Clinical characteristics: GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIα/β (ML IIIα/β), and phenotypes intermediate between ML II and ML IIIα/β.

1. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death.

2. ML IIIα/β becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood.

3. Phenotypes intermediate between ML II and ML IIIα/β are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIα/β.

Diagnosis/testing: The diagnosis of a GNPTAB-related disorder is established in a proband with suggestive clinical, radiographic, and biochemical findings and biallelic pathogenic (or likely pathogenic) variants in GNPTAB identified on molecular genetic testing.

Management: Treatment of manifestations: Management is supportive and symptomatic.

1. ML II. Low-impact therapies, including aqua therapy, to avoid joint and tendon strain; cognitive stimulation through interactive programs; gingivectomy as needed for oral health.

2. ML IIIα/β. Low-impact physical therapy is usually well tolerated. Carpal tunnel signs may require tendon release. In late childhood or early adolescence symptomatic relief of hip pain with over-the-counter analgesics; in some older adolescents and adults bilateral hip replacement has been successful. Later in disease course: management focuses on relief of general bone pain caused by osteoporosis; scheduled intermittent IV administration of the bisphosphonate pamidronate has been effective in some individuals.

3. All phenotypes. Because of concerns about airway management, surgical intervention should be avoided if possible and undertaken only in tertiary care settings.

Surveillance:

1. ML II. Outpatient follow-up visits approximately every three months for infants and toddlers; outpatient visits approximately every six months for older children until cardiac and respiratory monitoring need to be more frequent.

2. ML IIIα/β. Twice-yearly outpatient clinic visits for young children; annual routine follow-up visits after age six years unless bone pain, deteriorating ambulation, and/or cardiac and respiratory monitoring necessitate more frequent attention.

Genetic counseling: GNPTAB-related disorders are 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 GNPTAB pathogenic variants in the family are known, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.