Clinical Guidance

Genotype-phenotype correlations support the clinical distinction between the phenotypes ML II, ML III/, and at least the type of intermediate ML described in . ML II. Homozygous and compound heterozygous GNPTAB pathogenic variants that result in no functional GlcNAc-1-phosphotransferase (GNPT) activity (typically nonsense or frameshift variants) are consistently associated with the ML II phenotype. This severe phenotype is caused by complete loss of enzyme activity. ML III/. GNPTAB variants in the homozygous or compound heterozygous state in which some retained GNPT enzyme activity (between and 1% and 10% of the normal activity) usually result in the ML III/ phenotype [, , , , , , , , ]. Some missense and several splice site variants have been associated with ML III/.

Source: GeneReviews — "GNPTAB-Related Disorders"

Diagnostic Criteria

Suggestive Findings

GNPTAB-related disorders (which include the phenotypes mucolipidosis II [ML II] and mucolipidosis III/ [ML III/] and phenotypes intermediate between ML II and III/) should be suspected in individuals with the following age-related and findings and supportive findings .

Clinical Findings

ML II – Neonatal period

• Small to low-normal anthropometric measurements for gestational age

• Restricted range of passive motion in the shoulders

• Flat face, shallow orbits, and depressed nasal bridge

• Thick skin with wax-like texture (in neonates, most evident in and around the earlobes)

• Variable musculoskeletal findings that may include one or more of the following:

• Thoracic deformity including kyphosis

• Clubfeet

• Deformed long bones (See .)

• Dislocation of the hip(s)

ML II – Later infancy

Source: GeneReviews — "GNPTAB-Related Disorders"

Differential Diagnosis

In addition to the disorders to consider in the differential diagnosis of GNPTAB-related disorders listed in and , the disorder ML III, caused by biallelic pathogenic variants in GNPT and closely resembling ML III/, needs to be considered. Mucolipidosis II (ML II) Table 3. Autosomal Recessive Lysosomal Storage Disorders to Consider in the Differential Diagnosis of ML II

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a GNPTAB-related disorder, the evaluations for mucolipidosis II / mucolipidosis III/ summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Mucolipidosis II

Source: GeneReviews — "GNPTAB-Related Disorders"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "GNPTAB-Related Disorders"

Surveillance Guidelines

Mucolipidosis II. Infants and toddlers with ML II and their families benefit from outpatient follow-up visits approximately every three months. Subsequently throughout early childhood, two outpatient visits per year may be adequate until cardiac and respiratory monitoring need to be more frequent. Mucolipidosis III/. Young children with ML III/ and their families benefit from outpatient clinic visits about twice a year. From age six years similar follow-up visits are recommended on a yearly basis unless bone pain and/or deteriorating ambulation become major handicaps and require closer orthopedic follow up and/or cardiac and respiratory monitoring need to be more frequent.

Source: GeneReviews — "GNPTAB-Related Disorders"