7.1 Clinical Features and Laboratory Investigations
Multiple sulfatase deficiency (MSD) is a very rare disorder with an autosomal recessive mode of inheritance. It occurs with a prevalence of about 1 in 1.4 million births. The disease combines the features of metachromatic leukodystrophy and mucopolysac-charidosis. It is also called mucosulfatidosis, Austin variant or variant O. Three different types of MSD have been described: a neonatal form, an early-childhood form and a very rare juvenile form.
The early-childhood form is the usual, or classic, form of MSD. The clinical features are those of infantile metachromatic leukodystrophy with mild signs of mucopolysaccharidosis. Early development can be normal or delayed. Affected children usually acquire the ability to stand and to say a few words, but their development is less well advanced in the presympto-matic period than that of children with infantile metachromatic leukodystrophy. During the 2nd year of life the children develop signs of a progressive en-cephalopathy with loss of acquired abilities, progressive dementia, spasticity, microcephaly, blindness, hearing loss, and difficulties in swallowing. Tendon reflexes are variable. In the final stages there is often areflexia caused by the peripheral neuropathy. Features similar to those of mucopolysaccharidosis may occur early or later in the course of the disease. These include ichthyosis, mild coarsening of the facial features, hepatosplenomegaly, stiff joints, growth retardation, and skeletal anomalies. Hydrocephalus may occur. There is no corneal clouding. Optic atrophy, cherry-red macula, and retinal degeneration also occur in some cases. Death usually occurs when patients are between 10 and 18 years of age.
The neonatal form presents at birth with severe features suggestive of mucopolysaccharidosis, such as facial dysmorphism, short neck, corneal clouding, ichthyosis, cardiac valvular involvement, hepato-splenomegaly, and severe dysostosis multiplex. The children affected have macrocephaly caused by hydrocephalus. They have signs of a severe encephalopathy, with early death, usually before the end of the 1st year of life. A Saudi variant of the neonatal type of MSD has been described, with mild to moderate mental retardation, cranial synostosis and consequent deformities, and cervical cord compression or transection due to vertebral abnormalities. Severe facial dysmorphism, corneal clouding, hepatospleno-megaly, dwarfism, severe dysostosis multiplex, and hirsutism are present,but no ichthyosis,no retinal degeneration, no deafness, and no progressive dementia. Some patients are macrocephalic, but they are rarely hydrocephalic. Some suffer from cardiac valvular involvement.
A rare juvenile type of MSD has been reported with onset in childhood. The disease is characterized by short stature, ichthyosis, hepatomegaly, moderate dysostosis multiplex and slowly progressive neurological abnormalities consisting of dementia, ataxia, quadriplegia, retinal degeneration, and blindness. Corneal clouding is not present.
Additional investigations show changes on bone X-ray, such as a J-shaped sella turcica, structural changes in vertebral bodies, scoliosis, gibbus, flared ribs, broad phalanges, abnormal metacarpals and, in the Saudi variant, synostosis of cranial sutures. Large basophilic to azurophilic granules are seen in lymphocytes of bone marrow and peripheral blood. There is an increased urinary content of sulfatide and mucopolysaccharides, including dermatan sulfate and heparan sulfate. CSF protein is increased. Nerve conduction velocity is slowed.
Diagnosis is established by demonstrating a deficiency of arylsulfatases A, B, and C and a number of sulfatases necessary in the degradation of mucopolysaccharides. Prenatal diagnosis can be made by demonstrating markedly reduced activities of sulfatases in cultured amniotic cells or chorionic villi. DNA-based diagnostic procedures are also possible.
Pathological findings in MSD are those that might be expected in a combination of metachromatic leukodystrophy and mucopolysaccharidosis. There is widespread neuronal lipid storage in the cortex and subcortical gray matter structures. The storage is lysosomal. The neuronal deposits are finely granular and PAS positive, with slight reddish to purple metachromasia. On electron microscopy, neuronal inclusions range in configuration from zebra bodies, which are typically seen in mucopolysaccharidoses, to membranous cytoplasmic bodies such as are seen in neuronal gangliosidoses. There is loss of neurons in cerebral and cerebellar cortex and cortical atrophy.
