Abstract
Mucolipidosis type IV (MLIV) is an ultra-rare lysosomal storage disorder caused by biallelic mutations in MCOLN1 gene encoding the transient receptor potential channel mucolipin-1. So far, 35 pathogenic or likely pathogenic MLIV-related variants have been described. Clinical manifestations include severe intellectual disability, speech deficit, progressive visual impairment leading to blindness, and myopathy. The severity of the condition may vary, including less severe psychomotor delay and/or ocular findings. As no striking recognizable facial dysmorphism, skeletal anomalies, organomegaly, or lysosomal enzyme abnormalities in serum are common features of MLIV, the clinical diagnosis may be significantly improved because of characteristic ophthalmological anomalies. This review aims to outline the pathophysiology and genetic defects of this condition with a focus on the genotype–phenotype correlation amongst cases published in the literature. The authors will present their own clinical observations and long-term outcomes in adult MLIV cases.
Highlights
Mucolipidosis type IV (MLIV; #252650), is a rare autosomal recessive lysosomal storage disease (LSD) resulting from loss-of function mutations in the MCOLN1 gene (*605248), which encodes for mucolipin-1 (ML1). This transient receptor, known as potential channel protein mucolipin-1 (TRPML1), a vesicular Ca2+ release channel belonging to the transient receptor potential (TRP) superfamily [1,2,3], plays a role in endocytosis, and its dysfunction results in a build-up of lysosome substrates in the cytoplasm [4], aberrations in endosomal and autophagosomal trafficking, modifications to autophagy, abnormal regulation of lysosomal exocytosis, changes in the mammalian target of rapamycin complex 1/Transcription factor EB (TFEB) signaling axis, and dysregulation of heavy metal homeostasis [5]
Apart from TRPML1, the TRPML subfamily consists of two other members, TRPML2 and -3, which are encoded by MCOLN2 and -3 genes, respectively
The clinical and neuroimaging findings suggest that the MCOLN1 gene has a critical role in central nervous system development and in preserving neuronal integrity in the retina and cerebellum
Summary
Mucolipidosis type IV (MLIV; #252650), is a rare autosomal recessive lysosomal storage disease (LSD) resulting from loss-of function mutations in the MCOLN1 gene (*605248), which encodes for mucolipin-1 (ML1) This transient receptor, known as potential channel protein mucolipin-1 (TRPML1), a vesicular Ca2+ release channel belonging to the transient receptor potential (TRP) superfamily [1,2,3], plays a role in endocytosis, and its dysfunction results in a build-up of lysosome substrates in the cytoplasm [4], aberrations in endosomal and autophagosomal trafficking, modifications to autophagy, abnormal regulation of lysosomal exocytosis, changes in the mammalian target of rapamycin complex 1 (mTORC1)/Transcription factor EB (TFEB) signaling axis, and dysregulation of heavy metal homeostasis [5]. Apart from TRPML1, the TRPML subfamily consists of two other members, TRPML2 and -3, which are encoded by MCOLN2 and -3 genes, respectively In humans, these proteins exhibit a common six-membrane-spanning topology. TRPML2 and TRPML3 have not been linked with any human disease [6]
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