Multiple Sulfatase Deficiency

Disease Overview

Multiple sulfatase deficiency (MSD) is an ultra-rare genetic disorder in which all of the known sulfatase enzymes are unable to be fully activated by formylglycine-generating enzyme (FGE), which is encoded by the SUMF1 gene. Because of the multisystemic importance of sulfatases, this disorder affects many parts of the body. While neurologic impairment is universal, major systemic symptoms can be variable and include bone abnormalities, coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Because of deficient activation of steroid sulfatase, the skin of children affected by MSD can be usually dry and scaly (ichthyosis).

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Synonyms

• MSD

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Signs & Symptoms

Classically, the subtypes of MSD are defined by the age at symptom onset: neonatal, severe late infantile, mild infantile, and juvenile. The clinical relevance of these divisions is unknown, as subtle symptoms are present in infancy across all types. Because MSD is the result of a variable degree of deficiency across all human sulfatases, the systemic symptoms can be variable.

METABOLIC

• Metabolic acidosis-buildup of acid in body
• Growth delays

CRANIOFACIAL

• Coarse facial features
• Microcephaly
• Macrocephaly
• Progressive hydrocephalus

Eyes

• Corneal clouding
• Retinopathy, retinitis pigmentosa
• Strabismus (abnormal eye alignment)
• Optic nerve abnormalities
• Cataracts
• Glaucoma

Ears

• Hearing disorders
• Recurrent otitis media

Mouth/oral/Jaw

• Feeding difficulties
• Gingival hyperplasia (overgrowth of gum tissue around the teeth)
• Dental anomalies (abnormal enamel) and risk for dental cavities
• Oral, pharyngeal and upper airway obstruction with progressive narrowing of airway
• Airway obstruction
• Abnormal tracheal structure
• Micrognathia (small) or retrognathia (abnormal posterior position of jaw)
• Progressive difficulty with bite, teeth, and enamel

NEUROLOGICAL

• Global developmental delay or regression in all reported cases
• Epilepsy/ seizures
• Peripheral neuropathy
• Neuropathic pain

CARDIOVASCULAR

• Atrial septal defects
• Cardiac hypertrophy (enlarged heart)
• Heart valve issues
• Arrhythmias
• Hypertension (high blood pressure)
• Aortic insufficiency

RESPIRATORY

• Aspiration
• Recurrent pneumonia
• Sleep issues
• Central apnea and/or peripheral apnea
• Lung disease (obstructive and restrictive)
• Progressive respiratory insufficiency

DERMATOLOGIC (skin)

• Ichthyosis- dry, thick, scaly skin
• Hirsutism (excessive hair growth)

GASTROINTESTINAL (GI)/ URINARY

• Poor motility- feeding intolerance, constipation
• Hepatosplenomegaly (liver and spleen enlargement)
• Issues with gallbladder
• Gastroesophageal reflux disease (GERD)
• Swallowing difficulties
• Gall bladder wall thickening or polyps
• Urinary retention
• Urinary infections
• Neurogenic bladder

MUSCULOSKELETAL

• Short stature
• Broad thumbs and toes
• Irregular ribs
• Hypotonia or mixed tone
• Dysostosis multiplex- abnormalities in development of skeletal cartilage and bone
• Spasticity- persistent muscle contraction
  • Hyperreflexia with muscle weakness
• Mobility issues
• Joint stiffness and contractures of joints especially fingers, elbows and hips
• Hip dislocation or dysplasia (abnormal growth)
• Extreme weakness due to neurodegeneration and demyelination
• Osteopenia (weakened bones)
• Spinal instability
  • Cervical spine instability
  • Neck hyperextension
• Scoliosis and/or kyphosis

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Causes

Multiple sulfatase deficiency is an autosomal recessive disorder caused by a change (mutation) in the SUMF1 gene. This gene allows cells to make an enzyme called FGE (formylglycine-generating enzyme) that activates all sulfatases within the cell. Without activation, sulfatases are not able to do their jobs in the cell. The missing sulfatases are directly responsible for the changes in the body seen in MSD. More severe forms of the disease are associated with SUMF1 mutations that lead to the production of an unstable form of FGE, while the more mild forms are due to mutations that lead to reduced but correctly functioning FGE.

Recessive genetic disorders like multiple sulfatase deficiency occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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Affected populations

Multiple sulfatase deficiency is an ultra-rare disorder with a wide spectrum of disease. To date, over one hundred patients have been reported in the literature with 50 of those patients confirmed alive by patient organization registries. This number may be underestimated due under diagnosis or lack of reporting. Males and females are equally affected and no ethnic predisposition has been identified.

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Disorders with Similar Symptoms

Symptoms of the following disorders can resemble those of multiple sulfatase deficiency. In particular, disorders caused by single sulfatase deficiencies, such as arylsulfatase A in metachromatic leukodystrophy, share many similarities. Comparisons are useful for differential diagnosis:

Metachromatic leukodystrophy (MLD) is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system. Three types of MLD ultimately affect both intellectual and motor function. Symptoms vary by type but can include difficulty talking, seizures, difficulty walking, personality changes, and behavior and personality changes. MLD is caused by mutations in the ASA gene. All forms of MLD are progressive. (For more information on this condition, choose “metachromatic leukodystrophy” as your search term in the Rare Disease Database.)

