Neonatal Progeroid Syndrome Research Articles

POLR3A-mutated Wiedemann-Rautenstrauch fibroblasts display differential profile of intron retention and expression of TP53 isoforms

BACKGROUND: Wiedemann-Rautenstrauch Syndrome (WRS) is a neonatal progeroid syndrome for which biallelic pathogenic variants in RNA polymerase III subunit A (POLR3A) have recently been described. POLR3 is a 17 subunits protein complex responsible for the transcription of short RNAs including all the transfer RNAs (tRNAs), the 5 S subunit of ribosomal RNA, the short nuclear RNA U6, among other regulatory RNAs. OBJECTIVE: We aim to evaluate the impact of POLR3A pathogenic variants on the relative expression of the short nuclear RNA U6 and on the differential profile of intron retention RNA U6, p53 isoforms and in fibroblasts derived from patients with WRS and control fibroblasts. METHODS: RNA was extracted by the TRIzol method; intron retention analysis was performed by using IRFinder from an mRNA sequencing (RNA-Seq) platform; P53 isoforms, short nuclear RNA U6 and additional genes related to cell senescence were measured by RT-PCR. RESULTS: No significant differences were found in the percentage of intron retention (control: 7.8%, WRS1 : 6.3%and WRS2 : 8.14%). Genes showing higher intron retention profile in both groups were mainly related to RNA binding pathways, cell cycle regulation, positive regulation of transcription, positive regulation of inflammatory pathways, negative regulation of apoptosis, RNA transcription, mitochondria, and regulation of translation initiation. However, in WRS fibroblasts the genes with more intron retention were those related to the immune response and mitochondrial function; while in control those related to the response to oxidative stress had the most introns retained. WRS1 showed higher expression of short nuclear RNA U6 compared to control and WRS2; while both WRS cells showed higher expression of p53β and lower percentage of Δ133p63α, consistent with a higher expression of the cellular senescence markers p16 and p21. CONCLUSIONS: These results demonstrated the important role of POLR3A in the maintenance of cellular homeostasis and highlight its potential role in cell senescence in WRS.

Wiedemann-Rautenstrauch syndrome. The first description of a clinical case in the Russian Federation

Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) is an ultra-orphan disease from the group of premature aging syndromes with an autosomal recessive type of inheritance associated with mutations in the POLR3A, POLR3B, and POLR3GL genes encoding RNA polymerase III. The incidence of the disease is currently unknown. We present the first clinical description in Russian Federation of a patient 7 years 6 months old with Wiedemann-Rautenstrauch syndrome (compound heterozygous mutations in POLR3A gene) with progeroid features, adentia, growth retardation (height SDS -3,41, height velocity SDS -2,47), underweight (BMI SDS -6,20), and generalized lipodystrophy. The article presents the observation of the patient for 1.5 years, the world experience of dynamic follow-up of patients with neonatal progeroid syndrome, differential diagnosis, as well as recommendations for the management of patients with this syndrome. Given the lack of specific treatment to date, patients are observed by a multidisciplinary team of physicians.

Дифференциальная диагностика прогероидного неонатального синдрома

Aim. Аnalysis and synthesis of the literature data on the problem of differential diagnosis of neonatal progeroid syndrome. Key points. One of the rarest representatives of premature aging syndromes is neonatal progeroid syndrome (Wiedemann–Rautenstrauch syndrome). It is an ultra-orphan disease with autosomal recessive type of inheritance, associated with a mutation in the POLR3A, POLR3B, POLR3GL genes and characterized by congenital lipodystrophy and premature aging. The disease manifests from the first days of life: low body length and weight at birth, pronounced phenotypic features (pseudohydrocephaly, progeroid facial features, generalized lipodystrophy, neonatal incisors). Severe bronchopulmonary and skeletal damage is seen over the course of life, and average life expectancy ranges from 7 months to 2 years but can reach 27 years. The differential diagnosis is made with Hutchinson–Gilford syndrome (progeria), which clinical signs manifest at 1.5-2 years of age, and with Marfan-progeroid lipodystrophy, Fontaine syndrome, and Sekkel syndrome. Conclusion. Early diagnostics is necessary for predicting the course of the disease, selection of treatment, and determining of further management. Keywords: neonatal progeroid syndrome, Wiedemann–Rautenstrauch syndrome, premature aging syndromes

WIEDEMANN–RAUTENSTRAUCH SYNDROME: CASE REPORT

Neonatal-progeroid syndrome known as Wiedemann Rautenstrauch syndrome (WRS) is an extremely rare, autosomal recessive disorder. Neonatal progeroid disease characterized by progeroid appearance growth retardation, lipodystrophy, an unusual face (triangular shape, sparse hair, small mouth, macrocephaly, pointed jaw), thin skin, hard and thick joints and dental anomalies (newborn tooth; hypodontics). A 5-year-old boy case diagnosed with hypodontics is presented. In this case, a child prosthesis was performed to facilitate the nutrition of the patient and to increase the quality of life.

Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia.

CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3. In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients' fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients' fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence. The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.

A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A‐related pathologies

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.

Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations.

ObjectiveTo expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.MethodsWe performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [1H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.ResultsThe patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.ConclusionsMutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.

Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders.

The extracellular matrix microenvironment of adipose tissue is of critical importance for the differentiation, remodeling and function of adipocytes. Fibrillin-1 is one of the main components of microfibrils and a key player in this process. Furin processing of profibrillin-1 results in mature fibrillin-1 and releases the C-terminal propeptide as a circulating hunger hormone, asprosin. Mutations in the fibrillin-1 gene lead to adipose tissue dysfunction and causes Marfan syndrome, marfanoid progeroid lipodystrophy syndrome, and neonatal progeroid syndrome. Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils. Circulating asprosin on the other hand is secreted primarily by white adipose tissue under fasting conditions and in obesity. It increases hepatic glucose production and drives insulin secretion and appetite stimulation through inter-organ cross talk. This review discusses the metabolic consequences of fibrillin-1 and fibrillin-1-derived asprosin in pathological conditions. Understanding the dynamic role of fibrillin-1 in the adipose tissue milieu and of circulating asprosin in the body can provide novel mechanistic insights into how fibrillin-1 may contribute to metabolic syndrome. This could lead to new management regimens of patients with metabolic disease.

Energy Regulation Mechanism and Therapeutic Potential of Asprosin.

Genetic studies of patients with neonatal progeroid syndrome led to the discovery of the novel fasting-induced, glucogenic, and orexigenic hormone named asprosin, the C-terminal cleavage product of profibrillin. Upon secretion, asprosin travels to the liver, where it exerts a glucogenic effect through OR4M1, an olfactory G-protein-coupled receptor. It also crosses the blood-brain barrier to stimulate appetite-modulating neurons in the arcuate nucleus of the hypothalamus, exerting an orexigenic effect via an as yet unidentified receptor. Specifically, it stimulates appetite by activating orexigenic AgRP neurons and inhibiting anorexigenic POMC neurons. Studies have also focused on the therapeutic potential of inhibiting asprosin for treatment of obesity and type 2 diabetes, both of which are characterized by high levels of circulating asprosin. It has been shown that anti-asprosin monoclonal antibodies reduce blood glucose, appetite, and body weight, validating asprosin as a therapeutic target. Current work aims to uncover key features of the asprosin biology such as the identification of its neuronal receptor, identification of the secretion mechanism from adipose tissue, and development of anti-asprosin monoclonal antibodies as diabetes and obesity therapies.

Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

Neonatal progeroid syndrome (Weidman Rautenstrauch syndrome): A case report from Jammu &Kashmir, India.

A female one month old with features supporting a diagnosis of neonatal progeroid syndrome(WRS) presented to our neonatology section of GB pant children hospital Srinagar .she had prenatal and post natal growth failure, generalized lipotrophy, triangular face, psedohydrocephalous, sparse scalp hair and eye brows, prominent scalp veins and greatly widened anterior fontenella.

