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Multiple Sulfatase Deficiency

, MD, , MD, PhD, , MD, and , MD, PhD.

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Initial Posting: .

Estimated reading time: 23 minutes

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 analysis
    Note: 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 1MethodProportion of Pathogenic Variants 2 Detectable by This Method
SUMF1Sequence analysis 3~98%-99% 5
Gene-targeted deletion/duplication analysis 4~1.5% 5
1.
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:

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) (see also Leukodystrophy Overview). 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.

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)

DisorderGene(s)MOIClinical Features of Differential Diagnosis Disorder
Overlapping w/MSDDistinguishing from MSD
Arylsulfatase A deficiency (metachromatic leukodystrophy; MLD)ARSAARAll MLD features can be found in MSD, incl central & peripheral demyelination & progressive neurologic deteriorationAbsence of other systemic findings associated w/MSD
Saposin B deficiency
(OMIM 249900)
PSAPARAll saposin B deficiency features can be found in MSD, incl central & peripheral demyelination & progressive neurologic deteriorationAbsence of other systemic findings associated w/MSD
Mucolipidosis II (I-cell disease)GNPTABARSevere infantile onset, progressive neurologic deterioration, skeletal deformities (incl dysostosis multiplex), postnatal growth restriction, cardiac involvement, skin thickening, recurrent ear infectionsSevere contractures (although joint mobility issues may be seen in MSD)
Krabbe diseaseGALCARCentral & peripheral demyelination, progressive neurologic deteriorationAbsence of: cardiac & ophthalmologic complications, skeletal involvement (incl dysostosis multiplex), ichthyosis, hydrocephalus, hepatosplenomegaly, oral & dental issues, hearing loss, recurrent ear infections, upper airway obstruction
Alexander diseaseGFAPADCentral demyelination & hydrocephalus, progressive neurologic deteriorationAbsence of: cardiac & ophthalmologic complications, skeletal involvement (incl dysostosis multiplex), ichthyosis, hepatosplenomegaly, oral & dental issues, hearing loss, recurrent ear infections, upper airway obstruction
Canavan diseaseASPAARCentral demyelination, progressive neurologic deterioration, macrocephalyAbsence 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)
FUCA1ARProgressive neurologic deterioration, dysostosis multiplex, coarse facial featuresAbsence of: cardiac & ophthalmologic complications, ichthyosis, hepatosplenomegaly, oral & dental issues, hearing loss, recurrent ear infections, upper airway obstruction
MPS I 1IDUAARDD, skeletal involvement, growth restriction, corneal clouding, cardiac involvement, hepatosplenomegaly, dysmorphic featuresFacial dysmorphic features & cardiac involvement are more prominent in MPS I.
MPS II (Hunter syndrome)IDSXLDD, short stature, skeletal involvement, hepatosplenomegaly, dysmorphic featuresAffected females are rare.
Corneal clouding is not a typical feature.
MPS III (Sanfilippo syndrome)
(OMIM 252900, 252920, 252930, 252940)
GNS
HGSNAT
NAGLU
SGSH
ARNeurodegeneration, DD, hepatosplenomegaly (less than 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
ARSkeletal involvement, hearing loss, facial dysmorphic featuresMore severe skeletal involvement;
MPS IVA does not present w/ID.
MPS VI (Maroteaux-Lamy syndrome)
(OMIM 253200)
ARSBARDysmorphic features, hepatosplenomegaly, short stature, corneal clouding, skeletal involvementMore severe skeletal involvement;
Absence of ID
X-linked ichthyosis
(OMIM 308100)
STSXLCorneal opacities, ichthyosisAffected females are rare.
Absence of DD & neurodegeneration
Chondrodysplasia punctata 1, X-linkedARSEXLRDD in 15%-20% of affected individuals, short stature, epiphyseal stippling, cataracts, hearing lossAffected females are rare.
Characteristic facial appearance;
Absence of neurodegeneration
Hexosaminidase A deficiency (Tay-Sachs disease)HEXAARProgressive neurodegeneration, DD, spasticity, blindness, death in infancyCherry red spot of the fovea 2;
Absence of skeletal abnormalities & hepatomegaly
Hexosaminidase A/B deficiency (Sandhoff disease)
(OMIM 268800)
HEXBARProgressive neurodegeneration, DD, spasticity, blindness, death in infancyCherry red spot & increased startle response 3;
Hepatomegaly & skeletal abnormalities 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/ConcernEvaluationComment
NeurologicConsultation w/a neurologistDue to risk for central & peripheral demyelination, seizures, & hydrocephalus
Consideration of brain imagingTo assess for hydrocephalus w/increased intracranial pressure
Urgent head imaging should be considered for any rapid neurologic changes.
EEGIf seizures are suspected
MusculoskeletalConsideration of spine imaging (radiographs &/or MRI), including C-spine imagesTo assess for spine instability or stenosis leading to cord compression
Consultation w/neurosurgeon as indicated
Assessment of overall bone health w/consideration of 25(OH) vitamin D levelsIf clinical concerns, additional testing (e.g., DEXA scan) can be obtained.
OphthalmologicConsultation w/an ophthalmologist for evaluation of eye complications & measurement of intraophthalmic pressureTo assess for glaucoma, corneal clouding, retinopathy, strabismus, optic nerve abnormalities, and cataracts
CardiovascularConsultation w/a cardiologist for baseline EKG & echocardiogramTo assess for presence of cardiac hypertrophy, cardiac valve issues, arrhythmias, and hypertension
OtolaryngologicAudiologic evaluation, w/consideration of brain stem auditory-evoked response testingTo assess for hearing loss
Consultation w/otolaryngologists if neck manipulation &/or anesthesia is neededConsideration of direct airway visualization & C-spine imaging due to progressive airway obstruction (particularly w/neck hyperextension)
SkinConsider consultation w/a dermatologist.For those w/severe skin involvement or concerns for secondary infections
DentalConsider consultation w/a pediatric dentist.To assess for tooth enamel abnormalities and/or hyperplastic gums
GastrointestinalAssessment of growth parameters & feeding abilityMany individuals w/MSD are unable to safely & efficiently meet caloric needs by mouth; alternative routes such as gastrostomy tubes can be considered.
Consideration of baseline swallowing studyTo assess for swallowing dysfunction
Abdominal ultrasound & serum liver enzyme testing 1To assess for hepatosplenomegaly & liver dysfunction
RespiratoryConsideration of baseline sleep studyTo assess for obstructive sleep apnea
Consideration of pulmonary function assessment, end tidal CO2, &/or bronchoscopyTo assess for obstructive &/or restrictive airway disease, central &peripheral apneas, recurrent pneumonia, & tracheomalacia
Renal/metabolicAs the renal dysfunction is under-characterized at this time, labs should be obtained as clinically indicated.Consider consultation w/a nephrologist for those w/metabolic acidosis
DevelopmentalDevelopmental assessmentTo include assessment of age-appropriate motor, speech/language, cognitive skills
Miscellaneous/
Other
Baseline measurement of sulfatase activity, urinary extretion of sulfatide, & GAGsMeasurement of levels not needed for clinical monitoring
Consultation w/a clinical geneticist &/or genetic counselor

