Aspartylglucosaminuria: Clinical Presentation and Potential Therapies

2021 ◽  
pp. 088307382098090
Author(s):  
Kimberly Goodspeed ◽  
Cynthia Feng ◽  
Minna Laine ◽  
Troy C. Lund
Keyword(s):  
Sleep Problems ◽  
Premature Death ◽  
Tube Placement ◽  
Growth Spurt ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Clinical Benefits ◽  
Ear Infections ◽  
Upper Respiratory ◽  
Cellular Dysfunction

Aspartylglucosaminuria (AGU) is a recessively inherited neurodegenerative lysosomal storage disease characterized by progressive intellectual disability, skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures followed by premature death. AGU is caused by pathogenic variants in the aspartylglucosaminidase ( AGA) gene, leading to glycoasparagine accumulation and cellular dysfunction. Although more prevalent in the Finnish population, more than 30 AGA variants have been identified worldwide. Owing to its rarity, AGU may be largely underdiagnosed. Recognition of the following early clinical features may aid in AGU diagnosis: developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias, clumsiness, characteristic facial features, recurring upper respiratory and ear infections, tonsillectomy, multiple sets of tympanostomy tube placement, and sleep problems. Although no curative therapies currently exist, early diagnosis may provide benefit through the provision of anticipatory guidance, management of expectations, early interventions, and prophylaxis; it will also be crucial for increased clinical benefits of future AGU disease-modifying therapies.

scholarly journals Characterization and phosphoproteomic analysis of a human immortalized podocyte model of Fabry disease generated using CRISPR/Cas9 technology

2016 ◽  
Vol 311 (5) ◽  
pp. F1015-F1024 ◽  
Author(s):  
Ester M. Pereira ◽  
Anatália Labilloy ◽  
Megan L. Eshbach ◽  
Ankita Roy ◽  
Arohan R. Subramanya ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Human Kidney ◽  
Premature Death ◽  
Antibody Array ◽  
Cell Models ◽  
Lysosomal Storage ◽  
Protein Levels ◽  
Gla Gene ◽  
Fabry Nephropathy ◽  
And Control

Fabry nephropathy is a major cause of morbidity and premature death in patients with Fabry disease (FD), a rare X-linked lysosomal storage disorder. Gb3, the main substrate of α-galactosidase A (α-Gal A), progressively accumulates within cells in a variety of tissues. Establishment of cell models has been useful as a tool for testing hypotheses of disease pathogenesis. We applied CRISPR/Cas9 genome editing technology to the GLA gene to develop human kidney cell models of FD in human immortalized podocytes, which are the main affected renal cell type. Our podocytes lack detectable α-Gal A activity and have increased levels of Gb3. To explore different pathways that could have distinct patterns of activation under conditions of α-gal A deficiency, we used a high-throughput antibody array to perform phosphorylation profiling of CRISPR/Cas9-edited and control podocytes. Changes in both total protein levels and in phosphorylation status per site were observed. Analysis of our candidate proteins suggests that multiple signaling pathways are impaired in FD.

scholarly journals Fabry disease, a complex pathology not easy to diagnose

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Paolo Colomba ◽  
Simone Scalia ◽  
Giuseppe Cammarata ◽  
Carmela Zizzo ◽  
Daniele Francofonte ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Vascular Endothelium ◽  
Clinical Manifestations ◽  
Premature Death ◽  
Lysosomal Storage ◽  
Familial Data ◽  
Enzyme Replacement ◽  
Cerebrovascular Complications ◽  
Cellular Events

Fabry disease is a multisystemic lysosomal storage disorder, inherited in an X-linked manner. It is a defect of metabolism of the glycosphingolipids, due to the reduction or absence of the activity of lysosomal enzyme α-galactosidase A. This reduction of activity causes the storage of globotriaosylceramide and derivatives in the lysosomes, triggering a cascade of cellular events, mainly in vascular endothelium. These events are the responsible for the systemic clinical manifestations and the renal, cardiac and cerebrovascular complications, or a combination of them. The symptomatology can lead to the premature death of patient between the fourth or fifth decade of life. The first symptoms can occur at different ages, generally in childhood, with different severity and course. Fabry disease is suspected on the basis of clinical and anamnestic-familial data, and it is confirmed by enzymatic and genetic assays. However, Fabry disease could be a pathology more complex than previously considered, and the diagnostic tests that are currently in use could be not always sufficient to confirm the clinical diagnosis. Probably, other factors could be also involved in the onset of symptomatology. In the last years, the knowledge of the disease is considerably increased but other studies are necessary to make a prompt and reliable diagnosis. An early diagnosis of Fabry disease is essential for the beginning of the enzyme replacement therapy, which can contribute to arrest its progression and improve the quality of life of patients.

