Progressive deposition of glycosphingolipid means that the cardiac problems themselves are also progressive Since concomitant renal involvement occurs, the cardiac effects are exacerbated by, for example, renal hypertension The clinical course in the male homozygote is one of steady deterioration during early adult life, death being due to cardiac or renal disease The heterozygote female experiences little limitation of style and length of life The diagnosis can be confirmed (and heterozygotes identified) by demonstrating the enzymic deficiency in leukocytes and by an abnormally high content of accumulated substrates in tears or urinary sediment Prenatal diagnosis is available Enzyme replacement therapy was first reported in 2002,112 and positive effects on cardiac involvement are evident.113 Fabry disease should be considered whenever unexplained left ventricular hypertrophy is discovered, as early diagnosis and initiation of enzyme replacement therapy has shown clear benefit.114 Gangliosidoses The gangliosidoses are lysosomal storage diseases characterized by accumulation of gangliosides gm1 or gm2 (or related conjugates) owing to deficiency of specific lysosomal hydrolases The enzyme deficient in gm1 gangliosidosis is acid β-galactosidase Deficiency of hexosaminidase a or b (or both) or a deficiency of an enzyme activator results in gm2 gangliosidosis Gm1 Gangliosidosis There are many enzymatic and clinical subdivisions of gm1 gangliosidosis The gene locus is on the short arm of chromosome 3 Mutation at this locus results in absence of enzyme activity for acid β-galactosidase, leading to accumulation of gm1 ganglioside in the brain and viscera The wide variation in clinical picture has resulted in a broad classification of infant, juvenile, and adult forms All forms of gm1 gangliosidosis are inherited as autosomal recessive traits The infant form is a rapidly progressive disease characterized by hypotonia, poor feeding, and failure to make motor or intellectual progress Progressive neurologic deterioration results in spastic quadriplegia or decerebrate rigidity Rarefied bones and beaked vertebrae are some of the skeletal lesions encountered As in Tay-Sachs disease (see later), a cherry-red spot is seen in the macular region of the retina Death usually occurs by the age of 3 years, frequently from bronchopneumonia The heart is frequently involved The spectrum from CHF with systolic dysfunction to isolated valve thickening has been observed.115,116 Neonatal ascites has also been reported.117 Cardiac involvement usually includes cardiomegaly on chest radiography, left ventricular hypertrophy on the echocardiogram, and CHF.118 Interestingly, patients with gm1 gangliosidosis have a defect in the same enzyme that is involved in patients with Morquio syndrome type b The clinical heterogeneity among patients with this enzymatic defect is unclear but is probably related to residual activity of the enzyme, postprocessing of the enzyme, and other proteins involved such as saposin b.119 A novel treatment strategy is under investigation involving molecular chaperones, substances that stabilize the configuration of defective enzymes and enable them to remain enzymatically active.120 Treatment in a mouse model demonstrated improved enzyme activity121 and a reduced quantity of substrate in neuronal tissues; however, no viable therapy for humans yet exists.122,123 Gm2 Gangliosidoses The gm2 gangliosidoses are autosomal recessive conditions that result in variable deficiency of hexosaminidase, the locus for which has been mapped to the q arm of chromosome 5 This enzyme, which is composed of two subunits (α and β), comes in two forms Hexosaminidase a (found in the central nervous system) is composed of an α- and β-subunit, and hexosaminidase b (found in peripheral tissues) is composed of two β subunits Thus the gm2 gangliosidoses result from a defect in either the α-subunit (Tay-Sachs disease, severe deficiency of hexosaminidase a) or the β-subunit (Sandhoff disease, with severe deficiency of both types a and b of the enzyme) The juvenile and adult (chronic) gm2 gangliosidoses result from less severe deficiencies of hexosaminidase type a Treatment for these disorders is still under investigation using animal models Efforts have included gene therapy, substrate reduction therapy, and bone marrow transplantation, although none of these treatments has yet to show clinic benefit in humans.124–127 Tay-Sachs Disease Tay-Sachs disease is the most common of the gangliosidoses; it presents with motor weakness in the first 6 months of life There is progressive motor and mental deterioration, with convulsions, spasticity and decerebrate rigidity Death usually occurs by the age of 3 years, the most frequent cause being bronchopneumonia The children have doll-like facies Examination of the retina shows the typical cherry-red macula, which later becomes brown Cardiac accumulation of substrate is usual; however, save for a prolonged QT interval and nonspecific T-wave changes, cardiac manifestations are rare Although the hallmark of the disease is central nervous system accumulation of gm2 ganglioside, evidence of peripheral and autonomic nervous system involvement has been reported in patients with chronic disease.128 Sandhoff Disease Sandhoff disease is similar to Tay-Sachs disease in its presentation and course but is biochemically distinct Clinically relevant cardiac involvement is rare, but a cardiomyopathy has been described, along with thickening of the mitral valve and its tension apparatus.129 Another separate report describes a case of CHF due to aortic and mitral valve thickening with severe mitral regurgitation.130 The coronary arteries may also be narrowed.131 As with gm1 gangliosidoses, the inheritance is autosomal recessive