Sphingolipidoses Sphingomyelin Lipidosis (Niemann-Pick Disease) In Niemann-Pick disease, there is accumulation of sphingomyelin in the cells as a result of deficiency of sphingomyelinase (type a and b) A second distinct form (type c) was recently discovered, which arises from the defective function of cholesterol transport.99 The primary cells affected are those of monocytemacrophage lineage as they are frequently employed in the metabolic turnover of these substances In type a, patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement These individuals rarely survive beyond 3 years of age Type b patients also have hepatosplenomegaly along with pathologic alterations in their lungs, but there are usually no central nervous system signs In type c, psychosis predominates initially.100 Many of these patients are of Ashkenazi Jewish heritage The disease is characterized by hepatosplenomegaly and the occurrence of foam storage cells in many tissues The heart is not usually affected, but one infant with acute neuronopathic disease had endocardial fibroelastosis.101 Since there were no storage cells in the heart, however, this may have been a chance association Lipid profile abnormalities have also been described in children with Niemann-Pick disease types a and b, possibly leading to premature atherosclerosis.102 Low levels of high-density lipoprotein cholesterol was the most consistent finding, whereas elevated triglycerides and levels of low-density lipoprotein cholesterol were seen in approximately two-thirds These abnormalities were noted at an early age and may reflect deranged cholesterol metabolism in these cells as a result of sphingomyelin accumulation Niemann-Pick disease in most of its forms is inherited in an autosomal recessive fashion Glucosylceramidosis (Gaucher Disease) Gaucher disease is the most common inherited disorder of glycolipid metabolism In his original description,103 Phillippe Gaucher ascribed the changes to a primary epithelioma of the spleen There is excessive accumulation of glucosylceramide in cells of the reticuloendothelial system in organs throughout the body, resulting from deficiency of the enzyme glucocerebrosidase, which cleaves glucose from glucocerebroside Although over 150 different mutations of the gene encoding glucocerebrosidase have been described, the disease occurs in three varieties based on the presence or absence of neurologic manifestations and their rate of progression The first (type I, the chronic nonneuronopathic form) can be diagnosed at any age and is the most common form It is characterized by hypersplenism, hepatomegaly (with evidence of abnormal liver function), and skeletal lesions (including aseptic necrosis of the femoral head) Other long bones and vertebrae may also be eroded In patients with this type of disease, cardiac involvement may be seen, with myocardial infiltration or restrictive pericardial disease.104 The most frequently encountered cardiac problem, however, is cor pulmonale secondary to pulmonary involvement Mitral and aortic stenosis and insufficiency can also be seen,105 and severe valvar and aortic arch calcification has been reported.106 The course is variable Death may occur in early childhood or, particularly when the onset is late, there may be a normal life expectancy Further variability is apparently the consequence of the nonneuronopathic form at onset changing to one of the other forms with poorer prognosis The acute neuronopathic form (type II) is usually recognized within the second half of the first year of life Neurologic involvement is evident early, afflicting particularly the cranial nerves and extrapyramidal tracts The mechanism of death is usually a respiratory infection, since—owing to incoordination of the nasopharynx—aspiration is common The subacute neuronopathic form (type III) falls between the acute and chronic forms The neurologic involvement renders it less benign than the chronic variant, but its course usually stretches over many years Although describing Gaucher disease in terms of three distinct phenotypes is convenient, the actual observed behavior of this disease is much less well defined Patients with the same genotype can have widely differing phenotypes, and patients even within a particular type can have markedly differing clinical courses Thus, although the genetic defects leading to Gaucher disease are being elucidated and include over 150 specific mutations already identified, the genotype-phenotype link is still quite unclear The diagnosis of Gaucher disease is confirmed by the finding of typical storage cells in the bone marrow or by liver biopsy The Gaucher cell is large and lipid-laden The cytoplasm is described as having a “wrinkled tissue paper” or “crumpled silk” appearance The nucleus is eccentric These cells must be differentiated from cells found in multiple myeloma, leukemia, thalassemia, and congenital dyserythropoietic anemia Demonstration of the enzymic deficiency in cultured skin fibroblasts or in leukocytes confirms the diagnosis Treatment options include bone marrow transplantation and gene therapy in rare cases, but enzyme replacement therapy has become the standard of care in the majority of cases In fact, type I Gaucher disease was the first lysosomal storage disorder for which, in 1991, an effective enzyme replacement therapy was developed.107 Improvement in the visceral organ involvement is common, but neurologic damage is generally not responsive to exogenous enzyme therapy All three variants are inherited as autosomal recessive traits Intrauterine diagnosis is available, and heterozygotes can be identified at least for the acute and chronic types α-Galactosidase a Deficiency (Fabry Disease) Deficiency of α-galactosidase, a lysosomal enzyme, results in the accumulation of phosphosphingolipids in the lysosomes of many tissues and also in the body fluids The most frequently affected tissue is the vascular endothelium The disease is of X-linked inheritance, but heterozygous women can show severe manifestations of the disease.108 The gene locus for the enzyme is on the long arm of the X-chromosome The disease usually presents in childhood in the male homozygote, often with periodic crises of severe pain of burning character, which usually starts in the hands and feet Crises occur most usually in the afternoon Such crises, which become less frequent and severe with time, may, however, be followed by eruption of skin lesions, angiokeratomas, and typical opacities of the cornea and the lens The angiokeratomas are clusters of dark-red to purple punctate lesions, which are usually flat or slightly raised They occur most frequently between the umbilicus and the knees and do not blanch on pressure Hyperkeratosis and hypohydrosis usually accompany the angiokeratomas Ocular lesions include typical creamy whorl-like opacities in the cornea They are frequently found in the female heterozygote as well as the male homozygote Cardiac disease is manifest with increasing age Myocardial ischemia and infarction are common and are secondary to the vascular lesions Mitral regurgitation and aortic stenosis are the most frequently encountered valvar lesions.109 Infiltration of the conduction tissues also occurs This results in progressive shortening of the PR interval, as in other storage diseases that affect the specialized atrioventricular conduction axis.110 Myocardial deposition can be detected echocardiographically by the demonstration of septal and left ventricular wall thickening.111