ContextLysosomal storage disorders represent a group of at
least 41 genetically distinct, biochemically related, inherited
diseases. Individually, these disorders are considered rare, although
high prevalence values have been reported in some populations. These
disorders are devastating for individuals and their families and result
in considerable use of resources from health care systems; however, the
magnitude of the problem is not well defined. To date, no comprehensive
study has been performed on the prevalence of these disorders as a
group.ObjectiveTo determine the prevalence of lysosomal storage
disorders individually and as a group in the Australian population.DesignRetrospective case studies.SettingAustralia, from January 1, 1980, through December 31,
1996.Main Outcome MeasureEnzymatic diagnosis of a lysosomal storage
disorder.ResultsTwenty-seven different lysosomal storage disorders were
diagnosed in 545 individuals. The prevalence ranged from 1 per
57,000 live births for Gaucher disease to 1 per 4.2 million live
births for sialidosis. Eighteen of 27 disorders had more than 10
diagnosed cases. As a group of disorders, the combined prevalence was 1
per 7700 live births. There was no significant increase in the rate of
either clinical diagnoses or prenatal diagnoses of lysosomal storage
disorders during the study period.ConclusionsIndividually, lysosomal storage disorders are rare
genetic diseases. However, as a group, they are relatively common and
represent an important health problem in Australia.

https://jamanetwork.com/journals/jama/articlepdf/188380/JOC80368.pdf

Prevalence of lysosomal storage disorders.

Epidemiology of mucopolysaccharidoses

Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.

/pdf/hyaluronan-as-an-immune-regulator-in-human-diseases-2tqae9fxb7.pdf

Hyaluronan as an Immune Regulator in Human Diseases

A hallmark of tissue injury and repair is the turnover of extracellular matrix components. This review focuses on the role of the glycosaminoglycan hyaluronan in tissue injury and repair. Both the synthesis and degradation of extracellular matrix are critical contributors to tissue repair and remodeling. Fragmented hyaluronan accumulates during tissue injury and functions in ways distinct from the native polymer. There is accumulating evidence that hyaluronan degradation products can stimulate the expression of inflammatory genes by a variety of immune cells at the injury site. CD44 is the major cell-surface hyaluronan receptor and is required to clear hyaluronan degradation products produced during lung injury; impaired clearance of hyaluronan results in persistent inflammation. However, hyaluronan fragment stimulation of inflammatory gene expression is not dependent on CD44 in inflammatory macrophages. Instead, hyaluronan fragments utilize both Toll-like receptor (TLR) 4 and TLR2 to stimulate inflammatory genes in macrophages. Hyaluronan also is present on the cell surface of lung alveolar epithelial cells and provides protection against tissue damage by interacting with TLR2 and TLR4 on these parenchymal cells. The simple repeating structure of hyaluronan appears to be involved in a number of important aspects of noninfectious tissue injury and repair that are dependent on the size and location of the polymer as well as the interacting cells. Thus, the interactions between the endogenous matrix component hyaluronan and its signaling receptors initiate inflammatory responses, maintain structural cell integrity, and promote recovery from tissue injury.

/pdf/hyaluronan-in-tissue-injury-and-repair-5fnd16at3e.pdf

Hyaluronan in Tissue Injury and Repair

The blood-brain barrier (BBB) plays a key role in maintaining the specialized microenvironment of the central nervous system (CNS), and enabling communication with the systemic compartment. BBB changes occur in several CNS pathologies. Here, we review disruptive and non-disruptive BBB changes in systemic infections and other forms of systemic inflammation, and how these changes may affect CNS function in health and disease. We first describe the structure and function of the BBB, and outline the techniques used to study the BBB in vitro, and in animal and human settings. We then summarise the evidence from a range of models linking BBB changes with systemic inflammation, and the underlying mechanisms. The clinical relevance of these BBB changes during systemic inflammation are discussed in the context of clinically-apparent syndromes such as sickness behaviour, delirium, and septic encephalopathy, as well as neurological conditions such as Alzheimer's disease and multiple sclerosis. We review emerging evidence for two novel concepts: (1) a heightened sensitivity of the diseased, versus healthy, BBB to systemic inflammation, and (2) the contribution of BBB changes induced by systemic inflammation to progression of the primary disease process.

The blood-brain barrier in systemic inflammation

Enzyme replacement therapy in type III Gaucher disease A. and B. Czartoryska2 T ylki-Szyman ska1* 1 Department of Metabolic Diseases, The ChildrenÏs Memorial Health Institute, Warsaw; 2 Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland * Correspondence : The ChildrenÏs Memorial Health Institute, Department of Metabolic Diseases, al. Dzieci Polskich 20, 04-736 Warsaw, Poland

Enzyme replacement therapy in type III Gaucher disease.

