Sanfilippo Syndrome (Mucopolysaccharidosis Type III)

The mucopolysaccharidoses (MPSs) are a rare group of inherited lysosomal storage disorders that are caused by the deficiency or absence of specific lysosomal enzymes. Lack of these enzymes allows for the accumulation of complex carbohydrates in the body's cells and tissues and in the cellular organelles, the lysosomes. These complex carbohydrates, also known as mucopolysaccharides or glycosaminoglycans (GAGs), serve as the building blocks for connective tissues in the body.

The mucopolysaccharidoses comprise a group of 8 metabolic disorders, known as mucopolysaccharidoses types I-IV, VI, VII, and IX and mucolipidosis (ML; types II and III). Mucopolysaccharidosis V is defined as a form of type I and is known as mucopolysaccharidosis IS. Each lysosomal storage disorder is associated with a defined enzymatic deficiency, although as a group, these disorders share many clinical features. Without the proper enzymatic degradation of the mucopolysaccharides, clinical symptoms, such as auditory and visual defects, cardiovascular pathologies, hepatosplenomegaly, and dysostosis multiplex, occur due to their accumulation in organ systems.

Severe neurological impairment also occurs and is usually associated with Hurler syndrome (mucopolysaccharidosis IH), Hunter syndrome (mucopolysaccharidosis II), and Sanfilippo syndrome (mucopolysaccharidosis III).[35] The incidence of individual types of lysosomal storage disease is rare; however, the estimated combined incidence of all types of mucopolysaccharidoses is 1 in 20,000 live births.

In 1963, mucopolysaccharidosis III, also now known as Sanfilippo syndrome, was described at the American Pediatric Society Annual Meeting by pediatrician Sylvester Sanfilippo. Mucopolysaccharidosis III is considered the most common of these genetic disorders, occurring with an incidence of 1 in 70,000 newborns. Sanfilippo syndrome results from the deficiency or absence of 4 different enzymes that are necessary to degrade the GAG heparan sulfate. Each enzyme deficiency defines a different subtype of Sanfilippo syndrome, as follows: type IIIA (Sanfilippo A), type IIIB (Sanfilippo B), type IIIC (Sanfilippo C), and type IIID (Sanfilippo D).[1, 2, 3, 4] Other types of mucopolysaccharidoses are discussed in separate articles (see Differentials).

The clinical features of Sanfilippo syndrome, including the significant CNS component (brain and spinal cord), result from the progressive lysosomal accumulation of the GAG heparan sulfate.[5]

Four enzymes are involved in the different subtypes of Sanfilippo syndrome. Individuals with type A lack the enzyme heparan sulfate sulfatase.[34] Individuals with type B lack the enzyme N -acetyl-alpha-D-glucosaminidase (NAG).[6] Patients with type C lack acetyl-CoA:alpha-glucosaminide acetyltransferase. Patients with type D lack the enzyme N- acetylglucosamine-6-sulfatase. As a result of these differing enzyme deficiencies, there is an increase in the urinary excretion of heparan sulfate in patients with mucopolysaccharidosis type III.

The particular type of Sanfilippo syndrome cannot be determined based on clinical features alone. Precise identification of the specific form of Sanfilippo syndrome relies on enzymatic assays (see Workup).

Frequency

International

In 1997, Nelson reported an incidence of 1 case per 280,000 live births (0.36 cases per 100,000 live births) for Sanfilippo syndrome in Northern Ireland.[7] In 1999, Poorthuis and others reported an incidence of 4.5 cases per 100,000 live births for all mucopolysaccharidosis disorders in the Netherlands.[8] Within this incidence, mucopolysaccharidosis III accounted for 47% of all cases of mucopolysaccharidoses, with a prevalence of 1.89 cases per 100,000 live births. In this study, mucopolysaccharidosis IIIA had an estimated birth prevalence of 1.16 cases per 100,000 newborns.

