Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 56
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Brief Bioinform ; 24(5)2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37580177

RESUMO

Genomic variants affecting pre-messenger RNA splicing and its regulation are known to underlie many rare genetic diseases. However, common workflows for genetic diagnosis and clinical variant interpretation frequently overlook splice-altering variants. To better serve patient populations and advance biomedical knowledge, it has become increasingly important to develop and refine approaches for detecting and interpreting pathogenic splicing variants. In this review, we will summarize a few recent developments and challenges in using RNA sequencing technologies for rare disease investigation. Moreover, we will discuss how recent computational splicing prediction tools have emerged as complementary approaches for revealing disease-causing variants underlying splicing defects. We speculate that continuous improvements to sequencing technologies and predictive modeling will not only expand our understanding of splicing regulation but also bring us closer to filling the diagnostic gap for rare disease patients.


Assuntos
Doenças Raras , Transcriptoma , Humanos , Doenças Raras/diagnóstico , Doenças Raras/genética , Splicing de RNA , Proteínas , Aprendizado de Máquina , Mutação
2.
Glycobiology ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39255372

RESUMO

Congenital disorders of glycosylation (CDG) are a group of rare monogenic human disorders caused by defects in the genes encoding the proteins that generate, attach, and modify glycans, thus disrupting cellular glycosylation machinery. Over 200 CDG caused by disruptions of 189 different genes are currently known. The multi-system disease manifestations of the CDG disorders highlight the importance of glycosylation across the organ systems. Clinical manifestations of CDG tend to group among genes contributing to the same glycosylation pathways, suggesting shared pathophysiology related to the glycosylation disruptions. However, the underlying glycosylation disruptions and pathophysiologic mechanisms responsible for specific CDG clinical manifestations have been determined for only a few hypoglycosylated proteins. The Frontiers in CDG Consortium (FCDGC) is an international network of clinical sites, laboratories, and patient advocacy groups established in 2019 to improve clinical symptoms, quality of life, and life expectancy for individuals with CDG. FCDGC seeks to answer decades of unresolved questions, address knowledge gaps, develop and validate new biochemical diagnostic techniques and therapeutic biomarkers, and explore novel therapeutic options for CDG. Over the past 5 years, FCDGC has launched a Natural History Study with over 300 CDG patients, discovered novel biomarkers suggesting new mechanisms of disease, and launched clinical trials aiming to restore appropriate glycosylation and targeting newly identified potential mechanisms of disease. Technical advances in glycobiology are making it increasingly possible to comprehensively catalog glycoproteomic data and to probe functional impact of altered glycosylation. My laboratory applies glycoproteomic technologies to samples from human subjects and genetic model systems to identify glycosylation abnormalities and unlock new insights from translational glycobiology. Current findings and accomplishments highlight the ongoing bottlenecks and knowledge gaps at intersections of glycobiology and clinical care requiring further investigation.

3.
Am J Hum Genet ; 108(7): 1342-1349, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34143952

RESUMO

EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Defeitos Congênitos da Glicosilação/genética , Retículo Endoplasmático/genética , alfa-Manosidase/genética , Adolescente , Alelos , Proteínas de Ligação ao Cálcio/deficiência , Linhagem Celular , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/sangue , Deficiências do Desenvolvimento/genética , Feminino , Glicoproteínas/sangue , Glicosilação , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Mutação , Linhagem , Polissacarídeos/sangue , Deficiências na Proteostase/genética , alfa-Manosidase/deficiência
4.
Mol Genet Metab ; 142(4): 108530, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38968673

