Mucolipidosis IV

Clinical characteristics: Mucolipidosis IV (MLIV) is an ultra-rare lysosomal storage disorder characterized by severe psychomotor delay, progressive visual impairment, and achlorhydria. Individuals with MLIV typically present by the end of the first year of life with delayed developmental milestones (due to a developmental brain abnormality) and impaired vision (resulting from a combination of corneal clouding and retinal degeneration). By adolescence, all individuals with MLIV have severe visual impairment. A neurodegenerative component of MLIV has become more widely appreciated, with the majority of individuals demonstrating progressive spastic quadriparesis and loss of psychomotor skills starting in the second decade of life. About 5% of individuals have atypical MLIV, manifesting with less severe psychomotor impairment, but still exhibiting progressive retinal degeneration and achlorhydria.

Diagnosis/testing: MLIV is suspected in individuals with typical clinical findings and elevated plasma gastrin concentration or polymorphic lysosomal inclusions in skin or conjunctival biopsy. Identification of biallelic pathogenic variants in MCOLN1 confirms the diagnosis.

Management: Treatment of manifestations: Developmental and educational services including speech therapy; physical therapy and bracing for hypotonia and spasticity; intramuscular botulinum toxin injections or oral medications for muscle spasticity and rigidity as needed; anti-seizure medication as needed; surgical correction of strabismus; high-contrast black and white materials for those with visual impairment; topical lubricating eye drops, artificial tears, gels, or ointments for ocular irritation; feeding therapy and/or gastrostomy tube placement may be required for persistent feeding issues; management of constipation and bile reflux per gastroenterologist; treatment of renal failure per nephrologist; iron supplementation as needed.

Surveillance: Monitor those with seizures and assess for new neurologic manifestations at least annually; assessment of musculoskeletal complications as indicated; monitor developmental progress at least annually; annual ophthalmology examination; feeding and growth evaluation at least annually; cystatin C levels to monitor renal function at least annually; complete blood count and iron studies annually.

Agents/circumstances to avoid: Chloroquine may be contraindicated.

Genetic counseling: MLIV 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 MCOLN1 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 testing are possible.