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Clinical and radiographic features. A . Face of patient II-1. B . Face of patient II-3. C . Palate of patient II-1. D . Hands of patient II-3. E - J . Skeletal radiographs of Patient II-1 showing the left humerus (E) , left forearm (F) , left hand (G) , pelvis (H) , left femur (I) and left lower leg (J) . Note the gracile bones and undermineralization as well as the healing humeral fracture (E) .
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Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability disorder also characterized by osteoporosis, scoliosis, and dysmorphic facial features. It is caused by mutations in SMS, a ubiquitously expressed gene encoding the polyamine biosynthetic enzyme spermine synthase. We hypothesized that the tissue specificity of SRS arises from dif...
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Context 1
... acidosis (RTA), nephrocalcinosis and nephro- lithiasis. His renal stones were composed of carbonate apatite and calcium oxalate. His RTA has been managed with fluid and electrolyte replacement, spironolactone and hydrochlorothiazide. Although initially controlled with phenobarbital, his seizures progressed to infantile spasms by 15 months. Adrenocorticotropic hormone (ACTH) treatment transi- ently reduced seizure frequency. His current anticonvulsant therapy includes rufinamide, felbamate, clonazepam, and topiramate. He had delayed development with regression of several developmental milestones. He smiled and laughed by 4 months, reached for toys by 6 months, had vocalizations by 7 months, and could hold his head up and roll onto his side by 8 months. He achieved his pincer grasp at 18 months but lost it by 23 months. He never walked. He lost many motor skills and all vocalization by 26 months of age. A cranial MRI at 14 years revealed cys- tic encephalomalacia and a low parenchymal T2 signal in the right temporal and right occipital lobes. These findings were considered consequences of the perinatal intraventricular hemorrhage. When first evaluated at NIH at 15 years, Patient II-1 was awake but not interactive and could not sit inde- pendently or hold up his head; he withdrew from nox- ious stimuli. His height, weight and OFC were 129 cm (<3%ile), 30.8kg (<3%ile) and 50.3 cm (<3%ile), respectively. Facial dysmorphisms included a long, oval, asym- metric face, midface hypoplasia, down-slanting palpebral fissures, large, cupped ears, smooth philtrum, high- arched palate and prognathia (Figure 1). His dental en- amel was hypoplastic and secondary teeth 2, 6, 10, and 11 were absent. He had excessive drooling, sluggish pupillary reflexes and left-sided hearing loss. He had frequent seizures, severe hypotonia, decreased muscle bulk, hypoactive deep tendon reflexes, kyphoscoliosis and flexion contractures of most large and small joints (Figure 1). He had one prepubertal (1-2 mL) testis that was undescended but palpable in the inguinal canal and one undescended testis, Tanner stage III pubic hair and a prepubertal phallus. His skin was remarkable for excretions of carbonate apatite, reflecting calcium/phosphate dysregulation. His ophthalmologic exam revealed retinitis pigmentosa and cortical blindness. Previous skeletal problems included congenital bilateral hip dislocation and fractures of his distal fibula (2 years), right humerus (5 years) and spine (6 years). Kyphoscoliosis developed between 6 and 12 years of age. A dual-energy x-ray absorptiometry (DEXA) scan performed at age 15 years demonstrated a bone density of 0.341 gm/cm 2 BMD (height adjusted Z-Score: -2.9 [21]) for the anteroposterior Spine (L1-L4) and 0.342 gm/cm 2 bone mineral density (height adjusted Z-Score: -6.5 [21]) for the right forearm. Skeletal radiographs at 18 years revealed a 60° convex right scoliosis, gracile bones with reduced mineral density, and evidence of previous fractures (Figure 2E-J). Patient II-3, the brother of Patient II-1, was born at 37 weeks by cesarean section following an uncomplicated pregnancy. His birth weight was 2.81 kg (25%). During the immediate neonatal period his platelet count decreased from 90 to 45 k/ μ L, and he was admitted to the neonatal intensive care unit for treatment with dexamethasone and a platelet transfusion. He also had transient hypoglycemia, poor feeding and sensitivity to light. By 4 days of life, his condition had stabilized and he was discharged. Over the subsequent months, he manifested moderate laryngomalacia, mild tracheobro- chomalacia, severe torticollis and abnormally pigmen- ted retinas. Like his brother, he has also had episodic hyper- and hypoglycemia. He was diagnosed with nephrocalcinosis at 1 year and RTA by 2 years. The composition of his renal stones was carbonate apatite and calcium oxalate. Patient II-3 had global developmental delay, severe hypotonia, and regression of milestones; he lost vocalizations and most motor skills by 15 months. An EEG at 6 months showed generalized slowing and disorganization; at 18 months he manifested seizures and hypsarrhyth- mia. An MRI performed at 2 years of age showed a mild increase in ventricular size but no other abnormalities. There was no evidence of hemorrhage or malformation. Since age 5 years, he has required a vagal nerve stimula- tor and bi-pap for adequate respiration. He also had re- peated Pseudomonas aeruginosa pulmonary infections. His infections are more frequent and severe than are those of his brother. Patient II-3 has had multiple atraumatic fractures in- volving the clavicle, tibia, femur and humerus. He also had congenital bilateral hip dislocation and, by 4 years of age scoliosis. Illness prevented Patient II-3 from traveling to the NIH for evaluation, but review of his medical records and photographs showed that he was alert and non- ambulatory at age 10 years. He had facial features similar to those of his brother (Figure 1), superficial skin excretions, hypotonia, large joint contractures and muscle atrophy. The propositi had extensive laboratory testing. This identified an elevated antibody titer to myelin basic protein and a mild intermittent anemia with low iron satur- ation (7%; normal, 15-62) and ferritin (20 mcg/L; normal, 26 -388) for Patient II-1 and an elevated blood lactate level of 7.8 mmol/L (0.5-2.2) and mild elevations of urine carni- tine esters for Patient II-3. Testing for abnormalities in or- ganic acids, amino acids, acylcarnitines, very long chain fatty acids, lysosomal enzymes, biotinidase and copper were unremarkable. Molecular testing of MECP2 , mito- chondrial DNA, a panel of lysosomal storage disease- associated genes and the X-Linked Mental Retardation 9 Gene Panel (Greenwood Clinic, 2008), which did not include SMS and FRMPD4 , did not detect pathogenic mutations. Patient II-1 had a normal karyotype (46,XY), and clinical and research copy number