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Mucolipidosis

ML

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.


Presentation

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]:

Splenomegaly
  • In most ML II patients, the clinical conditions 'stand alone', 'walk without support' and 'speak single words' were impaired; however, the frequency of 'heart murmur', 'inguinal hernia' and 'hepatomegaly and/or splenomegaly' did not differ between ML[ncbi.nlm.nih.gov]
  • […] cholesterol 272.7 dystopic (hereditary) 272.7 glycolipid 272.7 hereditary, dystopic 272.7 Lipoid - see also condition histiocytosis 272.7 Lipoidosis (see also Lipidosis) 272.7 Mucolipidosis I, II, III 272.7 Niemann-Pick disease (lipid histiocytosis) (splenomegaly[icd9data.com]
  • Clinical manifestations, such as ‘heart murmur’, ‘inguinal hernia’ and ‘hepatomegaly and/or splenomegaly’, were found in both ML II and III.[nature.com]
Developmental Delay
  • Mucolipidosis II (MLII) is characterized by severe global developmental delay, coarse facial features, skeletal deformities, and other systemic involvement. It is caused by a deficiency in N-acetylglucosamine-1 phosphotransferase.[ncbi.nlm.nih.gov]
  • BACKGROUND: Mucolipidosis type IV (ML-IV) is a rare autosomal recessive lysosomal storage disorder which presents with nonspecific developmental delay.[ncbi.nlm.nih.gov]
  • delay and other structural abnormalities.[ncbi.nlm.nih.gov]
  • Mucolipidosis type IV (MLIV) is a neurodevelopmental as well as neurodegenerative disorder with severe psychomotor developmental delay, progressive visual impairment, and achlorydria.[ncbi.nlm.nih.gov]
  • Early symptoms can include skeletal abnormalities, vision problems, and developmental delays. Poor mental capacities, and difficulty reaching physical developmental milestones may also be result of mucolipidosis.[en.wikipedia.org]
Short Stature
  • Abstract The musculoskeletal manifestations of mucolipidosis III include short stature, claw hands, carpal tunnel syndrome, and limited joint mobility.[ncbi.nlm.nih.gov]
  • The enzymatic defect results in deficiencies of lysosomal degradative enzymes with concomitant intracellular accumulation of both partly degraded glycosaminoglycans and sphingolipids leading to clinical manifestations such as short stature, developmental[ncbi.nlm.nih.gov]
  • Abstract Mucolipidosis IIIalpha/beta (MLIIIalpha/beta) is a rare lysosomal storage disorder characterized by childhood onset of flexion contractures of fingers, joint stiffness in the shoulders, hips, and knees, and mild short stature.[ncbi.nlm.nih.gov]
  • Individuals with mucolipidosis III gamma grow slowly and have short stature. They also have stiff joints and dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray.[snpedia.com]
  • Coarse facies, a barrel chest, and short stature are characteristic. Hepatic cells contain numerous vacuoles and numerous inclusions. Sialidosis types I and II are both caused by mutations in the neuroaminidase gene.[disorders.eyes.arizona.edu]
Pediatric Disorder
  • Abstract Mucolipidosis II (ML-II) is a pediatric disorder caused by defects in the biosynthesis of mannose 6-phosphate, the carbohydrate recognition signal responsible for targeting certain acid hydrolases to lysosomes.[ncbi.nlm.nih.gov]
  • Abstract The severe pediatric disorder mucolipidosis II (ML-II; also known as I-cell disease) is caused by defects in mannose 6-phosphate (Man-6-P) biosynthesis.[ncbi.nlm.nih.gov]
Episodic Pain
  • Episodic pain in patients with mucolipidosis IV is an important symptom, presumably reflecting the distinctive corneal ultrastructural abnormality in this disease.[ncbi.nlm.nih.gov]
Hypoventilation
  • We report the progression of polysomnographic abnormalities in a child with mucolipidosis II, demonstrated by worsening sleep-related hypoventilation, OSA, and sleep state fragmentation despite advancing PAP therapy.[ncbi.nlm.nih.gov]
Hepatosplenomegaly
  • • The clinical characteristics of a 16-year-old white girl with mucolipidosis type III included early growth retardation, severe dysostosis multiplex, restricted joint motion, tight indurated skin, swollen eyelids, late-onset hepatosplenomegaly, umbilical[jamanetwork.com]
  • Myoclonus, mental deterioration, hepatosplenomegaly, muscle weakness and atrophy are common. The defect in neuraminidase activity leads to abnormal amounts of sialyl-oligosaccharides in the urine. Spinal deformities such as kyphosis are common.[disorders.eyes.arizona.edu]
  • Type II has an earlier onset with coarse facial features, dysostosis multiplex, short stature, developmental delay, mental retardation and hepatosplenomegaly.[genedx.com]
  • […] features a slowly progressive loss of intellect, hepatosplenomegaly, ataxia, myoclonic seizures, and spasticity; the neuronopathic forms are characterized by neuronal loss with neuronophagia, and accumulation of glucocerebroside in neurons Caused by[icd9data.com]
Hepatomegaly
  • Abstract We describe a patient with failure to thrive, hepatomegaly, liver dysfunction, and elevation of multiple plasma lysosomal enzyme activities mimicking mucolipidosis II or III, in whom a diagnosis of hereditary fructose intolerance (HFI) was ultimately[ncbi.nlm.nih.gov]