Maroteaux-Lamy syndrome (arylsulfatase-B deficiency; mucopolysaccharidosis VI; polydystrophic dwarfism), is a form of mucopolysaccharidosis. These are a group of genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes, resulting in an inability to metabolize certain complex carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, ungraded mucopolysaccharides in the cells of the body causes a number of symptoms. This syndrome can occur as a severe type, an intermediate type, and a mild type. Growth delay generally occurs from 2-3 years of age, with coarsening of facial features and abnormalities in the bones of hands and spine. Joint stiffness also occurs. The intellect is usually normal. (For more information on this condition, choose “Maroteaux-Lamy” as your search term in the Rare Disease Database.)
Ichthyosis can be a symptom of multiple sulfatase deficiency. X-linked ichthyosis is caused by a mutation in steroid sulfatase. It is characterized by an abnormal accumulation of large amounts of dead skin (squamous) cells in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to cause a defect in the metabolism of skin cells known as “corneocytes” or of the fat-rich matrix around these cells. The cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (For more information, chose “Ichthyosis” as your search term in the Rare Disease Database.)

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Diagnosis

MSD should be suspected in any individual with developmental delays, coarse facial features, bone abnormalities, and ichthyosis. MSD can be diagnosed when a child has low levels of at least two sulfatases and elevated sulfatide levels. Additional testing, such as glycosaminoglycan levels, can also be supportive, although can be normal in some individuals affected by MSD. Molecular genetic testing for mutations in the SUMF1 gene can be helpful as well, but with the rarity of the disease, only a limited number of disease-causing variants have been fully characterized.

The MRI associated with MSD can be variable and nonspecific. The images can demonstrate demyelination, perivascular space prominence, and/or hydrocephalus.

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Standard Therapies

There are currently no targeted therapies for MSD, and treatment is supportive and based upon symptoms. Care for patients with MSD requires a multidisciplinary team to evaluate the many body systems that may be affected by this disease. Due to the very broad spectrum of clinical problems a comprehensive approach is recommended. Depending on the needs of the child, important members of the team may include neurology and/or metabolism, complex care pediatrics, gastroenterology, nutrition, urology, orthopedics, and physiatry.

The neurologic delay and regression is the most common symptom shared by patients with MSD. Early evaluation and intervention by physical, occupational, and speech therapy can be helpful to manage the symptoms of MSD and maximize mobility and communication.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://clinicltrialsregister.eu/

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References

TEXTBOOKS
Mancini GMS, van Diggelen OP. Multiple Sulfatase Deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:484.

Hopwood JJ, Ballabio A. Multiple sulfatase deficiency and the nature of the sulfatase family. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 7th ed. McGraw-Hill Companies. New York, NY; 2001:3725-32.

JOURNAL ARTICLES
Rebecca Ahrens-Nicklas, Lars Schlotawa, Andrea Ballabio, et al. Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement. ,Molecular Genetics and Metabolism. 2018:123:3:337-346

Meshach Paul D, Chadah T, Senthilkumar B, Sethumadhavan R, Rajasekaran R Structural distortions due to missense mutations in human formylglycine generating enzyme leading to multiple sulfatase deficiency. Journal of Biomolecular Structure and Dynamics. 2018;36:13, 3575-3585.

Mancini GM, van Diggelen OP, Huijmans JG, et al. Pitfalls in the diagnosis of multiple sulfatase deficiency. Neuropediatrics. 2001;32:38-40.

Macaulay RJ, Lowry NJ, Casey RE. Pathological findings of multiple sulfatase deficiency reflect the pattern of enzyme deficiencies. Pediatr Neurol. 1998;19:372-76.

Castano Suarez E, Segurado Rodriguez, Guerra Tapia A, et al. Ichthyosis: the skin manifestation of multiple sulfatase deficiency. Pediatr Dermatol. 1997;14:269-72.

Schmidt B, Selmer T, Ingendoh A, et al. A novel amino acid modification in the sulfatases that is defective in multiple sulfatase deficiency. Cell. 1995;82:271-78.

Rommerskirch W, von Figura K. Multiple sulfatase deficiency: catalytically inactive sulfatases are expressed from retrovirally introduced sulfatase cDNAs. Proc Natl Acad Sci USA. 1992;89:2561-65

INTERNET
Multiple sulfatase deficiency. Genetics Home Reference. Reviewed: February 2019. https://ghr.nlm.nih.gov/condition/multiple-sulfatase-deficiency. Accessed Feb 13, 2020.

Schlotawa L, Adang L, De Castro M, et al. Multiple Sulfatase Deficiency. 2019 Mar 21. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538937/ Accessed Feb 13, 2020.

Multiple Sulfatase Deficiency.Online Mendelian Inheritance in Man (OMIM). 07/21/2011. https://www.omim.org/entry/272200. Accessed Feb 13, 2020.

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Programs & Resources

• Assistance Programs
• Patient Organizations

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