variant analysis did not detect any pathogenic variants (Additional file 1: Table S1). The propositi were accepted into the NIH Undiagnosed Diseases Program (UDP) and enrolled in clinical protocol 76-HG-0238, approved by the Institutional Review Board of the National Human Genome Research Institute. Their parents gave written, informed consent. The NHGRI Genomics Core lab performed SNP determinations using the Illumina Bead Array Platform (HumanOm- niExpress, Illumina Corp., San Diego, CA, USA). Genome- wide fluorescent intensities and genotype calls were analyzed using Bead Studio and Genome Studio (Illumina Corp.). Analysis of copy-number variations was performed using PennCNV software, [22] and visual inspection using Genome Studio version 2010v3 build37/hg19 [23]. Genomic DNA was extracted from whole blood using the Gentra Puregene Blood kit (Qiagen, Valencia, CA) according to the manufacturer ’ s specifications. Exome sequencing and analysis were performed as described [24-26]. The potential pathogenicity of identified variants was predicted using CDPred, SIFT, PolyPhen2 [27-33] or the BLOSUM62 scoring matrix [34]. For the SMS variant, Qiagen HotStarTaq master mix (Qiagen, Valencia, CA) was used to amplify the putative variant and 200 flanking nucleotides using the primers 5 ′ - TGTGGCTTTCTTTTGCACAC-3 ′ and 5 ′ -TGCATCT CAAAAACCAGCAG-3 ′ . Unincorporated primers and nucleotides were removed using ExoSAP-IT reagent (USB, Cleveland, OH, USA). Sanger capillary sequencing was used to sequence the PCR products (Macrogen, Rockville, MD), and the sequences were aligned and analyzed using Sequencher v.4.10.1 (Gene Codes, Ann Arbor, MI, USA). Mutation interpretation was conducted using Alamut 2.0 (Interactive Biosoftware, San Diego, CA, USA). Patient II-1 was given two courses of demeclocycline prior to the biopsy so that dynamic histomorphometry, including measurement of bone turnover, could be performed [35]. A bicortical transiliac crest core biopsy was performed and immediately split. The sample was placed in 70% ethanol and sent to The Johns Hopkins School of Medicine for histomorphometry, which was performed as described [35]. Protein was extracted from fibroblast and osteoblast cell lines with RIPA buffer (Thermo Scientific, Waltham, MA) or used directly from Clontech human protein library (Clontech Laboratories, Mountain View, CA). Lysates (30ug) were electrophoresed on a 4-10% SDS-polyacrylamide gel and transferred to a polyvinylidene fluoride (PVDF) membrane. Using gentle agitation, the membrane was blocked overnight at 4oC with casein blocking buffer (Thermo Scientific, Waltham, MA) and 10% horse serum. Anti-SMS (1:1000) (Novus Biologicals, Littleton, CO), anti- β -tubulin (1:1000, AbCam, Cambridge, UK), and anti-GAPDH (1:1000, Gene Tex, Irvine, CA) were used as primary antibodies. Horsera- dish peroxidase-conjugated secondary antibodies (1:10000, Bio-rad Laboratories, Hurcules, CA) were used to detect the primary antibodies. The antibody-enzyme complexes were detected by chemiluminescence using Amersham ECL west- ern blotting detection reagent (GE Life Sciences, Pittsburgh, PA) or WesternSure Premium Chemiluminescent Substrate (LI-COR, Lincoln, NE) according to the manufacturer ’ s specifications. β -tubulin or GAPDH was detected as a loading control. Cellular fractionation was performed using NE-PER Nuclear and Cytoplasmic Extraction Reagents (Thermo Scientific, Waltham, MA) per the manufacturer ’ s recommendations. Immunoblotting was performed as described above. β -tubulin and p84 (GeneTex, Irvine, CA) served as loading controls for the cytoplasmic and nuclear fractions, respectively. RNA was extracted from cells using the RNeasy Mini Kit (Qiagen, Valencia, CA) per the manufacturer ’ s specifications. RNA was converted to cDNA using the VILO cDNA synthesis kit (Life Technologies, Grand Island, NY) per the manufacturer ’ s protocol. 100ng of cDNA was amplified using Sso Advanced SYBR Green supermix (Bio-Rad Laboratories, Richmond, CA) ...
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... are ubiquitous, aliphatic, positively charged molecules that interact with anionic compounds such as DNA, RNA, and ATP [1,2]. Homeostasis of the polyamines putrescine, spermidine, and spermine is essential to cell growth and survival [3]. By addition of a propyla- mine moiety, spermidine synthase (SRM) converts putrescine into spermidine, and spermine synthase (SMS) converts spermidine into spermine [4]. The balance of spermine and spermidine is crucial for ion channel regulation, transcription and translation [5-9]. Mutations of SMS , the gene encoding spermine synthase, cause Snyder-Robinson syndrome (SRS), an X-linked disorder first reported in 1969 [10]. The clinical features of SRS include intellectual disability, dysmorphic facies, speech and gait abnormalities, seizures, muscle hypoplasia, kyphoscoliosis, and osteoporosis [11-17]. All affected males have hemizygous mutations in SMS that result in reduced SMS activity and a decreased spermine:spermidine ratio. Atraumatic osteoporotic fractures commonly occur in individuals with SRS, leading to significantly impaired quality of life. Osteoporosis arises from disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation [18], which is regulated by mechanical and endocrine stimuli [19]. This general un- derstanding of osteoporosis has led to established therapeutic interventions, but further insights are required to address the osteoporosis of SRS in a disease-specific manner. Here we define the osteoporotic disease of SRS in two brothers with a missense mutation in SMS [20] and report depletion of osteoblasts and osteoclasts, reduced cancel- lous and cortical bone, reduced calcium-phosphate mineralization in vitro , and markedly abnormal polyamine content in human bone marrow stromal cells (hBMSCs). These data offer new insights into the role of polyamines in bone formation. The propositus (II-1, Figure 1) is the 18-year-old son of non-consanguineous healthy parents with no family history of intellectual disability or skeletal problems. He was born by cesarean section at 40 weeks following a gestation complicated by poor maternal weight gain and, at 8 months, atypical fetal movements suggestive of in utero seizures. His birth weight, length and occipitofrontal circumference (OFC) were 2.38 kg (3%), 47 cm (13%) and 34.5 cm (26%), respectively. Apgar scores were 8 and 9 at one and five minutes. He had saggy skin but no other dysmorphic features. Following a perinatal intraventricular hemorrhage associated with thrombocytopenia (7×10 3 cells/ μ l) that corrected after 3 platelet transfusions, he developed seizures, apnea with cyanosis, temperature instability and hypoglycemia. His recurrent episodes of hyperglycemia and hypoglycemia resolved with age and the placement of a gastric tube that allowed more frequent