scholarly journals Neonatal Screening for MPS Disorders in Latin America: A Survey of Pilot Initiatives

2020 ◽  
Vol 6 (4) ◽  
pp. 90
Author(s):  
Francyne Kubaski ◽  
Inês Sousa ◽  
Tatiana Amorim ◽  
Danilo Pereira ◽  
Joe Trometer ◽  
...  
Keyword(s):  
Latin America ◽  
Newborn Screening ◽  
Treatment Options ◽  
Digital Microfluidics ◽  
Premature Death ◽  
Lysosomal Storage ◽  
Pilot Studies ◽  
The Usa ◽  
History Of ◽  
Mps I

Newborn screening enables the diagnosis of treatable disorders at the early stages, and because of its countless benefits, conditions have been continuously added to screening panels, allowing early intervention, aiming for the prevention of irreversible manifestations and even premature death. Mucopolysaccharidoses (MPS) are lysosomal storage disorders than can benefit from an early diagnosis, and thus are being recommended for newborn screening. They are multisystemic progressive disorders, with treatment options already available for several MPS types. MPS I was the first MPS disorder enrolled in the newborn screening (NBS) panel in the USA and a few other countries, and other MPS types are expected to be added. Very few studies about NBS for MPS in Latin America have been published so far. In this review, we report the results of pilot studies performed in Mexico and Brazil using different methodologies: tandem mass spectrometry, molecular analysis, digital microfluidics, and fluorimetry. These experiences are important to report and discuss, as we expect to have several MPS types added to NBS panels shortly. This addition will enable timely diagnosis of MPS, avoiding the long diagnostic odyssey that is part of the current natural history of this group of diseases, and leading to a better outcome for the affected patients.

scholarly journals Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

2020 ◽  
Vol 21 (15) ◽  
pp. 5188 ◽  
Author(s):  
Akhil Bhalla ◽  
Ritesh Ravi ◽  
Meng Fang ◽  
Annie Arguello ◽  
Sonnet S. Davis ◽  
...  
Keyword(s):  
Neuronal Damage ◽  
Lysosomal Storage ◽  
Mucopolysaccharidosis Type Ii ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Mps Ii ◽  
Cellular Dysfunction ◽  
The Relationship ◽  
The Brain

Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II.

scholarly journals Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

2020 ◽  
Vol 21 (17) ◽  
pp. 6355
Author(s):  
Marisa Encarnação ◽  
Maria Francisca Coutinho ◽  
Lisbeth Silva ◽  
Diogo Ribeiro ◽  
Souad Ouesleti ◽  
...  
Keyword(s):  
Rare Variants ◽  
Health Care Systems ◽  
Genetic Disorders ◽  
Case Series ◽  
In Silico Analysis ◽  
Analysis Data ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Number Of Patients

Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients.

scholarly journals Community-Associated Methicillin-ResistantStaphylococcus aureusNecrotizing Pneumonia without Evidence of Antecedent Viral Upper Respiratory Infection

2014 ◽  
Vol 25 (3) ◽  
pp. e76-e82 ◽  
Author(s):  
Cristina Moran Toro ◽  
Jack Janvier ◽  
Kunyan Zhang ◽  
Kevin Fonseca ◽  
Dan Gregson ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Case Series ◽  
Risk Groups ◽  
Tube Placement ◽  
Nucleic Acid Testing ◽  
Upper Respiratory Tract ◽  
Necrotizing Pneumonia ◽  
Upper Respiratory ◽  
Mrsa Strains ◽  
Tract Infections