RESUMO

Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) is a rare genetic disorder caused by biallelic variants in the PGM1 gene, leading to the deficiency of the PGM1 enzyme. The most common clinical presentations include muscle involvement, failure to thrive, cleft palate, and cardiac involvement. Abnormal serum N-glycosylation, hypoglycemia, and liver function abnormalities including coagulation abnormalities are the most common laboratory abnormalities. While PGM1-CDG has been extensively studied, little is known about the extent of the coagulation abnormalities in individuals with PGM1-CDG. Unlike most CDG, some symptoms of PGM1-CDG are treatable with D-galactose (D-gal) supplementation, though reliable clinical endpoints are necessary to appropriately evaluate the potential improvement with D-gal in PGM1-CDG. Here, we aimed to describe the incidence of coagulation abnormalities in PGM1-CDG and their evolution, their relation to clinical events, and the ability of D-gal treatment to improve them. A retrospective analysis was conducted on 73 reported individuals. All individuals had a molecularly confirmed PGM1-CDG diagnosis. All incidences of antithrombin (AT), aPTT, PT, factor (F) XI, FX, FIX, FVII, protein C and protein S data and major clinical events related to coagulation abnormalities, were collected. Coagulation information was available for only 58.9 % of the reported individuals, out of which 67.4 % of PGM1-CDG individuals were reported to have abnormalities. The most frequently observed abnormality was AT (mean: 30.8% R:80-120 %) deficiency. Four individuals had major thrombotic events. Coagulation status on D-gal treatment, were reported in 19 individuals. Several factors showed improvement including AT (mean: 64.5 %), indicating galactose is beneficial in treating coagulation abnormalities in PGM1-CDG. Due to the scarcity of the reported data on coagulation parameters, we also evaluated data collected in sixteen PGM1-CDG individuals enrolled in the FCDGC Natural History Study. Longitudinal data showed improvements in several coagulant parameters and disease severity improved for almost all patients of whom we had multiple datapoints on D-gal. AT showed significant improvement on D-gal. We conclude that coagulation abnormalities are frequently present in PGM1-CDG and show improvement on D-gal. We recommend coagulation parameters should be routinely checked in individuals with PGM1-CDG or suspected of having PGM1-CDG. Finally, AT may be used as a primary or secondary clinical endpoint for upcoming clinical trials in PGM1-CDG individuals.


Assuntos
Transtornos da Coagulação Sanguínea , Defeitos Congênitos da Glicosilação , Fosfoglucomutase , Humanos , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/patologia , Fosfoglucomutase/genética , Fosfoglucomutase/deficiência , Masculino , Feminino , Estudos Retrospectivos , Transtornos da Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/sangue , Lactente , Pré-Escolar , Criança , Adolescente , Galactose , Adulto , Adulto Jovem , Glicosilação , Recém-Nascido , Coagulação Sanguínea/genética
5.
Mol Genet Metab ; 142(2): 108472, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38703411

RESUMO

ALG13-Congenital Disorder of Glycosylation (CDG), is a rare X-linked CDG caused by pathogenic variants in ALG13 (OMIM 300776) that affects the N-linked glycosylation pathway. Affected individuals present with a predominantly neurological manifestation during infancy. Epileptic spasms are a common presenting symptom of ALG13-CDG. Other common phenotypes include developmental delay, seizures, intellectual disability, microcephaly, and hypotonia. Current management of ALG13-CDG is targeted to address patients' symptoms. To date, less than 100 individuals have been reported with ALG13-CDG. In this article, an international group of experts in CDG reviewed all reported individuals affected with ALG13-CDG and suggested diagnostic and management guidelines for ALG13-CDG. The guidelines are based on the best available data and expert opinion. Neurological symptoms dominate the phenotype of ALG13-CDG where epileptic spasm is confirmed to be the most common presenting symptom of ALG13-CDG in association with hypotonia and developmental delay. We propose that ACTH/prednisolone treatment should be trialed first, followed by vigabatrin, however ketogenic diet has been shown to have promising results in ALG13-CDG. In order to optimize medical management, we also suggest early cardiac, gastrointestinal, skeletal, and behavioral assessments in affected patients.


Assuntos
Defeitos Congênitos da Glicosilação , Humanos , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/terapia , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/complicações , Glicosilação , Fenótipo , Mutação , Hipotonia Muscular/genética , Hipotonia Muscular/terapia , Hipotonia Muscular/diagnóstico , Guias de Prática Clínica como Assunto , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/terapia , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Convulsões/genética , Convulsões/terapia , Convulsões/diagnóstico , N-Acetilglucosaminiltransferases
6.
Mol Genet Metab ; 142(4): 108513, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38917675

RESUMO

INTRODUCTION: Congenital disorders of glycosylation (CDG) are a continuously expanding group of monogenic disorders that disrupt glycoprotein and glycolipid biosynthesis, leading to multi-systemic manifestations. These disorders are categorized into various groups depending on which part of the glycosylation process is impaired. The cardiac manifestations in CDG can significantly differ, not only across different types but also among individuals with the same genetic cause of CDG. Cardiomyopathy is an important phenotype in CDG. The clinical manifestations and progression of cardiomyopathy in CDG patients have not been well characterized. This study aims to delineate common patterns of cardiomyopathy across a range of genetic causes of CDG and to propose baseline screening and follow-up evaluation for this patient population. METHODS: Patients with molecular confirmation of CDG who were enrolled in the prospective or memorial arms of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study were ascertained for the presence of cardiomyopathy based on a retrospective review of their medical records. All patients were evaluated by clinical geneticists who are members of FCDGC at their respective academic centers. Patients were screened for cardiomyopathy, and detailed data were retrospectively collected. We analyzed their clinical and molecular history, imaging characteristics of cardiac involvement, type of cardiomyopathy, age at initial presentation of cardiomyopathy, additional cardiac features, the treatments administered, and their clinical outcomes. RESULTS: Of the 305 patients with molecularly confirmed CDG participating in the FCDGC natural history study as of June 2023, 17 individuals, nine females and eight males, were identified with concurrent diagnoses of cardiomyopathy. Most of these patients were diagnosed with PMM2-CDG (n = 10). However, cardiomyopathy was also observed in other diagnoses, including PGM1-CDG (n = 3), ALG3-CDG (n = 1), DPM1-CDG (n = 1), DPAGT1-CDG (n = 1), and SSR4-CDG (n = 1). All PMM2-CDG patients were reported to have hypertrophic cardiomyopathy. Dilated cardiomyopathy was observed in three patients, two with PGM1-CDG and one with ALG3-CDG; left ventricular non-compaction cardiomyopathy was diagnosed in two patients, one with PGM1-CDG and one with DPAGT1-CDG; two patients, one with DPM1-CDG and one with SSR4-CDG, were diagnosed with non-ischemic cardiomyopathy. The estimated median age of diagnosis for cardiomyopathy was 5 months (range: prenatal-27 years). Cardiac improvement was observed in three patients with PMM2-CDG. Five patients showed a progressive course of cardiomyopathy, while the condition remained unchanged in eight individuals. Six patients demonstrated pericardial effusion, with three patients exhibiting cardiac tamponade. One patient with SSR4-CDG has been recently diagnosed with cardiomyopathy; thus, the progression of the disease is yet to be determined. One patient with PGM1-CDG underwent cardiac transplantation. Seven patients were deceased, including five with PMM2-CDG, one with DPAGT1-CDG, and one with ALG3-CDG. Two patients died of cardiac tamponade from pericardial effusion; for the remaining patients, cardiomyopathy was not necessarily the primary cause of death. CONCLUSIONS: In this retrospective study, cardiomyopathy was identified in ∼6% of patients with CDG. Notably, the majority, including all those with PMM2-CDG, exhibited hypertrophic cardiomyopathy. Some cases did not show progression, yet pericardial effusions were commonly observed, especially in PMM2-CDG patients, occasionally escalating to life-threatening cardiac tamponade. It is recommended that clinicians managing CDG patients, particularly those with PMM2-CDG and PGM1-CDG, be vigilant of the cardiomyopathy risk and risk for potentially life-threatening pericardial effusions. Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood. Subsequently, routine cardiac examinations every five years are advisable. Additionally, patients with diagnosed cardiomyopathy should receive ongoing cardiac care to ensure the effective management and monitoring of their condition. A prospective study will be required to determine the true prevalence of cardiomyopathy in CDG.


