Alternative titles; symbols
SNOMEDCT: 54898003; ICD10CM: E75.26; ORPHA: 585; DO: 0050441;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p26.1 | Multiple sulfatase deficiency | 272200 | Autosomal recessive | 3 | SUMF1 | 607939 |
A number sign (#) is used with this entry because multiple sulfatase deficiency (MSD) is caused by homozygous or compound heterozygous mutation in the sulfatase-modifying factor-1 gene (SUMF1; 607939) on chromosome 3p26.
Multiple sulfatase deficiency (MSD) is an autosomal recessive inborn error of metabolism resulting in tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. The enzymatic defect affects the whole family of sulfatase enzymes; thus, the disorder combines features of metachromatic leukodystrophy (250100) and of various mucopolysaccharidoses (see, e.g., MPS6; 253200). Affected individuals show neurologic deterioration with impaired intellectual development, skeletal anomalies, organomegaly, and ichthyosis. Different types of MSD can be distinguished according to the age of onset: neonatal, late infantile (0 to 2 years), and juvenile (2 to 4 years). Neonatal MSD is the most severe form with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. Late-infantile MSD, which includes the majority of cases, resembles late-infantile metachromatic leukodystrophy with progressive loss of mental and motor abilities and skeletal changes. There is also an attenuated form of late-infantile MSD with onset beyond the second year of life. Rare cases of juvenile-onset MSD have been reported with onset of symptoms in late childhood and slower progression (Blanco-Aguirre et al., 2001) (summary by Schlotawa et al., 2011).
The clinical features of multiple sulfatase deficiency are an interesting composite of those seen with deficiency of the individual sulfatases. Kihara (1982) pointed out that multiple sulfatase deficiency combines the enzyme deficiency and phenotypic features of at least six entities: metachromatic leukodystrophy (250100), Maroteaux-Lamy syndrome (253200), X-linked ichthyosis (308100), Hunter syndrome (309900), Sanfilippo A syndrome (252900), and Morquio syndrome (253000).
Mossakowski et al. (1961) reported 3 affected sibs, and Austin (1965) reported 2 affected sibs. Rampini et al. (1970) reported 3 cases.
Some patients initially suspected of having Hunter syndrome may have multiple sulfatase deficiency in which deficiency of iduronate sulfatase dominates. Burk et al. (1981, 1984) reported 2 cases that had been mistakenly diagnosed as Hunter syndrome. In both, developmental delay dated from birth. Increased urinary mucopolysaccharides had a pattern different from that in mucopolysaccharidosis (heparan sulfate 39%, dermatan sulfate 21%, chondroitin sulfate C 40%). Abnormally broad great toes were found in both, and ichthyosis developed at an early age. Limitation in extension at the elbows and radiologic changes of dysostosis multiplex were suggestive of a mucopolysaccharidosis. The defect in this disorder may be similar to that in combined beta-galactosidase/neuraminidase deficiency; the defect may reside in a molecule necessary to protect the multiple sulfatases against excessive intralysosomal degradation and to assure their full hydrolytic capacity. If this is the explanation, then the activity of the molecule must not be limited to the intralysosomal site: 6 of the enzymes are lysosomal, whereas steroid sulfatase is microsomal.
Burch et al. (1986) described a neonatal case of multiple sulfatase deficiency. In most reported cases the clinical phenotype resembles late infantile metachromatic leukodystrophy at presentation, but patients later develop ichthyosis and features of a mucopolysaccharidosis. The patient reported by Burch et al. (1986) had dysmorphic features and hydrocephalus present at birth and also had mild chondrodysplasia calcificans, heart abnormalities, and an abnormal fold of tissue between the laryngeal inlet and the esophagus. Excessive mucopolysacchariduria was present.
Soong et al. (1988) described an affected 9.75-year-old girl. They stated that only 20 cases had been described.
Blanco-Aguirre et al. (2001) reported 2 Mexican brothers with childhood onset of MSD at around age 3 years. After normal development in the first 2 years, both showed neurodegeneration with delayed speech and motor difficulties, including ataxia. Both developed ichthyosis, retinal degeneration, dysmetria, and hyperreflexia of the lower limbs. Examination at ages 22 and 17 years, respectively, showed coarse facies, nystagmus, high-arched palate, mental retardation, and broad thumbs and index fingers, but no organomegaly. Brain imaging showed cerebral and cerebellar atrophy, enlarged ventricles, and periventricular white matter abnormalities. Skeletal survey showed dysostosis multiplex. Laboratory studies showed some residual sulfatase activities, which Blanco-Aguirre et al. (2001) postulated was responsible for the slow progression and attenuated phenotype.
Steinmann et al. (1981) reported on a woman who during pregnancy excreted consistently low amounts of urinary estriols for which no apparent reason was found. After birth, the girl was diagnosed as having classic multiple sulfatase deficiency based on the clinical and biochemical features. The authors concluded that absent steroid sulfatase activity was responsible for the low urinary estriol excretion during pregnancy, reported for the first time in this condition, and for ichthyosis appearing soon after birth.
Ikeda et al. (1998) described a 3-year-old boy with multiple sulfatase deficiency who had the complication of hemophagocytic syndrome but recovered with conventional therapy. Hemophagocytic syndrome is characterized by fever, pancytopenia, coagulopathy, liver dysfunction, and proliferation of mature histiocytes. Ikeda et al. (1998) referred to the occurrence of hemophagocytic syndrome in methylmalonic aciduria (251000) and in lysinuric protein intolerance (222700).
