Multiple Sulfatase Deficiency

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/multiple-sulfatase-deficiency

Multiple sulfatase deficiency is a condition that mainly affects the brain, skin, and skeleton. Because the signs and symptoms of multiple sulfatase deficiency vary widely, researchers have split the condition into three types: neonatal, late-infantile, and juvenile.

genetic conditions

1. Introduction

The neonatal type is the most severe form, with signs and symptoms appearing soon after birth. Affected individuals have deterioration of tissue in the nervous system (leukodystrophy), which can contribute to movement problems, seizures, developmental delay, and slow growth. They also have dry, scaly skin (ichthyosis) and excess hair growth (hypertrichosis). Skeletal abnormalities can include abnormal side-to-side curvature of the spine (scoliosis), joint stiffness, and dysostosis multiplex, which refers to a specific pattern of skeletal abnormalities seen on x-ray. Individuals with the neonatal type typically have facial features that can be described as "coarse." Affected individuals may also have hearing loss, heart malformations, and an enlarged liver and spleen (hepatosplenomegaly). Many of the signs and symptoms of neonatal multiple sulfatase deficiency worsen over time.

The late-infantile type is the most common form of multiple sulfatase deficiency. It is characterized by normal cognitive development in early childhood followed by a progressive loss of mental abilities and movement (psychomotor regression) due to leukodystrophy or other brain abnormalities. Individuals with this form of the condition do not have as many features as those with the neonatal type, but they often have ichthyosis, skeletal abnormalities, and coarse facial features.

The juvenile type is the rarest form of multiple sulfatase deficiency. Signs and symptoms of the juvenile type appear in mid- to late childhood. Affected individuals have normal early cognitive development but then experience psychomotor regression; however, the regression in the juvenile type usually occurs at a slower rate than in the late-infantile type. Ichthyosis is also common in the juvenile type of multiple sulfatase deficiency.

Life expectancy is shortened in individuals with all types of multiple sulfatase deficiency. Typically, affected individuals survive only a few years after the signs and symptoms of the condition appear, but life expectancy varies depending on the severity of the condition and how quickly the neurological problems worsen.

2. Frequency

Multiple sulfatase deficiency is estimated to occur in 1 per million individuals worldwide. More than 140 cases have been reported in the scientific literature.

3. Causes

Multiple sulfatase deficiency is caused by mutations in the SUMF1 gene. This gene provides instructions for making an enzyme called formylglycine-generating enzyme (FGE). This enzyme is found in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport. The FGE enzyme modifies other enzymes called sulfatases, which aid in breaking down substances that contain chemical groups known as sulfates. These substances include a variety of sugars, fats, and hormones.

Most SUMF1 gene mutations severely reduce the function of the FGE enzyme or lead to the production of an unstable enzyme that is quickly broken down. The activity of multiple sulfatases is impaired because the FGE enzyme modifies all known sulfatase enzymes. Sulfate-containing molecules that are not broken down build up in cells, often resulting in cell death. The death of cells in particular tissues, specifically the brain, skeleton, and skin, cause many of the signs and symptoms of multiple sulfatase deficiency.

Research indicates that mutations that lead to reduced FGE enzyme function are associated with the less severe cases of the condition, whereas mutations that lead to the production of an unstable FGE enzyme tend to be associated with the more severe cases of multiple sulfatase deficiency.

4. Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

5. Other Names for This Condition

Austin syndrome
juvenile sulfatidosis, Austin type
MSD
mucosulfatidosis

References

Ahrens-Nicklas R, Schlotawa L, Ballabio A, Brunetti-Pierri N, De Castro M,Dierks T, Eichler F, Ficicioglu C, Finglas A, Gaertner J, Kirmse B, Klepper J,Lee M, Olsen A, Parenti G, Vossough A, Vanderver A, Adang LA. Complex care ofindividuals with multiple sulfatase deficiency: Clinical cases and consensusstatement. Mol Genet Metab. 2018 Mar;123(3):337-346. doi:10.1016/j.ymgme.2018.01.005.
Annunziata I, Bouchè V, Lombardi A, Settembre C, Ballabio A. Multiplesulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene. HumMutat. 2007 Sep;28(9):928.
Blanco-Aguirre ME, Kofman-Alfaro SH, Rivera-Vega MR, Medina C, Valdes-FloresM, Rizzo WB, Cuevas-Covarrubias SA. Unusual clinical presentation in two cases ofmultiple sulfatase deficiency. Pediatr Dermatol. 2001 Sep-Oct;18(5):388-92.
Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R, DiDomenico C, Di Natale P, Mankad A, Cox B, Uziel G, Mancini GM, Zammarchi E,Donati MA, Kleijer WJ, Filocamo M, Carrozzo R, Carella M, Ballabio A. Molecularand functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat. 2004 Jun;23(6):576-81.
Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, vonFigura K. Multiple sulfatase deficiency is caused by mutations in the geneencoding the human C(alpha)-formylglycine generating enzyme. Cell. 2003 May16;113(4):435-44.
Díaz-Font A, Santamaría R, Cozar M, Blanco M, Chamoles N, Coll MJ, Chabás A,Vilageliu L, Grinberg D. Clinical and mutational characterization of threepatients with multiple sulfatase deficiency: report of a new splicing mutation.Mol Genet Metab. 2005 Sep-Oct;86(1-2):206-11.
Incecik F, Ozbek MN, Gungor S, Pepe S, Herguner OM, Mungan NO, Gungor S,Altunbasak S. Multiple sulfatase deficiency: A case series of four children. Ann Indian Acad Neurol. 2013 Oct;16(4):720-2. doi: 10.4103/0972-2327.120449.
Schlotawa L, Ennemann EC, Radhakrishnan K, Schmidt B, Chakrapani A, ChristenHJ, Moser H, Steinmann B, Dierks T, Gärtner J. SUMF1 mutations affectingstability and activity of formylglycine generating enzyme predict clinicaloutcome in multiple sulfatase deficiency. Eur J Hum Genet. 2011 Mar;19(3):253-61.doi: 10.1038/ejhg.2010.219.
Schlotawa L, Preiskorn J, Ahrens-Nicklas R, Schiller S, Adang LA, Gärtner J,Friede T. A systematic review and meta-analysis of published cases reveals thenatural disease history in multiple sulfatase deficiency. J Inherit Metab Dis.2020 Nov;43(6):1288-1297. doi: 10.1002/jimd.12282.
Schlotawa L, Radhakrishnan K, Baumgartner M, Schmid R, Schmidt B, Dierks T,Gärtner J. Rapid degradation of an active formylglycine generating enzyme variantleads to a late infantile severe form of multiple sulfatase deficiency. Eur J HumGenet. 2013 Sep;21(9):1020-3. doi: 10.1038/ejhg.2012.291.
Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gärtner J. Molecularanalysis of SUMF1 mutations: stability and residual activity of mutantformylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency. Hum Mutat. 2008 Jan;29(1):205.

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Subjects: Genetics & Heredity

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Rita Xu

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Entry Collection: MedlinePlus

Update Date: 23 Dec 2020

Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The Gene Associated with Multiple Sulfatase Deficiency

4. Inheritance

5. Other Names for This Condition

References