Assuntos
Cardiomiopatias , Defeitos Congênitos da Glicosilação , Fenótipo , Humanos , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/patologia , Feminino , Masculino , Cardiomiopatias/genética , Cardiomiopatias/diagnóstico , Criança , Pré-Escolar , Adolescente , Lactente , Glicosilação , Seguimentos , Adulto , Estudos Retrospectivos , Adulto Jovem , Estudos Prospectivos , Recém-Nascido
7.
Am J Med Genet A ; : e63833, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39119839

RESUMO

Glycosylphosphatidylinositols (GPIs) are a type of glycolipid responsible for anchoring many important proteins to the cell membrane surface. Defects in the synthesis of GPIs can lead to a group of multisystem disorders known as the inherited GPI deficiencies (IGDs). Homozygosity for the c.-270C > G variant in the promoter of PIGM has been associated with a IGD subtype known as glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1). The several cases reported in the literature have been described to have a milder neurologic phenotype in comparison to the other IGDs and have been treated with sodium phenylbutyrate with some degree of success. These patients typically present with portal and hepatic vein thrombosis and mostly develop absence seizures. Here we describe a patient homozygous for a nonsynonymous variant in PIGM who deceased at 9 weeks of life and had multiple physical dysmorphisms (rocker bottom feet, midline cleft palate, thickened and lichenified skin), portal vein thrombosis, CNS structural anomalies (progressive multicystic encephalomalacia and ventriculomegaly), and a neurological phenotype of a diffuse encephalopathy. This is the first known case report of a PIGM-related IGD/CDG due to a coding variant.

8.
J Inherit Metab Dis ; 47(4): 766-777, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38597022

RESUMO

ALG3-CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol-P-Man to Dol-PP-Man5GlcNAc2 (Man5) forming Dol-PP-Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3-CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway. In addition, we show that N-linked Man3-4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non-hepatic origin. We found that like other CDGs such as ALG1- or PMM2-CDG, in transferrin, the assembling intermediate Man5 in ALG3-CDG, are likely further processed into a distinct glycan, NeuAc1Gal1GlcNAc1Man3GlcNAc2, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono-antennary glycan with the same molecular weight as the truncated glycan described in MGAT2-CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3-CDG which will have important implications in the pathogenesis of CDG.


Assuntos
Defeitos Congênitos da Glicosilação , Estresse do Retículo Endoplasmático , Fibroblastos , Manosiltransferases , Polissacarídeos , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/metabolismo , Humanos , Polissacarídeos/metabolismo , Manosiltransferases/genética , Manosiltransferases/metabolismo , Fibroblastos/metabolismo , Resposta a Proteínas não Dobradas , Retículo Endoplasmático/metabolismo , Glicosilação , Células Cultivadas , Degradação Associada com o Retículo Endoplasmático
9.
Mol Genet Metab ; 140(3): 107682, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37597336

RESUMO

We report a patient with an extremely rare, combined diagnosis of PMM2-CDG and hereditary fructose intolerance (HFI). By comparing with other patients, under-galactosylation was identified as a feature of HFI. Fructose/sorbitol/sucrose restriction was initiated right afterwards. The patient is at the mild end of the PMM2-CDG spectrum, raising the question of sorbitol's role in the pathogenesis of PMM2-CDG and whether fructose/sorbitol/sucrose restriction could benefit other PMM2-CDG patients. Additionally, epalrestat, an emerging potential PMM2-CDG therapy, may benefit HFI patients.


