Mucolipidosis

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 [1]:

• There are two subtypes of ML type 1. The more severe subtype may induce hydrops fetalis or manifest soon after birth. Affected individuals present dysmorphic facial features reminiscent of Hurler syndrome. They also suffer from severe skeletal dysplasia and learning impairment. Hepatosplenomegaly is frequently diagnosed. Death in the neonatal period or infancy is common. By contrast, prolonged survival is to be expected in those affected by cherry-red spot-myoclonus syndrome or normomorphic sialidosis. These patients present with myoclonus, ataxia, and cherry-red spots of the macula. Cognitive impairment is less severe and may not manifest until advanced age [2].
• Hurler-like, coarse facial features and severe skeletal dysplasia may also be observed in ML type 2 patients. These individuals are generally microcephalic, and hepatomegaly may be noted. Cardiorespiratory failure is a frequent cause of death and often occurs in or before childhood. Patients who survive for several years usually present learning difficulties.
• ML type 3 is an attenuated form of ML type 2, with symptom onset usually being delayed until childhood [3]. Skeletal dysplasia may be limited to the joints of shoulders, hips, and spine, and most of these patients are of short stature. They are predisposed to mild learning difficulties and valvular heart disease, but death from heart disease is rare.
• Motor developmental delays, ataxia, strabismus, and severe visual impairment due to corneal clouding, retinal degeneration, and optic atrophy are the clinical hallmarks of ML type 4, which is usually diagnosed in children aged 2-3 years [4] [5]. More or less severe cognitive impairment is common. The disease interferes with the secretion of gastric acid, leading to the formation of lysosomal inclusions in parietal cells and constitutive achlorhydria [4]. While laboratory analyses of blood samples reveal increased levels of gastrin, iron deficiency anemia may also be diagnosed.

The diagnosis of ML is based on clinical suspicion and confirmative studies:

• First, analyses of blood and urine samples should be carried out to detect an increased excretion of sialic acid (ML type 1), high concentrations of urinary oligosaccharides with a terminal mannose, sialic acid, or galactose (ML types 2 and 3), or elevated serum levels of gastrin (ML type 4) [1] [6] [7].
• If results are obtained that support a tentative diagnosis of ML, enzyme activity measurements should be realized. Deficiency of neuraminidase or N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT), as observed in those affected by ML type 1, or ML types 2 or 3, respectively, may be determined in cultured fibroblasts [1]. Because the lack of GlcNAc-PT triggers the release of lysosomal enzymes to the extracellular space, analyses of plasma samples and other body fluids from these patients yield enhanced concentrations of most lysosomal hydrolases. Acid sphingomyelinase, arylsulfatase A, iduronate 2-sulfatase, and N-sulfamidase shall be mentioned as examples [8].
• Histological examinations have long since been an essential part of the diagnosis of ML type 4. Lysosomal inclusions are found in most tissues, with skin biopsy specimens being most frequently assessed [5]. Of note, enlarged lysosomes filled with undigested macromolecules may also be observed in tissue samples obtained from those suffering from other types of ML [9].
• Finally, molecular biological studies should be conducted to identify the underlying mutation in genes NEU1, GNPTAB, GNPTG, or MCOLN1. In patients of Ashkenazi Jewish decent, a straightforward approach may be chosen to determine the presence of MCOLN1 mutations.

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 [5] [10].

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 [11] [12]. 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 [2] [13].

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 [4]. 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:

• ML type 1 is caused by neuraminidase deficiency. Due to pathogenic mutations of the NEU1 gene, the activity of this enzyme is severely decreased. Neuraminidase catalyzes the removal of sialic acid residues from lysosomal-membrane associated protein 1 (LAMP1). In the absence of neuraminidase, oversialylated LAMP1 accumulates in the plasma membrane and mediates the exocytosis of lysosomal hydrolases [14].
• ML types 2 and 3 are generally triggered by mutations of the GNPTAB gene, which is located at 12q23.2 and encodes for the α and β subunits of the membrane-bound GlcNAc-PT. Thus, ML types 2 and 3 are allelic disorders. They are usually defined as two variants of a single disease rather than as distinct entities. For the sake of completeness, it shall be mentioned that N-GlcNAc-PT contains a third subunit, the so-called γ subunit, which is encoded by the GNPTG gene. Mutations of this gene have also been related to ML type 3 but have never been identified in ML type 2 patients [3]. Both GNPTAB and GNPTG mutations impede the formation of a functional heterohexameric enzyme complex, which is required for the synthesis of mannose 6-phosphate recognition markers, that, in turn, attach to acid hydrolases and target them for transport to the lysosomes. Disease severity depends on the degree of enzyme deficiency: Complete loss of GlcNAc-PT activity causes ML type 2, which is the most severe variant of the disease, while ML type 3 is associated with residual enzyme activity [3].
• ML type 4 results from mutations of the MCOLN1 gene. This gene, to be found at 19p13.2, encodes for mucolipin 1, a transient receptor potential locating to the lysosomal and late endosomal membrane [15].

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 [16]. 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 [5].

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 [2] [14].

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 [1]. What's more, they may mediate pathological processes such as the loss of retention of hematopoietic progenitor cells [14].

The role of mucolipin 1 for lysosomal function is less clear. It has been implicated in chaperone-mediated autophagy [15]. 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 [4]. However, concentrations of the aforementioned carbohydrates and lipids as well as levels of lysosomal hydrolases in blood samples are normal [5].

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 [1]. 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 [17]. For the Ashkenazi Jewish population, screenings for common mutations of the MCOLN1 gene have been proposed [18].

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:

• ML type 1, which is also referred to as sialidosis
• ML type 2, otherwise known as I cell disease
• ML type 3, or pseudo-Hurler polydystrophy, is allelic to ML type 2
• ML type 4

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.

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