In 1999, Meikle and others cited a prevalence of mucopolysaccharidosis IIIA of 1 in 114,000 live births and the prevalence of mucopolysaccharidosis IIIB as 1 in 211,000 live births.[9] Mucopolysaccharidosis IIIC and mucopolysaccharidosis IIID were much rarer, at 1 in 1,407,000 and 1 in 1,056,000 live births, respectively. In 2000, a registry compiled by MPS Australia cited an incidence of 1 case per 66,000 live births for all subtypes of Sanfilippo syndrome. Within this combined statistic, the incidence reported for each subtype of mucopolysaccharidosis III equaled the prevalence cited earlier in 1999 by Meikle.

Mortality/Morbidity

Sanfilippo syndrome is characterized by a worsening clinical progression with a devastating prognosis. Over time, patients develop CNS degeneration and progress to a vegetative state. Death usually occurs before age 20 years, primarily from cardiopulmonary arrest due to airway obstruction and/or pulmonary infection. Type IIIA is the most severe subtype; most patients with type IIIA die during their teenage years.

Race

The mucopolysaccharidoses are pan-racial.

Sex

All subtypes of mucopolysaccharidosis III are inherited in an autosomal recessive Mendelian pattern. The genetic mutations are located in the autosomes and not in the sex chromosomes[10] ; therefore, Sanfilippo syndrome affects males and females equally.

Age

Children with Sanfilippo syndrome are born without clinical features of a metabolic disorder. In the toddler years, aggressive behaviors emerge, with marked hyperactivity and destructive tendencies. Somatic features, such as mild organomegaly, little to no corneal clouding, and orthopedic abnormalities, may be present. Neurologic degeneration usually begins in children aged 6 years or older (sometimes even younger). Death may not occur until after puberty.

Sanfilippo syndrome is a progressive disorder with a very poor prognosis. Severe CNS degeneration occurs, with progression to a vegetative state.

Most patients do not live beyond age 20 years, with death primarily due to respiratory complications.

Support groups and organizations that parents and caregivers might find helpful include the following:

• Alliance Sanfilippo

  • Website: www.eurordis.org/content/member-profile-alliance-sanfilippo 

• Canadian Society for Mucopolysaccharide and Related Diseases, Inc.

  • Website: www.mpssociety.ca

  • Toll-free: 800-667-184

• Children Living with Inherited Metabolic Diseases (CLIMB)

  • Website: www.climb.org.uk

  • Toll-free: 800-652-3181

• Genetic Home Reference

  • Website: ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-iii

• Hide and Seek Foundation for Lysosomal Disease Research

  • Website: www.hideandseek.org

  • Toll-free: 888-858-7894

• National Organization for Rare Disorders (NORD)

  • Website: www.rarediseases.org

• National MPS Society

  • Website: www.mpssociety.org

  • E-mail: info@mpssociety.org

  • Toll-free: 877.MPS.1001

  • Telephone 919.806.0101

• Society for Mucopolysaccharide Diseases

  • Website: www.mpssociety.org.uk

  • Telephone: 44-0845-389-9901 (UK)

Patients with Sanfilippo syndrome are born without symptoms and typically have normal development for the first 2 years of life. In all subtypes of this syndrome, CNS disease predominates, with less skeletal and soft tissue involvement compared with the other mucopolysaccharidoses (MPSs). Type IIIA has the most CNS involvement. This subtype represents the most severe form of Sanfilippo syndrome with an earlier and more rapid onset of symptoms than others within mucopolysaccharidosis III. Note the following:

• Onset of symptoms usually occurs between age 2 and 6 years in a previously healthy-appearing child. Some patients may show developmental delays in infancy. Growth parameters are normal or accelerated prior to age 3 years, with growth delays seen in older children.

• Initial symptoms present as behavioral changes. Patients are hyperactive and show aggressive and destructive behaviors. More aggressive behaviors have been reported in females when compared with male patients.

• Sleep disturbances are common.

• Mental development slows after the toddler years; then, progressive deterioration occurs in regard to gait and speech articulation. Some patients may never speak.

• Seizures may occur but usually are well-controlled with medication.

• During the early school years, symptoms worsen and patients show shortened attention spans and difficulties with concentration. Mental and physical disabilities prevent most children from progressing in their school academics.