Assuntos
Defeitos Congênitos da Glicosilação , Intolerância à Frutose , Fosfotransferases (Fosfomutases) , Humanos , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Frutose/uso terapêutico , Sorbitol/uso terapêutico , Sacarose/uso terapêutico
10.
Mol Genet Metab ; 139(2): 107606, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37224763

RESUMO

BACKGROUND: Given the lack of reliable data on the prevalence of bleeding abnormalities and thrombotic episodes in PMM2-CDG patients, and whether coagulation abnormalities change over time, we prospectively collected and reviewed natural history data. Patients with PMM2-CDG often have abnormal coagulation studies due to glycosylation abnormalities but the frequency of complications resulting from these has not been prospectively studied. METHODS: We studied fifty individuals enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study with molecularly confirmed diagnosis of PMM2-CDG. We collected data on prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelets, factor IX activity (FIX), factor XI activity (FXI), protein C activity (PC), protein S activity (PS) and antithrombin activity (AT). RESULTS: Prothrombotic and antithrombotic factor activities were frequently abnormal in PMM2-CDG patients, including AT, PC, PT, INR, and FXI. AT deficiency was the most common abnormality in 83.3% of patients. AT activity was below 50% in 62.5% of all patients (normal range 80-130%). Interestingly, 16% of the cohort experienced symptoms of spontaneous bleeding and 10% had thrombosis. Stroke-like episodes (SLE) were reported in 18% of patients in our cohort. Based on the linear growth models, on average, patients did not show significant change in AT (n = 48; t(23.8) = 1.75, p = 0.09), FIX (n = 36; t(61) = 1.60, p = 0.12), FXI (n = 39; t(22.8) = 1.88, p = 0.07), PS (n = 25; t(28.8) = 1.08, p = 0.29), PC (n = 38; t(68) = 1.61, p = 0.11), INR (n = 44; t(184) = -1.06, p = 0.29), or PT (n = 43; t(192) = -0.69, p = 0.49) over time. AT activity positively correlated with FIX activity. PS activity was significantly lower in males. CONCLUSION: Based on our natural history data and previous literature, we conclude that caution should be exercised when the AT levels are lower than 65%, as most thrombotic events occur in patients with AT below this level. All five, male PMM2-CDG patients in our cohort who developed thrombosis had abnormal AT levels, ranging between 19% and 63%. Thrombosis was associated with infection in all cases. We did not find significant change in AT levels over time. Several PMM2-CDG patients had an increased bleeding tendency. More long-term follow-up is necessary on coagulation abnormalities and the associated clinical symptoms to provide guidelines for therapy, patient management, and appropriate counseling. SYNOPSIS: Most PMM2-CDG patients display chronic coagulation abnormalities without significant improvement, associated with a frequency of 16% clinical bleeding abnormalities, and 10% thrombotic episodes in patients with severe antithrombin deficiency.


Assuntos
Defeitos Congênitos da Glicosilação , Fosfotransferases (Fosfomutases) , Trombose , Humanos , Masculino , Glicosilação , Estudos Prospectivos , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Trombose/epidemiologia , Trombose/genética , Fosfotransferases (Fosfomutases)/genética , Antitrombinas/uso terapêutico
11.
Am J Med Genet A ; 191(6): 1626-1631, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36930724

