Mucopolysaccharidosis Type Iii

Clinical characteristics.

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.

Diagnosis/testing.

The diagnosis of MPS III is established in a proband with suggestive clinical and laboratory findings in whom either biallelic pathogenic variants in one of four genes (GNS, HGSNAT, NAGLU, and SGSH) or deficiency of the respective lysosomal enzyme has been identified.

Management.

Treatment of manifestations: Supportive therapies for neurodevelopmental delays, hearing loss, and visual impairment; medications (rather than behavioral therapy) for psychiatric/behavioral issues; physical therapy and/or orthopedic management of musculoskeletal manifestations; and management as prescribed by consulting specialists for seizures, cardiac involvement, sleep disorders, feeding difficulties.

Surveillance: Routine monitoring of: developmental capabilities and educational needs, destructive or disruptive behaviors; musculoskeletal involvement; hearing; cardiac involvement.

Agents/circumstances to avoid: Procedures requiring anesthesia in centers ill-equipped or inexperienced in caring for patients with complex airway-management issues; hip surgery (due to high risk of osteonecrosis of the femoral head); environments not adapted to minimize risk from unpredictable behaviors.

Therapies under investigation: Despite ongoing research for a variety of therapeutic options, no treatments are currently clinically available for treatment of the primary manifestations of MPS III.

Genetic counseling.

MPS III is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the MPS III-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible.

Suggestive Findings

MPS III should be suspected in individuals with the following clinical findings and supportive laboratory or imaging findings.

Clinical findings

• Age 1-3 years. Language and motor delays
• Age 3-10 years
  • Language and motor delays
  • Behavioral problems including hyperactivity and aggressive or defiant behaviors
  • Sleep disturbances
• Age ≥10 years
  • Intellectual disability
  • Progressive developmental regression including loss of toilet training, language (if acquired), and motor skills
  • Seizures
  • Gait disorders
• General findings
  • Coarse facies
  • Thick hair and hirsutism
  • Hepatosplenomegaly
  • Joint stiffness
  • Hearing loss
  • Frequent upper-respiratory and ear infections
  • Inguinal and/or umbilical hernias

Note: Clinical findings alone are not diagnostic and may vary by disease severity.

Supportive laboratory findings. Analysis of urinary glycosaminoglycans (GAG) (i.e., heparan sulfate) may be quantitative (measurement of total urinary GAG amount) or qualitative (GAG electrophoresis to analyze specific GAGs present in the urine).

• While quantitative and qualitative analysis of GAGs cannot diagnose specific lysosomal enzyme deficiencies, including MPS III, an abnormality in either quantitative or qualitative GAG analysis is suggestive of an MPS disorder.
• GAG electrophoresis can assist in excluding and including certain MPS disorders; however, definitive diagnosis requires additional testing (see Establishing the Diagnosis).
• Both methods of urinary GAG analysis have reduced sensitivity, especially if urine is dilute. Normal results on urinary GAG analysis cannot rule out an MPS disorder, particularly in the case of MPS III.

Imaging findings

• Radiographs. Skeletal survey reveals mild signs of dysostosis multiplex (e.g., thickened "oar-shaped" ribs, scoliosis, kyphosis, misshaped or hypoplastic vertebral bodies, thickened diploic space), particularly in older children with a rapidly progressing form. Hip deformities such as acetabular dysplasia and osteonecrosis of the femoral head are also observed.
• MRI
  • Brain MRI demonstrates abnormalities such as white matter alterations (diffuse prolonged T₁ and T₂ relaxation times), enlarged subarachnoid and perivascular spaces, ventriculomegaly, and widening of the cortical sulci consistent with diffuse cerebral atrophy.
  • Spine MRI reveals spinal stenosis or spinal cord compression that can lead to narrowing of the central canal.
• Echocardiogram often exhibits valvular anomalies including mitral or aortic valve thickening, mitral or aortic regurgitation, and mitral valve prolapse.

Note: These findings may not be present in early life, may vary by disease severity, and are not specific to MPS III.

Establishing the Diagnosis

The diagnosis of MPS III is established in a proband with suggestive clinical and laboratory findings in whom either biallelic pathogenic variants in one of four genes (GNS, HGSNAT, NAGLU, and SGSH) (see Table 2) or deficiency of the respective lysosomal enzyme (see Table 1) has been identified.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the presenting phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MPS III is broad and age dependent, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas:

• Those with a phenotype indistinguishable from many other inherited disorders with intellectual disability, developmental regression, and/or significant behavioral issues are more likely to be diagnosed using genomic testing (see Option 2).
• Those in whom the diagnosis of MPS III has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Mucopolysaccharidosis type III (MPS III), a multisystem lysosomal storage disease that results from glycosaminoglycan (GAG) accumulation, is characterized by extreme clinical variability. Progressive central nervous system degeneration resulting in severe intellectual disability and developmental regression is the most prominent manifestation. Although often present, the somatic findings characteristic of other mucopolysaccharidoses (MPSs) are generally less clinically striking in individuals with MPS III.

Despite the universal neurologic decline in affected individuals, clinical severity varies within and among the four MPS III subtypes and even among members of the same family. Individuals with MPS III may have rapidly or slowly progressing disease [Valstar et al 2010c]. Some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without history of intellectual disability [Berger-Plantinga et al 2004, Verhoeven et al 2010].

Life span of individuals with MPS III is unpredictable, but shortened. Death usually occurs in the second or third decade of life secondary to neurologic disease or respiratory tract infections [Valstar et al 2010a, Lavery et al 2017]. Although some individuals with more slowly progressive, later-onset, or mild disease can live into their 30s, 40s, or even 50s with excellent medical care, this is atypical. In very rare instances, adults with MPS III have survived into their 60s [Verhoeven et al 2010].

In the following descriptions of clinical involvement in MPS III, it is important to note the potential for bias in the medical literature toward ascertaining/reporting clinical data regarding individuals with the most severe and rapidly progressive disease course.

Craniofacial and physical appearance. Many children have dolicocephaly or macrocephaly. Coarse facies, present in most affected individuals, tend to become more evident over time as GAGs accumulate in soft tissues. Dysmorphisms can include thick alae nasi, lips, and ear helices or lobules and macroglossia. Coarse and thick hair are frequently observed, as are synophrys and hirsutism. Skin is often tough and thick, sometimes causing difficulty with venipuncture.

Hepatosplenomegaly. Abdominal protuberance due to progressive organomegaly can be observed but is not universal. GAG accumulation that results in hepatomegaly and splenomegaly does not lead to dysfunction despite increases in size.

Neurologic. Ventriculomegaly is hypothesized to occur secondary to cerebral atrophy and impaired reabsorption of cerebrospinal fluid. Some individuals may experience symptomatic hydrocephalus.

Seizure disorders, common during later disease stages, are not universal.

Progressive neurodegeneration can result in gait disorders, hyperactive reflexes, or spasticity.

Development and cognition. Early childhood development may be normal; however, it is not uncommon for language or other developmental delays to be present from as early as age one year. Developmental delays are frequently evident in affected children by age two to six years; language development is often more delayed than motor development.

After development plateaus, a progressive loss of motor and cognitive skills begins. In rapidly progressing MPS III, regression may start as early as age three to four years. In those with very mild disease, regression may not become apparent until much later [Shapiro et al 2016, Whitley et al 2018]. If language was acquired, verbal skills are often lost by ages ten to 15 years. Although loss of independent ambulation in most affected individuals occurs between the teen years and the third decade, it can be earlier in those with a more severe disease course. Eventually, neurodegeneration leads to dysphagia, immobility, and unresponsiveness [Ruijter et al 2008].

Psychiatric and behavioral. The behavioral phenotype of MPS III, often a hallmark of the disease, usually begins between ages three and five years. Almost all affected children exhibit hyperactivity often unresponsive to medication. Aggressive and destructive behaviors such as outbursts and tantrums are common and can be difficult to control, particularly in individuals with normal mobility and strength. Behavior becomes less problematic with age due to decreased mobility and initiative resulting from progressive neurodegeneration.

Klüver-Bucy syndrome (a distinct set of neurobehavioral manifestations with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis) has been reported in individuals with MPS III [Potegal et al 2013, Hu et al 2017].

Early-onset dementia is observed in some individuals, particularly those with later-onset or more slowly progressing disease.

Sleep disturbances, present in 80%-95% of individuals, include difficulties with settling and frequent waking. These sleep disorders are thought to result from irregular sleep/wake patterns; some affected individuals demonstrate complete circadian rhythm reversal [Cross & Hare 2013].

Musculoskeletal. Stature of children is often normal or just below normal.

Joint stiffness or contractures and features of dysostosis multiplex are common, although much less severe than in other MPS disorders. Skeletal manifestations are usually not clinically obvious until after the onset of developmental regression and behavioral concerns.