feedings. Patient II-1 had tracheomalacia, upper airway obstruc- tion, increased respiratory secretions, frequent aspira- tions, and pulmonary infections from infancy. By age 7 years, he had chronic Pseudomonas aeruginosa respiratory infection. At 6 years, he developed proximal renal tubular acidosis (RTA), nephrocalcinosis and nephro- lithiasis. His renal stones were composed of carbonate apatite and calcium oxalate. His RTA has been managed with fluid and electrolyte replacement, spironolactone and hydrochlorothiazide. Although initially controlled with phenobarbital, his seizures progressed to infantile spasms by 15 months. Adrenocorticotropic hormone (ACTH) treatment transi- ently reduced seizure frequency. His current anticonvulsant therapy includes rufinamide, felbamate, clonazepam, and topiramate. He had delayed development with regression of several developmental milestones. He smiled and laughed by 4 months, reached for toys by 6 months, had vocalizations by 7 months, and could hold his head up and roll onto his side by 8 months. He achieved his pincer grasp at 18 months but lost it by 23 months. He never walked. He lost many motor skills and all vocalization by 26 months of age. A cranial MRI at 14 years revealed cys- tic encephalomalacia and a low parenchymal T2 signal in the right temporal and right occipital lobes. These findings were considered consequences of the perinatal intraventricular hemorrhage. When first evaluated at NIH at 15 years, Patient II-1 was awake but not interactive and could not sit inde- pendently or hold up his head; he withdrew from nox- ious stimuli. His height, weight and OFC were 129 cm (<3%ile), 30.8kg (<3%ile) and 50.3 cm (<3%ile), respectively. Facial dysmorphisms included a long, oval, asym- metric face, midface hypoplasia, down-slanting palpebral fissures, large, cupped ears, smooth philtrum, high- arched palate and prognathia (Figure 1). His dental en- amel was hypoplastic and secondary teeth 2, 6, 10, and 11 were absent. He had excessive drooling, sluggish pupillary reflexes and left-sided hearing loss. He had frequent seizures, severe hypotonia, decreased muscle bulk, hypoactive deep tendon reflexes, kyphoscoliosis and flexion contractures of most large and small joints (Figure 1). He had one prepubertal (1-2 mL) testis that was undescended but palpable in the inguinal canal and one undescended testis, Tanner stage III pubic hair and a prepubertal phallus. His skin was remarkable for excretions of carbonate apatite, reflecting calcium/phosphate dysregulation. His ophthalmologic exam revealed retinitis pigmentosa and cortical blindness. Previous skeletal problems included congenital bilateral hip dislocation and fractures of his distal fibula (2 years), right humerus (5 years) and spine (6 years). Kyphoscoliosis developed between 6 and 12 years of age. A dual-energy x-ray absorptiometry (DEXA) scan performed at age 15 years demonstrated a bone density of 0.341 gm/cm 2 BMD (height adjusted Z-Score: -2.9 [21]) for the anteroposterior Spine (L1-L4) and 0.342 gm/cm 2 bone mineral density (height adjusted Z-Score: -6.5 [21]) for the right forearm. Skeletal radiographs at 18 years revealed a 60° convex right scoliosis, gracile bones with reduced mineral density, and evidence of previous fractures (Figure 2E-J). Patient II-3, the brother of Patient II-1, was born at 37 weeks by cesarean section following an uncomplicated pregnancy. His birth weight was 2.81 kg (25%). During the immediate neonatal period his platelet count decreased from 90 to 45 k/ μ L, and he was admitted to the neonatal intensive care unit for treatment with dexamethasone and a platelet transfusion. He also had transient hypoglycemia, poor feeding and sensitivity to light. By 4 days of life, his condition had stabilized and he was discharged. Over the subsequent months, he manifested moderate laryngomalacia, mild tracheobro- chomalacia, severe torticollis and abnormally pigmen- ted retinas. Like his brother, he has also had episodic hyper- and hypoglycemia. He was diagnosed with nephrocalcinosis at 1 year and RTA by 2 years. The composition of his renal stones was carbonate apatite and calcium oxalate. Patient II-3 had global developmental delay, severe hypotonia, and regression of milestones; he lost vocalizations and most motor skills by 15 months. An EEG at 6 months showed generalized slowing and disorganization; at 18 months he manifested seizures and hypsarrhyth- mia. An MRI performed at 2 years of age showed a mild increase in ventricular size but no other abnormalities. There was no evidence of hemorrhage or malformation. Since age 5 years, he has required a vagal nerve stimula- tor and bi-pap for adequate respiration. He also had re- peated Pseudomonas aeruginosa pulmonary infections. His infections are more frequent and severe than are those of his brother. Patient II-3 has had multiple atraumatic fractures in- volving the clavicle, tibia, femur and humerus. He also had congenital bilateral hip dislocation and, by 4 years of age scoliosis. Illness prevented Patient II-3 from traveling to the NIH for evaluation, but review of his medical records and photographs showed that he was alert and non- ambulatory at age 10 years. He had facial features similar to those of his brother (Figure 1), superficial skin excretions, hypotonia, large joint contractures and muscle atrophy. The propositi had extensive laboratory testing. This identified an elevated antibody titer to myelin basic protein and a mild intermittent anemia with low iron satur- ation (7%; normal, 15-62) and ferritin (20 mcg/L; normal, 26 -388) for Patient II-1 and an elevated blood lactate level of 7.8 mmol/L (0.5-2.2) and mild elevations of urine carni- tine esters for Patient II-3. Testing for abnormalities in or- ganic acids, amino acids, acylcarnitines, very long chain fatty acids, lysosomal enzymes, biotinidase and copper were unremarkable. Molecular testing of MECP2 , mito- chondrial DNA, a panel of lysosomal storage disease- associated genes and the X-Linked Mental Retardation 9 Gene Panel (Greenwood Clinic, 2008), which did not include SMS and FRMPD4 , did not detect pathogenic mutations. Patient II-1 had a normal karyotype (46,XY), and clinical and research copy number variant analysis did not detect any pathogenic variants (Additional file 1: Table S1). The propositi were accepted into the NIH Undiagnosed Diseases Program (UDP) and enrolled in clinical protocol 76-HG-0238, approved by the Institutional Review Board of the National Human Genome Research Institute. Their parents gave written, informed consent. The NHGRI Genomics Core lab performed SNP determinations using the Illumina Bead Array Platform (HumanOm- niExpress, Illumina Corp., San Diego, CA, USA). Genome- wide fluorescent intensities and genotype calls were analyzed using Bead Studio and Genome Studio (Illumina Corp.). ...
