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Mucopolysaccharidosis, MPS-III-C(MPS3C)

MedGen UID:
39477
Concept ID:
C0086649
Disease or Syndrome
Synonyms: Acetyl-CoA alpha-glucosaminide n-acetyltransferase deficiency; MPS 3C; MPS III C; MPS3C; Mucopoly-saccharidosis type 3C; Mucopolysaccharidosis type IIIC (Sanfilippo C); MUCOPOLYSACCHARIDOSIS, TYPE IIIC; Sanfilippo syndrome C
SNOMED CT: Acetyl-CoA alpha-glucosaminide acetyltransferase deficiency (75238000); Mucopolysaccharidosis III-C (75238000); MPS III-C - Mucopolysaccharidosis III-C (75238000); N-Acetyl transferase deficiency (75238000); Sanfilippo syndrome C (75238000); MPSIIIC - Mucopolysaccharidosis type IIIC (75238000); Mucopolysaccharidosis, MPS-III-C (75238000); Acetyl-CoA: heparan-alpha-D-glucosaminide N-acetyltransferase deficiency (75238000); Sanfilippo syndrome, type C (75238000); Heparan-alpha-glucosaminide acetyltransferase deficiency (75238000)
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): HGSNAT (8p11.21-11.1)
 
Monarch Initiative: MONDO:0009657
OMIM®: 252930
Orphanet: ORPHA79271

Disease characteristics

Excerpted from the GeneReview: Mucopolysaccharidosis Type III
Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections. [from GeneReviews]
Authors:
Victoria F Wagner  |  Hope Northrup   view full author information

Additional descriptions

From OMIM
Sanfilippo syndrome comprises several forms of lysosomal storage diseases due to impaired degradation of heparan sulfate. The deficient enzyme in Sanfilippo syndrome C, or MPS IIIC, is an acetyltransferase that catalyzes the conversion of alpha-glucosaminide residues to N-acetylglucosaminide in the presence of acetyl-CoA. For a general phenotypic description and a discussion of genetic heterogeneity of Sanfilippo syndrome, see MPS IIIA (252900).  http://www.omim.org/entry/252930
From MedlinePlus Genetics
Mucopolysaccharidosis type III (MPS III), also known as Sanfilippo syndrome, is a disorder that primarily affects the brain and spinal cord (central nervous system). It is characterized by deterioration of neurological function (neurodegeneration), resulting in many of the features of the condition. Other body systems can also be involved, although the physical features are usually mild in the early stages.

People with MPS III generally do not display any features of the condition at birth, but they begin to show signs and symptoms of the disorder during early childhood. Early signs and symptoms of MPS III can include frequent ear and throat infections or bowel problems, though most common are mild developmental delay or delayed speech. Behavioral problems often worsen with affected children becoming restless, hyperactive, destructive, anxious, impulsive, fearless, or aggressive. Some affected children display features of autism spectrum disorder, which is a condition characterized by difficulty with social interactions and communication. Children with MPS III may have an increased tendency to chew on objects or put things in their mouth (be hyperoral). Sleep disturbances are also very common in children with MPS III. This condition causes progressive intellectual disability and the loss of previously acquired skills (developmental regression or dementia). In later stages of the disorder, people with MPS III may develop seizures, loss of mobility, and movement disorders.

MPS III is divided into types IIIA, IIIB, IIIC, and IIID, which are distinguished by their genetic cause. The different types of MPS III have similar signs and symptoms, although the features of MPS IIIA typically appear earlier in life and progress more rapidly. People with MPS III usually live into adolescence or early to mid-adulthood.

The physical features of MPS III are less pronounced than those of other types of mucopolysaccharidosis. Individuals with MPS III typically have mildly "coarse" facial features, a prominent forehead, a large head (macrocephaly), and thick hair and eyebrows. Some people with MPS III have short stature, joint stiffness, or mild dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. 

