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:

1. 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.

2. 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).

3. 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.