RESUMO

ALG13-CDG is a rare X-linked disorder of N-linked glycosylation. Given the lack of long-term outcome data in ALG13-CDG, we collected natural history data and reviewed individuals surviving to young adulthood with confirmed pathogenic variants in ALG13 in our own cohort and in the literature. From the 14 ALG13-CDG patients enrolled into our Frontiers of Congenital Disorders of Glycosylation Consortium natural history study only two patients were older than 16 years; one of these two females is so far unreported. From the 52 patients described in the medical literature with confirmed pathogenic variants in ALG13 only five patients were older than 16 years (all females), in addition to the new, unreported patient from our natural history study. Two male patients have died due to ALG13-CDG, and there were no surviving males older than 16 years with a confirmed ALG13-CDG diagnosis. Our adolescent and young adult cohort of six patients presented with epilepsy, muscular hypotonia, speech, and developmental delay. Intellectual disability was present in all female patients with ALG13-CDG. Unreported features included ataxia, neuropathy, and severe gastrointestinal symptoms requiring G/J tube placement. In addition, two patients from our natural history study developed unilateral hearing loss. Skeletal abnormalities were found in four patients, including osteopenia and scoliosis. Major health problems included persistent seizures in three patients. Ketogenic diet was efficient for seizures in three out of four patients. Although all patients were mobile, they all had severe communication problems with mostly absent speech and were unable to function without parental support. In summary, long-term outcome in ALG13-CDG includes gastrointestinal and skeletal involvement in addition to a chronic, mostly non-progressive neurologic phenotype.


Assuntos
Doenças Ósseas Metabólicas , Perda Auditiva Unilateral , Deficiência Intelectual , Feminino , Masculino , Humanos , Glicosilação , Ataxia , Doenças Raras , N-Acetilglucosaminiltransferases
12.
J Inherit Metab Dis ; 46(2): 300-312, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36651831

RESUMO

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.


Assuntos
Defeitos Congênitos da Glicosilação , ATPases Vacuolares Próton-Translocadoras , Humanos , Defeitos Congênitos da Glicosilação/genética , Glicoproteínas/metabolismo , Transferrina/metabolismo , Fenótipo , Polissacarídeos , Hidrolases/genética , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética
13.
Am J Hum Genet ; 104(5): 835-846, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982613

RESUMO

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.


Assuntos
Defeitos Congênitos da Glicosilação/metabolismo , Fibroblastos/metabolismo , Galactose/administração & dosagem , Fosfoglucomutase/deficiência , Uridina Difosfato Galactose/metabolismo , Uridina Difosfato Glucose/metabolismo , Células Cultivadas , Estudos de Coortes , Defeitos Congênitos da Glicosilação/tratamento farmacológico , Defeitos Congênitos da Glicosilação/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Glicosilação , Humanos
14.
Genet Med ; 24(6): 1227-1237, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35300924

RESUMO

PURPOSE: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. METHODS: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. RESULTS: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. CONCLUSION: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required.


Assuntos
Catarata , Nanismo , Hepatoblastoma , Deficiência Intelectual , Neoplasias Hepáticas , Micrognatismo , Criança , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , Síndrome
15.
Ann Neurol ; 90(6): 887-900, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34652821

RESUMO

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a.


Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Inibidores Enzimáticos/uso terapêutico , Fosfotransferases (Fosfomutases)/deficiência , Rodanina/análogos & derivados , Sorbitol/urina , Tiazolidinas/uso terapêutico , Adolescente , Adulto , Idoso , Biomarcadores/urina , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/tratamento farmacológico , Defeitos Congênitos da Glicosilação/urina , Feminino , Glicosilação , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Fosfotransferases (Fosfomutases)/urina , Prognóstico , Rodanina/uso terapêutico , Adulto Jovem
16.
Am J Med Genet A ; 188(8): 2438-2442, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35665995

RESUMO

Achalasia is rare in the pediatric population and should prompt clinicians to consider genetic disorders associated with this condition. While AAA syndrome (also known as Allgrove or Triple A syndrome) is commonly considered, GMPPA-congenital disorder of glycosylation (CDG) should also be in the differential diagnosis. We report a 9-month-old female born to nonconsanguineous parents with achalasia and alacrima found to have two novel compound heterozygous variants in the GMPPA gene associated with GMPPA-CDG. This rare disorder is commonly associated with developmental delay and intellectual disability. We discuss management of this disorder including the importance of confirming a genetic diagnosis and summarize reported cases.


