Several genes were linked to myelin malformation, namely PLP1, GFC2 and FA2H. The mutations alter myelin composition, thickness and integrity.Endoplasmic reticulum (ER) is the main organelle for lipid synthesis. Mutations in genes encoding proteins that have a role in shaping ER morphology and lipid metabolism were linked to HSP. Mutations in ATL1, BSCL2 and ERLIN2 alter ER structure, specifically the tubular network and the formation of three-way junctions in ER tubules. Many mutated genes are linked to abnormal lipid metabolism. The most prevalent effect is on arachidonic acid (CYP2U1) and cholesterol (CYP7B1) metabolism, phospholipase activity (DDHD1 and DDHD2), ganglioside formation (B4GALNT-1) and the balance between carbohydrate and fat metabolism (SLV33A1). Endosomal trafficking
Neurons take in substances from their surrounding by endocytosis. Endocytic vesicles fuse to endosomes in order to release their content. There are three main compartments that have endosome trafficking: Golgi to/from endosomes; plasma membrane to/from early endosomes (via recycling endosomes) and late endosomes to lysosomes. Dysfunction of endosomal trafficking can have severe consequences in motor neurons with long axons, as reported in HSP. Mutations in AP4B1 and KIAA0415 are linked to disturbance in vesicle formation and membrane trafficking including selective uptake of proteins into vesicles. Both genes encode proteins that interact with several other proteins and disrupt the secretory and endocytic pathways. Mitochondrial function
Mitochondrial dysfunctions have been connected with developmental and degenerative neurological disorders. Only a few HSP genes encode mitochondrial proteins. Two mitochondrial resident proteins are mutated in HSP: paraplegin and chaperonin 60. Paraplegin is a m-AAA metalloprotease of the inner mitochondrial membrane.
Mutations that alter only the C-terminal of the protein also result in a mild phenotype of the disorder, usually sparing the brain. ML IV causes affected cells to accumulate auto-fluorescent vacuoles considered to be aberrant lysosomes. Several evidences exist for a defect in both exocytosis and endocytosis. There are conflicting indications of abnormal lysosomal pH in MLIV. It is not yet clear why these abnormalities will cause incomplete development of the brain, achlorhydria, and failure in the maintenance of retinal tissue. Diagnosis
Diagnosis includes genetic testing and Gastrin blood test to check for low iron in the blood. Treatment
There is no specific treatment to this disorder. However, several symptoms may be alleviated. For instance, anemia is treated by iron supplements. Some of the movement deficiencies may be corrected with orthopedic intervention. The corneal clouding can be, at least, temporarily corrected by corneal transplantation. See the equivalent section in the main mucolipidosis article. Epidemiology
Mucolipidosis type IV is severely under-diagnosed. It is often misdiagnosed as cerebral palsy. In the  Ashkenazi Jewish population there are two severe mutations with a higher carrier frequency of 1:90 to 1:100. References
External links

Mucolipidosis type 4 at NIHs Office of Rare Diseases