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... and ATP [1,2]. Homeostasis of the polyamines putrescine, spermidine, and spermine is essential to cell growth and survival [3]. By addition of a propyla- mine moiety, spermidine synthase (SRM) converts putrescine into spermidine, and spermine synthase (SMS) converts spermidine into spermine [4]. The balance of spermine and spermidine is crucial for ion channel regulation, transcription and translation [5-9]. Mutations of SMS , the gene encoding spermine synthase, cause Snyder-Robinson syndrome (SRS), an X-linked disorder first reported in 1969 [10]. The clinical features of SRS include intellectual disability, dysmorphic facies, speech and gait abnormalities, seizures, muscle hypoplasia, kyphoscoliosis, and osteoporosis [11-17]. All affected males have hemizygous mutations in SMS that result in reduced SMS activity and a decreased spermine:spermidine ratio. Atraumatic osteoporotic fractures commonly occur in individuals with SRS, leading to significantly impaired quality of life. Osteoporosis arises from disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation [18], which is regulated by mechanical and endocrine stimuli [19]. This general un- derstanding of osteoporosis has led to established therapeutic interventions, but further insights are required to address the osteoporosis of SRS in a disease-specific manner. Here we define the osteoporotic disease of SRS in two brothers with a missense mutation in SMS [20] and report depletion of osteoblasts and osteoclasts, reduced cancel- lous and cortical bone, reduced calcium-phosphate mineralization in vitro , and markedly abnormal polyamine content in human bone marrow stromal cells (hBMSCs). These data offer new insights into the role of polyamines in bone formation. The propositus (II-1, Figure 1) is the 18-year-old son of non-consanguineous healthy parents with no family history of intellectual disability or skeletal problems. He was born by cesarean section at 40 weeks following a gestation complicated by poor maternal weight gain and, at 8 months, atypical fetal movements suggestive of in utero seizures. His birth weight, length and occipitofrontal circumference (OFC) were 2.38 kg (3%), 47 cm (13%) and 34.5 cm (26%), respectively. Apgar scores were 8 and 9 at one and five minutes. He had saggy skin but no other dysmorphic features. Following a perinatal intraventricular hemorrhage associated with thrombocytopenia (7×10 3 cells/ μ l) that corrected after 3 platelet transfusions, he developed seizures, apnea with cyanosis, temperature instability and hypoglycemia. His recurrent episodes of hyperglycemia and hypoglycemia resolved with age and the placement of a gastric tube that allowed more frequent feedings. Patient II-1 had tracheomalacia, upper airway obstruc- tion, increased respiratory secretions, frequent aspira- tions, and pulmonary infections from infancy. By age 7 years, he had chronic Pseudomonas aeruginosa respiratory infection. At 6 years, he developed proximal renal tubular acidosis (RTA), nephrocalcinosis and nephro- lithiasis. His renal stones were composed of carbonate apatite and calcium oxalate. His RTA has been managed with fluid and electrolyte replacement, spironolactone and hydrochlorothiazide. Although initially controlled with phenobarbital, his seizures progressed to infantile spasms by 15 months. Adrenocorticotropic hormone (ACTH) treatment transi- ently reduced seizure frequency. His current anticonvulsant therapy includes rufinamide, felbamate, clonazepam, and topiramate. He had delayed development with regression of several developmental milestones. He smiled and laughed by 4 months, reached for toys by 6 months, had vocalizations by 7 months, and could hold his head up and roll onto his side by 8 months. He achieved his pincer grasp at 18 months but lost it by 23 months. He never walked. He lost many motor skills and all vocalization by 26 months of age. A cranial MRI at 14 years revealed cys- tic encephalomalacia and a low parenchymal T2 signal in the right temporal and right occipital lobes. These findings were considered consequences of the perinatal intraventricular hemorrhage. When first evaluated at NIH at 15 years, Patient II-1 was awake but not interactive and could not sit inde- pendently or hold up his head; he withdrew from nox- ious stimuli. His height, weight and OFC were 129 cm (<3%ile), 30.8kg (<3%ile) and 50.3 cm (<3%ile), respectively. Facial dysmorphisms included a long, oval, asym- metric face, midface hypoplasia, down-slanting palpebral fissures, large, cupped ears, smooth philtrum, high- arched palate and prognathia (Figure 1). His dental en- amel was hypoplastic and secondary teeth 2, 6, 10, and 11 were absent. He had excessive drooling, sluggish pupillary reflexes and left-sided hearing loss. He had frequent seizures, severe hypotonia, decreased muscle bulk, hypoactive deep tendon reflexes, kyphoscoliosis and flexion contractures of most large and small joints (Figure 1). He had one prepubertal (1-2 mL) testis that was undescended but palpable in the inguinal canal and one undescended testis, Tanner stage III pubic hair and a prepubertal phallus. His skin was remarkable for excretions of carbonate apatite, reflecting calcium/phosphate dysregulation. His ophthalmologic exam revealed retinitis pigmentosa and cortical blindness. Previous skeletal problems included congenital bilateral hip dislocation and fractures of his distal fibula (2 years), right humerus (5 years) and spine (6 years). Kyphoscoliosis developed between 6 and 12 years of age. A dual-energy x-ray absorptiometry (DEXA) scan performed at age 15 years demonstrated a bone density of 0.341 gm/cm 2 BMD (height adjusted Z-Score: -2.9 [21]) for the anteroposterior Spine (L1-L4) and 0.342 gm/cm 2 bone mineral density (height adjusted Z-Score: -6.5 [21]) for the right forearm. Skeletal radiographs at 18 years revealed a 60° convex right scoliosis, gracile bones with reduced mineral density, and evidence of previous fractures (Figure 2E-J). Patient II-3, the brother of Patient II-1, was born at 37 weeks by cesarean section following an uncomplicated pregnancy. His birth weight was 2.81 kg (25%). During the immediate neonatal period his platelet count decreased from 90 to 45 k/ μ L, and he was admitted to the neonatal intensive care unit for treatment with dexamethasone and a platelet transfusion. He also had transient hypoglycemia, poor feeding and sensitivity to light. By 4 days of life, his condition had stabilized and he was discharged. Over the subsequent months, he manifested moderate laryngomalacia, mild tracheobro- chomalacia, severe torticollis and abnormally pigmen- ted retinas. Like his brother, he has also had episodic hyper- and hypoglycemia. He was diagnosed with nephrocalcinosis at 1 year and RTA by 2 years. The composition of his renal stones was carbonate apatite and calcium oxalate. Patient II-3 had global developmental delay, severe hypotonia, and regression of milestones; he lost vocalizations and most motor skills by 15 months. An EEG at 6 months showed generalized slowing and disorganization; at 18 months he manifested seizures and hypsarrhyth- mia. An MRI performed at 2 years of age showed a mild increase in ventricular size but no other abnormalities. There was no evidence of hemorrhage or malformation. Since age 5 years, he has required a vagal nerve stimula- tor and bi-pap for adequate respiration. He also had re- peated Pseudomonas aeruginosa pulmonary infections. His infections are more frequent and severe than are those of his brother. Patient II-3 has had multiple atraumatic fractures in- volving the clavicle, tibia, femur and humerus. He also had congenital bilateral hip dislocation and, by 4 years of age scoliosis. Illness prevented Patient II-3 from traveling to the NIH for evaluation, but review of his medical records and photographs showed that he was alert and non- ambulatory at age 10 years. He had facial features similar to those of his brother (Figure 1), superficial skin excretions, hypotonia, large joint contractures and muscle atrophy. The propositi had extensive laboratory testing. This identified an elevated antibody titer to myelin basic protein and a mild intermittent anemia with low iron satur- ation (7%; normal, 15-62) and ferritin (20 mcg/L; normal, 26 -388) for Patient II-1 and an elevated blood lactate level of 7.8 mmol/L (0.5-2.2) and mild elevations of urine carni- tine esters for Patient II-3. Testing for abnormalities in or- ganic acids, amino acids, acylcarnitines, very long chain fatty acids, lysosomal enzymes, biotinidase and copper were unremarkable. Molecular testing of MECP2 , mito- chondrial DNA, a panel of lysosomal storage disease- associated genes and the X-Linked Mental Retardation 9 Gene Panel (Greenwood Clinic, 2008), which did not include SMS and FRMPD4 , did not detect pathogenic mutations. Patient II-1 had a normal karyotype (46,XY), and clinical and research copy number variant analysis did not detect any pathogenic variants (Additional file 1: Table S1). The propositi were accepted into the NIH Undiagnosed Diseases Program (UDP) and enrolled in clinical protocol 76-HG-0238, approved by the Institutional Review Board of the National Human Genome Research Institute. Their parents gave written, informed consent. The NHGRI Genomics Core lab performed SNP determinations using the Illumina Bead Array Platform (HumanOm- niExpress, Illumina Corp., San Diego, CA, USA). Genome- wide fluorescent intensities and genotype calls were analyzed using Bead Studio and Genome Studio (Illumina Corp.). Analysis of copy-number variations was performed using PennCNV software, [22] and visual inspection using Genome Studio version 2010v3 build37/hg19 [23]. Genomic DNA was extracted from whole blood using the Gentra Puregene Blood kit (Qiagen, Valencia, CA) according to the manufacturer ’ s specifications. Exome sequencing and analysis were performed as ...
Context 4
... are ubiquitous, aliphatic, positively charged molecules that interact with anionic compounds such as DNA, RNA, and ATP [1,2]. Homeostasis of the polyamines putrescine, spermidine, and spermine is essential to cell growth and survival [3]. By addition of a propyla- mine moiety, spermidine synthase (SRM) converts putrescine into spermidine, and spermine synthase (SMS) converts spermidine into spermine [4]. The balance of spermine and spermidine is crucial for ion channel regulation, transcription and translation [5-9]. Mutations of SMS , the gene encoding spermine synthase, cause Snyder-Robinson syndrome (SRS), an X-linked disorder first reported in 1969 [10]. The clinical features of SRS include intellectual disability, dysmorphic facies, speech and gait abnormalities, seizures, muscle hypoplasia, kyphoscoliosis, and osteoporosis [11-17]. All affected males have hemizygous mutations in SMS that result in reduced SMS activity and a decreased spermine:spermidine ratio. Atraumatic osteoporotic fractures commonly occur in individuals with SRS, leading to significantly impaired quality of life. Osteoporosis arises from disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation [18], which is regulated by mechanical and endocrine stimuli [19]. This general un- derstanding of osteoporosis has led to established therapeutic interventions, but further insights are required to address the osteoporosis of SRS in a disease-specific manner. Here we define the osteoporotic disease of SRS in two brothers with a missense mutation in SMS [20] and report depletion of osteoblasts and osteoclasts, reduced cancel- lous and cortical bone, reduced calcium-phosphate mineralization in vitro , and markedly abnormal polyamine content in human bone marrow stromal cells (hBMSCs). These data offer new insights into the role of polyamines in bone formation. The propositus (II-1, Figure 1) is the 18-year-old son of non-consanguineous healthy parents with no family history of intellectual disability or skeletal problems. He was born by cesarean section at 40 weeks following a gestation complicated by poor maternal weight gain and, at 8 months, atypical fetal movements suggestive of in utero seizures. His birth weight, length and occipitofrontal circumference (OFC) were 2.38 kg (3%), 47 cm (13%) and 34.5 cm (26%), respectively. Apgar scores were 8 and 9 at one and five minutes. He had saggy skin but no other dysmorphic features. Following a perinatal intraventricular hemorrhage associated with thrombocytopenia (7×10 3 cells/ μ l) that corrected after 3 platelet transfusions, he developed seizures, apnea with cyanosis, temperature instability and hypoglycemia. His recurrent episodes of hyperglycemia and hypoglycemia resolved with age and the placement of a gastric tube that allowed more frequent feedings. Patient II-1 had tracheomalacia, upper airway obstruc- tion, increased respiratory secretions, frequent aspira- tions, and pulmonary infections from infancy. By age 7 years, he had chronic Pseudomonas aeruginosa respiratory infection. At 6 years, he developed proximal renal tubular acidosis (RTA), nephrocalcinosis and nephro- lithiasis. His renal stones were composed of carbonate apatite and calcium oxalate. His RTA has been managed with fluid and electrolyte replacement, spironolactone and hydrochlorothiazide. Although initially controlled with phenobarbital, his seizures progressed to infantile spasms by 15 months. Adrenocorticotropic hormone (ACTH) treatment transi- ently reduced seizure frequency. His current anticonvulsant therapy includes rufinamide, felbamate, clonazepam, and topiramate. He had delayed development with regression of several developmental milestones. He smiled and laughed by 4 months, reached for toys by 6 months, had vocalizations by 7 months, and could hold his head up and roll onto his side by 8 months. He achieved his pincer grasp at 18 months but lost it by 23 months. He never walked. He lost many motor skills and all vocalization by 26 months of age. A cranial MRI at 14 years revealed cys- tic encephalomalacia and a low parenchymal T2 signal in the right temporal and right occipital lobes. These findings were considered consequences of the perinatal intraventricular hemorrhage. When first evaluated at NIH at 15 years, Patient II-1 was awake but not interactive and could not sit inde- pendently or hold up his head; he withdrew from nox- ious stimuli. His height, weight and OFC were 129 cm (<3%ile), 30.8kg (<3%ile) and 50.3 cm (<3%ile), respectively. Facial dysmorphisms included a long, oval, asym- metric face, midface hypoplasia, down-slanting palpebral fissures, large, cupped ears, smooth philtrum, high- arched palate and prognathia (Figure 1). His dental en- amel was hypoplastic and secondary teeth 2, 6, 10, and 11 were absent. He had excessive drooling, sluggish pupillary reflexes and left-sided hearing loss. He had frequent seizures, severe hypotonia, decreased muscle bulk, hypoactive deep tendon reflexes, kyphoscoliosis and flexion contractures of most large and small joints (Figure 1). He had one prepubertal (1-2 mL) testis that was undescended but palpable in the inguinal canal and one undescended testis, Tanner stage III pubic hair and a prepubertal phallus. His skin was remarkable for excretions of carbonate apatite, reflecting calcium/phosphate dysregulation. His ophthalmologic exam revealed retinitis pigmentosa and cortical blindness. Previous skeletal problems included congenital bilateral hip dislocation and fractures of his distal fibula (2 years), right humerus (5 years) and spine (6 years). Kyphoscoliosis developed between 6 and 12 years of age. A dual-energy x-ray absorptiometry (DEXA) scan performed at age 15 years demonstrated a bone density of 0.341 gm/cm 2 BMD (height adjusted Z-Score: -2.9 [21]) for the anteroposterior Spine (L1-L4) and 0.342 gm/cm 2 bone mineral density (height adjusted Z-Score: -6.5 [21]) for the right forearm. Skeletal radiographs at 18 years revealed a 60° convex right scoliosis, gracile bones with reduced mineral density, and evidence of previous fractures (Figure 2E-J). Patient II-3, the brother of Patient II-1, was born at 37 weeks by cesarean section following an uncomplicated pregnancy. His birth weight was 2.81 kg (25%). During the immediate neonatal period his platelet count decreased from 90 to 45 k/ μ L, and he was admitted to the neonatal intensive care unit for treatment with dexamethasone and a platelet transfusion. He also had transient hypoglycemia, poor feeding and sensitivity to light. By 4 days of life, his condition had stabilized and he was discharged. Over the subsequent months, he manifested moderate laryngomalacia, mild tracheobro- chomalacia, severe torticollis and abnormally pigmen- ted retinas. Like his brother, he has also had episodic hyper- and hypoglycemia. He was diagnosed with ...
Context 5
... propositus (II-1, Figure 1) is the 18-year-old son of non-consanguineous healthy parents with no family his- tory of intellectual disability or skeletal problems. ...
Context 6
... height, weight and OFC were 129 cm (<3%ile), 30.8kg (<3%ile) and 50.3 cm (<3%ile), respect- ively. Facial dysmorphisms included a long, oval, asym- metric face, midface hypoplasia, down-slanting palpebral fissures, large, cupped ears, smooth philtrum, high- arched palate and prognathia (Figure 1). His dental en- amel was hypoplastic and secondary teeth 2, 6, 10, and 11 were absent. ...
Context 7
... had excessive drooling, sluggish pupillary reflexes and left-sided hearing loss. He had fre- quent seizures, severe hypotonia, decreased muscle bulk, hypoactive deep tendon reflexes, kyphoscoliosis and flexion contractures of most large and small joints (Figure 1). He had one prepubertal (1-2 mL) testis that was undescended but palpable in the inguinal canal and one undescended testis, Tanner stage III pubic hair and a prepubertal phallus. ...
Context 8
... prevented Patient II-3 from traveling to the NIH for evaluation, but review of his medical records and photographs showed that he was alert and non- ambulatory at age 10 years. He had facial features similar to those of his brother (Figure 1), superficial skin excre- tions, hypotonia, large joint contractures and muscle atrophy. ...
Context 9
... formation is decreased in patient II-1 SMS is widely expressed (Additional file 1: Figure S1); consequently, we questioned why specific tissues such as bone are particularly affected in SRS patients. To define better the osteoporosis of SRS, we performed a bicortical transiliac crest core biopsy of Patient II-1. ...
Similar publications
Polyamines have been reported to be involved in grain filling and they might contribute to the construction of heat resistance of some cereals. In this study, the hybrid rice ‘YLY 689’ was used to explore the possible effects of exogenous spermidine (Spd) on seed quality under high temperature during the filling stage. Rice spikes were treated with...
Citations
... p.Q148R and p.I150T are located in the central domain. p.Q148R [34] alters the 5′-methylthioadenosine (MTA)binding site, whereas p.I150T [35] induces structural changes in the vicinity of the MTA-binding site and reduces the stability of the C-terminal domain. p.L277F, p.M303Kfs*3, and p.Y328C are located in the C-terminal domain. ...
Polyamines are ubiquitous in almost all biological entities and involved in various crucial physiological processes. They are also closely associated with the onset and progression of many diseases. Polyaminopathies are a group of rare genetic disorders caused by alterations in the function of proteins within the polyamine metabolism network. Although the identified polyaminopathies are all rare diseases at present, they are genetically heritable, rendering high risks not only to the carriers but also to their descendants. Meanwhile, more polyaminopathic patients might be discovered with the increasing accessibility of gene sequencing. This review aims to provide a comprehensive overview of the structural variations of mutated proteins in current polyaminopathies, in addition to their causative genes, types of mutations, clinical symptoms, and therapeutic approaches. We focus on analyzing how alterations in protein structure lead to protein dysfunction, thereby facilitating the onset of diseases. We hope this review will offer valuable insights and references for the future clinical diagnosis and precision treatment of polyaminopathies.
... Various groups have reported on the effect of polyamines on osteogenic differentiation of MSCs in culture, with widely discordant results [6][7][8][9][10] that may be attributed to the low number of biological replicates, tissue of origin of MSCs (adipose vs. bone marrow), species, outcome measurements, and concentrations of both polyamines and inhibitors tested. Work by Albert et al. has suggested that mesenchymal stem cells/multipotent stromal cells (MSCs) derived from SRS patients show impaired osteogenic differentiation in vitro [11]. To model the disease in a dish, we have previously silenced Sms expression using shRNA in MSCs derived from healthy donors and confirmed that SMS deficiency impairs osteogenesis, both in vitro and after implantation into immune-deficient mice [12]. ...
... To modify intracellular polyamine levels, we chemically inhibited SMS and ODC1 using CDAP and DFMO, respectively ( Figure 1). CDAP is expected to lead to increased spermidine and reduced spermine, as previously described in SRS patients [11] and when using a shRNA targeting SMS [12]. Inhibition of ODC1 is expected to cause a reduction of putrescine, spermidine, and spermine [9,15]. ...
Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels. As a result, the intracellular spermidine to spermine ratio is significantly reduced during the early stages of osteoblastogenesis. Supplementation of cells with exogenous spermidine or spermine decreases matrix mineralization in a dose-dependent manner. Employing N-cyclohexyl-1,3-propanediamine (CDAP) to chemically inhibit spermine synthase (SMS), the enzyme catalyzing conversion of spermidine into spermine, also suppresses mineralization. Intriguingly, this reduced mineralization is rescued with DFMO, an inhibitor of the upstream polyamine enzyme ornithine decarboxylase (ODC1). Similarly, high concentrations of CDAP cause cytoplasmic vacuolization and alter mitochondrial function, which are also reversible with the addition of DFMO. Altogether, these studies suggest that excess polyamines, especially spermidine, negatively affect hydroxyapatite synthesis of primary MSCs, whereas inhibition of polyamine synthesis with DFMO rescues most, but not all of these defects. These findings are relevant for patients with Snyder–Robinson syndrome (SRS), as the presenting skeletal defects—associated with SMS deficiency—could potentially be ameliorated by treatment with DFMO.
... Deficiency of spermine synthase causes excessive spermidine accumulation and a lack of spermine. 141 Patients with Snyder-Robinson syndrome, a syndrome caused by loss-of-function mutations of the spermine synthase gene, exhibit severe OP and kyphoscoliosis and have BMSCs with impaired capacities for osteogenic differentiation and mineralization. 142 Hydrogen sulfide. ...