People with MPS III often have a slightly enlarged liver (mild hepatomegaly) or spleen (mild splenomegaly), and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). Cardiac abnormalities may also occur in this condition, including weakening of the heart muscle (cardiomyopathy), disruption of the heart's normal rhythm (arrhythmia), or problems with the heart's valves. Affected individuals often experience chronic diarrhea and recurrent upper respiratory and ear infections. People with MPS III may also have hearing loss and vision problems.  https://medlineplus.gov/genetics/condition/mucopolysaccharidosis-type-iii

Clinical features

From HPO
Heparan sulfate excretion in urine
MedGen UID:
340721
Concept ID:
C1854827
Finding
An increased concentration of heparan sulfates in the urine.
Asymmetric septal hypertrophy
MedGen UID:
104705
Concept ID:
C0205700
Disease or Syndrome
Hypertrophic cardiomyopathy with an asymmetrical pattern of hypertrophy, with a predilection for the interventricular septum and myocyte disarray.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
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.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Sleep abnormality
MedGen UID:
52372
Concept ID:
C0037317
Sign or Symptom
An abnormal pattern in the quality, quantity, or characteristics of sleep.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Loss of speech
MedGen UID:
107445
Concept ID:
C0542223
Finding
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Motor deterioration
MedGen UID:
356495
Concept ID:
C1866284
Finding
Loss of previously present motor (i.e., movement) abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hernia
MedGen UID:
6816
Concept ID:
C0019270
Finding
The protrusion of part of an organ or fibroadipose tissue through an abnormal opening.
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.
Joint stiffness
MedGen UID:
56403
Concept ID:
C0162298
Sign or Symptom
Joint stiffness is a perceived sensation of tightness in a joint or joints when attempting to move them after a period of inactivity. Joint stiffness typically subsides over time.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Thickened ribs
MedGen UID:
98096
Concept ID:
C0426820
Finding
Increased thickness (diameter) of ribs.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Dense calvaria
MedGen UID:
343213
Concept ID:
C1854834
Finding
An abnormal increase of density of the bones making up the calvaria.
Beaking of vertebral bodies
MedGen UID:
341588
Concept ID:
C1856599
Finding
Anterior tongue-like protrusions of the vertebral bodies.
Ovoid thoracolumbar vertebrae
MedGen UID:
401469
Concept ID:
C1868556
Finding
Recurrent upper respiratory tract infections
MedGen UID:
154380
Concept ID:
C0581381
Disease or Syndrome
An increased susceptibility to upper respiratory tract infections as manifested by a history of recurrent upper respiratory tract infections (running ears - otitis, sinusitis, pharyngitis, tonsillitis).
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
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.
Everted lower lip vermilion
MedGen UID:
344003
Concept ID:
C1853246
Finding
An abnormal configuration of the lower lip such that it is turned outward i.e., everted, with the Inner aspect of the lower lip vermilion (normally opposing the teeth) being visible in a frontal view.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Hypertrichosis
MedGen UID:
43787
Concept ID:
C0020555
Disease or Syndrome
Hypertrichosis is increased hair growth that is abnormal in quantity or location.
Coarse hair
MedGen UID:
124454
Concept ID:
C0277959
Finding
Hair shafts are rough in texture.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones.
Cellular metachromasia
MedGen UID:
871114
Concept ID:
C4025583
Finding
Metachromasia (also known as metachromacy) is a characteristic color change which certain aniline dyes exhibit when bound to particular substances or when concentrated in solution. For example, the basic dye toluidine blue becomes distinctly pink when bound to cartilage matrix. In the sense used here, the metachromasia refers to a change in color not observed with normal tissues, anomalous staining with the cationic dyes toluidine blue O and Alcian blue resulting from excessive amounts of the polyanionic glycosaminoglycans.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Mucopolysaccharidosis, MPS-III-C in Orphanet.

Professional guidelines

PubMed

Muschol N, Giugliani R, Jones SA, Muenzer J, Smith NJC, Whitley CB, Donnell M, Drake E, Elvidge K, Melton L, O'Neill C; MPS III Guideline Development Group
Orphanet J Rare Dis 2022 Oct 27;17(1):391. doi: 10.1186/s13023-022-02484-6. PMID: 36303195Free PMC Article
Spahiu L, Behluli E, Peterlin B, Nefic H, Hadziselimovic R, Liehr T, Temaj G
Pediatr Endocrinol Diabetes Metab 2021;27(3):201-208. doi: 10.5114/pedm.2021.109270. PMID: 34743503Free PMC Article
Sawamoto K, Álvarez González JV, Piechnik M, Otero FJ, Couce ML, Suzuki Y, Tomatsu S
Int J Mol Sci 2020 Feb 23;21(4) doi: 10.3390/ijms21041517. PMID: 32102177Free PMC Article

