De Barsy Research Articles

De Barsy syndrome due to ALDH18A1 mutation – Expanding the spectrum of a rare neurocutaneous syndrome

De Barsy syndrome is a rare autosomal recessive genetic disorder that manifests with cutis laxa, progeroid appearance, and neurologic and eye abnormalities. It was initially described by De Barsy et al. in 1968. Mutations in the ALDH18A1 gene or PYCR1 genes have been implicated in this syndrome. ALDH18A1 mutations are associated with cutis laxa type IIIA and hereditary spastic paraplegia 9A. We describe an 8-month-old male with cutis laxa, developmental delay and seizures harbouring the ALDH18A1 mutation. Our patient has certain phenotypic manifestations and radiologic findings that make it unique from the other cases described till date.

Abstract 2938: Comprehensive genomic profiling of solid tumor patients with the OncoDEEP assay for broad analysis in clinical diagnostics

Abstract Somatic multi-gene analysis by Next Generation Sequencing (NGS) becomes standardly integrated in medical oncology for clinical decision making. However, with the fast-growing number of recommended and required genomic biomarkers, small panels have become vastly insufficient for most tumor types. Comprehensive Genomic Profiling (CGP) is amenable to screen for single nucleotide variants (SNVs) and subtle insertions and deletions (indels) in several hundreds of genes. Moreover, it provides information on copy number variations (CNVs) and gene fusions of the most relevant genes for optimal patient management. Currently, most comprehensive panels also allow for screening of tumor-agnostic genomic biomarkers, including microsatellite instability (MSI), tumor mutation burden (TMB) and homologous recombination deficiency (HRD), which are implemented as prognostic and therapeutic signatures in a wide variety of solid tumors. So far, only a handful of CGP assays have been validated for their diagnostic utility in routine laboratory practice for the care of cancer patients. In this study we report on an extensive multicentric analysis across multiple centers in Belgium and The Netherlands comparing the novel OncoDEEP CGP assay (OncoDNA) with the diagnostically validated TSO500 assay (Illumina). We describe the technical differences between both assays as well as their outcome and shortcomings. Detection of clinically relevant SNVs, indels and CNVs was very similar and differences were often due to assay-specific settings. Similarly, TMB, MSI and HRD data were concordant for most samples but those with scores close to the cut-offs could deviate. For fusion detection, concordance was found for the limited number of 11 clinically-actionable driver genes covered by the OncoDEEP kit. The uniformity of coverage was much higher with the OncoDEEP assay thereby allowing to pool 2- to 3-times more samples per NGS run. For the diagnostic implementation of the OncoDEEP assay we then performed an extensive validation with clinical samples representing a wide variety of solid tumor types, as well as reference samples. All performance metrics passed the validation criteria. In conclusion, the OncoDEEP kit can be used for reliable diagnostic comprehensive profiling of solid tumors, but currently, extensive fusion analysis requires an additional screening method. Citation Format: Ernst-Jan M. Speel, Pieter-Jan Volders, Joni Van der Meulen, Aaron De Cock, Stefanie Vermeire, Jacques Van Huysse, Marie De Barsy, Gabriela Beniuga, Wendy de Leng, Anne Jansen, Sharon Thijssen, Hendrikus Jan Dubbink, Zeliha Ozgur, Wilfred van Ijcken, Brigitte Maes, Guy Froyen. Comprehensive genomic profiling of solid tumor patients with the OncoDEEP assay for broad analysis in clinical diagnostics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2938.

SAT670 Is Myostatin A Biomarker Of Skeletal Muscle Mass?