• By age 10 years, patients are severely limited in their activities and movement. Most children with type IIIA have severe neurologic impairment by age 6 years. Recurrent or chronic diarrhea occurs in mucopolysaccharidosis III patients. The etiology for this abnormal gut motility is thought to be due to lysosomal glycosaminoglycans (GAG) storage in the neurons of the myenteric plexus of the small intestine.

• Respiratory compromise can occur and is related to airway obstruction due to anatomic changes, excessive thick secretions, and neurologic impairment. Upper respiratory tract infections and sinopulmonary disease are common.

The striking clinical features of coarse facial features and skeletal abnormalities seen in the mucopolysaccharidoses are not as apparent in patients with mucopolysaccharidosis III. Mild facial coarsening may be present, and the skeletal differences are typically subtle. Corneal clouding, as seen in the other mucopolysaccharidoses, is not usually present. However, classic clinical features are an abundance of coarse facial and body hair (hirsutism). Note the following[11] :

Head, eyes, ears, nose, and throat (HEENT)

• Mild coarse facial features

• Synophrys

• Clear corneas (some patients may have mild corneal opacities)

• Hearing loss with speech delay

Cardiac

• Asymmetric septal hypertrophy

• Cardiomegaly

Gastrointestinal

• Mild hepatomegaly

• Mild splenomegaly

Genitourinary

• Inguinal hernia,

• Umbilical hernia

Skeletal

• Dense calvaria

• Mild dysostosis multiplex (constellation of characteristic skeletal abnormalities seen in mucopolysaccharidoses)

• Joint stiffness

Neurologic

• Mentally challenged

• Behavioral and sleep disturbances

• Severe progressive neurologic degeneration

The deficiency or lack of a specific lysosomal enzyme is responsible for each subtype of Sanfilippo syndrome. Specifically, for type IIIA, the enzyme is heparan sulfate sulfatase; for type IIIB, the enzyme is N -acetyl-alpha-D-glucosaminidase; for type IIIC, the enzyme is acetyl-CoA:alpha-glucosaminide acetyltransferase; and for type IIID, the enzyme is N -acetylglucosamine-6-sulfatase.

Heparan sulfate accumulates in the lysosomes of tissues and organs, causing the diverse morphological abnormalities seen in mucopolysaccharidosis type III patients. Large amounts of heparan sulfate are excreted in the urine.

The enzymatic defects defining all subtypes of Sanfilippo syndrome are inherited as autosomal recessive disorders; this genetic inheritance also is true of the other mucopolysaccharidoses, except for mucopolysaccharidosis type II or Hunter syndrome, which has X-linked recessive inheritance. Due to the autosomal recessive inheritance pattern, biological parents of an affected child have a 25% risk of having another affected child with each pregnancy.

The gene mutations for the 4 different types have been mapped on the human genome. Their chromosomal or cytogenetic locations are as follows[11] :

• Type IIIA - 17q25.3

• Type IIIB - 17q21.2

• Type IIIC - 8p11.21

• Type IIID - 12q14.3

Biochemical differentiation of the different subtypes of mucopolysaccharidosis (MPS) type III is possible, and diagnosis is confirmed by specific enzymatic assay.

Enzymatic activity for all subtypes of Sanfilippo syndrome can be assayed in cultured skin fibroblasts and in peripheral blood leukocytes. If mucopolysaccharidosis type III is suspected, enzymatic cell analysis is the recommended test.

In all subtypes of mucopolysaccharidosis type III, urinary excretion of heparan sulfate is increased. To measure the concentration of glycosaminoglycans or glycosaminoglycans (GAGs) in the urine, a total quantitative test and a fractionation test should be performed using electrophoresis or chromatography. Ideally, a first-morning urine specimen should be analyzed because a concentrated urine specimen is needed to avoid a false-negative result due to dilutional effect. This sample recommendation is especially important for the diagnosis of mucopolysaccharidosis type III because of the low urinary GAG levels and smaller heparan fragments seen in this syndrome. Urinary GAG levels are higher in newborns and infants than in older children. Interpretation of results must include age-specific controls and fractionation to properly identify pathologic GAG levels (ie, heparan sulfate) from normal GAG levels present in the urine (ie, chondroitins).