The white matter shows demyelination with deposition of metachromatic material, oligodendroglial loss, relative axonal preservation, and marked gliosis. The U fibers are relatively spared. Mucopolysaccharides are stored in perivascular mesenchymal tissue, which may lead to the formation of macroscopically visible pseudocystic cavities. Meninges are thickened and cloudy. Obliteration of the subarachnoid spaces can lead to hydrocephalus. Abnormalities in peripheral nerves are typical of metachromatic leukodystro-phy.
from the lack of a posttranslational modification that is common to all sulfatases. The reduced activity of the enzymes is caused by a defect in the modification of a conserved cysteine residue to form formyl-glycine. The modification of the cysteine residue appears to be a prerequisite for the catalytic activity of sulfatases.
The gene mutated in MSD is SUMF1, which is located on chromosome 3p26. SUMF1, standing for sulfatase-modifying factor 1, encodes the protein formylglycine-generating enzyme (FGE).
Chemical analysis of the brain has shown increases in sulfatide, sulfated steroids (e.g. cholesterol sulfate), gangliosides, and mucopolysaccharides. The lipids stored in the white matter are predominantly sulfatides, while those stored in the gray matter are predominantly gangliosides and mucopolysaccha-rides.
In MSD activity of all known sulfatases is found to be reduced, including arylsulfatase A (metachromatic leukodystrophy), arylsulfatase B = N-acetylgalac-tosamine-4-sulfatase (Maroteaux-Lamy syndrome), arylsulfatase C = steroid sulfatase (X-linked ichthyosis), N-acetylgalactosamine-6-sulfate sulfatase (Morquio syndrome type A), heparan sulfate sulfatase (Sanfilippo A), iduronate-2-sulfate sulfatase (Hunter syndrome), N-acetylglucosamine-6-sulfate sulfatase (Sanfilippo D), and some other sulfatases. The residual activities of the sulfatases vary considerably in fibroblast lines from different patients. The lysosomal storage of sulfatides, mucopolysaccharides and sulfated steroids is a direct consequence of the enzyme deficiencies mentioned. The accumulation of gan-gliosides may be caused by inhibition of other lysosomal hydrolases due to the present lysosomal storage. It is probable that the different phenotypic expressions of MSD are due to differences in relative residual activity of the various enzymes.
The genes coding for the various deficient sulfatases are intact. The rate of synthesis of various sulfatases is normal in MSD, but they are degraded at an enhanced rate. The deficiency of the sulfatases results
No effective form of treatment is known.
Imaging findings are scarce in MSD. In the classic early-childhood variant images are indistinguishable from those of infantile and juvenile metachromatic leukodystrophy with severe cerebral white matter abnormalities. The corpus callosum and long corticospinal tracts are also involved. The cerebellar white matter can be abnormal, but is not in all cases. In some patients a pattern of radiating stripes of more normal signal intensity is seen within the affected cerebral white matter (Fig. 7.1). In these patients the images are indistinguishable from those seen in metachromatic leukodystrophy. However, these stripes are not seen in all patients (Fig. 7.2). In the later stages of the disease severe white matter atrophy is seen (Fig. 7.2).
In the neonatal form of MSD more variable white matter involvement has been described. Myelination is delayed. In addition, scattered, small high-signal-intensity spots are sometimes seen in the white matter, which are more suggestive of mucopolysac-charidosis than of metachromatic leukodystrophy (Fig. 7.3). In some of the patients,white matter abnormalities are more extensive and confluent. Severe, highly confluent white matter disease can also be found. Dilatation of the ventricular system and prominence of the sulci are possible findings. Enlarged perivascular spaces within the white matter can be expected. At the cranio-cervical junction signs of cervical cord compression may be found, which is caused by atlantoaxial abnormalities.
signal intensity.Within the brain stem the corticospinal tracts are involved. Courtesy of Dr. G. Mancini and Dr. H. Stroink, Sophia Children's Hospital, Erasmus Medical Center, Rotter-dam,The Netherlands (see also Mancini et al. 2001)
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