BACKGROUND: USA300 community-associated (CA) methicillin-resistantStaphylococcus aureus(MRSA) strains causing necrotizing pneumonia have been reported in association with antecedent viral upper respiratory tract infections (URI).METHODS: A case series of necrotizing pneumonia presenting as a primary or coprimary infection, secondary to CA-MRSA without evidence of antecedent viral URI, is presented. Cases were identified through the infectious diseases consultation service records. Clinical and radiographic data were collected by chart review and electronic records. MRSA strains were isolated from sputum, bronchoalveolar lavage, pleural fluid or blood cultures and confirmed using standard laboratory procedures. MRSA strains were characterized by susceptibility testing, pulsed-field gel electrophoresis,spatyping,agrtyping and multilocus sequence typing. Testing for respiratory viruses was performed by appropriate serological testing of banked sera, or nucleic acid testing of nasopharyngeal or bronchoalveloar lavage specimens.RESULTS: Ten patients who presented or copresented with CA necrotizing pneumonia secondary to CA-MRSA from April 2004 to October 2011 were identified. The median length of stay was 22.5 days. Mortality was 20.0%. Classical risk factors for CA-MRSA were identified in seven of 10 (70.0%) cases. Chest tube placement occurred in seven of 10 patients with empyema. None of the patients had historical evidence of antecedent URI. In eight of 10 patients, serological or nucleic acid testing testing revealed no evidence of acute viral coinfection. Eight strains were CMRSA-10 (USA300). The remaining two strains were a USA300 genetically related strain and a USA1100 strain.CONCLUSION: Pneumonia secondary to CA-MRSA can occur in the absence of an antecedent URI. Infections due to CA-MRSA are associated with significant morbidity and mortality. Clinicians need to have an awareness of this clinical entity, particularly in patients who are in risk groups that predispose to exposure to this bacterium.

scholarly journals Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches

2020 ◽  
Vol 21 (21) ◽  
pp. 7819
Author(s):  
Noelia Benetó ◽  
Lluïsa Vilageliu ◽  
Daniel Grinberg ◽  
Isaac Canals
Keyword(s):  
Heparan Sulfate ◽  
Disease Modeling ◽  
Neuronal Degeneration ◽  
Lysosomal Storage ◽  
Sanfilippo Syndrome ◽  
Therapeutic Approaches ◽  
Cellular Mechanisms ◽  
Cellular Models ◽  
Induced Pluripotent ◽  
Cellular Dysfunction

Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.

scholarly journals 0946 Parent-Perceived Sleep Problems Associated with Common Medical Issues During Infancy

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A359-A360
Author(s):  
J A Mindell ◽  
E S Leichman ◽  
A A Williamson ◽  
R A Gould ◽  
H Hiscock ◽  
...  
Keyword(s):  
Medical Care ◽  
Sleep Problem ◽  
Sleep Problems ◽  
Primary Care Providers ◽  
Care Providers ◽  
Care Needs ◽  
Medical Problems ◽  
Child Sleep ◽  
Medical Issues ◽  
Ear Infections

Abstract Introduction Sleep problems are highly prevalent during infancy. However, little research has been conducted on associations between these sleep issues and common medical concerns in early development. Thus, the purpose of this study was to assess the prevalence of parent-perceived sleep problems in infants with common medical problems. Methods Participants were 5,097 children from the Longitudinal Study of Australian Children—Birth Cohort. Caregiver-reported child sleep problems and medical concerns were assessed at ages 0-1 year. Chi-square analyses were used to examine associations between the presence of a parent-perceived sleep problem and medical concerns. Results Wheezing (29.6%), eczema (14.9%), and food/digestive allergies (5.0%) were the most commonly identified medical concerns. In addition, 17.1% of caregivers reported a moderate/severe child sleep problem. Infants who had a moderate to severe parent-identified sleep problem experienced higher rates of overall medical care/needs, wheezing, eczema, food/digestive allergies (p<.001), ear infections (p<.05), and other illnesses (p<.01) than those infants without a sleep problem. No differences were observed with regard to hearing problems, vision problems, developmental delay, diarrhea/colitis, anemia, or other (non-ear) infections. Furthermore, parents reported higher rates of sleep problems for infants with medical problems (20.0-37.5%) than for infants without medical problems (16-17%), especially related to needing medical care (sleep problems = 27%), food/digestive allergies (27%), eczema (23%), and wheezing (20%), p=.001. Conclusion Overall, common medical issues during infancy, including food/digestive allergies, eczema, and wheezing, are associated with greater parent-endorsed child sleep problems. Primary care providers should assess for and address sleep problems when treating common medical concerns during infancy. Support This project was partially supported by Johnson and Johnson Consumer Health (JAM, ESL, and RAG) and NIH K23HD094905 (AAW).

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