The gut microbiota (GM) plays a crucial role in maintaining the overall health and well-being of the host. Recent studies have demonstrated that the GM may significantly influence bone metabolism and degenerative skeletal diseases, such as osteoporosis (OP). Interventions targeting GM modification, including probiotics or antibiotics, have been found to affect bone remodeling. This review provides a comprehensive summary of recent research on the role of GM in regulating bone remodeling and seeks to elucidate the regulatory mechanism from various perspectives, such as the interaction with the immune system, interplay with estrogen or parathyroid hormone (PTH), the impact of GM metabolites, and the effect of extracellular vesicles (EVs). Moreover, this review explores the potential of probiotics as a therapeutic approach for OP. The insights presented may contribute to the development of innovative GM-targeted therapies for OP.
... dietary SPM supplementation (5,6,(10)(11)(12)(13)(14)(15)(16). The degree to which this ratio is altered in individual patients depends on the specific SMS mutation and appears to correlate with SMS enzymatic activity as well as phenotype severity, though existing data are insufficient to conclude a genotype-phenotype correlation (14). ...
Snyder-Robinson Syndrome (SRS) is caused by mutations in the spermine synthase ( SMS ) gene, the enzyme product of which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonic musculature, and seizures, along with other more variable symptoms. Currently, medical management focuses on treating these symptoms without addressing the underlying molecular cause of the disease.
Reduced SMS catalytic activity in cells of SRS patients causes the accumulation of spermidine, while spermine levels are reduced. The resulting exaggeration in spermidine-to-spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity in the patient. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this polyamine imbalance and investigate the potential of this approach as a therapeutic strategy for affected individuals.
Here we report the use of difluoromethylornithine (DFMO; eflornithine), an FDA-approved inhibitor of polyamine biosynthesis, in re-establishing normal spermidine-to-spermine ratios in SRS patient cells. Through mechanistic studies, we demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of existing spermidine into spermine in cell lines with hypomorphic variants of SMS . Further, DFMO treatment induces a compensatory uptake of exogenous polyamines, including spermine and spermine mimetics, cooperatively reducing spermidine and increasing spermine levels. In a Drosophila SRS model characterized by reduced lifespan, adding DFMO to the feed extended lifespan. As nearly all known SRS patient mutations are hypomorphic, these studies form a foundation for future translational studies with significant therapeutic potential.
... Polyamine biosynthesis is upregulated during placentation 6 , and knockout or pharmacological inhibition of ODC in rodents results in embryo lethality 7 and abnormal placental development 8 . Moreover, human infants with loss-of-function mutations in spermine synthase (SMS), a condition known as Snyder Robinson Syndrome (SRS), are born small-for-gestational age (SGA) 9,10 . Despite these profound phenotypes, it is still unclear how impairments in polyamine metabolism cause these effects. ...
Placental function and dysfunction differ by sex but the mechanisms are unknown. Here we show that sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding spermine synthase (SMS). Female placental trophoblasts demonstrate biallelic SMS expression, associated with increased SMS mRNA and enzyme activity. Polyamine depletion in primary trophoblasts reduced glycolysis and oxidative phosphorylation resulting in decreased acetyl-coA availability and global histone hypoacetylation in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA-sequencing identifies progesterone biosynthesis as a target of polyamine regulated gene expression, and polyamine depletion reduced progesterone release in male trophoblasts. The effects of polyamine depletion can be attributed to spermine as SMS-silencing recapitulated the effects on energy metabolism, histone acetylation, and progesterone release. In summary, spermine metabolism alters trophoblast gene expression through acetyl-coA biosynthesis and histone acetylation, and SMS escape from X inactivation explains some features of human placental sex differences.
... Daily administration of spermine to rats ameliorated bone and cartilage destruction due to collagen-induced arthritis . Albert et al. (2015) reported that specific alterations in polyamines metabolism led to Snyder-Robinson Syndrome (SRS), a disease characterized by profound depletion of osteoclasts and osteoblasts. Recently, it has also been reported that warmth exposure prevents osteoporosis in mice by inducing the production of polyamines. ...
A growing body of scientific evidence supports the notion that gut microbiota plays a key role in the regulation of various physiological and pathological processes related to human health. Recent findings have now established that gut microbiota also contributes to the regulation of bone homeostasis. Studies on animal models have unraveled various underlying mechanisms responsible for gut microbiota-mediated bone regulation. Normal gut microbiota is thus required for the maintenance of bone homeostasis. However, dysbiosis of gut microbiota communities is reported to be associated with several bone-related ailments such as osteoporosis, rheumatoid arthritis, osteoarthritis, and periodontitis. Dietary interventions in the form of probiotics, prebiotics, synbiotics, and postbiotics have been reported in restoring the dysbiotic gut microbiota composition and thus could provide various health benefits to the host including bone health. These dietary interventions prevent bone loss through several mechanisms and thus could act as potential therapies for the treatment of bone pathologies. In the present review, we summarize the current knowledge of how gut microbiota and its derived microbial compounds are associated with bone metabolism and their roles in ameliorating bone health. In addition to this, we also highlight the role of various dietary supplements like probiotics, prebiotics, synbiotics, and postbiotics as promising microbiota targeted interventions with the clinical application for leveraging treatment modalities in various inflammatory bone pathologies.
... In vitro studies have indicated that Smad4 interacts with transcription factors that affect MSC osteoblast differentiation, such as Runx2 and AP-1 (c-Fos-JunD) (Aspera-Werz et al., 2019). Osteoporosis associated with Snyder-Robinson syndrome is characterized by impaired osteoblast and osteoclast function (Albert et al., 2015). Smad4 is closely associated with the osteoblast differentiation factor Runx2. Smad4 deficiency impairs chondrocyte hypertrophy during mouse skeletal development through the Runx2 transcription factor (Yan et al., 2018). ...
Osteoblast differentiation is a complex process that is essential for normal bone formation. A growing number of studies have shown that microRNAs (miRNAs) are key regulators in a variety of physiological and pathological processes, including osteogenesis. In this study, BMP2 was used to induce MC3T3-E1 cells to construct osteoblast differentiation cell model. Then, we investigated the effect of miR-452-3p on osteoblast differentiation and the related molecular mechanism by RT-PCR analysis, Western blot analysis, ALP activity, and Alizarin Red Staining. We found that miR-452-3p was significantly downregulated in osteoblast differentiation. Overexpression miR-452-3p (miR-452-3p mimic) significantly inhibited the expression of osteoblast marker genes RUNX2, osteopontin (OPN), and collagen type 1 a1 chain (Col1A1), and decreased the number of calcium nodules and ALP activity. In contrast, knockdown miR-452-3p (miR-452-3p inhibitor) produced the opposite effect. In terms of mechanism, we found that Smad4 may be the target of miR-452-3p, and knockdown Smad4 (si-Smad4) partially inhibited the osteoblast differentiation enhanced by miR-452-3p. Our results suggested that miR-452-3p plays an important role in osteoblast differentiation by targeting Smad4. Therefore, miR-452-3p is expected to be used in the treatment of bone formation and regeneration.