  • In most ML II patients, the clinical conditions 'stand alone', 'walk without support' and 'speak single words' were impaired; however, the frequency of 'heart murmur', 'inguinal hernia' and 'hepatomegaly and/or splenomegaly' did not differ between ML[ncbi.nlm.nih.gov]
  • Additional clinical symptoms of I-cell disease include hepatomegaly, cardiomegaly, umbilical hernias, and recurrent upper respiratory infections. The disease progresses rapidly with developmental delay and failure to thrive.[themedicalbiochemistrypage.org]
  • 272.7 splenomegaly (cerebroside lipidosis) 272.7 Hepatomegaly (see also Hypertrophy, liver) 789.1 Gaucher's 272.7 Histiocytosis (acute) (chronic) (subacute) 277.89 lipid, lipoid (essential) 272.7 Hyperlipidosis 272.7 hereditary 272.7 Lipidosis 272.7[icd9data.com]
  • […] very rare, like Hurler, but spectrum from hydrops fetalis to almost unaffected Oligosaccharidoses Mannosidosis features similar to Hurler, but variable severity hearing loss Fucosidosis wide picture severe neurological picture, mild skeletal changes, hepatomegaly[emilytam.com]
Flushing
  • A 5-year-old boy with mucolipidosis IV experienced recurrent episodes of severe ocular pain, tearing, and ipsilateral facial flushing. This was suggestive of reflex sympathetic dystrophy, a syndrome of pain and sympathetic hyperactivity.[ncbi.nlm.nih.gov]
  • Episodes of ocular pain, with ipsilateral flushing of the face and tearing were frequently reported, as was shortening of the Achilles tendon. Since the identification of the ML-IV gene, diagnosis is made earlier in life.[ncbi.nlm.nih.gov]
Visual Impairment
  • Mucolipidosis type IV (MLIV) is a neurodevelopmental as well as neurodegenerative disorder with severe psychomotor developmental delay, progressive visual impairment, and achlorydria.[ncbi.nlm.nih.gov]
  • Abstract Mucolipidosis type IV (MLIV) is a very rare disorder of late endosome/lysosome transport, characterized by neurodevelopmental abnormalities and progressive visual impairment owing to corneal clouding and retinal dystrophy.[ncbi.nlm.nih.gov]
  • This condition interferes with mental and physical development and predisposes to developmental delays, skeletal dysplasia and dysmorphic features, heart disease, and visual impairment.[symptoma.com]
  • Mucolipidosis IV (ML4) is a neurodegenerative condition that is characterised by significant psychomotor and cognitive development delay, visual impairment, and poor muscle tone.[jnetics.org]
  • Background information for Mucolipidosis, Type IV ( MCOLN1), 2 Variants: Characteristics: Mucolipidosis type IV is characterized by early onset of severe psychomotor delay and progressive visual impairment due to corneal clouding and retinal degeneration[ltd.aruplab.com]
Corneal Opacity
  • Her vision began deteriorating at 12 years of age, due to bilateral corneal opacities and retinal degeneration. At present she attends a regular high school, although she is slow and scholastic achievements are lower than average.[ncbi.nlm.nih.gov]
  • Abstract Mucolipidosis type IV is a rare neurodegenerative lysosomal storage disorder that usually presents during the first year of life with severe mental retardation, delayed motor milestones and corneal opacities.[ncbi.nlm.nih.gov]
  • MLIV typically results in intellectual disability, corneal opacities, and delayed motor milestones during infancy, with a relatively static course. To date, reports of MLIV in other ethnic groups have been sparse.[ncbi.nlm.nih.gov]
  • This presentation provides guidelines for the clinical diagnosis of mucolipidosis type IV. lysosomal storage disorder mucolipidosis IV corneal opacity Received June 30, 1986.[pediatrics.aappublications.org]
  • ., delayed development of movement and coordination), corneal opacity, retinal degeneration and other ophthalmological abnormalities.[en.wikipedia.org]
Strabismus
  • These included strabismus, white matter signal abnormalities, and a hypoplastic corpus callosum at 2years of age. After a molecular diagnosis, a markedly elevated serum gastrin level (which is also common in MLIV) was confirmed.[ncbi.nlm.nih.gov]
  • Definition An autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmologic abnormalities, including corneal opacity, retinal degeneration and strabismus.[uniprot.org]
  • Ocular findings also include retinal degeneration, myopia, strabismus, and photophobia. Neurological symptoms include hypotonia and pyramidal tract signs. There are cytoplasmic inclusions (“storage bodies”) in almost every cell type of the patients.[genedx.com]
  • Related Pages Requisition Clinical Significance Mucolipidosis IV (MLP4) is a neurodegenerative lysosomal storage disorder characterized by severe psychomotor delay, ophthalmological abnormalities including corneal clouding, retinal degeneration and strabismus[sickkids.ca]
