Mucolipidosis type IV: An update

Abstract

Mucolipidosis type IV (MLIV) is a neurodevelopmental as well as neurodegenerative disorder with severe psychomotor developmental delay, progressive visual impairment, and achlorydria. It is characterized by the presence of lysosomal inclusions in many cell types in patients. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1, a member of the transient receptor potential (TRP) cation channel family. Although approximately 70-80% of patients identified are Ashkenazi Jewish, MLIV is a pan-ethnic disorder. Importantly, while MLIV is thought to be a rare disease, its frequency may be greater than currently appreciated, for its common presentation as a cerebral palsy-like encephalopathy can lead to misdiagnosis. Moreover, patients with milder variants are often not recognized as having MLIV. This review provides an update on the ethnic distribution, clinical manifestations, laboratory findings, methods of diagnosis, molecular genetics, differential diagnosis, and treatment of patients with MLIV. An enhanced awareness of the manifestations of this disorder may help to elucidate the true frequency and range of symptoms associated with MLIV, providing insight into the pathogenesis of this multi-system disease.

A novel homozygous MCOLN1 double mutant allele leading to TRP channel domain ablation underlies Mucolipidosis IV in an Italian Child

“…The non-specific, static neurological course initially led to a misdiagnosis of cerebral palsy, similar to other reported patients [Wakabayashi et al 2011]. However, the association of neurological impairment, characteristic ocular abnormalities, neuroradiological findings, and hypergastrinemia prompted us to consider MLIV.…”

“…The majority of patients presents with psychomotor delay, hypotonia gradually progressing to spasticity, bilateral pyramidal tract signs, corneal clouding, strabismus and retinal dystrophy. Achlorhydria and hypergastrinemia are hallmark findings [Schiffmann et al 2010;Wakabayashi et al 2011], while dysmorphic features, hepatosplenomegaly, and skeletal deformities are absent. Typical MRI findings include white matter dysmyelination with small corpus callosum and cerebellar atrophy.…”

“…Although MLIV is a pan-ethnic disorder, about 70-80 % of patients have Ashkenazi Jewish (AJ) ancestry [Bach et al 2005;Wakabayashi et al 2011]. Two founder mutations, a splice mutation (c.416-2A>G) and a partial gene deletion (c.1_788del), comprise 95 % of the MLIV alleles in this ethnic group [Bargal et al 2000;Bach et al 2005].…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Over 21, mostly loss-offunction, mutations in the Trpml1 gene have been identified in patients with ML-IV. Channel defects result in impairment of organelle Ca 2+ release, which is required for the correct fusion/fission events and causes malfunctions in late endosome-lysosome formation (Lloyd-Evans and Platt, 2011; for a recent review, see Wakabayashi et al, 2011).…”

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

“…Danon disease (D'Souza R et al, 2014)) or ion channels (e.g. Mucolipidosis type IV (Wakabayashi et al, 2011)) of the lysosome, causing impairments of CMA, reduced vesicle maturation, and impaired acidification, which collectively may contribute to secondary failure of lysosomal hydrolysis. In less common cases, lysosomal dysfunction arises through mutations in genes encoding proteins that reside in another organelle but impact the function of a lysosomal constituent as their primary disease effect.…”