Mucopolysaccharidosis Type VII

Excerpt

Clinical characteristics: Individuals with mucopolysaccharidosis type VII (MPS VII) can present perinatally with early demise, nonimmune hydrops fetalis, cholestatic jaundice, and hepatosplenomegaly, or in early childhood with developmental delay and characteristic musculoskeletal features (e.g., short neck, short-trunk short stature, pectus deformity, gibbus, and joint stiffness/contractures) and craniofacial features (e.g., macrocephaly, coarse hair, coarse facies, corneal clouding, and macroglossia). Skeletal survey shows features of dysostosis multiplex including thickened cortical bone, abnormal J-shaped sella turcica, paddle- or oar-shaped ribs, short, thickened clavicles, platyspondyly with anterior beaking of the lower thoracic and lumbar vertebrae, and proximal pointing of the metacarpals and metatarsals. Complications include developmental delay, intellectual disability, hepatosplenomegaly, spinal stenosis, recurrent otitis media, hearing loss, pulmonary disease, obstructive sleep apnea, hernias, feeding difficulties, and heart valve disease.

Diagnosis/testing: The diagnosis of MPS VII is established in a proband with characteristic clinical and radiographic findings, urine glycosaminoglycan (GAG) analysis with elevated concentrations of total GAGs with increased dermatan and chondroitin sulfate, and absent or reduced beta-glucuronidase enzyme activity in leukocytes, fibroblasts, or dried blood spots; and/or biallelic pathogenic variants in GUSB identified by molecular genetic testing.

Management: Targeted therapy: Enzyme replacement therapy with vestronidase alfa.

Supportive care: Neonatal intensive care for infants with nonimmune hydrops fetalis; surgical fusion for atlantoaxial instability, surgery as needed for scoliosis, spine monitoring during surgery; anti-inflammatory medications and/or analgesics as needed for pain due to joint stiffness; physical medicine and rehabilitation, physical therapy, and occupational therapy for issues with mobility and activities of daily living; surgical decompression for spinal stenosis, wrist splints and surgery for carpal tunnel syndrome; early intervention services, speech therapy, and school support for developmental issues; tonsillectomy and adenoidectomy for airway obstruction and sleep apnea; positive pressure ventilation as needed; pulmonary toilet for restrictive lung disease; tympanostomy tubes and hearing aids for hearing loss; treatment per ophthalmologist for corneal clouding; thickeners and gastrostomy tube placement as needed for feeding difficulties; surgical repair for hernia; treatment of cardiac disease per cardiologist; hospice care when needed.

Surveillance: Urine dermatan and chondroitin sulfate levels every six to 12 months in individuals on enzyme replacement therapy; assess growth parameters every six to 12 months throughout childhood, then annually; developmental assessment every six to 12 months throughout childhood; orthopedic evaluation annually with radiographs per orthopedist; rehabilitation medicine evaluation as needed; neurologic exam and spine MRI annually throughout childhood and then every two years or per orthopedist in those who have had spinal decompression; ENT and pulmonary evaluations annually with sleep study and pulmonary function tests based on age and clinical manifestations; audiology examination annually throughout childhood and then every two years in adolescents and adults; ophthalmology examination every one to two years; echocardiogram and EKG every one to two years; abdominal MRI every two years or until organomegaly is improved on treatment; nerve conduction study every two years starting in school age or as needed; dental exams every six to 12 months.

Agents/circumstances to avoid: Individuals who have not had cervical fusion should not participate in activities that may result in cervical spine injury such as gymnastics. Cervical spine precautions must be taken during intubation for anesthesia.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted to identify as early as possible those who would benefit from prompt initiation of enzyme replacement therapy and preventive measures.

Genetic counseling: MPS VII is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GUSB pathogenic variant, each sib of an affected individual has at conception 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 GUSB pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.