Multiple Sulfatase Deficiency

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.

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).

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).

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.

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.

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.

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].

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.