CPG_SG_Artigos publicados em revistas indexadas na Pubmed/Medline
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- Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative TranscriptsPublication . Encarnação, Marisa; Ribeiro, Isaura; David, Hugo; Coutinho, Maria Francisca; Quelhas, D; Alves, SandraNiemann-Pick type C (NPC, ORPHA: 646) is a neuro-visceral, psychiatric disease caused predominantly by pathogenic variants in the NPC1 gene or seldom in NPC2. The rarity of the disease, and its wide range of clinical phenotypes and ages of onset, turn the diagnosis into a significant challenge. Other than the detailed clinical history, the typical diagnostic work-up for NPC includes the quantification of pathognomonic metabolites. However, the molecular basis diagnosis is still of utmost importance to fully characterize the disorder. Here, the authors provide an overview of splicing variants in the NPC1 and NPC2 genes and propose a new workflow for NPC diagnosis. Splicing variants cover a significant part of the disease-causing variants in NPC. The authors used cDNA analysis to study the impact of such variants, including the collection of data to classify them as leaky or non-leaky pathogenic variants. However, the presence of naturally occurring spliced transcripts can misdiagnose or mask a pathogenic variant and make the analysis even more difficult. Analysis of the NPC1 cDNA in NPC patients in parallel with controls is vital to assess and detect alternatively spliced forms. Moreover, nonsense-mediated mRNA decay (NMD) analysis plays an essential role in evaluating the naturally occurring transcripts during cDNA analysis and distinguishing them from other pathogenic variants' associated transcripts.
- Parental gonadossomatic mosaicism in HIVEP2-related intellectual disability and impact on genetic counseling–case reportPublication . Abreu, Maria; Branco, Tiago; Figueiroa, Sónia; Falcao Reis, Claudiantellectual development disorder, autosomal dominant 43 (MRD43) is an autosomal dominant disorder caused by heterozygous mutations in the HIVEP2 gene. In this report, we describe a case of a 4-year-old boy with global development delay, hypotonia, and dysmorphic features, in whom the finding of a heterozygous nonsense pathogenic variant in exon 5 of HIVEP2 [c.2827C>T p. (Arg943*)] through WES established a MRD43 diagnosis. Our patient's phenotype overlaps with other MRD43 descriptions in the literature. Unlike previously reported cases, where the condition was almost invariably de novo, the healthy mother in this case presented mosaicism for the pathogenic variant. Thus, the recurrence risk increased significantly from 1% to up to 50%. The description of a variant inherited for MDR43 is singular in the literature and this description highlights the importance of parental studies for accurate genetic counseling, particularly for family planning.
- SLC35A2-CDG: Novel variant and reviewPublication . Quelhas, D; Correia, Joana; Jaeken, Jaak; Azevedo, Luísa; Lopes-Marques, Mónica; Bandeira, Anabela; Keldermans, Liesbeth; Matthijs, Gert; Sturiale, Luisa; Martins, EsmeraldaSLC35A2 encodes the X-linked transporter that carries uridine diphosphate (UDP)-galactose from the cytosol to the lumen of the Golgi apparatus and the endoplasmic reticulum. Pathogenic variants have been associated to a congenital disorder of glycosylation (CDG) with epileptic encephalopathy as a predominant feature. Among the sixty five patients described so far, a strong gender bias is observed as only seven patients are males. This work is a review and reports a SLC35A2-CDG in a male without epilepsy and with growth deficiency associated with decreased serum IGF1, minor neurological involvement, minor facial dysmorphism, and camptodactyly of fingers and toes. Sequence analysis revealed a hemizygosity for a novel de novo variant: c.233A > G (p.Lys78Arg) in SLC35A2. Further analysis of SLC35A2 sequence by comparing both orthologous and paralogous positions, revealed that not only the variant found in this study, but also most of the reported mutated positions are conserved in SLC35A2 orthologous, and many even in the paralogous SLC35A1 and SLC35A3. This is strong evidence that replacements at these positions will have a critical pathological effect and may also explain the gender bias observed among SLC35A2-CDG patients.
- Defining tetrahydrobiopterin responsiveness in phenylketonuria: Survey results from 38 countriesPublication . Evers, R.A.F.; van Wegberg, A.M.J.; Ahring, K.; Beblo, S.; Bélanger-Quintana, A.; Bosch, A.M.; Burlina, A.; Campistol, J.; Coskun, T.; Feillet, F.; Giżewska, M.; Huijbregts, S.C.J.; Kearney, S.; Langeveld, M.; Leuzzi, V.; Maillot, F.; Muntau, A.C.; Rocha, J.C.; Romani, C.; Trefz, F.K.; MacDonald, A.; van Spronsen, F.J.Background: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH4), although there is no consensus on the definition of BH4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH4 responsiveness being used around the world. Methods: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). Results: We analysed 166 responses. Long-term BH4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. Conclusion: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH4 treatment.
- Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?Publication . Čechová, Anna; Honzík, Tomáš; Edmondson, Andrew C.; Ficicioglu, Can; Serrano, Mercedes; Barone, Rita; De Lonlay, Pascale; Schiff, Manuel; Witters, Peter; Lam, Christina; Patterson, Marc; Janssen, Mirian C.H.; Correia, Joana; Quelhas, D; Sykut-Cegielska, Jolanta; Plotkin, Horacio; Morava, Eva; Sarafoglou, KyriakiePMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.
- Continuous use of glycomacropeptide in the nutritional management of patients with phenylketonuria: a clinical perspectivePublication . Pena, Maria João; Pinto, Alex; de Almeida, Manuela Ferreira; de Sousa Barbosa, Catarina; Ramos, Paula Cristina; Rocha, Sara; Guimas, Arlindo; Ribeiro, Rosa; Martins, Esmeralda; Bandeira, Anabela; Dias, Cláudia Camila; MacDonald, Anita; Borges, Nuno; Rocha, Júlio CésarBackground: In phenylketonuria (PKU), modified casein glycomacropeptide supplements (CGMP-AA) are used as an alternative to the traditional phenylalanine (Phe)-free L-amino acid supplements (L-AA). However, studies focusing on the long-term nutritional status of CGMP-AA are lacking. This retrospective study evaluated the long-term impact of CGMP-AA over a mean of 29 months in 11 patients with a mean age at CGMP-AA onset of 28 years (range 15-43) [8 females; 2 hyperphenylalaninaemia (HPA), 3 mild PKU, 3 classical PKU and 3 late-diagnosed]. Outcome measures included metabolic control, anthropometry, body composition and biochemical parameters. Results: CGMP-AA, providing 66% of protein equivalent intake from protein substitute, was associated with no significant change in blood Phe with CGMP-AA compared with baseline (562 ± 289 µmol/L vs 628 ± 317 µmol/L; p = 0.065). In contrast, blood tyrosine significantly increased on CGMP-AA (52.0 ± 19.2 μmol/L vs 61.4 ± 23.8 μmol/L; p = 0.027). Conclusions: Biochemical nutritional markers remained unchanged which is an encouraging finding in adults with PKU, many of whom are unable to maintain full adherence with nutritionally fortified protein substitutes. Longitudinal, prospective studies with larger sample sizes are necessary to fully understand the metabolic impact of using CGMP-AA in PKU.
- Genotype-Phenotype Correlations in PMM2-CDGPublication . Vaes, Laurien; Rymen, Daisy; Cassiman, David; Ligezka, Anna; Vanhoutvin, Nele; Quelhas, D; Morava, Eva; Witters, PeterPMM2-CDG is a rare disease, causing hypoglycosylation of multiple proteins, hence preventing full functionality. So far, no direct genotype-phenotype correlations have been identified. We carried out a retrospective cohort study on 26 PMM2-CDG patients. We collected the identified genotype, as well as continuous variables indicating the disease severity (based on Nijmegen Pediatric CDG Rating Score or NPCRS) and dichotomous variables reflecting the patients' phenotype. The phenotypic effects of patients' genotype were studied using non-parametric and Chi-Square tests. Seventeen different pathogenic variants have been studied. Variants with zero enzyme activity had no significant impact on the Nijmegen score. Pathogenic variants involving the stabilization/folding domain have a significantly lower total NPCRS (p = 0.017): presence of the p.Cys241Ser mutation had a significantly lower subscore 1,3 and NPCRS (p = 0.04) and thus result in a less severe phenotype. On the other hand, variants involving the dimerization domain, p.Pro113Leu and p.Phe119Leu, resulted in a significantly higher NPCRS score (p = 0.002), which indicates a worse clinical course. These concepts give a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base.
- Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental DisorderPublication . Bain, Jennifer M.; Thornburg, Olivia; Pan, Cheryl; Rome-Martin, Donnielle; Boyle, Lia; Fan, Xiao; Devinsky, Orrin; Frye, Richard; Hamp, Silke; Keator, Cynthia G.; LaMarca, Nicole M.; Maddocks, Alexis B.R.; Madruga-Garrido, Marcos; Niederhoffer, Karen Y.; Novara, Francesca; Peron, Angela; Poole-Di Salvo, Elizabeth; Salazar, Rachel; Skinner, Steven A.; Soares, Gabriela; Goldman, Sylvie; Chung, Wendy K.Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.
- NPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann‐Pick type C patientPublication . Encarnação, Marisa; Coutinho, Maria Francisca; Cho, Soo Min; Cardoso, Maria Teresa; Ribeiro, Isaura; Chaves, Paulo; Santos, Juliana Inês; Quelhas, D; Lacerda, Lucia; Leão Teles, Elisa; Futerman, Anthony H.; Vilarinho, Laura; Alves, SandraBackground: Niemann-Pick type C (NPC, MIM #257220) is a neuro-visceral disease, caused predominantly by pathogenic variants in the NPC1 gene. Here we studied patients with clinical diagnosis of NPC but inconclusive results regarding the molecular analysis. Methods: We used a Next-Generation Sequencing (NGS)-panel followed by cDNA analysis. Latter, we used massively parallel single-cell RNA-seq (MARS-Seq) to address gene profiling changes and finally the effect of different variants on the protein and cellular levels. Results: We identified novel variants and cDNA analysis allowed us to establish the functional effect of a silent variant, previously reported as a polymorphism. We demonstrated that this variant induces the skipping of exon 11 leading to a premature stop codon and identified it in NPC patients from two unrelated families. MARS-Seq analysis showed that a number of upregulated genes were related to the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in one specific patient. Also, for all analyzed variants, the NPC1 protein was partially retained in the ER. Conclusion: We showed that the NPC1 silent polymorphism (p.V562V) is a disease-causing variant in NPC and that the UPR is upregulated in an NPC patient.
- Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the LiteraturePublication . de Stefano, Maria Chiara; Gallagher, Louise; Rakic, Severin; Jorge, Paula; Cuturilo, Goran; Markovska-Simoska, Silvana; Borg, Isabella; Wolstencroft, Jeanne; Tümer, Zeynep; Harwood, Adrian J.; Kodra, Yllka; Skuse, DavidCopy number variants (CNVs) play an important role in the genetic underpinnings of neuropsychiatric/neurodevelopmental disorders. The chromosomal region 16p11.2 (BP4-BP5) harbours both deletions and duplications that are associated in carriers with neurodevelopmental and neuropsychiatric conditions as well as several rare disorders including congenital malformation syndromes. The aim of this article is to provide a review of the current knowledge of the diverse neurodevelopmental disorders (NDD) associated with 16p11.2 deletions and duplications reported in published cohorts. A literature review was conducted using the PubMed/MEDLINE electronic database limited to papers published in English between 1 January 2010 and 31 July 2020, describing 16p11.2 deletions and duplications carriers' cohorts. Twelve articles meeting inclusion criteria were reviewed from the 75 articles identified by the search. Of these twelve papers, eight described both deletions and duplications, three described deletions only and one described duplications only. This study highlights the heterogeneity of NDD descriptions of the selected cohorts and inconsistencies concerning accuracy of data reporting.