Clinical Guidance

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

Table 2.

Genotype-Phenotype Correlations in Mucopolysaccharidosis Type III

Gene(MPSSubtype) | Genotype-Phenotype Correlation

NAGLU(MPS IIIB) |

• Homozygosity for variants causing premature termination of the protein product (nonsense or frameshift pathogenic variants) results in more severe or rapidly progressing phenotypes .

• Homozygosity for nonsense variant or missense variants or is associated with severe disease course .

• The missense pathogenic variants , , , and are only reported in individuals w/attenuated or slowly progressing phenotypes .

SGSH(MPS IIIA) |

Source: GeneReviews — "Mucopolysaccharidosis Type III"

Diagnostic Criteria

Formal diagnostic criteria for mucopolysaccharidosis type III (MPS III) have not been established.

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

Source: GeneReviews — "Mucopolysaccharidosis Type III"

Differential Diagnosis

Table 4.

Genes of Interest in the Differential Diagnosis of Mucopolysaccharidosis Type III

Gene | DiffDxDisorder | MOI | Clinical Features of DiffDx Disorder

Overlapping w/MPS III | Distinguishing from MPS III

GNPTAB

| ML II | AR |

• Coarse facies

• Frequent ear infections

• Inguinal umbilical hernias

|

• Dysostosis multiplex

• Corneal clouding

• Significant DD seen in 1st year of life

• Death at age ~2 yrs from neurologic decline multisystem involvement

ML III alpha/beta

|

• Coarse facies

• Frequent upper-respiratory ear infections

|

Management Guidelines

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 (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with Mucopolysaccharidosis Type III

Source: GeneReviews — "Mucopolysaccharidosis Type III"

Clinical Guidance

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 . Hip surgery is not recommended for individuals with MPS III due to the development of osteonecrosis and collapse of the femoral head . 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

Source: GeneReviews — "Mucopolysaccharidosis Type III"

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.

Source: GeneReviews — "Mucopolysaccharidosis Type III"

Surveillance Guidelines

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. Table 7. Recommended Surveillance for Individuals with Mucopolysaccharidosis Type III

Source: GeneReviews — "Mucopolysaccharidosis Type III"