Hepatomegaly and Splenomegaly: An Approach to the Diagnosis of Lysosomal Storage Diseases.

Clinical findings of hepatomegaly and splenomegaly, the abnormal enlargement of the liver and spleen, respectively, should prompt a broad differential diagnosis that includes metabolic, congestive, neoplastic, infectious, toxic, and inflammatory conditions. Among the metabolic diseases, lysosomal storage diseases (LSDs) are a group of rare and ultrarare conditions with a collective incidence of 1 in 5000 live births. LSDs are caused by genetic variants affecting the lysosomal enzymes, transporters, or integral membrane proteins.

Long-term outcomes in two adult siblings with Fucosidosis - Diagnostic odyssey and clinical manifestations.

Fucosidosis (OMIN# 230000) is a rare lysosomal storage disorder (LSDs) caused by mutations in the gene, leading to alpha-L-fucosidase deficiency; it is inherited as an autosomal recessive trait. Fucosidosis represents a disease spectrum with a wide variety of clinical features, but most affected patients have slow neurologic deterioration. Many patients die young and the long-term clinical outcomes in adult patients are poorly documented.

Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.

A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular membrane-tethering protein complexes, HOPS, and CORVET. Whole exome sequencing identified a novel VPS33A mutation in a patient suffering from a variant form of mucopolysaccharidosis. Electron and confocal microscopy, immunoblotting, and glycosphingolipid trafficking experiments were undertaken to investigate the effects of the mutant VPS33A in patient-derived skin fibroblasts.

Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study.

Aims: Lysosomal α-galactosidase A deficiency (Fabry disease (FD)) was considered an X-linked recessive disorder but is now viewed as a variable penetrance dominant trait. The prevalence of FD is 1 in 40 000-117 000 but the ascertainment of late-onset cases and degree of female penetrance makes this unclear. Its prevalence in the general population, especially in patients with abnormal renal function is unclear.

The lysosomal disease caused by mutant VPS33A.

A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts-a nomadic Turkic ethnic group of Southern Siberia. VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway.

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update on GNPTAB and GNPTG mutations.

Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function.

Sleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcome.

Background: The lysosomal storage disorder, mucopolysaccharidosis I (MPS I), commonly manifests with upper airway obstruction and sleep disordered breathing (SDB). The success of current therapies, including haematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) may be influenced by a number of factors and monitored using biomarkers of metabolic correction. We describe the pattern of SDB seen in the largest MPS I cohort described to date and determine therapies and biomarkers influencing the severity of long-term airway disease.

Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy.

Background: Antibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investigated the response of a large panel of biomarkers to long term ERT in MPS I patients and correlate these responses with antibody formation and antibody mediated cellular uptake inhibition.

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy.

Background: Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme.