) gene causing Repenning Syndrome. Variants of c641G>A (p.Arg214Gln) were seen. In the second, homozygous c.569G>A (p.Gly190Asp) variant was detected in the GLB1 (Galactosidase, Beta-1) gene responsible for GM1 Ganliosidosis. In the third case whose clinical progress was neurodegenerative, homozygous c.1078delA (p.Ile360fs) in the DDHD2 (Domain-Containing Protein 2) gene that causes Hereditary Spastic Paraplegia and homozygous c509G in the NAGLU (N-Acetylglucosaminidase, Alpha) gene responsible for Sanfilippo Type B> (pGly170Val) variants were seen. In the WES analysis of the fourth case, homozygous c.569_571delGAG (p.Gly190del) variant was found in the OXA1L gene. As a result of WES, a HPMRS-related variant that could explain the clinical picture was not detected in one case. In the cases with PGAP3 and PIGB-related variants, the median ALP value was found to be 1104 U/L (minimum: 747 U/L, maximum: 1314U/L). In addition to elevated ALP, two cases with variants in PGAP3 also had global developmental delay, intellectual retardation, and hypotonia. When we examined it phenotypically, it was observed that both had wide nasal root and bridge, long filtrum, tent thin upper lip and cleft palate. In the first of the cases, additionally microcephaly, upward sloping palpebral fissures, and large fleshy ears were observed. In the second case, phenotypic findings such as macrocephaly, large palpebral fissures and ataxic gait were detected. When the files of the cases were examined, cerebral atrophy was observed in the cranial magnetic resonance (MR) imaging of the first case. In the case with homozygous missense variant in the PIGB gene, global developmental delay and seizure activity were detected, as well as high serum ALP levels. In addition, in the physical examination of the case; Narrow forehead, frontal cambering, prominent and large ears, upturned earlobes, full cheeks, faint philtrum, thin-tent upper lip, hypoplasia in finger and toenails, brachydactyly in hands, short distal phalanges were detected. Conclusıon: In our study, variants associated with the PGAP3 gene in 2 patients and the PIGB gene in 1 patient were found as a result of WES performed on 8 patients with high ALP and developmental delay. In addition to mental retardation and high ALP, various dysmorphic findings and congenital anomalies are common in hyperphosphatasia syndromes. These syndromes, which are quite rare but have been found to be clinically important in recent studies, should be considered in all cases with growth retardation and elevated ALP.
Açıklama
Anahtar Kelimeler
Alkalen Fosfataz, Hiperfosfatazya, PGAP3, PIGB, Global Gelişim Geriliği, Glikozilfosfatidilinozitol Ankor Protein, Alkaline Phosphatase, Hyperphosphatasia, PGAP3, PIGB, Global Growth Retardation, Glycosylphosphatidylinositol Anchor Protein
