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Multiple sulfatase deficiency(MSD)

MedGen UID:
75664
Concept ID:
C0268263
Disease or Syndrome
Synonyms: Juvenile sulfatidosis; MSD; Mucosulfatidosis; Multiple Sulfatase Deficiency Disease; Sulfatidosis, Juvenile, Austin Type
SNOMED CT: Multiple sulfatase deficiency (54898003); Mucosulfatidosis (54898003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): SUMF1 (3p26.1)
 
Monarch Initiative: MONDO:0010088
OMIM®: 272200
Orphanet: ORPHA585

Disease characteristics

Excerpted from the GeneReview: Multiple Sulfatase Deficiency
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. [from GeneReviews]
Authors:
Lars Schlotawa  |  Laura Adang  |  Mauricio De Castro, et. al.   view full author information

Additional descriptions

From OMIM
Multiple sulfatase deficiency is an autosomal recessive inborn error of metabolism resulting in tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. The enzymatic defect affects the whole family of sulfatase enzymes; thus, the disorder combines features of metachromatic leukodystrophy (250100) and of various mucopolysaccharidoses (see, e.g., MPS6; 253200). Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and ichthyosis. Different types of MSD can be distinguished according to the age of onset: neonatal, late infantile (0 to 2 years), and juvenile (2 to 4 years). Neonatal MSD is the most severe form with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. Late-infantile MSD, which includes the majority of cases, resembles late-infantile metachromatic leukodystrophy with progressive loss of mental and motor abilities and skeletal changes. There is also an attenuated form of late-infantile MSD with onset beyond the second year of life. Rare cases of juvenile-onset MSD have been reported with onset of symptoms in late childhood and slower progression (Blanco-Aguirre et al., 2001) (summary by Schlotawa et al., 2011).  http://www.omim.org/entry/272200
From MedlinePlus Genetics
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.

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.  https://medlineplus.gov/genetics/condition/multiple-sulfatase-deficiency

Clinical features

From HPO
Mucopolysacchariduria
MedGen UID:
870284
Concept ID:
C4024726
Finding
Excessive amounts of mucopolysaccharide in the urine.
Broad thumb
MedGen UID:
140880
Concept ID:
C0426891
Finding
Increased thumb width without increased dorso-ventral dimension.
Broad hallux
MedGen UID:
401165
Concept ID:
C1867131
Finding
Visible increase in width of the hallux without an increase in the dorso-ventral dimension.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
CNS demyelination
MedGen UID:
137898
Concept ID:
C0338474
Disease or Syndrome
A loss of myelin from nerve fibers in the central nervous system.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Peripheral demyelination
MedGen UID:
451074
Concept ID:
C0878575
Pathologic Function
A loss of myelin from the internode regions along myelinated nerve fibers of the peripheral nervous system.
Lower limb hyperreflexia
MedGen UID:
322973
Concept ID:
C1836696
Finding
Abnormal periventricular white matter morphology
MedGen UID:
435926
Concept ID:
C2673431
Finding
A structural abnormality of the myelinated axons (white matter) located near the cerebral ventricles.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Rapid neurologic deterioration
MedGen UID:
870462
Concept ID:
C4024908
Finding
Hurler syndrome
MedGen UID:
39698
Concept ID:
C0086795
Disease or Syndrome
Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals 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. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.
Hypoplastic vertebral bodies
MedGen UID:
354963
Concept ID:
C1863353
Congenital Abnormality
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Periorbital edema
MedGen UID:
56223
Concept ID:
C0151205
Pathologic Function
Edema affecting the region situated around the orbit of the eye.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Large forehead
MedGen UID:
326962
Concept ID:
C1839783
Finding
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Flat face
MedGen UID:
342829
Concept ID:
C1853241
Finding
Absence of concavity or convexity of the face when viewed in profile.
Ichthyosis
MedGen UID:
7002
Concept ID:
C0020757
Disease or Syndrome
An abnormality of the skin characterized the presence of excessive amounts of dry surface scales on the skin resulting from an abnormality of keratinization.
Corneal opacity
MedGen UID:
40485
Concept ID:
C0010038
Finding
A reduction of corneal clarity.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMultiple sulfatase deficiency
Follow this link to review classifications for Multiple sulfatase deficiency in Orphanet.

Professional guidelines

PubMed

Al-Kouatly HB, Makhamreh MM, Rice SM, Smith K, Harman C, Quinn A, Valcarcel BN, Firman B, Liu R, Hegde M, Critchlow E, Berger SI
Genet Med 2021 Jul;23(7):1325-1333. Epub 2021 Mar 8 doi: 10.1038/s41436-021-01121-0. PMID: 33686258
Wood T, Bodamer OA, Burin MG, D'Almeida V, Fietz M, Giugliani R, Hawley SM, Hendriksz CJ, Hwu WL, Ketteridge D, Lukacs Z, Mendelsohn NJ, Miller N, Pasquali M, Schenone A, Schoonderwoerd K, Winchester B, Harmatz P
Mol Genet Metab 2012 May;106(1):73-82. Epub 2012 Feb 10 doi: 10.1016/j.ymgme.2012.02.005. PMID: 22405600
Meikle PJ, Grasby DJ, Dean CJ, Lang DL, Bockmann M, Whittle AM, Fietz MJ, Simonsen H, Fuller M, Brooks DA, Hopwood JJ
Mol Genet Metab 2006 Aug;88(4):307-14. Epub 2006 Apr 4 doi: 10.1016/j.ymgme.2006.02.013. PMID: 16600651

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Iduronate 2-Sulfatase Deficiency, Mucopolysaccharidosis Type II, 2022

American College of Medical Genetics and Genomics, Algorithm, Mucopolysacchardosis Type II (MPSII): Decreased Iduronate 2-Sulfatase (I2S) activity, 2022

Recent clinical studies

Etiology

Cappuccio G, Alagia M, Brunetti-Pierri N
Mol Genet Metab 2020 Aug;130(4):283-288. Epub 2020 Jun 17 doi: 10.1016/j.ymgme.2020.06.005. PMID: 32620537
Schlotawa L, Adang LA, Radhakrishnan K, Ahrens-Nicklas RC
Int J Mol Sci 2020 May 13;21(10) doi: 10.3390/ijms21103448. PMID: 32414121Free PMC Article
Hijazi L, Kashgari A, Alfadhel M
J Child Neurol 2018 Nov;33(13):820-824. Epub 2018 Aug 20 doi: 10.1177/0883073818790851. PMID: 30124108
Wood TC, Harvey K, Beck M, Burin MG, Chien YH, Church HJ, D'Almeida V, van Diggelen OP, Fietz M, Giugliani R, Harmatz P, Hawley SM, Hwu WL, Ketteridge D, Lukacs Z, Miller N, Pasquali M, Schenone A, Thompson JN, Tylee K, Yu C, Hendriksz CJ
J Inherit Metab Dis 2013 Mar;36(2):293-307. Epub 2013 Feb 1 doi: 10.1007/s10545-013-9587-1. PMID: 23371450Free PMC Article
Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gärtner J
Hum Mutat 2008 Jan;29(1):205. doi: 10.1002/humu.9515. PMID: 18157819

Diagnosis

Finglas A
J Inherit Metab Dis 2020 Nov;43(6):1143-1153. Epub 2020 Sep 24 doi: 10.1002/jimd.12305. PMID: 32845037
Schlotawa L, Adang LA, Radhakrishnan K, Ahrens-Nicklas RC
Int J Mol Sci 2020 May 13;21(10) doi: 10.3390/ijms21103448. PMID: 32414121Free PMC Article
Wood TC, Harvey K, Beck M, Burin MG, Chien YH, Church HJ, D'Almeida V, van Diggelen OP, Fietz M, Giugliani R, Harmatz P, Hawley SM, Hwu WL, Ketteridge D, Lukacs Z, Miller N, Pasquali M, Schenone A, Thompson JN, Tylee K, Yu C, Hendriksz CJ
J Inherit Metab Dis 2013 Mar;36(2):293-307. Epub 2013 Feb 1 doi: 10.1007/s10545-013-9587-1. PMID: 23371450Free PMC Article
Valayannopoulos V, Nicely H, Harmatz P, Turbeville S
Orphanet J Rare Dis 2010 Apr 12;5:5. doi: 10.1186/1750-1172-5-5. PMID: 20385007Free PMC Article
Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gärtner J
Hum Mutat 2008 Jan;29(1):205. doi: 10.1002/humu.9515. PMID: 18157819

Therapy

Vollebregt AAM, Ebbink BJ, Rizopoulos D, Lequin MH, Aarsen FK, Shapiro EG, van der Ploeg AT, van den Hout JMP
J Inherit Metab Dis 2021 May;44(3):751-762. Epub 2021 Jan 25 doi: 10.1002/jimd.12342. PMID: 33330992Free PMC Article
Schlotawa L, Preiskorn J, Ahrens-Nicklas R, Schiller S, Adang LA, Gärtner J, Friede T
J Inherit Metab Dis 2020 Nov;43(6):1288-1297. Epub 2020 Jul 22 doi: 10.1002/jimd.12282. PMID: 32621519
Farooqui AA, Horrocks LA
Neurochem Pathol 1984 Fall;2(3):189-218. doi: 10.1007/BF02834352. PMID: 6152665

Prognosis

Adang LA, Schlotawa L, Groeschel S, Kehrer C, Harzer K, Staretz-Chacham O, Silva TO, Schwartz IVD, Gärtner J, De Castro M, Costin C, Montgomery EF, Dierks T, Radhakrishnan K, Ahrens-Nicklas RC
J Inherit Metab Dis 2020 Nov;43(6):1298-1309. Epub 2020 Aug 20 doi: 10.1002/jimd.12298. PMID: 32749716Free PMC Article
Cappuccio G, Alagia M, Brunetti-Pierri N
Mol Genet Metab 2020 Aug;130(4):283-288. Epub 2020 Jun 17 doi: 10.1016/j.ymgme.2020.06.005. PMID: 32620537
Schlotawa L, Radhakrishnan K, Baumgartner M, Schmid R, Schmidt B, Dierks T, Gärtner J
Eur J Hum Genet 2013 Sep;21(9):1020-3. Epub 2013 Jan 16 doi: 10.1038/ejhg.2012.291. PMID: 23321616Free PMC Article
Valayannopoulos V, Nicely H, Harmatz P, Turbeville S
Orphanet J Rare Dis 2010 Apr 12;5:5. doi: 10.1186/1750-1172-5-5. PMID: 20385007Free PMC Article
Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gärtner J
Hum Mutat 2008 Jan;29(1):205. doi: 10.1002/humu.9515. PMID: 18157819

Clinical prediction guides

Adang LA, Schlotawa L, Groeschel S, Kehrer C, Harzer K, Staretz-Chacham O, Silva TO, Schwartz IVD, Gärtner J, De Castro M, Costin C, Montgomery EF, Dierks T, Radhakrishnan K, Ahrens-Nicklas RC
J Inherit Metab Dis 2020 Nov;43(6):1298-1309. Epub 2020 Aug 20 doi: 10.1002/jimd.12298. PMID: 32749716Free PMC Article
Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gärtner J
Hum Mutat 2008 Jan;29(1):205. doi: 10.1002/humu.9515. PMID: 18157819
Rommerskirch W, von Figura K
Proc Natl Acad Sci U S A 1992 Apr 1;89(7):2561-5. doi: 10.1073/pnas.89.7.2561. PMID: 1348358Free PMC Article
Conary JT, Hasilik A, von Figura K
Biol Chem Hoppe Seyler 1988 Apr;369(4):297-302. doi: 10.1515/bchm3.1988.369.1.297. PMID: 3165268
Steckel F, Hasilik A, von Figura K
Eur J Biochem 1985 Aug 15;151(1):147-52. doi: 10.1111/j.1432-1033.1985.tb09079.x. PMID: 2863139

Recent systematic reviews

Schlotawa L, Preiskorn J, Ahrens-Nicklas R, Schiller S, Adang LA, Gärtner J, Friede T
J Inherit Metab Dis 2020 Nov;43(6):1288-1297. Epub 2020 Jul 22 doi: 10.1002/jimd.12282. PMID: 32621519

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Iduronate 2-Sulfatase Deficiency, Mucopolysaccharidosis Type II, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Mucopolysacchardosis Type II (MPSII): Decreased Iduronate 2-Sulfatase (I2S) activity, 2022

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