Abstract Disclosure: L. Orioli: None. S. Samaras: None. P. Lause: None. M. de Barsy: None. J.M. Thissen: None. A. Loumaye: None. Rationale: Our study aims to determine whether myostatin is a biomarker of muscle mass in cancer cachexia and obesity. Methods: The ACTICA study included cancer patients with and without cachexia. The MYDIASECRET study included obese patients evaluated before and 3 months after bariatric surgery. Body composition was assessed using bioelectrical impedance analysis (BIA101 device, Akern). Skeletal muscle mass (SMM) and appendicular SMM (ASMM) were calculated from Janssen’s and Sergi’s equations, respectively. Results were expressed as indexes (kg/m²). Myostatin plasma concentrations were determined using ELISA. Spearman’s coefficient was used to correlate muscle mass indexes and myostatin. Results: The ACTICA study included 143 patients of whom 70 with cachexia. SMM index (SMMI) and ASMM index (ASMMI) were lower in patients with cachexia compared to those without cachexia (SMMI: 8.0 kg/m² [6.7-9.5] vs 9.0 kg/m² [7.8-10.1], p=0.004; ASMMI: 6.2 kg/m² [5.5-7.1] vs 7.2 kg/m² [6.4-7.8], p<0.001). Myostatin was also lower in patients with cachexia (1434 pg/mL [999-2118] vs 2149 pg/mL [1551-2984], p<0.001). Myostatin was positively correlated with SMMI and ASMMI (SMMI: R=0.500, p<0.001; ASMMI: R=0.479, p<0.001). The MYDIASECRET study included 62 patients. SMMI and ASMMI were decreased after surgery (SMMI: -0.8 kg/m², p<0.001; ASMMI: -1.1 kg/m², p<0.001). Myostatin was also decreased after surgery (1773 pg/mL [1440-2309] vs 2582 pg/mL [1708-3522], p<0.001). Myostatin was positively correlated with SMMI before (R=0.388, p=0.002) and after surgery (R=0.435, p<0.001). Change in myostatin after surgery was also positively correlated with change in SSMI (R=0.287, p=0.023). Conclusion: Myostatin is positively correlated with muscle mass indexes in different conditions, suggesting its potential role as a biomarker of muscle mass. Presentation: Saturday, June 17, 2023

Incomplete cleft palate in a child with De Barsy syndrome

De Barsy syndrome, a rare genetic disorder, is characterized by progeroid features, cutis laxa, ocular abnormalities, growth retardation, and intellectual disability. We present a case of 1½- year-old male child with De Barsy syndrome associated with incomplete cleft palate.

Clinical implications of de Barsy syndrome

De Barsy syndrome is a rare, autosomal recessive syndrome characterized by cutis laxa, progeroid appearance, ophthalmic opacification, skeletal malformations, growth delays, and intellectual disability. The aim of this case series is to identify the anesthetic considerations in the clinical management of patients with de Barsy syndrome. A retrospective case review from 1968 to 2016 was performed at a single tertiary medical center to identify patients with de Barsy syndrome who underwent anesthesia for diagnostic and surgical procedures. We collected and analyzed the perioperative records and following data: age, sex, American Society of Anesthesiologists physical status, relevant comorbidities, surgical procedures, anesthesia management, and observed complications. Three patients underwent 64 unique anesthetics for a diverse collection of diagnostic and surgical procedures. An array of anesthetics and techniques were successfully used. Observations of the perioperative period found 7 episodes of intraoperative hyperthermia (>38.3°), a single difficult airway requiring fiberoptic bronchoscopic-guided intubation, and repeatedly difficult intravenous access. This expanded case series suggests that providers caring for patients with de Barsy syndrome should be aware of potential challenges with airway management, vascular access, and temperature monitoring.