Scoliosis and hip dysplasia, two of the more common skeletal findings, are usually not severe enough to require surgical correction. Femoral head osteonecrosis is a common cause of hip pain.

Carpal tunnel syndrome and trigger digits can occur [White et al 2011].

Low bone mass and vitamin D insufficiency or deficiency are prevalent and can be observed as early as the teenage years. Patients with decreased mobility or a history of antiepileptic drug use are especially at risk for osteoporosis and fractures [Nur et al 2017].

Hearing loss is common and can be conductive, sensorineural, or mixed due to a combination of dysostosis of the ossicles of the middle ear, inner ear abnormalities, and frequent otitis media.

ENT (otolaryngologic). Chronic and recurrent otitis media and rhinitis accompanied by poor sinus drainage are common as are frequent infections of the adenoids and tonsils, which may be enlarged.

Respiratory. Respiratory tract and sinopulmonary infections are common. Abnormal respiration can also be secondary to neurodegeneration, thick secretions with inefficient drainage, and anatomic airway obstruction. Rarely, the adenoids or tonsils are so enlarged that they cause obstructive sleep apnea. However, sleep apnea may also be due to the significant CNS involvement.

Gastrointestinal. Chronic or recurrent loose stools and/or constipation are common, though the primary cause is unknown. Diarrhea typically is episodic, but can be persistent in some. These concerns may be affected by activity or diet and may be exacerbated by frequent antibiotic treatment of recurrent infections.

Inguinal and umbilical hernias are common. Inguinal hernias may recur after surgical intervention. Umbilical hernias are not usually treated unless they are large or cause other medical concerns.

With progression of neurodegeneration, many affected individuals develop dysphagia and/or problems with chewing and swallowing food, increasing risks for aspiration pneumonia and weight loss secondary to poor feeding in later disease stages.

Cardiovascular. Although GAG storage in the mitral valve, aortic valve, myocardium, and/or cardiac conduction system (causing atrioventricular block) is common, most individuals with MPS III do not require cardiac intervention. Left ventricle ejection fraction is normal in children, but slightly impaired in adults [Nijmeijer et al 2019]. Shortened life span and inactivity of older individuals may explain the paucity of clinical cardiac disease in this population to date.

Ophthalmologic. Corneal opacities, such as corneal clouding, are not usually present in individuals with MPS III. Nonetheless, individuals with MPS III can have atrophy of the optic nerve and retinal degeneration (manifesting as pigmentary retinopathy, poor peripheral vision, and night blindness), particularly in late stages of the disease.

Phenotype Correlations by Gene

The subtypes of MPS III, (Table 1) caused by biallelic pathogenic variants in SGSH (MPS IIIA), NAGLU (MPS IIIB), HGSNAT (MPS IIIC), or GNS (MPS IIID), are mainly distinguished by their associated enzymatic deficiencies rather than clear phenotypic differences. While each MPS III subtype exhibits variable expressivity, individuals with MPS IIIA typically have the most severe and rapidly progressing disease course [Valstar et al 2010c].

Genotype-Phenotype Correlations

No genotype-phenotype correlations for pathogenic variants in GNS and HGSNAT have been identified. Table 3 summarizes genotype-phenotype correlations for NAGLU and SGSH.

Nomenclature

The four lysosomal enzymes associated with MPS III may be referred to by an alternate naming system (see Table 4).

Prevalence

The combined estimated prevalence of MPS III is between 1:50,000 and 1:250,000 depending on the population studied [Khan et al 2017]. This may be an underestimate due to variable expressivity and often mild somatic features of the disease.

Subtypes MPS IIIA and MPS IIIB are the most commonly observed, with estimated incidences of 1:100,000 and 1:200,000, respectively [Zelei et al 2018]. MPS IIIC and MPS IIID are, overall, much less common, with estimated incidences of 1:1,500,000 and 1:1,000,000, respectively [Andrade et al 2015].

Of note, some subtypes of MPS III are more common in certain geographic regions:

• MPS IIIA is globally the most common form of MPS III and the most common type observed in many northern and eastern European nations. It is particularly common in the Cayman Islands, with an incidence estimated as high as 1:400 births, secondary to 1/10 carrier frequency of c.734G>A in SGSH [Rady et al 2002].
• MPS IIIB is more common in southern European populations.
• MPS IIID has a higher-than-usual prevalence in Italian and Turkish populations [Valstar et al 2010a].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type III (MPS III), the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

It is important to note that developmental advances made by individuals with MPS III secondary to implementation of therapy may be short-lived as a result of the progressive nature of disease.

Surveillance

Due to the progression of MPS III manifestations over time, improvements in symptoms resulting from proper management are not typically long lasting. Consequently, monitoring for deterioration in the affected individual is an appropriate and important part of surveillance.

Agents/Circumstances to Avoid

Though airway management during procedures with anesthesia is not typically difficult, anesthesia conducted in ill-equipped medical centers or by personnel with limited experience with patients with difficult airways is not recommended [Clark et al 2018].

Hip surgery is not recommended for individuals with MPS III due to the development of osteonecrosis and collapse of the femoral head [White et al 2011].

To minimize risks posed by unpredictable behavior, children with MPS III should be supervised around or have their environment adapted to avoid the following for their safety:

• Sharp or fragile furniture
• Sharp or fragile toys
• Large electronics
• High structures or surfaces that pose risks of falls and other injuries

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Very few individuals with MPS III are known to have reproduced. In one case report a woman with slowly progressive MPS IIIB had an unremarkable pregnancy and a healthy child [Verhoeven et al 2010]. Due to the prevalence of valvular disease in MPS III, corresponding evaluation and management is appropriate if a woman with MPS III does achieve pregnancy.

Therapies Under Investigation

Despite ongoing research for a variety of therapeutic options for affected individuals, no treatments are currently clinically available for treatment of primary manifestations of MPS III.

Hematopoietic stem cell transplantation (HSCT) and umbilical cord blood transplantation (UCBT) are not currently considered effective treatment options for MPS III due to the lack of evidence of neurologic benefit.

Enzyme replacement therapy (ERT). Due to the inability of intravenous ERT to permeate the blood-brain barrier sufficiently to prevent neurologic disease progression, intravenous ERT has not been investigated in MPS III as intensively as it has for other lysosomal storage diseases.

Other methods of ERT administration, such as intrathecal injections, are effective in delivering ERT to normalize substrate storage in the CNS of MPS III animal models [King et al 2016]. A clinical trial currently in progress has demonstrated that intrathecal administration of recombinant human heparan-N-sulfatase, which is well tolerated in individuals with MPS IIIA, results in consistent decrease of heparan sulfate in the CSF [Jones et al 2016].

Substrate reduction therapy (SRT) is used successfully to treat other lysosomal storage diseases, such as Gaucher disease. Ongoing research suggests SRT as a future therapeutic option for MPS III.

In vitro studies have shown that siRNA targeting of genes that play a role in synthesis of heparan sulfate leads to decreased heparan sulfate synthesis, decreased GAG storage, and a reversal of the phenotype in fibroblasts of patients with MPS IIIC [Canals et al 2015].

Although genistein inhibits heparan sulfate synthesis and decreases accumulation of heparan sulfate in plasma and urine, it does not improve manifestations of MPS III at doses of 5 mg/kg/day or 10 mg/kg/day [de Ruijter et al 2012]. Future studies regarding genistein use at higher doses may determine whether it has clinical efficacy as a treatment for MPS III.

Chaperone-mediated therapy. The use of pharmacologic chaperones to increase residual lysosomal activity is being explored in MPS III. Certain mutated forms of enzymes implicated in the pathogenesis of MPS III can be rescued by chaperones that restore the natural folding of the enzyme to increase its activity. Chaperones are small enough in size to presumably cross the blood-brain barrier and target the cells with mutant enzyme that are the source of neurologic manifestations of MPS III. It has been proposed that low concentrations of specific chaperone molecules could function as partial enzymatic rescues in MPS IIIB or MPS IIIC.

Gene therapy. Ongoing advances in gene therapy may influence treatment of MPS III.

The use of a variety of MPS III-related gene-encoding viral vectors in mouse and canine models of MPS IIIA, MPS IIIB, and MPS IIID has increased deficient enzyme activity and decreased GAG storage [Scarpa et al 2017].

In children with MPS IIIA or MPS IIIB, intracerebral gene therapy has been well tolerated; findings suggest neurocognitive benefits, including moderate improvements in sleep and behavior. The most remarkable results are observed in the youngest patients, suggesting that earlier therapy may be more beneficial [Tardieu et al 2014, Tardieu et al 2017]. Additional trials regarding gene therapy for MPS III are under way.

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