Multiple Sulfatase Deficiency
Summary
Clinical characteristics.
Initial symptoms of multiple sulfatase deficiency (MSD) can develop from infancy through early childhood, and presentation is widely variable. Some individuals display the multisystemic features characteristic of mucopolysaccharidosis disorders (e.g., developmental regression, organomegaly, skeletal deformities) while other individuals present primarily with neurologic regression (associated with leukodystrophy). Based on age of onset, rate of progression, and disease severity, several different clinical subtypes of MSD have been described:
- Neonatal MSD is the most severe with presentation in the prenatal period or at birth with rapid progression and death occurring within the first two years of life.
- Infantile MSD is the most common variant and may be characterized as attenuated (slower clinical course with cognitive disability and neurodegeneration identified in the 2nd year of life) or severe (loss of the majority of developmental milestones by age 5 years).
- Juvenile MSD is the rarest subtype with later onset of symptoms and subacute clinical presentation.
Many of the features found in MSD are progressive, including neurologic deterioration, heart disease, hearing loss, and airway compromise.
Diagnosis/testing.
The diagnosis of multiple sulfatase deficiency is established in a proband with low activity levels in at least two sulfatase enzymes and/or biallelic pathogenic variants in SUMF1 identified by molecular genetic testing.
Management.
Treatment of manifestations: Progressive hydrocephalus, seizures, spasticity, spine instability or stenosis, eye anomalies, cardiovascular disease, hearing loss, poor growth, dental anomalies, developmental delays, and respiratory issues are managed in the standard fashion. Obstructive sleep apnea may be treated with adenoidectomy and/or tonsillectomy, although affected individuals have a higher surgical complication rate; ventilator support (CPAP, BiPAP) can also be considered. Precautions are needed during anesthesia to address airway maintenance, as progressive upper airway obstruction and cervical spine instability are common. Poor bone health may require supplementation with vitamin D and encouragement of weight-bearing exercises. Alternative routes for nutrition (tube feeding) are frequently necessary.
Surveillance: Monitoring of head circumference at each visit; serial brain/spine imaging, as needed based on symptoms; cervical spine imaging prior to any procedure that requires neck extension. At least annual vitamin D level, eye examination with intraocular pressure measurement, EKG, echocardiogram, and audiology evaluation. Abdominal ultrasound, sleep study and pulmonary function tests, neuropsychiatric testing, and assessment of blood and urine acid-base balance as clinically indicated.
Agents/circumstances to avoid: Neck hyperextension (including hyperextension used for intubation) because of the risk of spinal cord compression; foods that are a choking hazard.
Genetic Counseling.
Multiple sulfatase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known.
Diagnosis
Formal clinical diagnostic criteria for multiple sulfatase deficiency have not been established.
Suggestive Findings
Multiple sulfatase deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.
Clinical findings
- Developmental delay with subsequent neurologic regression and psychomotor retardation
- Macrocephaly with or without hydrocephalus
- Epilepsy
- Poor growth with a progressive decrease in growth rate
- Coarse facial features
- Recurrent otitis media and/or upper respiratory tract infections
- Progressive hearing loss
- Hepatosplenomegaly
- Skeletal changes including kyphosis, gibbus deformity, hip dislocation, genu valgum
- Cardiac hypertrophy or thickening of cardiac valves
- Ichthyosis
Laboratory findings
- Decreased activity of at least two sulfatase enzymes on lysosomal enzyme testing analysisNote: Individual enzyme activities may be higher than those seen in individuals with single enzyme deficiencies and some may be within normal ranges.
- Elevated urinary glycosaminoglycan levels
- Elevated urinary sulfatides
Imaging findings
- Abnormal brain MRI showing progressive demyelination, prominence of the perivascular spaces, cerebral volume loss, and/or hydrocephalus
- Skeletal radiographs demonstrating features of dysostosis multiplex including anomalies of the vertebrae, hands, feet, long bones, and skull
Establishing the Diagnosis
The diagnosis of multiple sulfatase deficiency is established in a proband with low activity levels in at least two sulfatase enzymes and/or biallelic pathogenic variants in SUMF1 identified by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panels) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of multiple sulfatase deficiency is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of multiple sulfatase deficiency has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of multiple sulfatase deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of SUMF1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes SUMF1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in unrelated genes. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene may vary by laboratory. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of multiple sulfatase deficiency is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Multiple Sulfatase Deficiency
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by This Method |
|---|---|---|
| SUMF1 | Sequence analysis 3 | ~98%-99% 5 |
| Gene-targeted deletion/duplication analysis 4 | ~1.5% 5 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 5.
Review of all available cases in the literature revealed three large deletions and no duplications out of 201 alleles [Author observation, in preparation for publication].
Clinical Characteristics
Clinical Description
Multiple sulfatase deficiency (MSD) is a multisystem lysosomal storage disorder with variable age of onset and wide variability in clinical presentation and rate of progression. Initial symptoms can present from infancy through early childhood [Sabourdy et al 2015, Ahrens-Nicklas et al 2018]. Many individuals experience global regression between age two and six years, approximately 12-60 months after symptom onset. Earlier onset of regression correlates with increased disease severity [Sabourdy et al 2015]. Some individuals display the multisystemic features characteristic of mucopolysaccharidosis disorders, while others present primarily with neurologic regression (see Pathophysiology).
Natural History
Based on age of onset, rate of progression and disease severity, several different subtypes of MSD have been described [Eto et al 1987]. The severity of the condition may correlate with the stability of the enzyme and residual enzyme activity (see Genotype-Phenotype Correlations). The subtypes are as follows.
Neonatal MSD is the most severe form, in which affected Individuals typically have intrauterine growth restriction and respiratory distress at birth [Busche et al 2009, Garavelli et al 2014]. Dysmorphic features may include coarse facial features, thick eyebrows, hypoplastic nasal bone, bulbous nasal tip, posteriorly rotated ears, high arched palate, micrognathia, retrognathia, flared thorax, inverted nipples, and broad thumbs. Corneal clouding is frequently present. Disease progression is rapid and mortality is high, with death typically occurring within the first two years of life [Burch et al 1986, Busche et al 2009].
Infantile MSD, the most common clinical presentation, is characterized by progressive neurodegeneration with loss of sensory and motor skills, similar to arylsulfatase A deficiency (metachromatic leukodystrophy). Typically, symptom onset is within the first three years of life. This phenotype may be further subdivided into attenuated (formally called "mild") and severe subtypes.
- Attenuated infantile MSD is characterized by a slower clinical course in which affected individuals are noted to have growth deficiency (1.5-3 SD below the mean), feeding difficulties, and developmental delay [Ahrens-Nicklas et al 2018], with cognitive disability and neurodegeneration identified in the second year of life (range 3-36 months).
- The ability to ambulate and communicate with a limited vocabulary may be preserved into late childhood (age 3-9 years), although by age nine most have significant impairments.
- Among eight individuals with infantile MSD, all demonstrated psychomotor retardation, hypotonia, and neurodegeneration, while 75% had ichthyosis and 25% had dysmorphic features [Sabourdy et al 2015]. In a second series, nine individuals identified to have infantile MSD all demonstrated cognitive delay, neurodegeneration, and ichthyosis [Schlotawa et al 2011].
- Dysmorphic features, if present, are subtle but may become more prominent with age.
- Prenatal manifestations, hepatosplenomegaly, and corneal clouding are rare [Sabourdy et al 2015].
- Severe infantile MSD is characterized by a faster rate of disease progression and more extensive systemic involvement. Symptoms present within the first year of life and most individuals lose a majority of developmental milestones by age five years [Sabourdy et al 2015, Jaszczuk et al 2017].
- Dysmorphic features, skeletal changes, and organomegaly are common [Schlotawa et al 2011].
- Life span is significantly shortened, and many die within the first decade of life.
Juvenile MSD is a rare subtype, although this could be influenced by ascertainment bias. It has a later onset with an attenuated clinical presentation. The diagnosis can sometimes be difficult to make owing to borderline residual sulfatase activity [Church et al 2018]. Brain MRI findings are nonspecific and may include white matter signal abnormalities, corpus callosum thinning, and cerebellar atrophy.
- Age of onset is between three and seven years with an insidious clinical presentation and neurologic decline.
- Presenting symptoms can include generalized tremor, hypotonia, and mild-moderate developmental delays [Sabourdy et al 2015].
- Affected individuals can also develop ichthyosis, visual loss (although corneal clouding is rare), and behavioral abnormalities, and may have minor dysmorphic features (broad thumbs and index fingers) that frequently become more prominent with age [Blanco-Aguirre et al 2001].
- The oldest known person with the condition survived until the fourth decade of life [Author, personal communication].
- Individuals with juvenile MSD can retain the ability to walk into their teenage years.
Clinical Features Common To All Subtypes
Many of the features found in MSD can be progressive, including the neurologic deterioration, heart disease, hearing loss, and airway compromise. The progressive nature of the disease is at least in part due to the accumulation of glycosaminoglycans (GAGs) and other substrates, including sulfatides.
Neurologic features include:
- Developmental delay and progressive neurologic deterioration, including long track signs (spasticity)
- Ataxia
- Autistic features
- Epilepsy [Incecik & Herguner 2017]
- Microcephaly [Miskin et al 2016] or macrocephaly; hydrocephalus has been reported [Incecik & Herguner 2017].
Musculoskeletal features:
- Short stature
- Irregular ribs (typically paddle-shaped with widening anteriorly and tapering posteriorly) associated with dysostosis multiplex
- Scoliosis and/or kyphosis
- Vertebral abnormalities, including odontoid dysplasia, atlanto-axial instability, cervical spinal canal stenosis, and vertebral body abnormalities (wedge-shaped vertebral bodies, anterior beaking with posterior scalloping, and platyspondyly)
- Vertebral instability and risk of spinal cord compression, which can be dangerous with neck hyperextension (such as occurs during intubation)
- Short metacarpals
- Joint stiffness and contractures, which may pose a prominent issue that can impede mobility [Burk et al 1984]
- Broad thumbs and toes [Santos & Hoo 2006]
Growth restriction may be of prenatal onset, particularly in the neonatal form [Incecik et al 2013, Sabourdy et al 2015].
Ophthalmologic features:
- Glaucoma
- Strabismus
- Retinal degeneration
- Corneal clouding
- Cataracts
- Retinitis pigmentosa [Sabourdy et al 2015]
- Myopia
Cardiovascular manifestations may include atrial septal defects [Incecik et al 2013] and aortic insufficiency [Guerra et al 1990]. Individuals with MSD are at risk of developing cardiac manifestations similar to those seen in other lysosomal storage disorders: secondary valve disease, cardiac hypertrophy, coronary artery disease, arrhythmias, and hypertension [Braunlin et al 2011, Sabourdy et al 2015, Jaszczuk et al 2017].
Ear, nose, and throat. Progressive conductive and/or sensorineural hearing loss and recurrent otitis media are common [Sabourdy et al 2015].
Skin. Ichthyosis (dry, scaly skin) and hypertrichosis are common [Incecik et al 2013].
Dental abnormalities can be detected early in life and are progressive. They can include thin enamel of deciduous and permanent teeth, dark discoloration of dentin, malocclusion, and anterior open bite [Zilberman & Bibi 2016].
Gastrointestinal system. Many affected individuals develop hepatosplenomegaly, which is possibly secondary to GAG accumulation. Swallowing dysfunction may lead to sialorrhea and feeding difficulties. Many individuals require feeding tubes to safely and efficiently meet their caloric needs.
Respiratory. Individuals are at risk of progressive upper airway obstruction. Many individuals experience both central and peripheral sleep apnea. Individuals are also at risk for aspiration pneumonia.
Metabolic acidosis. Loss of arylsulfatase A (ARSA) activity has been associated with renal dysfunction and increased predisposition to metabolic acidosis [Lorioli et al 2015]. The true risk in MSD is not currently known, but given that most affected individuals have decreased ARSA activity, this should be considered.
Brain MRI features. The most common findings are white matter (periventricular) abnormalities with U fiber sparing, radiating stripes, and severe white matter atrophy [Prasad et al 2014]. Other abnormal imaging findings include [van der Knaap & Valk 2013, Sabourdy et al 2015, Ahrens-Nicklas et al 2018]:
- Cerebral atrophy and/or cerebellar atrophy
- Abnormalities of the corpus callosum
- Dilatation of the ventricular system
- Prominence of the sulci
- Enlarged perivascular spaces
- Cervical cord compression
- Delayed myelination
Pathophysiology
The wide clinical spectrum seen in MSD is largely a function of the unique pathophysiology of this condition, as multiple pathways are affected by a common enzymatic defect. All known 17 human sulfatases may be affected; thus, the clinical presentation is a composite of the effects of each individual sulfatase deficiency [Hopwood & Ballabio 2001]. Of these sulfatases, nine have each been implicated in distinct human diseases (albeit with overlapping features) [Dierks et al 2009, Khateb et al 2018]. The clinical presentation is a combination of these nine enzymatic defects, with affected individuals having signs and symptoms of arylsulfatase A deficiency (metachromatic leukodystrophy), Maroteaux-Lamy syndrome, X-linked ichthyosis, mucopolysaccharidosis type II (Hunter syndrome), mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), and mucopolysaccharidosis type IVA (Morquio syndrome). The contribution to clinical phenotype from the sulfatases without a clinically defined phenotype is unknown.
Genotype-Phenotype Correlations
Sulfatase-modifying-factor-1 (SUMF1) protein stability and residual formylglycine-generating enzyme (FGE) activity influence the clinical presentation in individuals with pathogenic changes in SUMF1. Individuals with unstable SUMF1 protein and low residual FGE activity display a severe late-infantile onset phenotype with rapid progression of MSD and neurologic deterioration. Individuals with higher levels of residual FGE enzyme activity often have attenuated forms of MSD with fewer symptoms, slower disease progression, and later onset of regression. Biallelic nonsense variants and deletions have been reported and are associated with a severe neonatal presentation [Schlotawa et al 2008, Schlotawa et al 2013, Sabourdy et al 2015].
For a small subset of pathogenic missense variants, experimental evidence for residual SUMF1 activity and FGE stability has been published and specific genotype-phenotype correlations exist.
- Homozygosity for the p.Gly263Val or p.Ala279Val SUMF1 alleles is associated with attenuated late-infantile MSD.
- Homozygosity for the p.Ser155Pro, p.Gly247Arg, or p.Arg349Trp SUMF1 alleles is associated with severe late-infantile MSD [Cosma et al 2004, Schlotawa et al 2008, Schlotawa et al 2011, Schlotawa et al 2013].
Non-experimental prediction methods attempting to correlate a particular SUMF1 variant with FGE stability and clinical phenotype are not exact. There is no reliable genotype-phenotype correlation possible for affected individuals with compound heterozygous pathogenic missense variants. Finally, laboratory parameters, especially single sulfatase activity, GAG, and sulfatide levels, do not correlate well with the clinical presentation and can be normal in some cases [Sabourdy et al 2015, Ahrens-Nicklas et al 2018].
Nomenclature
Other terms used to describe MSD are Austin disease (named after Dr James Austin, who first described the condition [Austin et al 1964]), juvenile sulfatidosis, and mucosulfatidosis.
Prevalence
The estimated prevalence of MSD is one in 1.4 million individuals. There have been approximately 75-100 cases reported to date [Hopwood & Ballabio 2001, Ahrens-Nicklas et al 2018], with approximately 50 living affected individuals identified through support and advocacy groups. MSD has been reported in individuals of all ethnicities throughout the world [Artigalás et al 2009, Incecik et al 2013, Meng et al 2013, Garavelli et al 2014]. It is likely that this condition is underrecognized and underdiagnosed, particularly in areas of the world where access to advanced molecular genetic testing is not readily available.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Multiple Sulfatase Deficiency (MSD)
| Disorder | Gene(s) | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/MSD | Distinguishing from MSD | |||
| Arylsulfatase A deficiency (metachromatic leukodystrophy; MLD) | ARSA | AR | All MLD features can be found in MSD, incl central & peripheral demyelination & progressive neurologic deterioration | Absence of other systemic findings assoc w/MSD |
| Saposin B deficiency (OMIM 249900) | PSAP | AR | All saposin B deficiency features can be found in MSD, incl central & peripheral demyelination & progressive neurologic deterioration | Absence of other systemic findings assoc w/MSD |
| Mucolipidosis II (I-cell disease) | GNPTAB | AR | Severe infantile onset, progressive neurologic deterioration, skeletal deformities (incl dysostosis multiplex), postnatal growth restriction, cardiac involvement, skin thickening, recurrent ear infections | Severe contractures (although joint mobility issues may be seen in MSD) |
| Krabbe disease | GALC | AR | Central & peripheral demyelination, progressive neurologic deterioration | Absence of: cardiac & ophthalmologic complications, skeletal involvement (incl dysostosis multiplex), ichthyosis, hydrocephalus, hepatosplenomegaly, oral & dental issues, hearing loss, recurrent ear infections, upper airway obstruction |
| Alexander disease | GFAP | AD | Central demyelination & hydrocephalus, progressive neurologic deterioration | Absence of: cardiac & ophthalmologic complications, skeletal involvement (incl dysostosis multiplex), ichthyosis, hepatosplenomegaly, oral & dental issues, hearing loss, recurrent ear infections, upper airway obstruction |
| Canavan disease | ASPA | AR | Central demyelination, progressive neurologic deterioration, macrocephaly | Absence of: cardiac & ophthalmologic complications, skeletal involvement (incl dysotosis multiplex), ichthyosis, hepatosplenomegaly, oral & dental issues, hearing loss, recurrent ear infections, upper airway obstruction |
| Fucosidosis (OMIM 230000) | FUCA1 | AR | Progressive neurologic deterioration, dysostosis multiplex, coarse facial features | Absence of: cardiac & ophthalmologic complications, ichthyosis, hepatosplenomegaly, oral & dental issues, hearing loss, recurrent ear infections, upper airway obstruction |
| MPS I 1 | IDUA | AR | DD, skeletal involvement, growth restriction, corneal clouding, cardiac involvement, hepatosplenomegaly, dysmorphic features | Facial dysmorphic features & cardiac involvement are more prominent in MPS I. |
| MPS II (Hunter syndrome) | IDS | XL | DD, short stature, skeletal involvement, hepatosplenomegaly, dysmorphic features | Affected females are rare. Corneal clouding is not a typical feature. |
| MPS III (Sanfilippo syndrome) (OMIM 252900, 252920, 252930, 252940) | GNS HGSNAT NAGLU SGSH | AR | Neurodegeneration, DD, hepatosplenomegaly (<50% of individuals w/Sanfilippo syndrome) | May have slower, more insidious course presenting mainly w/cognitive & neurologic signs & symptoms |
| MPS IV (Morquio syndrome) (see MPS IVA, GLB1-Related Disorders) | GALNS GLB1 | AR | Skeletal involvement, hearing loss, facial dysmorphic features | More severe skeletal involvement; MPS IVA does not present w/ID. |
| MPS VI (Maroteaux-Lamy syndrome) (OMIM 253200) | ARSB | AR | Dysmorphic features, hepatosplenomegaly, short stature, corneal clouding, skeletal involvement | More severe skeletal involvement; Absence of ID |
| X-linked ichthyosis (OMIM 308100) | STS | XL | Corneal opacities, ichthyosis | Affected females are rare. Absence of DD & neurodegeneration |
| Chondrodysplasia punctata 1, X-linked | ARSL (ARSE) | XLR | DD in 15%-20% of affected individuals, short stature, epiphyseal stippling, cataracts, hearing loss | Affected females are rare. Characteristic facial appearance; Absence of neurodegeneration |
| Hexosaminidase A deficiency (Tay-Sachs disease) | HEXA | AR | Progressive neurodegeneration, DD, spasticity, blindness, death in infancy | Cherry red spot of the fovea 2; Absence of skeletal abnormalities & hepatomegaly |
| Hexosaminidase A/B deficiency (Sandhoff disease) (OMIM 268800) | HEXB | AR | Progressive neurodegeneration, DD, spasticity, blindness, death in infancy | Cherry red spot & ↑ startle response 3; hepatomegaly & skeletal abnormalities are less common than in MSD |
AD = autosomal dominant, AR = autosomal recessive, MOI = mode of inheritance: XL = X-linked; DD = developmental delay; ID = intellectual disability; MPS = mucopolysaccharidosis
- 1.
Severe or attenuated MPS I; Note: while individuals with MPS I have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe or attenuated MPS I.
- 2.
Cherry red spot of the fovea is not a typical finding in MSD.
- 3.
Cherry red spot and increased startle response are not typical findings in MSD.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with multiple sulfatase deficiency, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Multiple Sulfatase Deficiency
| System/Concern | Evaluation |
|---|