De Barsy Syndrome: Orthopedic Case report and Literature Review

De Barsy Syndrome: Orthopedic Case report and Literature Review

Severe Phenotype of De Barsy Syndrome in Two Siblings with Novel Mutations in the ALDH18A1 Gene

De Barsy syndrome is a rare autosomal recessive genetic disorder characterized by growth retardation, intellectual disability, a prematurely-aged appearance (progeroid features) and loose skin (cutis laxa) as well as eye abnormalities and others. Some cases of de Barsy syndrome have been linked with mutations PYCR1 or ALDH18A1. We describe a family with two siblings with clinically severe de Barsy syndrome in whom two novel mutations in ALDH18A1 (p.Glu100* and p.Arg724His) were found by clinical exome sequencing using TruSight One panel. The p.Glu100* is a novel mutation predicted to cause absence of the protein. The p.Arg724His has been found with low frequency (0.000016) but not in association with human disease; it has been scored as pathogenic by CADD, MetaSVM, Polyphen2, MutationAssessor, SIFT and MutationTaster. The level of ammonia in serum was determined in second sibling and was in normal range. Amino acid profile in serum revealed decreased concentration of arginine, cytruline, homocysteine, PHE and ornithine. The patients suffer from severe symptoms of GERD such as vomiting, feeding problems instead of multistage therapy including Nissen fundoplication procedure as well as from epilepsy requires complex multidrug therapy. L-Arginine (200 mg/kg) and citrulline (100 mg/kg) were supplemented in the second sibling. The disease leads to premature apoptosis, so antioxidants (coenzyme Q, vitamin A and E) as well as carnitine were supplemented but without spectacular clinical results. We provide clinical description of severe phenotype of de Barsy syndrome. Our molecular report broadens the spectrum of ALDH18A1 mutations causing de Barsy syndrome.

De Barsy syndrome type B presenting with cardiac and genitourinary abnormalities.

De Barsy syndrome type B presenting with cardiac and genitourinary abnormalities.

A 5-year Journey with Cutis Laxa in an Indian Child: The De Barsy Syndrome Revisited.

De Barsy syndrome (DBS), synonymously known as autosomal recessive cutis laxa type III, is an extremely rare condition clinically characterized by cutis laxa, a progeroid appearance, and ophthalmologic abnormalities. We present here an account of 5-year follow-up since the birth of an Indian boy with DBS, who had a few rare and unusual manifestations. In addition, our case probably represents the first reported case of DBS from India.

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.

Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1

Autosomal recessive cutis laxa (ARCL) type 2 constitutes a heterogeneous group of diseases mainly characterized by lax and wrinkled skin, skeletal anomalies, and a variable degree of intellectual disability. ALDH18A1-related ARCL is the most severe form within this disease spectrum. Here we report on the clinical and molecular findings of two affected individuals from two unrelated families. The patients presented with typical features of de Barsy syndrome and an overall progeroid appearance. However, the phenotype was highly variable including cardiovascular involvement in the more severe case. Investigation of a skin biopsy of one patient revealed not only the typical alterations of elastic fibers, but also an altered structure of mitochondria in cutaneous fibroblasts. Using conventional sequencing and copy number analysis we identified a frameshift deletion of one nucleotide and a microdeletion affecting the ALDH18A1 gene, respectively, in a homozygous state in both patients. Expression analysis in dermal fibroblasts from the patient carrying the microdeletion showed an almost complete absence of the ALDH18A1 mRNA resulting in an absence of the ALDH18A1 protein. So far, only 13 affected individuals from seven unrelated families suffering from ALDH18A1-related cutis laxa have been described in literature. Our findings provide new insights into the clinical spectrum and show that beside point mutations microdeletions are a possible cause of ALDH18A1-ARCL.

A case of de Barsy syndrome with a severe eye phenotype

A case of de Barsy syndrome with a severe eye phenotype

De Barsy Syndrome: A genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction

De Barsy Syndrome: A genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction

Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome

De Barsy syndrome (DBS) is characterized by progeroid features, ophthalmological abnormalities, intrauterine growth retardation, and cutis laxa. Recently, PYCR1 mutations were identified in cutis laxa with progeroid features. Herein, we report on a DBS patient born to a nonconsanguineous Chinese family. The exceptional observation of congenital glaucoma, aortic root dilatation, and idiopathic hypertrophic pyloric stenosis in this patient widened the range of symptoms that have been noted in DBS. Mutation analysis of PYCR1 revealed compound heterozygous PYCR1 mutations, including a p.P115fsX7 null mutation allele and a second allele with two missense mutations in cis: p.G248E and p.G297R. The effect of mutation results in a reduction of PYCR1 mRNA expression and PYCR1 protein expression in skin fibroblasts from the patient. The findings presented here suggest a mutation screening of PYCR1 and cardiovascular survey in patients with DBS.