DEXA = dual energy x-ray absorptiometry; GAGs = glycosaminoglycans

1.

Measurement of serum AST, ALT, and GGT

Treatment of Manifestations

A detailed clinical management guide was recently published delineating a symptomatic management strategy [Ahrens-Nicklas et al 2018] (full text).

While there are no targeted therapeutic options to date, many complications are amenable to symptomatic management [Adang et al 2017]. An individualized care plan can be designed by the primary and specialist providers. In addition to the primary care provider, the care team will often include neurologists, metabolic geneticists with genetic counselors, gastroenterologists, ophthalmologists, cardiologists, and physiatrists. Additional care providers may include speech therapists, occupational therapists, physical therapists, nutritionists, and dentists. Special efforts should be made to maintain mobility and social communication skills until such skills are lost.

Table 4.

Treatment of Manifestations in Individuals with Multiple Sulfatase Deficiency

Manifestation/ConcernTreatmentConsiderations/Other
Progressive hydrocephalusStandard management by neurosurgeryUrgent head imaging should be considered in anyone w/sudden changes in neurologic status (e.g., altered mental status, increased vomiting)
SeizuresStandard antiepileptic medication 1
SpasticityStandard therapeutic options may include baclofen &/or botulinum toxin type A.Physical therapy & physiatry consultations for optimization of mobility & tone
Spine instability or stenosisReferral to orthopedist &/or neurosurgeon
Poor bone healthSupplementation w/vitamin DConsider referral to endocrinology
Encourage weight bearing exercise, as toleratedPhysical therapy & physiatry consultations for optimization of mobility & tone
Glaucoma, strabismus, corneal clouding, &/or cataractsStandard treatment per ophthalmologist
Cardiac hypertrophy, cardiac valve issues, arrhythmias, & hypertensionStandard therapy per cardiologist
Hearing lossTreatment of SNHL & conductive hearing loss per ENT/audiologist 2
Anesthesia precautionsSafe airway maintenance particularly during procedures that may require neck hyperextensionDue to progressive upper-airway obstruction & risk for cervical spine instability
Assessment of airway constriction so that if required, appropriate-size devices (e.g., endotracheal tubes) are used
Poor growthStandard treatment per nutrition specialists
Feeding difficultiesConsideration of alternative routes for nutrition (e.g., NG or G-tube)Speech therapy consultation if concerns about efficiency or safety of oral feeding
GI or surgery consulation as clinically indicated
Tooth & gum anomaliesStandard treatment per pediatric dentist
Obstructive sleep apneaMany children with MPS receive an adenoidectomy and/or tonsillectomy, although a higher complication rate should be notedConsider referral to a sleep medicine specialist &/or pulmonologist.
Some children may benefit from ventilatory support (CPAP, BiPAP).Advanced testing such as PFTs & sleep studies can be considered.
Respiratory issuesStandard treatment per pulmonologist

G = gastrostomy; NG = nasogastric; PFTs = pulmonary function tests

1.

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

2.

See Hereditary Hearing Loss and Deafness Overview for details about treatment options.

Surveillance

No definitive surveillance guidelines have been established, although particular attention to and monitoring of the cardiac, respiratory, ophthalmologic, neurologic, skeletal, and gastroenterologic systems is indicated [Ahrens-Nicklas et al 2018].

Table 5.

Surveillance to Consider for Individuals with Multiple Sulfatase Deficiency

System/ConcernEvaluationFrequency
NeurologicHead circumference measurementAt each visit
Serial brain/spine imaging 1As needed based on symptoms
MusculoskeletalVitamin D level 2Annually or as needed
C-spine imaging (radiographs and/or MRI)Prior to any procedure (including intubation) that requires neck extension
OphthalmologicEye examination & intraocular pressure assessmentAt least annually or as needed
CardiovascularSerial EKG & echocardiography 3At least annually
OtolaryngologicAudiology evaluationAt least annually, or as needed
Gastrointestinal/
Nutrition
Weight & height measurementsW/all clinical assessments
Serial abdominal ultrasound evaluation 4As clinically indicated
RespiratoryConsideration of sleep study& PFTsPeriodically
Renal/MetabolicMonitoring of blood & urine acid-base balanceAs clinically indicated & w/episodes of physiologic stress
DevelopmentalAssessment of developmental milestones & current developmental levelAt each visit
Neuropsychiatric testingAs clinically indicated

PFT = pulmonary function test

1.

To screen for progressive hydrocephalus and/or cord compression

2.

To monitor bone health

3.

To monitor for cardiac hypertrophy, progressive valvular abnormalities, arrhythmia, and hypertension

4.

With special attention to the liver, gallbladder, and spleen

Agents/Circumstances to Avoid

Individuals should avoid neck hyperextension, including hyperextension used for intubation, because of the risk of spinal cord compression. Foods that are choking hazards should also be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A multi-institutional natural history study is underway through the Myelin Disorders Biorepository Project (Clinical Trials Identifier: NCT03047369).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Multiple sulfatase deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one SUMF1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with multiple sulfatase deficiency are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SUMF1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SUMF1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SUMF1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • MSD Action Foundation
    Grattan Lodge
    Dublin
    Ireland
    Email: alanfinglas@gmail.com; info@msdactionfoundation.org
  • United MSD Foundation
    Phone: 228-295-7084
  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
    Email: contact@metabolicsupportuk.org
  • Society for Mucopolysaccharide Diseases (MPS)
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: 0345 389 9901
    Email: mps@mpssociety.co.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Multiple Sulfatase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SUMF13p26​.1Formylglycine-generating enzymeSUMF1 databaseSUMF1SUMF1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Multiple Sulfatase Deficiency (View All in OMIM)

272200MULTIPLE SULFATASE DEFICIENCY; MSD
607939SULFATASE-MODIFYING FACTOR 1; SUMF1

Molecular Pathogenesis

Multiple sulfatase deficiency (MSD) is the result of a defect of the post-translational modification of cellular sulfatases. Sulfatases are a group of enzymes necessary for the breakdown of sulfate residues on macromolecules in cells (e.g., sulfatides, glycosaminoglycans, transcription factors). All newly synthesized sulfatases require activation by formylglycine-generating enzyme (FGE), encoded by SUMF1, for full catalytic activity. As the majority of cellular sulfatases are located in the lysosome, sulfatase dysfunction induces lysosomal storage of several substrates and cellular pathology (e.g., blockade of autophagy) leading to the symptoms that individuals with MSD experience [Dierks et al 2003, Cosma et al 2004, Dierks et al 2005, Sardiello et al 2005, Settembre et al 2008]).

Gene structure. SUMF1 encodes a 2,152-bp transcript that contains nine exons. Eight alternatively spliced transcripts – encoding five protein isoforms with unknown clinical significance – have been predicted.

See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. More than 50 pathogenic SUMF1 variants have been reported. Variant types include missense variants, insertions and deletions, and splicing and nonsense variants. Large copy number changes have also been reported. The most frequently observed MSD-causing variants are p.Gly247Arg, p.Ser155Pro, p.Arg349Trp, p.Ala279Val, p.Arg345Cys, and p.Gly263Val. Abundant hot spots for missense loss-of-function variants are p.Asn259 (variants p.Asn259Ile,Lys,Ser) and p.Arg349 (variants p.Arg349Gly,Glu,Trp). 31% of all variants are private [Authors, unpublished data].

Table 6.

SUMF1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.463T>Cp.Ser155PrpNM_182760​.3
NP_877437​.2
c.739G>Cp.Gly247Arg
c.788G>Tp.Gly263Val
c.836C>Tp.Arg279Val
c.1033C>Tp.Arg345Cys
c.1045C>Tp.Arg349Trp

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. SUMF1 encodes the sulfatase-modifying-factor-1 protein, alternatively named formylglycine-generating enzyme (FGE), a 374-amino acid protein. FGE contains a single core domain with an N-terminal extension (amino acids 34-72) and a low amount of secondary structure. It is stabilized by two cysteine interactions. Four additional cysteine residues are involved in the enzyme's catalytic function with p.Cys336 and p.Cys341 forming the active site of FGE.

FGE recognizes newly synthesized sulfatases via an amino acid motif (CXPSR) that is present in all sulfatases. FGE oxidizes the cysteine to an aldehyde, C-alpha-formylglycine,which is indispensable for sulfatase catalytic function [Dierks et al 2005, Sardiello et al 2005].

Abnormal gene product. MSD occurs though a loss-of-function mechanism as evidenced by missense variants reducing protein stability and enzymatic activity. The majority of disease-associated missense variants result in an unstable FGE protein with a reduced half-life and reduced enzymatic activity.

A minority of FGE protein pathogenic variants alter regulation by the ER quality-control process, protein-disulfide-isomerase (PDI). These variants result in an abnormal arrangement of intramolecular stabilizing disulfide bridges; PDI recognizes the misfolded FGE and induces early degradation [Dierks et al 2005, Schlotawa et al 2008, Schlotawa et al 2011, Schlotawa et al 2013, Meshach Paul et al 2017, Schlotawa et al 2018].

Both the SUMF1 and sulfatase genes and protein structures are highly evolutionarily conserved. No alternative sulfatase activation mechanism exists in eukaryotes. FGE is predominantly localized to the endoplasmic reticulum but is also secreted. The function of secreted FGE is unknown. Known interacting partners are redox proteins in the ER (e.g., PDI and ERp44) and its non-functional homolog SUMF2 (pFGE) [Landgrebe et al 2003, Preusser-Kunze et al 2005, Fraldi et al 2008, Mariappan et al 2008a, Mariappan et al 2008b].

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Chapter Notes

Revision History

  • 21 March 2019 (ma) Review posted live
  • 27 August 2018 (ran) Original submission
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