... The mechanism of decreased bone mineral density is not well understood. To better define the osteoporosis of SRS, Albert et al. [2015] performed detailed studies on affected individuals and provided the first evidence supporting that SRS patients lose osteoblast and osteoclast activity and that the low bone density ocurring in SRS most likely arises by an intrinsic cellular process [Albert et al., 2015]. Furthermore, Ramsay et al. [2019] modeled the disease by silencing SMS in multipotent stromal cells in human bone marrow and found what led to reduced cell proliferation and deficient bone formation in vitro, as evidenced by reduced mineralization and decreased bone sialoprotein expression. ...
... The mechanism of decreased bone mineral density is not well understood. To better define the osteoporosis of SRS, Albert et al. [2015] performed detailed studies on affected individuals and provided the first evidence supporting that SRS patients lose osteoblast and osteoclast activity and that the low bone density ocurring in SRS most likely arises by an intrinsic cellular process [Albert et al., 2015]. Furthermore, Ramsay et al. [2019] modeled the disease by silencing SMS in multipotent stromal cells in human bone marrow and found what led to reduced cell proliferation and deficient bone formation in vitro, as evidenced by reduced mineralization and decreased bone sialoprotein expression. ...
... Calcium supplementation has slightly improved bone mineral density in a few individuals. On the other hand, the use of bisphosphonates is reserved for the most severe cases of osteoporosis and under certain conditions in children [Albert et al., 2015]. Clinical examination, including assessment for kyphoscoliosis and dual-energy x-ray absorptiometry (DXA) scans for diagnosis and follow-up of osteoporosis should be performed on a regular basis. ...
Snyder-Robinson syndrome (SRS) is an extremely rare X-linked intellectual disability syndrome (MRXSSR; MIM #309583). The main clinical features of SRS include psychomotor delay, hypotonia, and asthenic-type body habitus – reduced body weight and bone abnormalities (osteoporosis, fractures, kyphoscoliosis). We report a case of SRS with a hemizygous missense variant in the SMS gene,c.334C>G (p.Pro112Ala), in a 4-year-old boy, who initially developed hypotonia, delayed motor skills, and subsequently epilepsy. This variant in SMS was found to be de novo. To the best of our knowledge, this novel SMS gene variant has never been previously reported in disease-related variation databases, such as ClinVar or HGMD.
... Many factors play a key roles in the establishment and maintenance of bone density suggesting that common factors could be commonly involved in regulating bone density and autism [46]. In addition, osteoclast dysfunction was also observed in another neurodevelopmental/intellectual development disorder, Snyder Robinson syndrome [47]. Another pathway, the TNF signaling pathway, was also significantly deregulated in ASD. ...
Background:
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with deficits in social communication ability and repetitive behavior. The pathophysiological events involved in the brain of this complex disease are still unclear.
Methods:
In this study, we aimed to profile the gene expression signatures of brain cortex of ASD patients, by using two publicly available RNA-seq studies, in order to discover new ASD-related genes.
Results:
We detected 1567 differentially expressed genes (DEGs) by meta-analysis, where 1194 were upregulated and 373 were downregulated genes. Several ASD-related genes previously reported were also identified. Our meta-analysis identified 235 new DEGs that were not detected using the individual RNA-seq studies used. Some of those genes, including seven DEGs (PAK1, DNAH17, DOCK8, DAPP1, PCDHAC2, and ERBIN, SLC7A7), have been confirmed in previous reports to be associated with ASD. Gene Ontology (GO) and pathways analysis showed several molecular pathways enriched by the DEGs, namely, osteoclast differentiation, TNF signaling pathway, complement and coagulation cascade. Topological analysis of protein-protein interaction of the ASD brain cortex revealed proteomics hub gene signatures: MYC, TP53, HDAC1, CDK2, BAG3, CDKN1A, GABARAPL1, EZH2, VIM, and TRAF1. We also identified the transcriptional factors (TFs) regulating DEGs, namely, FOXC1, GATA2, YY1, FOXL1, USF2, NFIC, NFKB1, E2F1, TFAP2A, HINFP.
Conclusion:
Novel core genes and molecular signatures involved with ASD were identified by our meta-analysis.
... As spermine synthase catalyzes the synthesis of spermine from spermidine, the deficiency of this enzyme causes excessive spermidine accumulation with a lack of spermine. In bone biopsies and primary cultures from patients with SMS mutation, bone histopathology and morphometry showed a profound depletion of osteoblasts with a low bone volume and the absence of a trabecular meshwork (35). In addition, in bone marrow stromal cells of SRS patients, osteogenic differentiation was impaired, with decreased calcium phosphate mineralization (35). ...
... In bone biopsies and primary cultures from patients with SMS mutation, bone histopathology and morphometry showed a profound depletion of osteoblasts with a low bone volume and the absence of a trabecular meshwork (35). In addition, in bone marrow stromal cells of SRS patients, osteogenic differentiation was impaired, with decreased calcium phosphate mineralization (35). This suggests that spermidine excess with spermine depletion may contribute to low bone density. ...
Context
Metabolomics is an emerging tool that provides insights into the dynamics of phenotypic changes. It is a potential method for the discovery of novel serum markers of fracture.
Objective
To identify metabolite parameters that can be used as a proxy for osteoporotic fracture risk
Design
Prospective study based on the Ansung cohort in Korea.
Setting
The general community.
Participants
1,504 participants with metabolomic analyses.
Interventions
None.
Main Outcome Measure
Fragility fractures.
Results
We measured 135 baseline metabolite profiles in fasting serum of the participants. The participants had a mean age of 60.2 years and comprised of 585 (38.9%) men. During a mean 9-year follow-up, 112 osteoporotic fracture events occurred. Of all metabolites measured, only serum spermidine concentrations were positively associated with the risk of fracture (hazard ratio [HR] per 1 μM of spermidine 1.35, 95% confidence interval [CI]= 1.03-1.65, p=0.020) after adjustments for age, sex, BMI, diabetes, hypertension, smoking status, previous fracture history, and baseline tibial quantitative ultrasound. Participants with spermidine concentrations >1.57 μM had a 2.2-fold higher risk of fractures (95% CI 1.08-4.51, p=0.030) compared to those with concentrations ≤1.57 μM after adjustment. In a subgroup analysis, women with baseline spermidine concentrations >1.57 μM also had a 2.4-fold higher risk of fracture than those with concentrations ≤1.57 μM (95% CI 1.02-5.48, p=0.047).
Conclusions
Increased baseline spermidine concentrations were associated with a risk of osteoporotic fracture during a mean 9-year follow-up. The biological significance of the metabolites in the musculoskeletal system could be a subject for future studies.