Lipoprotein Lipase Is a Novel Amyloid β (Aβ)-binding Protein That Promotes Glycosaminoglycan-dependent Cellular Uptake of Aβ in Astrocytes

Lipoprotein lipase (LPL) is a member of a lipase family known to hydrolyze triglyceride molecules in plasma lipoprotein particles. LPL also plays a role in the binding of lipoprotein particles to cell-surface molecules, including sulfated glycosaminoglycans (GAGs). LPL is predominantly expressed in adipose and muscle but is also highly expressed in the brain where its specific roles are unknown. It has been shown that LPL is colocalized with senile plaques in Alzheimer disease (AD) brains, and its mutations are associated with the severity of AD pathophysiological features. In this study, we identified a novel function of LPL; that is, LPL binds to amyloid β protein (Aβ) and promotes cell-surface association and uptake of Aβ in mouse primary astrocytes. The internalized Aβ was degraded within 12 h, mainly in a lysosomal pathway. We also found that sulfated GAGs were involved in the LPL-mediated cellular uptake of Aβ. Apolipoprotein E was dispensable in the LPL-mediated uptake of Aβ. Our findings indicate that LPL is a novel Aβ-binding protein promoting cellular uptake and subsequent degradation of Aβ.

De Barsy syndrome in an extreme preterm infant

We report a rare case of an extreme preterm infant with De Barsy syndrome characterized by severe mental retardation, cutis laxa, cloudy corneas, muscular hypotonia, and lax joints. The etiology of this syndrome is unknown but it is probably heterogeneous. Recently a autosomal recessive glycosylation disorder (ATP6V0A2-CDG) has been associated with De Barsy syndrome.

Anesthesia considerations for patients with de Barsy syndrome

Study Objective To determine anesthetic considerations for patients with de Barsy syndrome, a rare complex whose hallmark findings include cutis laxa, progeria, and multiple orthopedic and ophthalmologic abnormalities. Design Retrospective chart review. Setting Medical center. Measurements A search of Mayo Clinic medical records from 1968 to 2007 identified two patients with de Barsy syndrome who underwent a combined total of 35 anesthetics for diagnostic and surgical procedures. Data collected included: age, gender, ASA physical status, relevant comorbidities, surgical procedures, airway management, vascular access, monitoring, anesthetic induction, maintenance, and other observations. Main Results A wide range of anesthetics and techniques were used. Apart from 4 episodes of intraoperative hyperthermia and postoperative tachycardia, no complications were noted. These episodes may be similar to the nonmalignant hyperthermia reported in osteogenesis imperfecta and Costello syndrome patients. Conclusions While the safety of any anesthetic technique cannot be established or extrapolated from a small series, given the extreme rarity of the syndrome, these cases suggest the relative safety of anesthesia in de Barsy syndrome patients.

Niemann-Pick C1 Functions Independently of Niemann-Pick C2 in the Initial Stage of Retrograde Transport of Membrane-impermeable Lysosomal Cargo