Grzegorz Węgrzyn,* Anna Tylki-Szymańska, Anna Liberek, Ewa Piotrowska, Joanna Jakóbkiewicz-Banecka, Jolanta Marucha, Barbara Czartoryska, and Alicja Węgrzyn Department of Molecular Biology, University of Gdańsk, Kładki 24, Gdańsk, Poland Department of Metabolic Diseases, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, Warsaw, Poland Department of Pediatrics, Children’s Gastroenterology and Oncology, Medical University of Gdańsk, Nowe Ogrody 1-6, Gdańsk, Poland Laboratory of Molecular Biology (affiliated with the University of Gdańsk), Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Kładki 24, Gdańsk, Poland Department of Genetics, Institute of Psychiatry and Neurology, Sobieskiego 9, Warsaw, Poland

Rapid deterioration of a patient with mucopolysaccharidosis type I during interruption of enzyme replacement therapy.

Familial X-chromosome inactivation (XCI) skewing was investigated in a family in which a female mucopolysaccharidosis type II (MPS II) (Hunter syndrome, an X-linked genetic disease) occurred. Among eight related females aged under 60 years from three generations who were tested, four revealed a non-random pattern of XCI. Detailed genetic analysis failed to find mutations in genes that were previously reported as important for the XCI process. Haplotype analysis excluded linkage of non-random XCI with genes localized on the X-chromosome. We propose that analysis of the XCI pattern should be taken into consideration when assessing risk factors for X-linked recessive genetic disorders.

Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders

In 25-alcohol-dependent patients in whom detoxication treatment has been introduced serum total beta-hexosaminidase, thermostable beta-hexosaminidase, alpha-mannosidase and gamma glutamylotransferase (GGT) and serum high density lipoprotein (HDL) cholesterol were determined during alcohol withdrawal. The assays were also performed in a group of dependent individuals after a 1 month or longer period of abstinence. Marked increase in beta-hexosaminidase activity was observed in intoxicated patients. The activity decreased rapidly after the cessation of drinking, resembling the decrease in HDL cholesterol level in its dynamics. The alpha-mannosidase activity rise was less pronounced and its normalization was slow, similar to the GGT activity normalization rate. The rise of beta-hexosaminidase activity was mostly due to the thermostable component of the enzyme. Total beta-hexosaminidase or thermostable beta-hexosaminidase activity determinations appear to be simple and reliable markers of alcohol abuse.

Serum beta-hexosaminidase and alpha-mannosidase activities as markers of alcohol abuse.

The occurrence and genotype-phenotype correlations of the eight most common mutations in the arylsulfatase A (ARSA) gene were studied in 43 unrelated Polish patients suffering from different types of metachromatic leukodystrophy (MLD). Screening for mutations p.R84Q, p.S96F, c.459+1G>A, p.I179S, p.A212V, c.1204+1G>A, p.P426L, and c.1401-1411del allowed the identification of 53.5% of the mutant alleles. In the whole investigated group of patients, mutations c.459+1G>A and p.P426L were the most frequent, 19 and 17%, respectively. The prevalence of the third most frequent mutation, i.e. p.I179S (13%), seems to be higher than that in other populations. The incidence of c.1204+1G>A was 5%, which is higher than reported earlier (2%). It seems that p.I179S and c.1204+1G>A are more prevalent in MLD patients from Poland than from other countries. In the group examined by us, mutations p.R84Q, p.S96F, p.A212V, and c.1401-1411del were not detected; thus, 46.5% of MLD alleles remained unidentified. This indicates that other, novel or already described, but rare, mutations exist in Polish population. In late infantile homozygotes for c.459+1G>A and one homozygote for c.1204+1G>A, first clinical symptom was motor deterioration. In adult homozygotes for p.P426L, the disease onset manifested as gait disturbances, followed by choreoathetotic movements, difficulties in swallowing, dysarthria, tremor, and nystagmus. In the carriers of the p.I179S mutation, the hallmark of the clinical picture was psychotic disturbances.

Barbara Czartoryska

Papers

Enzyme replacement therapy in type III Gaucher disease.

Rapid deterioration of a patient with mucopolysaccharidosis type I during interruption of enzyme replacement therapy.

Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders

Serum beta-hexosaminidase and alpha-mannosidase activities as markers of alcohol abuse.

Molecular and phenotypic characteristics of metachromatic leukodystrophy patients from Poland.