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- 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.
- Congenital disorders of glycosylationPublication . Mendes, Ana Raquel; Quelhas, D; Correia, Joana; Paiva Coelho, Margarida; Bandeira, Anabela; Martins, EsmeraldaCongenital disorders of glycosylation are a highly variable, rapidly expanding family of genetic diseases that result from defects in the synthesis of glycans. The vast majority of these monogenic diseases are inherited in an autosomal recessive way, but some types follow an autosomal dominant or X-linked inheritance. The present work aimed to review the state of the art of congenital disorders of glycosylation, including available therapeutic options, and present a simplified diagnostic approach to this group of diseases. Congenital disorders of glycosylation can be classified into four categories: N-linked glycosylation defects, O-linked glycosylation defects, combined glycosylation defects, and glycosphingolipid and glycosylphosphatidylinositol anchor synthesis defects. The phenotype may range from mild to severe, depending on disease severity. Clinical features include dysmorphic features, neurologic, dermatologic, cardiac, endocrine, immunologic, hematologic, gastrointestinal and liver involvement, and skeletal muscle abnormalities. As there is no universal or pathognomonic sign or symptom and no sensitive diagnostic test, it is of foremost importance to keep a high index of suspicion of these diseases. When a congenital disorder of glycosylation is suspected, the first step in screening is to perform serum transferrin isoelectric focusing. Molecular genetic testing is the most specific diagnostic test. Treatment is usually symptomatic, with specific treatment only available for some of these disorders. Since congenital defects of glycosylation may affect any organ at any age and have variable clinical presentation, they should be considered in the differential diagnosis of any patient with multiorgan involvement.
- TYROSINEMIA TYPE III: A CASE REPORT OF SIBLINGS AND LITERATURE REVIEWPublication . Barroso, Fábio; Correia, Joana; Bandeira, Anabela; Carmona, Carla; Vilarinho, Laura; MF, Almeida; Rocha, Júlio César; Martins, EsmeraldaObjective: Tyrosinemia type III (HT III) is the rarest form of tyrosinemia, and the full clinical spectrum of this disorder is still unknown. The neurological involvement varies, including intellectual impairment and attention deficit disorder with hyperactivity (ADHD). We report the case of two siblings diagnosed with HT III at different ages. Case description: The index case was diagnosed by newborn screening for endocrine and metabolic disorders, starting a low-protein diet immediately, with a consistent decrease in tyrosine levels. By the age of three, the child displayed a hyperactive behavior, starting treatment for ADHD two years later. At seven years of age, he shows a slight improvement in terms of behavior and attention span and has a cognitive performance slightly lower than his peers, despite maintaining acceptable tyrosine levels. His sister, who had a history of ADHD since age five, was diagnosed with HT III after family screening at the age of eight. Despite initiating a dietetic treatment, her behavior did not improve, and she has a mild intellectual impairment. Comments: This is the first case report describing siblings with HT III who underwent nutritional treatment with a low-protein diet in different phases of life, with a better neurological and behavioral evaluation in the patient who started treatment earlier.
- 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.