Murphy et al. (1971) described a case in which the mucopolysaccharides in the liver were thought to consist of both heparan sulfate and dermatan sulfate, as well as showing accumulated cholesterol sulfate.
Fluharty et al. (1978) demonstrated apparently normal arylsulfatase A in cultured fibroblasts under some conditions, indicating that this disorder may be one of regulation.
Horwitz (1979) concluded that the defect probably concerns either a regulatory process for production of sulfatases or a posttranslational modification common to sulfatases. At least 9 sulfatases are known to be deficient (Basner et al., 1979); some are lysosomal, some microsomal.
Fedde and Horwitz (1984) listed 7 sulfatases as deficient in MSD. In addition, they identified 2-deoxyglucoside 2-sulfamate sulfatase (heparin-N sulfatase; EC 3.1.10.10), for which an isolated genetically determined deficiency has not been identified.
Rommerskirch and von Figura (1992) provided strong evidence that the defect in this disorder indeed involves a posttranslational process common to 7 or more sulfatases. In accordance with this concept, they detected RNAs of normal size and amount in MSD fibroblasts for 3 sulfatases tested. When they introduced cDNAs encoding arylsulfatase A, arylsulfatase B, or steroid sulfatase into MSD fibroblasts and fibroblasts with a single sulfatase deficiency by retroviral gene transfer, they found that infected fibroblasts overexpressed the respective sulfatase polypeptides. Whereas a concomitant increase of sulfatase activities was observed in single sulfatase deficiency fibroblasts, MSD fibroblasts expressed sulfatase polypeptides with a severely diminished catalytic activity. From these results, Rommerskirch and von Figura (1992) concluded that the mutation in MSD severely decreases the capacity of a posttranslational, or cotranslational, process that renders sulfatases enzymatically active or prevents their premature inactivation.
Schmidt et al. (1995) found from structural analysis of 2 catalytically active sulfatases that a cysteine residue that is predicted from the cDNA sequence and conserved among all known sulfatases is replaced by a 2-amino-3-oxopropionic acid residue, while in sulfatases derived from MSD cells, the cysteine residue is retained. Schmidt et al. (1995) proposed that the co- or posttranslational conversion of a cysteine to 2-amino-3-oxopropionic acid is required for generating catalytically active sulfatases and that deficiency of this protein modification is the cause of MSD. The 2 sulfatases that they studied were arylsulfatase A (ARSA; 607574) and arylsulfatase B (ARSB; 611542).
Ahrens-Nicklas et al. (2018) proposed a multisystem approach to the care of patients with multiple sulfatase deficiency, with specialist care for the major organ systems involved. Recommendations included spine imaging for signs of cervical spine instability and referral to neurosurgery as necessary, hip imaging for hip dysplasia, and monitoring for scoliosis; assessment and management for respiratory issues including obstructive or restrictive lung disease, central or obstructive apnea, and tracheomalacia; ophthalmologic evaluation for issues including glaucoma, corneal clouding, and retinitis pigmentosa; hearing testing; attention to gastrointestinal issues and nutritional status with assessment for safe feeding and tube feeding as needed, and regular screening of the gallbladder by ultrasound or CT; regular electrocardiograms and echocardiograms; ongoing neurologic care for issues such as peripheral neuropathy, hydrocephalus, and seizures; and urgent brain imaging for acute neurologic changes.
Multiple sulfatase deficiency is an autosomal recessive disorder. Mossakowski et al. (1961) observed 3 affected sibs, 2 female and 1 male, in a French Canadian family. The 2 patients reported by Austin (1965) were sibs (in the M family).
Dierks et al. (2003) and Cosma et al. (2003) identified homozygous or compound heterozygous mutations in the SUMF1 gene in patients with MSD (see, e.g., 607939.0001-607939.0010).
Schlotawa et al. (2011) observed clear genotype/phenotype correlations among 10 patients with MSD, including 1 with neonatal onset, 7 with severe late-infantile onset, and 2 with mild late-infantile onset. The most severely affected patient with neonatal onset had marked impairments in both SUMF1 stability and enzyme activity and was compound heterozygous for a splice site and a nonsense mutation (607939.0001 and 607939.0003, respectively). Sulfatase activities in this patient were almost undetectable. In contrast, 2 patients with mild late-infantile onset were homozygous for a missense mutation (G263V; 607939.0018), which showed the highest residual enzymatic activity among the studied variants. Patients with the intermediate severe late-infantile form had mutations that compromised stability and caused low levels of residual activity (see, e.g., S155P; 607939.0010).
Settembre et al. (2007) found that Sumf1-null mice displayed early mortality, congenital growth retardation, skeletal abnormalities, and neurologic deficits, similar to human patients with MSD. Massive lysosomal storage of glycosaminoglycans was observed in all tissues examined and was associated with systemic inflammation, apoptosis, and neurodegeneration. Sumf1-null mice completely lacked all sulfatase activities, indicating that mammals have a single sulfatase modification system.
In brain tissue of MSD mice, Settembre et al. (2008) observed increased autophagosomes resulting from impaired autophagosome-lysosome fusion. Cells showed impaired ability to degrade aggregation-prone proteins. There was also an accumulation of ubiquitin-positive inclusions and increased numbers of dysfunctional mitochondria. Similar findings were observed in a mouse model of another lysosomal storage disorder, MPS IIIA (252900). The findings were consistent with these diseases being disorders of autophagy, which may be a common mechanism in neurodegenerative lysosomal storage diseases.
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