Assuntos
Insuficiência Adrenal , Defeitos Congênitos da Glicosilação , Acalasia Esofágica , Oftalmopatias Hereditárias , Insuficiência Adrenal/genética , Criança , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/genética , Oftalmopatias Hereditárias/genética , Feminino , Glicosilação , Humanos , Lactente
17.
J Inherit Metab Dis ; 45(5): 969-980, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35716054

RESUMO

Congenital disorders of glycosylation are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid glycan biosynthesis. These disorders mostly manifest with multisystem involvement. Individuals with ALG8-CDG commonly present with hypotonia, protein-losing enteropathy, and hepatic involvement. Here, we describe seven unreported individuals diagnosed with ALG8-CDG based on biochemical and molecular testing and we identify nine novel variants in ALG8, bringing the total to 26 individuals with ALG8-CDG in the medical literature. In addition to the typical multisystem involvement documented in ALG8-CDG, our cohort includes the two oldest patients reported and further expands the phenotype of ALG8-CDG to include stable intellectual disability, autism spectrum disorder and other neuropsychiatric symptoms. We further expand the clinical features in a variety of organ systems including ocular, musculoskeletal, dermatologic, endocrine, and cardiac abnormalities and suggest a comprehensive evaluation and monitoring strategy to improve clinical management.


Assuntos
Transtorno do Espectro Autista , Defeitos Congênitos da Glicosilação , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/terapia , Glucosiltransferases/genética , Glicosilação , Humanos , Fenótipo
18.
Neurobiol Dis ; 148: 105176, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33197557

RESUMO

CDKL5 deficiency disorder (CDD) is an infantile, epileptic encephalopathy presenting with early-onset seizures, intellectual disability, motor impairment, and autistic features. The disorder has been linked to mutations in the X-linked CDKL5, and mouse models of the disease recapitulate several aspects of CDD symptomology, including learning and memory impairments, motor deficits, and autistic-like features. Although early-onset epilepsy is one of the hallmark features of CDD, evidence of spontaneous seizure activity has only recently been described in Cdkl5-deficient heterozygous female mice, but the etiology, prevalence, and sex-specificity of this phenotype remain unknown. Here, we report the first observation of disturbance-associated seizure-like events in heterozygous female mice across two independent mouse models of CDD: Cdkl5 knockout mice and CDKL5 R59X knock-in mice. We find that both the prevalence and severity of this phenotype increase with aging, with a median onset around 28 weeks of age. Similar seizure-like events are not observed in hemizygous knockout male or homozygous knockout female littermates, suggesting that X-linked cellular mosaicism is a driving factor underlying these seizure-like events. Together, these findings not only contribute to our understanding of the effects of CDKL5 loss on seizure susceptibility, but also document a novel, pre-clinical phenotype for future therapeutic investigation.


Assuntos
Síndromes Epilépticas/fisiopatologia , Mosaicismo , Proteínas Serina-Treonina Quinases/genética , Convulsões/fisiopatologia , Espasmos Infantis/fisiopatologia , Fatores Etários , Animais , Modelos Animais de Doenças , Síndromes Epilépticas/genética , Feminino , Técnicas de Introdução de Genes , Heterozigoto , Camundongos , Camundongos Knockout , Fenótipo , Convulsões/genética , Fatores Sexuais , Espasmos Infantis/genética
19.
Genet Med ; 23(10): 1873-1881, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34113002

RESUMO

PURPOSE: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. METHODS: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. RESULTS: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. CONCLUSION: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Humanos , Proteínas de Membrana , Linhagem , Convulsões , Virulência
20.
Mol Genet Metab ; 133(4): 397-399, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34140212

RESUMO

PMM2-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.


Assuntos
Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/fisiopatologia , Fosfotransferases (Fosfomutases)/sangue , Adolescente , Insuficiência Adrenal/etiologia , Adulto , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação , Feminino , Glicosilação , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fosfotransferases (Fosfomutases)/genética , Sistema Hipófise-Suprarrenal/fisiologia , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA