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Mucolipidosis type IV (MLIV) is rare in the general population but is more prevalent among Ashkenazi Jews, among whom the prevalence at birth is 1/40 000.

The clinical spectrum of MLIV can range from severe to mild. MLIV patients typically have severe cognitive impairment, ocular abnormalities and achlorhydria with iron deficiency anemia. The most common presentation is of severe global developmental delay by the end of the first year of life and a progressive visual impairment during the first decade of life secondary to bilateral corneal opacities and retinal degeneration and resulting in blindness by adolescence. Development is usually limited to few or no words and poor hand use, and most patients do not achieve independent walking. Neurologic deficits (dys-/anarthria, slow chewing, eating and swallowing, spastic di- or quadriplegia, and hyperreflexive hypotonia) usually remain static during the first three decades of life, but in up to 15% neurologic deterioration may be observed. Brain MRI typically shows hypoplasia of the corpus callosum, signal abnormalities in the white matter, increased ferritin deposition in the thalamus and basal ganglia and (later in life) atrophy of the cerebellum. Progressive renal failure develops in the third decade of life. Strabismus and iron deficiency are present in about 50% of the patients. Milder manifestations or disproportionate affection of one of the organ systems may be observed. All of the MLIV patients have (asymptomatic) constitutive achlorhydria.

MLIV is caused by biallelic mutations in the MCOLN1 (19p13.2) gene coding for mucolipin-1 protein, a nonselective cation channel which is distributed in the membranes of late endosomes and lysosomes in all tissues, with the highest expression in brain, kidney, liver, spleen, and heart. The exact pathophysiological mechanism is unknown, but is hypothesized that abnormal flux of calcium is probably the most important, resulting in disruption in sorting and/or transport of late endosomes/lysosomes. Two variants, c.406-2A>G and 6.4 kb del, account for 95% of pathogenic variants in individuals of Ashkenazi Jewish heritage.

MLIV is suspected in the individuals with typical clinical findings and elevated plasma gastrin levels or polymorphic lysosomal inclusions in skin or conjunctival biopsy. Identification of biallelic pathogenic variants in MCOLN1 (19p13.2) confirms the diagnosis. Periodic Acid-Schiff staining of conjunctival cells reveals autofluorescent amorphous inclusions. Urine mucopolysaccharides, oligosaccharides and plasma lysosomal hydrolase assays are normal.

Corneal clouding may initially lead to suspicion of mucolipidoses and mucopolysaccharidoses but MLIV is distinguished by absence of dysmorphism. The developmental profile is different to GM1 gangliosidosis.

Prenatal diagnosis is done by molecular testing.

MLIV is transmitted as an autosomal recessive trait. Parents of an affected child bear a 25% risk of disease recurrence among the future offspring.

No specific treatment exists, and management is symptomatic and targeted towards the visual manifestations and the neurological problems (cognitive delay, spasticity and speech deficit). Physical therapy with special focus on spasticity and ataxia can improve motor function. A speech therapist can advise patients with swallowing problems. Iron supplementation is used to treat iron deficiency. Cataract or strabismus surgery is often necessary.

Compared to other mucolipidoses (I and II), MLIV patients have a prolonged survival.