progress.39 Scheie Syndrome Patients with Scheie syndrome are less severely affected and have normal stature and intellect They also have a near normal life span The most striking features are corneal clouding and stiff joints Typical cardiac manifestations are aortic stenosis and regurgitation or mitral regurgitation.40,41 These should be managed in a similar fashion to that employed in otherwise normal subjects Scheie syndrome is inherited in autosomal recessive fashion Hurler-Scheie Syndrome Hurler-Scheie syndrome falls in severity between the two extremes of α-Liduronidase deficiency The patients have short stature with mental retardation and multiple bony defects There is clouding of the cornea and stiff joints, clawhand being particularly common Aortic and mitral valve involvement is the primary manifestation, but asymmetric septal hypertrophy has also been reported.42 The clinical course is intermediate between Hurler and Scheie syndromes, patients living into adolescence or even to the third decade Mucopolysaccharidosis Type II (Hunter Syndrome, Iduronate Sulfatase Deficiency) Deficiency of iduronate sulfate results in blocked degradation of dermatan sulfate The difference in clinical profile between this and Hurler and Scheie syndromes (e.g., the absence of corneal clouding in Hunter syndrome) may result from specific variability in the degree of blockage of degradation of the mucopolysaccharide Furthermore, it may be that the block to degradation caused by the accumulation of iduronate sulfate may be bypassed by hyaluronidase The severe and mild forms of Hunter syndrome both have total (or near total) deficiency of iduronate sulfatase However, as with mucopolysaccharidosis type I, the clinical phenotype may be representative of the degree of residual enzyme activity specific to certain gene mutations, of which more than 300 have been found for Hunter syndrome.43 The condition can occur with a wide variation in severity, which tends to run true in any given family Apart from the extreme rarity of corneal clouding in Hunter syndrome and the presence of hearing loss, the clinical features are those of Hurler syndrome, although usually less severe A positive distinguishing physical sign pointed out by Hunter himself (1916) is the occurrence of pebblelike ivory-colored skin lesions These are seen over the scapulae and occasionally on the pectoral regions Cardiac involvement produces all the manifestations so far mentioned, namely aortic and mitral regurgitation or stenosis, ischemic changes, and evidence of myocardial deposition and dysfunction Echocardiography is a useful method for evaluating cardiac involvement in Hunter syndrome The clinical course is extremely variable Severely affected individuals may die in adolescence At the opposite end of the spectrum, however, survival beyond the sixth decade has been reported Death in younger patients is usually associated with progressive neurologic deterioration The disease is inherited as an X-linked recessive trait, although cases in females have been reported.44 Since the reproductive fitness of the Hunter gene is low, a large proportion of cases result from new mutations Recently a new treatment for Hunter syndrome has emerged with the development of recombinant human iduronate-2-sulfatase This is well tolerated and associated with improvement in several outcome parameters, including forced vital capacity, urinary excretion of glycosaminoglycans, liver and spleen volume, and 6-minute walk distance.45,46 However, the effect of enzyme therapy on the cardiac lesions remains to be determined.47 Mucopolysaccharidosis Type III (Sanfilippo Syndrome) The degradation of heparan sulfate and N-sulfated or N-acetylated α-linked glucosamine requires five enzymes: N-sulfoglucosamine sulfohydrolase (sulfamidase), α-2-acetamido-2-deoxy-D-glucoside acetamidodeoxyglucohydrolase (α-N-acetylglucosaminidase), heparan acetyl CoA:α-glucosaminide N-acetyltransferase, N-acetylglucosamine-6-sulfatase, and N-glucosamine-3-O-sulfatase Deficiency of one of the five enzymes required for this degradation results in the Sanfilippo syndrome, which is an autosomal recessive disorder Consequently there are five biochemically distinct types of the disease (designated a to e), although they all present the same clinical features Incidentally, type e has yet to be uncovered in humans, although it exists in animal models.48 The onset is usually evident in the first few years of life with “behavioral” problems Mental and neurologic deterioration are severe and lead to death in the first two decades Bone, joint, and cardiac involvement is generally less severe than in Hurler syndrome Corneal clouding is never seen There is wide variation in the severity and age at death in all four forms, but type a is likely to be the most severe Inheritance is in autosomal recessive fashion Cardiac involvement is similar to that of other mucopolysaccharidoses, with a number of patients reported to have mitral valve involvement.49,50 Although treatment is primarily supportive, animal studies have been undertaken to assess enzyme replacement therapy in a mouse model with mucopolysaccharidosis type III-b.51 Mucopolysaccharidosis Type IV (Morquio Syndrome) Morquio syndrome results from defective degradation of keratan sulfate It occurs in two biochemically distinct forms So-called type a is due to a deficiency of n-acetylgalactosamine-6-sulfate sulfatase, whereas type b results from deficiency of β-galactosidase The two types have similar clinical features, but type b is less severe, sometimes being called the “long-legged” variant Despite the generally increased severity of features with type a, more mild forms of type a can occur Keratan sulfate is excreted in the urine in type a, but this is less evident in type b Keratan sulfate is found in cartilage, intervertebral discs, and the cornea Thus skeletal involvement with dwarfism, pectus excavatum, and bowed legs are the most obvious manifestations Corneal clouding is common In contrast to the mucopolysaccharidoses described earlier, the joints in patients with Morquio syndrome are hyperextensible Absence or severe hypoplasia of the odontoid process, together with laxity of its associated ligaments, leads to atlanto-occipital subluxation and consequent cervical myelopathy Sinus tachycardia is a common feature of this disease, but the mechanism is unclear Valves of the heart are often involved, with thickening of mitral and aortic leaflets, although significant valve dysfunction is less common Aortic root dilation, concentric left ventricular hypertrophy and, rarely, asymmetric septal hypertrophy have all been described.52,53 Survival beyond the third or fourth decade is not unusual The effects of the cervical myelopathy and respiratory problems are the usual cause of death Experimentation with enzyme replacement therapy in animals has been