Wiedemann–Rautenstrauch syndrome: Report of a variant case

Wiedemann-Rautenstrauch syndrome (WRS) is a rare autosomal recessive disorder that includes premature aging phenotype at birth. The condition is also known as a neonatal progeroid syndrome. Up to now only a few published case reports have been documented. The syndrome is characterized by progeroid appearance, decreased subcutaneous fat, hypotrichosis, macrocephaly, and in some natal teeth. We describe a new patient with features of bilaterally pelvicalyceal ectasia and partial syndactyly on 2th and 3th toes, not previously described, to our knowledge.

Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome) in an Egyptian child with premature loss of teeth, and café au lait skin patches

A female, 26months old with features supporting the diagnosis of neonatal progeroid syndrome was presented. She had prenatal and postnatal growth failure, generalized lipoatrophy except for fat pads in the suprabuttock areas, triangular face, pseudohydrocephalous, sparse scalp hair and eyebrows, prominent scalp veins, greatly widened anterior fontanels, and moderate mental retardation. The patient had also some features not reported previously as premature loss of milk teeth, large mouth, atrophic gums, protruded lower jaw, and café aulait skin patches on lower limbs. Nail dystrophy was also detected. She had local depression of the left parietal bone on CT brain, white matter demyelination in MRI brain, and high level of cholesterol.

Wiedemann–Rautenstrauch Syndrome: First Indian Case

Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome (NPS), is an extremely rare genetic disorder characterised by an aged appearance at birth. About thirty cases have been reported in the literature. The authors report first Indian baby with Wiedemann-Rautenstrauch syndrome with the lowest birth weight documented in such a patient, who is still surviving at 24 months. This ethnicity has not been reported previously in literature.

Marfan syndrome with neonatal progeroid syndrome‐like lipodystrophy associated with a novel frameshift mutation at the 3′ terminus of the FBN1‐gene

We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth, who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy. She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. Mutation analysis in the gene encoding fibrillin 1 (FBN1) revealed a novel de novo heterozygous deletion, c.8155_8156del2 in exon 64. The severe generalized lipodystrophy in this patient with progeroid features has not previously been described in other patients with MFS and FBN1 mutations. We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C). Other progeria syndromes were considered unlikely because premature greying, hypogonadism, and scleroderma-like skin disease were not present. Our patient shows striking similarity to two patients who have been published in this journal by O'Neill et al. [O'Neill et al. (2007); Am J Med Genet Part A 143A:1421-1430] with the diagnosis of neonatal progeroid syndrome (NPS). This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features. The course is usually progressive with early lethality. However this entity seems heterogeneous. We suggest that our patient and the two similar cases described before represent a new entity, a subgroup of MFS with overlapping features to NPS syndrome.

Natural Course of Neonatal Progeroid Syndrome

Several progeroid disorders presenting a specific "old-man" appearance since birth or childhood have been described. Here, five patients with a history of severe intrauterine and postnatal growth retardation and pseudohydrocephaloid cranium noted after birth that were suggestive of neonatal progeroid syndrome (NPS) or Wiedemann-Rautenstrauch syndrome are reported. We discuss the natural course of the syndrome. A series of anthropometric measurements, imaging, dual energy X-ray absorptiometry, and endocrine investigations to assess metabolic complications such as hyperinsulinemia and dyslipidemia were performed on these five patients who were followed for 1-7 years. Screening of inborn errors, karyotyping, chromosomal breakage rates and DNA mutational studies with direct sequencing of LMNA, ERCC8 and ZMPSTE24 genes were also performed. Generalized lipodystrophy was noted in all patients except for regions such as the cheeks, hands and feet. All cases had failure to thrive, microcephaly, ear dysplasia, laryngomalacia, hearing impairment, gastro-esophageal reflux disease, constipation, abnormal dentition, dermatitis/acrodermatitis enteropathica, hyperpigmentation of the skin, very low insulin-like growth factor I levels with delayed bone age, relative hypolipidemia, initial camptodactyly/joint contracture, progressive kyphoscoliosis, osteoporosis with loose joints, ventriculomegaly, and generalized organic aciduria. Other findings included inguinal hernia, hypothyroidism or persistent hyperthyrotropinemia, cryptorchidism, hip dysplasia, growth hormone deficiency, cloudy cornea with congenital glaucoma, neonatal teeth, cardiac defects, basal ganglia calcification and seizure disorder. These patients with NPS did not show hyperinsulinemia or dyslipidemia. Their karyotypes were all normal, while the chromosomal breakage test showed markedly increased breakage rates in four patients. LMNA, ERCC8, or ZMPSTE24 gene mutations could not account for the disorders in these patients. Four patients died after sepsis or aspiration pneumonia at the age of 1.1, 4, 6.2 and 7.5 years. Increased chromosomal breakage and the presence of basal ganglia calcification after early childhood suggest that DNA repair defects are involved in the pathogenesis of this disorder. This rare disorder represents a complex of symptoms with unknown cause and pathogenesis, and more than one disease may account for the clinical variability of NPS.

