Mucolipidosis IV Foundation

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Retinal degeneration severely limits their vision and blindness in the teen years is common. There is currently no treatment for this tragic disorder.

The earliest sign is corneal clouding; however, approximately 30% of patients develop clouding between three and five years of age.  Other eye findings may include pseudostrabismus (false appearance of crossed eyes) and/or retinal degeneration, which may lead to blindness in later years.  The is no gross involvement of the skeletal system nor urinary mucopolysaccharide excretion.  Patients currently range from one to 45 years of age.  Prognosis and life expectancy beyond the latter age is unknown.  Recently, a few very mildly affected children with ML4 have been diagnosed. This raises the possibility of other undiagnosed mildly involved patients.

The name, ML4, derives from the presence of diagnostic storage bodies (cytoplasmic inclusions seen under electron microscope) in almost every cell of these patients.  The storage bodies are similar to those observed in the mucopolysaccharide and lipid storage diseases; thus the designation mucolipidosis.  The diagnosis should be considered in retarded children who have corneal clouding.  The electron microscopic demostration of characteristic storage bodies in a conjunctival biopsy supports the clinical diagnosis.

The specific biochemical and genetic defects which cause ML4 are known to be associated with chromosome 19. This permits precise methods for diagnosis including identification of carriers of the gene which causes ML4 and prenatal diagnosis. Further research is required to isolate the disease gene.

The disease is inherited as an autosomal recessive trait.  Although both parents are normal, they carry the disease-causing gene.  Such carrier couples have a 25% risk for an affected fetus with each pregnancy.  The prenatal diagnosis of this disease has been successfully accomplished by electron microscopic demonstration of characterisic storage bodies in cultured amniotic cells obtained by amniocentesis.  The prenatal diagnosis is difficult and must be performed in centers with expertise in the specialized techniques required for this diagnosis. Carrier testing is available by blood test.

At present, no specific therapy is available.  Optimal supportive care, including physical, occupational and speech therapy, can significantly improve the function and quality of life of affected children.  Families with affected children should seek genetic counseling  and be offered the option of prenatal diagnosis for future pregnancies.

Electron micrograph of dermal fibroblast in patient with Mucolipidosis IV demonstrating cytoplasmic membranous inclusions some of which contain a granular core. Magnification x 32,640.

Mucolipidosis IV - Pathology

Ultrastructural examination reveals striking lysosomal storage inclusions in cells from almost every organ or tissue in the body. These inclusions resemble the membranous cytoplasmic bodies seen in the gangliosidoses, but differ in their localization. In the gangliosidoses, cytoplasmic membranous bodies are not found in liver, spleen, cultured fibroblasts, or dermal epithelial cells. They are prominent in these locations in Mucolipidosis IV. In addition to the cytoplasmic membranous bodies, granulofibrillar material also accumulates, often surrounded by cytoplasmic membranous lamellae with lamellar and granular components blending into one another.

Biochemical analysis of cultured fibroblasts in tissue obtained from brain biopsy reveals elevated ganglioside content. In febroblasts, accumulation especially involves the polysialylated species (gangliosides G_DIAand G_T). In addition, phospholipids and acidic mucopolysacchrides accumulate within cultured bibroblasts. The fundamental enzyme defect in this desease that leads to accumulation of this diverse group of storage compounds is unknown. It had been proposed that the fundamental defect was a deficiency of a ganglioside sialidase which is distinct from the sialidase which cleaves water-soluble oligosaccharides that is deficient in sialidosis. The ganglioside sialidase cleaves sialic acid from a variety of gangliosides, including the monosialoganglioside G_M3and the disialoganglioside G_DIA. However, growing evidence indicates that ganglioside sialidase deficiency is not the primary defect in ML IV. It has also been proposed that an appripriate term for Mucolipidosis type IV is sialolipidosis. This was meant to distinguish this disorder eponymically from sialidosis, which is due to a defect in the dialidase that hydrolyzes sialo-oligosaccharide. The disease is transmitted as an autosomal recessive trait. A higher frequency of patients of Ashkenazi Jewish origin has been noted, although several non-Jewish patients have also been described. ...The disease is characterized by severe visual impairment and psychomotor retardation. Corneal clouding is a characteristic clinical feature and is the initial diagnostic sign in most patients. The age of onset of corneal clouding varies from infancy to 5 years. However, retinal degeneration is also present and often produces visual impairment within the first year of life before corneal opacities are sufficient to impair vision. Psychomotor retardation is present in all patients, with psychomotor skills being retarded to approximately the 1-year level. After the initial retardation in motor and language function, little further psychomotor deterioration is apparent, even in patients with life spans beyond 10 years of age. In fact, some patients exhibit slow but continuous improvement in cognitive language and motor function with time. However, most patients remain severly retarded, exhibiting both mental and growth retardation. Source: The Metabolic Basis of Inherited Disease, 2nd edition.