Mucolipidosis (ML) is a general term referring to a group of hereditary lysosomal storage diseases. There are four types of ML, namely ML type 1 or sialidosis, ML type 2 or I cell disease, ML type 3 or pseudo-Hurler polydystrophy, and ML type 4. Their clinical presentation varies largely. In sum, the mutation of distinct genes results in an extensive deficiency of lysosomal enzymes and the progressive accumulation of glycosaminoglycans and lipids in virtually all types of cells. This condition interferes with mental and physical development and predisposes to developmental delays, skeletal dysplasia and dysmorphic features, heart disease, and visual impairment. While ML may be fatal in the neonatal period, mild forms of the disease have been described and are associated with a near-to-normal life expectancy.
The clinical presentation of ML is heterogeneous and ranges from hydrops fetalis to severe cardiac or respiratory disease, often fatal in the neonatal period, to mild cognitive impairment and near-to-normal life expectancy. Even within determined types of ML, the phenotypic spectrum is broad :
The diagnosis of ML is based on clinical suspicion and confirmative studies:
To date, all types of ML remain incurable. A multidisciplinary approach is required to maintain the patients' quality of life. In this context, symptomatic treatment and supportive care should be provided, and they may comprise physical and occupational therapy, surgery, visual aids, dietary supplementation, and psychological support  .
Hematopoietic stem cell transplantation has been realized in few individuals diagnosed with ML type 2, but the neurological outcome was poor, with few patients ever achieving maturity for education. Most of them also required tracheostomy for mechanical ventilation and gastrostomy tubes for nutrition. Disease progression couldn't be halted and eventually lead to death in the majority of cases  . Beyond that, enzyme replacement therapy has been considered in patients diagnosed with ML types 1, 2, or 3. Although no such therapy has yet been approved, research is conducted to this end  .
ML are progressive disorders, but there are slowly progressive forms of the disease and those leading to death in the neonatal period or infancy. The entire spectrum of disease severity may be observed in those suffering from ML type 1. In case of ML types 2 and 3, residual enzyme activity is a favorable prognostic marker. Older age at symptom onset, a lower degree of severity, a more slowly progressive course, and higher life expectancy are to be expected in those with partial deficiencies of GlcNAc-PT. ML type 4 is one of the slowly progressive forms of ML. After symptom onset in early childhood, there is little to no deterioration in the clinical picture for several decades . Data regarding the long-term outcome have yet to be provided.
ML are genetic disorders. They are all inherited in an autosomal recessive manner. Both homozygosity and compound heterozygosity may trigger the disease. The underlying mutations differ between distinct types of ML:
In general, ML are rare disorders. The overall incidence of ML is <1 per 100,000 life births. The incidence of distinct types of ML has been estimated as follows: 0.05, 0.016, and 0.08 for ML types 1, 2, and 3, respectively, per 100,000 life births . Similar to the aforementioned types of ML, ML type 4 is a panethnic disease. However, >80% of affected individuals are of Ashkenazi Jewish descent. In this population, the incidence of the disease is 1 per 40,000 life births. About 1% of Ashkenazi Jews are carriers of pathogenic mutations of the MCOLN1 gene .
The pathogenesis of ML type 1 is incompletely understood. The accumulation of oversialylated LAMP1 is assumed to be the cause of excessive lysosomal exocytosis, which, in turn, induces alterations of the characteristics and composition of the plasma membrane and extracellular matrix. This results in an overall loss of tissue homeostasis, but further research is required to shed more light on the pathophysiological events leading to developmental delays, skeletal dysplasia, and ophthalmological complications  .
In ML types 2 and 3, the insufficient synthesis of mannose 6-phosphate recognition markers hinders the transport of distinct enzymes to the lysosomal compartment. Thus, enzymes required for lysosomal functions are released to the extracellular space and may be detected in body fluids. Here they are, however, unable to fulfill their metabolic functions . What's more, they may mediate pathological processes such as the loss of retention of hematopoietic progenitor cells .
The role of mucolipin 1 for lysosomal function is less clear. It has been implicated in chaperone-mediated autophagy . A broad spectrum of acid glycosaminoglycans, gangliosides, phospholipids, and neutral lipids has been identified as the storage substances, suggesting the deficiency of diverse lysosomal enzymes, similar to what is known for the other types of ML . However, concentrations of the aforementioned carbohydrates and lipids as well as levels of lysosomal hydrolases in blood samples are normal .
Affected families may benefit from genetic counseling and targeted prenatal diagnosis. Precise knowledge regarding the disease' molecular background and metabolic consequences largely facilitates the identification of affected fetuses . Beyond that, newborn screening programs for lysosomal storage diseases have been implemented in some countries. Depending on the method of testing, these screening programs may or may not cover all types of ML: The assessment of concentrations of lysosomal hydrolases, for instance, will identify only those suffering from ML types 2 and 3 . For the Ashkenazi Jewish population, screenings for common mutations of the MCOLN1 gene have been proposed .
ML refers to the progressive accumulation of carbohydrates and lipids within the lysosomes of cells and is the result of enzyme deficiencies. There are four types of ML:
These types of ML differ largely with regards to their clinical presentation, to hematological and biochemical parameters. Accordingly, distinct studies are required to confirm a tentative diagnosis of either type of ML. Curative treatment is available for neither of them.
Mucolipidosis (ML) is a general term referring to a heterogeneous group of hereditary metabolic disorders. There are four types of ML, namely ML type 1 or sialidosis, ML type 2 or I cell disease, ML type 3 or pseudo-Hurler polydystrophy, and ML type 4. They are all caused by rare mutations of genes that interfere with the function of lysosomes. Lysosomes are cell organelles whose task is to break down and recycle a myriad of substances produced by cells of all tissues. In those affected by ML, these substances are inadequately digested and accumulate within the lysosomes. This may lead to severe delays in physical and mental development, dysmorphic features, skeletal dysplasia, visual impairment, heart disease, and recurrent respiratory infections. The severity of ML varies largely. While the more severe forms of the disease may be fatal in the neonatal period or infancy, mild ML may be associated with mild learning difficulties and a near-to-normal life expectancy. Unfortunately, there is no curative treatment. Patients are provided symptomatic therapy and supportive care, but, according to current knowledge, disease progression can hardly be halted.