Recent clinical studies

Etiology

Almenabawy N, Ramadan M, Kamel M, Mahmoud IG, Amer F, Shaheen Y, Elnaggar W, Selim L
Am J Med Genet A 2023 Sep;191(9):2354-2363. Epub 2023 Jul 10 doi: 10.1002/ajmg.a.63342. PMID: 37596900
Muschol N, Giugliani R, Jones SA, Muenzer J, Smith NJC, Whitley CB, Donnell M, Drake E, Elvidge K, Melton L, O'Neill C; MPS III Guideline Development Group
Orphanet J Rare Dis 2022 Oct 27;17(1):391. doi: 10.1186/s13023-022-02484-6. PMID: 36303195Free PMC Article
Bigger BW, Begley DJ, Virgintino D, Pshezhetsky AV
Mol Genet Metab 2018 Dec;125(4):322-331. Epub 2018 Aug 10 doi: 10.1016/j.ymgme.2018.08.003. PMID: 30145178
Scarpa M, Orchard PJ, Schulz A, Dickson PI, Haskins ME, Escolar ML, Giugliani R
Mol Genet Metab 2017 Dec;122S:25-34. Epub 2017 Oct 16 doi: 10.1016/j.ymgme.2017.10.007. PMID: 29153844
Khan SA, Peracha H, Ballhausen D, Wiesbauer A, Rohrbach M, Gautschi M, Mason RW, Giugliani R, Suzuki Y, Orii KE, Orii T, Tomatsu S
Mol Genet Metab 2017 Jul;121(3):227-240. Epub 2017 May 26 doi: 10.1016/j.ymgme.2017.05.016. PMID: 28595941Free PMC Article

Diagnosis

Muschol N, Giugliani R, Jones SA, Muenzer J, Smith NJC, Whitley CB, Donnell M, Drake E, Elvidge K, Melton L, O'Neill C; MPS III Guideline Development Group
Orphanet J Rare Dis 2022 Oct 27;17(1):391. doi: 10.1186/s13023-022-02484-6. PMID: 36303195Free PMC Article
Spahiu L, Behluli E, Peterlin B, Nefic H, Hadziselimovic R, Liehr T, Temaj G
Pediatr Endocrinol Diabetes Metab 2021;27(3):201-208. doi: 10.5114/pedm.2021.109270. PMID: 34743503Free PMC Article
Seker Yilmaz B, Davison J, Jones SA, Baruteau J
J Inherit Metab Dis 2021 Jan;44(1):129-147. Epub 2020 Sep 28 doi: 10.1002/jimd.12316. PMID: 32944950Free PMC Article
Sawamoto K, Álvarez González JV, Piechnik M, Otero FJ, Couce ML, Suzuki Y, Tomatsu S
Int J Mol Sci 2020 Feb 23;21(4) doi: 10.3390/ijms21041517. PMID: 32102177Free PMC Article
Jakobkiewicz-Banecka J, Gabig-Ciminska M, Kloska A, Malinowska M, Piotrowska E, Banecka-Majkutewicz Z, Banecki B, Wegrzyn A, Wegrzyn G
Front Biosci (Landmark Ed) 2016 Jun 1;21(7):1393-409. doi: 10.2741/4463. PMID: 27100513

Therapy

Okuyama T, Eto Y, Sakai N, Nakamura K, Yamamoto T, Yamaoka M, Ikeda T, So S, Tanizawa K, Sonoda H, Sato Y
Mol Ther 2021 Feb 3;29(2):671-679. Epub 2020 Sep 30 doi: 10.1016/j.ymthe.2020.09.039. PMID: 33038326Free PMC Article
Seker Yilmaz B, Davison J, Jones SA, Baruteau J
J Inherit Metab Dis 2021 Jan;44(1):129-147. Epub 2020 Sep 28 doi: 10.1002/jimd.12316. PMID: 32944950Free PMC Article
Scarpa M, Orchard PJ, Schulz A, Dickson PI, Haskins ME, Escolar ML, Giugliani R
Mol Genet Metab 2017 Dec;122S:25-34. Epub 2017 Oct 16 doi: 10.1016/j.ymgme.2017.10.007. PMID: 29153844
Sorrentino NC, Fraldi A
Pediatr Endocrinol Rev 2016 Jun;13 Suppl 1:630-8. PMID: 27491210
BioDrugs 2002;16(4):316-8. doi: 10.2165/00063030-200216040-00009. PMID: 12196045

Prognosis

Shapiro EG, Eisengart JB
Mol Genet Metab 2021 May;133(1):8-34. Epub 2021 Mar 11 doi: 10.1016/j.ymgme.2021.03.002. PMID: 33741271
Concolino D, Deodato F, Parini R
Ital J Pediatr 2018 Nov 16;44(Suppl 2):120. doi: 10.1186/s13052-018-0562-1. PMID: 30442189Free PMC Article
Khan SA, Peracha H, Ballhausen D, Wiesbauer A, Rohrbach M, Gautschi M, Mason RW, Giugliani R, Suzuki Y, Orii KE, Orii T, Tomatsu S
Mol Genet Metab 2017 Jul;121(3):227-240. Epub 2017 May 26 doi: 10.1016/j.ymgme.2017.05.016. PMID: 28595941Free PMC Article
Jakobkiewicz-Banecka J, Gabig-Ciminska M, Kloska A, Malinowska M, Piotrowska E, Banecka-Majkutewicz Z, Banecki B, Wegrzyn A, Wegrzyn G
Front Biosci (Landmark Ed) 2016 Jun 1;21(7):1393-409. doi: 10.2741/4463. PMID: 27100513
Ashworth JL, Biswas S, Wraith E, Lloyd IC
Surv Ophthalmol 2006 Jan-Feb;51(1):1-17. doi: 10.1016/j.survophthal.2005.11.007. PMID: 16414358

Clinical prediction guides

Ludwig J, Sawant OB, Wood J, Singamsetty S, Pan X, Bonilha VL, Rao S, Pshezhetsky AV
Exp Eye Res 2023 Apr;229:109433. Epub 2023 Feb 27 doi: 10.1016/j.exer.2023.109433. PMID: 36858249Free PMC Article
Minami K, Morimoto H, Morioka H, Imakiire A, Kinoshita M, Yamamoto R, Hirato T, Sonoda H
Int J Mol Sci 2022 Oct 3;23(19) doi: 10.3390/ijms231911724. PMID: 36233030Free PMC Article
Shapiro EG, Eisengart JB
Mol Genet Metab 2021 May;133(1):8-34. Epub 2021 Mar 11 doi: 10.1016/j.ymgme.2021.03.002. PMID: 33741271
Lin HY, Chen MR, Lin SM, Hung CL, Niu DM, Chang TM, Chuang CK, Lin SP
Orphanet J Rare Dis 2019 Jun 13;14(1):140. doi: 10.1186/s13023-019-1112-7. PMID: 31196149Free PMC Article
Jakobkiewicz-Banecka J, Gabig-Ciminska M, Kloska A, Malinowska M, Piotrowska E, Banecka-Majkutewicz Z, Banecki B, Wegrzyn A, Wegrzyn G
Front Biosci (Landmark Ed) 2016 Jun 1;21(7):1393-409. doi: 10.2741/4463. PMID: 27100513

Recent systematic reviews

Kong W, Wu S, Zhang J, Lu C, Ding Y, Meng Y
J Pediatr Endocrinol Metab 2021 Oct 26;34(10):1225-1235. Epub 2021 Jul 19 doi: 10.1515/jpem-2020-0742. PMID: 34271605
Kuiper GA, Nijmeijer SCM, Roelofs MJM, van der Lee JH, Hollak CEM, Bosch AM
J Inherit Metab Dis 2019 Sep;42(5):762-775. Epub 2019 May 16 doi: 10.1002/jimd.12103. PMID: 31020996
Zelei T, Csetneki K, Vokó Z, Siffel C
Orphanet J Rare Dis 2018 Apr 10;13(1):53. doi: 10.1186/s13023-018-0796-4. PMID: 29631636Free PMC Article
Clark BM, Sprung J, Weingarten TN, Warner ME
Bosn J Basic Med Sci 2018 Feb 20;18(1):1-7. doi: 10.17305/bjbms.2017.2201. PMID: 28590232Free PMC Article
Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, Moore D
Health Technol Assess 2006 Jun;10(20):iii-iv, ix-113. doi: 10.3310/hta10200. PMID: 16729919

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