glycoproteins with consequent accumulation of glycoproteins in many tissues, especially the nervous system They became recognized when patients with presentations similar to those with the mucopolysaccharidoses were found to have biochemically distinct diseases The five primary disorders of glycoprotein degradation, mannosidosis, fucosidosis, sialidosis, galactosialidosis, and aspartylglycosaminuria, can all be diagnosed by demonstration of the enzyme defect in cultured fibroblasts Prenatal diagnosis is often possible Mannosidosis Deficiency of α-mannosidase is a rare, autosomal recessive disorder that results in the accumulation of oligosaccharides, as their degradation is dependent on lysosomal activity of this enzyme Oligosaccharides are excreted in the urine Several defects in the gene encoding α-mannosidase have been discovered The specific defect may result in decreased enzyme synthesis, decreased enzyme activity within the lysosomal environment, decreased localization of the enzyme within the lysosome, or faulty posttranslational modification of the enzyme The patients present with features suggestive of mucopolysaccharidosis but have an increased susceptibility to infections Progressive mental retardation is typical Early onset of the disease categorized as type I is associated with increased severity Death occurs between 3 and 10 years of age Late-onset disease (type II) runs a more benign course Cardiac manifestations are not frequently reported However, a short PR interval has been reported in several patients The mechanism for this is unknown.75 Treatment has been attempted with bone marrow transplantation, and strategies currently under investigation include various forms of enzyme replacement therapy.76 Fucosidosis Deficiency of α-L-fucosidase results in the accumulation of fucosylated oligosaccharides and glycolipids Two clinical types are recognized The first type presents in infancy with coarse facies, growth retardation, mental retardation, and neurologic deterioration Convulsions and respiratory infections often occur The second type has a more benign course and a later onset Cardiomegaly, probably as part of a generalized visceromegaly, is the most common cardiac feature but is benign These two types probably represent both ends of a continuum that is dictated by a patient's specific enzyme activity as determined by his or her specific gene defect Bone marrow transplantation has been performed with good results, and further experimentation with enzyme replacement therapy is ongoing.77,78 Sialidosis The basic defect in sialidosis is deficiency of α-neuraminidase, with accumulation of sialoglycoconjugates Two forms exist The first is of late onset and patients are of normal appearance but develop the cherry-red spot myoclonus syndrome Decreased visual acuity is associated with a cherry-red spot in the macular region Neurologic (and occasional renal) manifestations dominate the clinical picture The second type has an early onset, even on occasion being obvious at birth The patients have coarse features and enlargement of various organs including the heart Echocardiography has shown an increased left ventricular wall thickness along with thickening of the mitral valve.79 There is great variability in the spectrum of severity, even in the group with early onset Survival beyond 20 years is rare; occasionally, however, affected subjects are stillborn Fetal hydrops has been reported as a presenting feature.80 Sialidosis is inherited in autosomal recessive fashion Enzyme replacement therapy and gene transfer treatments are under investigation.81 Galactosialidosis In galactosialidosis, patients have a defect in the production of lysosomal protective protein/cathepsin A, which helps to form a stable and activated complex with β-galactosidase and α-neuraminidase.82 Thus the symptoms are a combination of those seen in sialidosis and Morquio syndrome, the severity of which is likely determined by the specific genetic defect and its overall effect on the production of functional levels of the protein An infantile form has been described,83 and there appears to be a fair amount of clinical variation even in those diagnosed as infants.84 Structural congenital heart disease has been reported in patients with galactosialidosis,85 but the cardiac manifestations are usually similar to those seen in Morquio syndrome and sialidosis, with aortic and mitral valve thickening,86 which is progressive.87 Recently the role of these enzymes and protective protein/cathepsin A in elastogenesis has begun to be unraveled, helping to further explain the phenotype associated with these genetic disorders.88 Although no specific treatment yet exists, early work has begun on therapies involving enzyme replacement or gene transfer.89–91 Aspartylglycosaminuria Aspartylglycosaminuria is a lysosomal storage disease due to a defective or deficient glycosylasparaginase This enzyme is required for complete breakdown of asparagine-linked glycoproteins within the lysosome.92 Accumulation of these glycoprotein residues leads to severe and progressive neurologic impairment It is associated with coarse features, joint laxity, and early rapid somatic growth followed by a reduced adolescent growth spurt leading ultimately to short stature and mental retardation Animal models demonstrate residue accumulation within the heart, but clinical cardiac involvement does not appear to predominate Therapy via enzyme replacement is currently being studied in animal models.93,94 Acid Lipase Deficiency (Wolman Disease and Cholesterol Ester Storage Disease) Lysosomal acid lipase is necessary for the cleavage of triglycerides and cholesterol esters from lipoproteins delivered to the lysosome Complete or partial deficiency of lysosomal acid lipase results in accumulation of cholesterol in most tissues of the body The disease occurs in two forms Wolman disease, with complete absence of enzymatic activity, is a disease of infancy presenting with vomiting, diarrhea, hepatosplenomegaly, failure to thrive, anemia, and calcification of the adrenal glands Cardiac manifestations are not usually evident, but microscopic examination of the arteries shows excess fatty deposits Hepatomegaly is frequently the only sign in the milder form of the disease, cholesterol ester storage disease, although premature atherosclerosis is also seen.95 The diagnosis of Wolman disease is suggested by the association of hepatosplenomegaly with adrenal calcification Definitive diagnosis of either disease can be made by assessing acid lipase activity in cultured skin fibroblasts The disease is inherited in autosomal recessive fashion Successful treatment with hematopoietic stem cell, bone marrow, and cord blood transplantation has been reported.96–98