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1.
Orphanet J Rare Dis ; 19(1): 125, 2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38500130

ABSTRACT

BACKGROUND: CLN3 disease (also known as CLN3 Batten disease or Juvenile Neuronal Ceroid Lipofuscinosis) is a rare pediatric neurodegenerative disorder caused by biallelic mutations in CLN3. While extensive efforts have been undertaken to understand CLN3 disease etiology, pathology, and clinical progression, little is known about the impact of CLN3 disease on parents and caregivers. Here, we investigated CLN3 disease progression, clinical care, and family experiences using semi-structured interviews with 39 parents of individuals with CLN3 disease. Analysis included response categorization by independent observers and quantitative methods. RESULTS: Parents reported patterns of disease progression that aligned with previous reports. Insomnia and thought- and mood-related concerns were reported frequently. "Decline in visual acuity" was the first sign/symptom noticed by n = 28 parents (70%). A minority of parents reported "behavioral issues" (n = 5, 12.5%), "communication issues" (n = 3, 7.5%), "cognitive decline" (n = 1, 2.5%), or "seizures" (n = 1, 2.5%) as the first sign/symptom. The mean time from the first signs or symptoms to a diagnosis of CLN3 disease was 2.8 years (SD = 4.1). Misdiagnosis was common, being reported by n = 24 participants (55.8%). Diagnostic tests and treatments were closely aligned with observed symptoms. Desires for improved or stabilized vision (top therapeutic treatment concern for n = 14, 32.6%), cognition (n = 8, 18.6%), and mobility (n = 3, 7%) dominated parental concerns and wishes for therapeutic correction. Family impacts were common, with n = 34 (81%) of respondents reporting a financial impact on the family and n = 20 (46.5%) reporting marital strain related to the disease. CONCLUSIONS: Collectively, responses demonstrated clear patterns of disease progression, a strong desire for therapies to treat symptoms related to vision and cognition, and a powerful family impact driven by the unrelenting nature of disease progression.


Subject(s)
Neuronal Ceroid-Lipofuscinoses , Humans , Child , Neuronal Ceroid-Lipofuscinoses/genetics , Molecular Chaperones/genetics , Molecular Chaperones/therapeutic use , Membrane Glycoproteins/genetics , Parents , Disease Progression , Surveys and Questionnaires
2.
Biochim Biophys Acta Mol Basis Dis ; 1866(9): 165773, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32224155

ABSTRACT

This review will summarise the achievements of Patient Organisations and Foundations started by affected Batten disease families, with an emphasis on their recent contribution to Batten disease, examine the benefits and pitfalls of their interactions with scientists and propose a way forward.


Subject(s)
Biomedical Research , Neuronal Ceroid-Lipofuscinoses/diagnosis , Organizations , Patient Advocacy , Humans
3.
Biochim Biophys Acta ; 1852(10 Pt B): 2324-8, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26056946

ABSTRACT

The neuronal ceroid lipofuscinoses, collectively called NCLs, are rare and fatal lysosomal storage diseases that mainly affect children. Due to the fact that NCLs are both rare and heterogeneous (mutations in thirteen different genes) significant gaps exist in both preclinical and clinical research. Altogether, these gaps are major hurdles to bring therapies to patients while the need for new therapies is urgent to help them and their families. To define gaps and discuss solutions, a round table discussion involving teams and different stake holders took place during the 14th International Conference on Neuronal Ceroid Lipofuscinoses (Batten Disease) in Cordóba, Argentina. Topics covered by the teams and their leaders (in parentheses) included basic and translational research gaps with regard to large animal models (I. Tammen, D.N. Palmer), human NCL pathology and access to human tissue (J.D. Cooper, H.H. Goebel), rare NCLs (S. Hofman, I. Noher), links of NCLs to other diseases (F.M. Platt), gaps between clinic and clinical trials (H. Adams, A. Schulz), international collaborative efforts working towards a cure (S.E. Mole, H. Band) perspectives on palliative care from patient organizations (M. Frazier, A. West), and issues NCL researchers face when progressing to independent career in academia (M. Bond). Thoughts presented by the team leaders include previously unpublished opinions and information on the lack of understanding of disease pathomechanisms, gene function, assays for drug discovery and target validation, natural history of disease, and biomarkers for monitoring disease progression and treatment effects. This article is not intended to review the NCL literature. It includes personal opinions of the authors and it provides the reader with a summary of gaps discussed and solutions proposed by the teams. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease).

4.
Microbes Infect ; 11(14-15): 1131-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19703582

ABSTRACT

A reconstituted human tissue model was used to mimic Candida albicans and Candida parapsilosis infection in order to investigate the protective effects of acetylsalicylic acid (aspirin, ASA). We found that therapeutic concentrations of ASA reduced tissue damage in the in vitro infection model. We further evaluated the lipase inhibitory effects of ASA by investigating the growth of C. albicans, C. parapsilosis and C. parapsilosis lipase negative (Deltacplip1-2/Deltacplip1-2) mutants in a lipid rich minimal medium supplemented with olive oil and found that a therapeutic concentration of ASA inhibited the growth of wild type fungi. The lipase inhibitors quinine and ebelactone B were also shown to reduce growth and protect against tissue damage from Candida species, respectively. A lipolytic activity assay also showed that therapeutic concentrations of ASA inhibited C. antarctica and C. cylindracea purified lipases obtained through a commercial kit. The relationship between ASA and lipase was characterized through a computed structural model of the Lipase-2 protein from C. parapsilosis in complex with ASA. The results suggest that development of inhibitors of fungal lipases could result in broad-spectrum therapeutics, especially since fungal lipases are not homologous to their human analogues.


Subject(s)
Aspirin/pharmacology , Candida/drug effects , Candida/pathogenicity , Epithelium/microbiology , Fungal Proteins/antagonists & inhibitors , Lipase/antagonists & inhibitors , Mouth/cytology , Candida/classification , Candida/enzymology , Candida albicans/drug effects , Candida albicans/enzymology , Candidiasis/microbiology , Cell Line, Tumor , Cells, Cultured , Epithelium/growth & development , Humans
5.
Infect Immun ; 75(10): 4710-8, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17646357

ABSTRACT

The production of lipases can affect microbial fitness and virulence. We examined the role of the lipase 8 (LIP8) gene in the virulence of Candida albicans by constructing Deltalip8 strains by the URA-blaster disruption method. Reverse transcription-PCR experiments demonstrated the absence of LIP8 expression in the homozygous knockout mutants. Reconstituted strains and overexpression mutants were generated by introducing a LIP8 open reading frame under control of a constitutive actin promoter. Knockout mutants produced more mycelium, particularly at higher temperatures and pH >or=7. Diminished LIP8 expression resulted in reduced growth in lipid-containing media. Mutants deficient in the LIP8 gene were significantly less virulent in a murine intravenous infection model. The results clearly indicate that Lip8p is an important virulence factor of C. albicans.


Subject(s)
Candida albicans/enzymology , Candida albicans/pathogenicity , Candidiasis/microbiology , Lipase/physiology , Virulence Factors/physiology , Animals , Candida albicans/genetics , Colony Count, Microbial , Fungal Proteins/genetics , Fungal Proteins/physiology , Gene Deletion , Lipase/genetics , Liver/microbiology , Mice , Mice, Inbred BALB C , Mutagenesis, Insertional , Survival Analysis , Virulence Factors/genetics
6.
FEMS Yeast Res ; 4(4-5): 401-8, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14734020

ABSTRACT

Secreted lipases of Candida albicans are encoded by a gene family with at least 10 members (LIP1-LIP10). The expression pattern of this multigene family was investigated using reverse transcription polymerase chain reaction in experimental infections and in samples of patients suffering from oral candidosis. The findings illustrate that individual lipase genes are differentially regulated in a mouse model of systemic candidosis with some members showing sustained expression and others being transiently expressed or even silent. The lipase gene expression profile depended on the stage of infection rather than on the organ localization. This temporal regulation of lipase gene expression was also detected in an experimental model of oral candidosis. Furthermore, the expression of candidal lipase genes in human specimens is shown for the first time.


Subject(s)
Candida albicans/genetics , Candidiasis/enzymology , Isoenzymes/genetics , Lipase/genetics , Animals , Base Sequence , Candida albicans/enzymology , Candida albicans/isolation & purification , Candidiasis/pathology , DNA Primers , Disease Models, Animal , Humans , Mice , Mice, Inbred BALB C , Multigene Family , Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction/methods
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