Prenatal diagnosis can be performed by measuring for the specific enzymatic activity in cultured amniocytes or chorionic villi cells.[12]

Imaging studies include the following:

• Neuroimaging to diagnosis hydrocephalus and to look for changes in brain structure 

  Noncommunicating obstructive hydrocephalus caused by obstruction of the foramina of Luschka and Magendie. This MRI sagittal image demonstrates dilatation of lateral ventricles with stretching of corpus callosum and dilatation of the fourth ventricle.

• Echocardiography to assess for asymmetric septal hypertrophy, cardiomegaly, and valvular disease

• Abdominal imaging, such as ultrasonography or CT scanning, to evaluate for organomegaly

• Radiographic skeletal survey to identify cases of dysostosis multiplex

Other tests include the following:

• Electroencephalography (EEG) to diagnose seizure activity

• Audiologic evaluation to identify patients with hearing loss

• Polysomnography for those patients who demonstrate clinical signs of airway obstruction due to anatomical changes, such as obstructive sleep apnea

No treatment for the underlying cause is available. Medical treatment is supportive and is directed toward improving the patient's quality of life. Because of the varied symptoms seen in mucopolysaccharidosis (MPS) type III, a multidisciplinary approach is indicated (see Consultations). Specific therapies such as bone marrow transplantation (BMT) and enzyme replacement therapy (ERT) are not options for patients with Sanfilippo syndrome.[13]

BMT has been shown to improve the clinical outcomes of patients with mucopolysaccharidosis disorders; however, this therapy has been most successful in patients with mucopolysaccharidosis types I, II, and VI. Patients with mucopolysaccharidosis type III have not shown positive clinical benefit from BMT.

HSCT (hematopoietic stem cell transplantation) has shown mixed results and an unclear neurocognitive benefit.

ERT has been approved in the United States for patients with mucopolysaccharidosis types I, II, and VI. Recombinant enzymes for the deficiencies seen in mucopolysaccharidosis types IIIA and IIIB are available; however, medical trials in ERT have not been favorable in improving prognosis because the enzymes are not able to cross the blood-brain barrier to enter the CNS. Presently, enzyme injections directly into the CNS are being investigated, with clinical trials underway for mucopolysaccharidosis type IIIA and in development for mucopolysaccharidosis type IIIB.

Substrate reduction therapy (SRT), with synthetic genistein (4',5,7'-trihydroxyisoflavone) derivatives, is being investigated as a potential treatment approach in mucopolysaccharidosis. Genistein, a phytoestrogen, has shown GAG synthesis inhibition in in vitro skin fibroblasts from patients with mucopolysaccharidosis and from corresponding in vivo mouse models.[14]

Gene therapy to treat mucopolysaccharidosis type IIIB is being researched in the United States and France using animal models.

Patients with mucopolysaccharidoses (MPSs) have greater risks for complications during general anesthesia.[15, 33] Complications during anesthesia have been attributed to excessive oral secretions and airway obstruction due to abnormal airway anatomy. Prior to any surgical intervention, proper precautions in regard to airway management are critical for patients with mucopolysaccharidosis.

Patients and their families require evaluation by a medical genetics team for diagnosis, counseling, up-to-date treatment options, and referrals to support groups and organizations (see Patient Education). Biological parents and their families must be offered genetic counseling to discuss the recurrence risk after the birth of an affected child.

The treatment of each patient requires consultation and ongoing care with trained pediatric specialists in the fields of neurology, ophthalmology, audiology, otolaryngology, cardiology, gastroenterology, orthopedics, and child development/child psychiatry.

Consultation with a developmental pediatrician is especially helpful in addressing behavioral concerns and to assist caregivers in establishing a sleep routine.

Pediatric surgical consultation is indicated for those patients in need of hernia repair.

Neurosurgical evaluation is indicated for those patients who show clinical signs of cervical cord compression or other nerve compression disorders (ie, claw hand deformity).

Drug therapy is not part of the standard of care for mucopolysaccharidosis (MPS) type III. Medications are used for symptomatic treatment, such as anticonvulsants for seizure activity.

Sedative medications and melatonin have been used to help patients improve their quality of sleep in conjunction with establishing a bedtime routine to foster rest. See Medical Care.