The rare neurodegenerative disease Niemann-Pick Type C (NPC) results from mutations in either NPC1 or NPC2, which are membrane-bound and soluble lysosomal proteins, respectively. Previous studies have shown that mutations in either protein result in biochemically indistinguishable phenotypes, most notably the hyper-accumulation of cholesterol and other cargo in lysosomes. We comparatively evaluated the kinetics of [(3)H]dextran release from lysosomes of wild type, NPC1, NPC2, and NPC1/NPC2 pseudo-double mutant cells and found significant differences between all cell types examined. Specifically, NPC1 or NPC2 mutant fibroblasts treated with NPC1 or NPC2 siRNA (to create NPC1/NPC2 pseudo-double mutants) secreted dextran less efficiently than did either NPC1 or NPC2 single mutant cell lines, suggesting that the two proteins may work independently of one another in the egress of membrane-impermeable lysosomal cargo. To investigate the basis for these differences, we examined the role of NPC1 and NPC2 in the retrograde fusion of lysosomes with late endosomes to create so-called hybrid organelles, which is believed to be the initial step in the egress of cargo from lysosomes. We show here that cells with mutated NPC1 have significantly reduced rates of late endosome/lysosome fusion relative to wild type cells, whereas cells with mutations in NPC2 have rates that are similar to those observed in wild type cells. Instead of being involved in hybrid organelle formation, we show that NPC2 is required for efficient membrane fission events from nascent hybrid organelles, which is thought to be required for the reformation of lysosomes and the release of lysosomal cargo-containing membrane vesicles. Collectively, these results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo.

De Barsy syndrome and ATP6V0A2-CDG

We read with interest the nice review of Morava et al1 on the autosomal recessive cutis laxa syndromes. The authors mention the De Barsy syndrome and state that the genetic background of the De Barsy syndrome has not yet been identified. However, in the paper by Kornak et al2 on impaired glycosylation and cutis laxa caused by mutations in ATP6V0A2 (ATP6V0A2-CDG according to the novel nomenclature3, 4), one of the patients (see patient CoFe in Table 1 of Kornak et al2) shows the full clinical picture of the De Barsy syndrome, including cutis laxa, facial dysmorphy, dwarfism, psychomotor retardation, dystonia, congenital hip dysplasia, and corneal dystrophy necessitating repeated corneal transplantation. These data suggest that a subgroup of patients with De Barsy syndrome5 belongs to the spectrum of ATP6V0A2-CDG. Another cause of De Barsy syndrome has very recently been identified as mutations in PYCR1, coding for a mitochondrial enzyme involved in proline metabolism.6 Therefore, we recommend a systematic screen for ATP6V0A2-CDG and for mutations in PYCR1 in patients with De Barsy syndrome.

Reply to Leao-Teles et al

We appreciate the comments1 on our review on autosomal recessive cutis laxa syndromes,2 especially the novel information on the Portuguese patient CoFe3 (Table 1, Kornak et al), who was diagnosed with a combined N- and O-linked glycosylation disorder and ATP6V0A2-CDG. De Barsy syndrome is a challenging diagnosis, and has overlapping features with ARCL type 2, including cutis laxa, short stature, late closure of the fontanel, congenital hip dysplasia, some aspects of facial dysmorphism and psychomotor retardation.4 Still, dystonic movements and progressive corneal abnormalities are highly suggestive of De Barsy syndrome. So far no cobble-stone-like brain dysgenesis has been observed in De Barsy syndrome patients. Although the clinical differentiation is not always straightforward, progeroid features, the presence of pergamen-like skin and the absence of subcutaneous fat are distinctive.2 Interestingly, some of the patients, recently reported to have PYCR1 mutations, were previously diagnosed with De Barsy syndrome,5 while other De Barsy patients were found to not harbour PYCR1 mutations (unreported data), thus supporting genetic heterogeneity. We would appreciate further description and photo documentation of this unique patient, reported by Leao-Teles, as in our own cohort of six patients with De Barsy syndrome and those studied by Kornak et al (personal communication) none of the children had either N-linked or O-linked glycosylation abnormalities, nor mutations in the ATP6V0A2 gene. Eye anomalies are common in N-glycosylation disorders,6 and strabismus and high myopia have been reported in combined glycosylation disorders.4 The exceptional observation of corneal abnormalities with a movement disorder in association with ATP6V0A2-CDG indeed widens the range of symptoms evoking glycosylation studies in patients with cutis laxa.