The neonatal progeroid syndrome (Wiedemann–Rautenstrauch): A model for the study of human aging?

The Wiedemann–Rautenstrauch syndrome (WRS) characterises a premature aging syndrome in which several features of human aging are apparent at birth therefore allowing their grouping as a neonatal progeroid condition. This differentiates WRS from other progeroid entities such as Hutchinson–Gilford progeria syndrome (HGPS) in which characteristics of premature aging become apparent some time after birth. The etiology of WRS remains unknown. Some studies have observed an autosomal recessive mode of inheritance. Several studies analysing telomere length and lamin A gene have not revealed any alterations. However, mutations in LMNA have been reported in several other atypical progeroid syndromes. Based on these observations, several hypothesis could be withdrawn concerning the etiology of WRS. The study of genes associated with lamin A metabolism, such as Zmpste24, and the metabolic pathways associated with insulin, such as protein kinase B or AKT, are of particular interest. We believe that WRS characteristics indicate that discovery of the gene and the metabolic pathway associated with this syndrome will most likely lead to new knowledge about the physiopathology of human aging.

Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome

Neonatal progeroid syndrome (NPS), also known as Wiedemann-Rautenstrauch Syndrome, is a rare autosomal recessive disorder characterized by accelerated aging and lipodystrophy from birth. Affected children have extreme intrauterine growth retardation, poor postnatal weight gain, and characteristic facial dysmorphic features such as a triangular shape, pinched nose, pseudohydrocephalus with wide fontanelles and prominent subcutaneous (sc) veins. Generalized loss of sc fat has been reported as a cardinal feature; however, the pattern of fat loss and its association with insulin resistance and its metabolic complications have not been systematically studied. The aim of the current study was to examine body fat distribution and body composition in two girls with NPS using anthropometric measures, whole-body magnetic resonance imaging (MRI) and dual energy X-ray absorptiometry (DEXA), and to assess metabolic complications such as hyperinsulinemia and dyslipidemia. Both the girls (aged 17 years and 10 years, respectively) had generalized paucity of sc fat on physical examination. However, measurements of skin-fold thickness revealed that sc fat was decreased over the extremities, but preserved over the chest and abdomen. MRI studies confirmed the presence of normal amounts of sc truncal fat, and marked loss of fat from the face and distal extremities. Striking fat loss was also noted in the paravertebral and lateral gluteal regions. Interestingly, body composition analysis with DEXA scan revealed a marked reduction in both the fat and lean tissue mass. Fasting glucose, lipids and insulin levels were not elevated. We conclude that patients with NPS do not have generalized lipodystrophy as previously reported, but fat loss is confined to the face, distal extremities, and possibly the paravertebral and lateral gluteal regions. Metabolic abnormalities related to insulin resistance are also uncommon in this condition.

Propofol infusion syndrome during anaesthesia for scoliosis surgery in an adolescent with neonatal progeroid syndrome

Propofol infusion syndrome during anaesthesia for scoliosis surgery in an adolescent with neonatal progeroid syndrome

Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: Report of five new cases and review

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.