  • […] development delay (e.g. speech) Visual problems including: Corneal clouding (onset varies from infancy to 5 years old) Retinal degeneration, leading to severe visual impairment and possible blindness later in life False appearance of crossed eyes (pseudo-strabismus[jnetics.org]
Retinal Pigmentation
  • Our data show that RPE1 (retinal pigmented epithelial 1) cells develop a punctate mitochondrial phenotype within 48 h of siRNA-induced TRPML1-KD (knockdown).[ncbi.nlm.nih.gov]
Joint Stiffness
  • Mucolipidosis type III gamma (MLIII gamma) is a lysosomal storage disease characterized by joint stiffness, mild coarse face and corneal clouding, which becomes recognizable usually in childhood.[ncbi.nlm.nih.gov]
  • Carpal tunnel syndrome was treated surgically but joint stiffness and hip and knee contractures were managed by physiotherapy.[ncbi.nlm.nih.gov]
  • We herein report on a 13-year-old adolescent who was admitted to our rheumatology clinic because of progressive joint stiffness and deformities of her hands.[ncbi.nlm.nih.gov]
  • Abstract Mucolipidosis IIIalpha/beta (MLIIIalpha/beta) is a rare lysosomal storage disorder characterized by childhood onset of flexion contractures of fingers, joint stiffness in the shoulders, hips, and knees, and mild short stature.[ncbi.nlm.nih.gov]
  • These may include joint stiffness, heart problems, corneal clouding and hearing loss. Individuals with Hurler/Scheie syndrome usually have variable clinical symptoms of intermediate severity between the mildest and most severe forms of MPS I.[luriechildrens.org]
Skeletal Dysplasia
  • A radiologist with special expertise in skeletal dysplasias evaluated the radiographs.[ncbi.nlm.nih.gov]
  • They also suffer from severe skeletal dysplasia and learning impairment. Hepatosplenomegaly is frequently diagnosed. Death in the neonatal period or infancy is common.[symptoma.com]
  • Abstract Pacman dysplasia has been previously reported to be a lethal skeletal dysplasia with epiphyseal stippling and osteoclastic overactivity. We report on a sibling of a fetus previously reported as Pacman dysplasia.[ncbi.nlm.nih.gov]
  • Skeletal Dysplasia Program Our skeletal dysplasia program is a multidisciplinary service that provides care to patients with disorders that primarily involve the skeletal system, including patients with MPS IV.[luriechildrens.org]
  • In the late 1960s, a small number of patients with mild Hurlerlike facies, skeletal dysplasia , psychomotor retardation, and normal excretion of urinary mucopolysaccharides were reported.[emedicine.medscape.com]
Back Pain
  • pain 3 months Chronic back pain greater than 3 months duration Chronic coccyx pain 3 months Chronic pain in coccyx for more than 3 months (finding) Fabry disease Fabrys disease Fabry's disease Ganglioside sialidase deficiency Gaucher disease Gauchers[icd9data.com]
Hydrops Fetalis
  • 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.[symptoma.com]
  • Type II patients may also present with a congenital-onset form associated with ascites and hydrops fetalis prenatally, an infantile-onset form with the absence of symptoms at birth or a juvenile form that has onset in late childhood and a relatively milder[genedx.com]
  • fetalis to almost unaffected Oligosaccharidoses Mannosidosis features similar to Hurler, but variable severity hearing loss Fucosidosis wide picture severe neurological picture, mild skeletal changes, hepatomegaly angiokeratoma of the skin is suggestive[emilytam.com]
  • The more severe congenital form of type II sialidosis has onset in utero and results in hydrops fetalis , hepatomegaly, and either still birth or death within a period of months.[emedicine.medscape.com]
  • The more severe congenital form of type II sialidosis has onset in utero and results in hydrops fetalis, hepatomegaly, and either still birth or death within a period of months.[emedicine.medscape.com]
Severe Mental Retardation
  • Abstract Mucolipidosis type IV is a rare neurodegenerative lysosomal storage disorder that usually presents during the first year of life with severe mental retardation, delayed motor milestones and corneal opacities.[ncbi.nlm.nih.gov]
Ataxia
  • , followed by myoclonus, mental decline mild skeletal features Salla disease mental retardation, ataxia, progressive psychomotor decline ISSD (infantile sialic storage disease) more severe than Salla disease, although same mutation Mucolipidoses Sialidosis[emilytam.com]
  • About 5% of patients have a milder, atypical form characterized by progressive ataxia and eye abnormalities, and they may learn to walk. Most patients live into adulthood, although life expectancy is shorter than normal.[sema4.com]
  • Ataxia and hearing loss may be present. Coarse facies, a barrel chest, and short stature are characteristic. Hepatic cells contain numerous vacuoles and numerous inclusions.[disorders.eyes.arizona.edu]
  • 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.[symptoma.com]
  • Ataxia and seizures have also been reported in type I patients. Type II has an earlier onset with coarse facial features, dysostosis multiplex, short stature, developmental delay, mental retardation and hepatosplenomegaly.[genedx.com]
Spastic Paraplegia
  • The presenting symptoms were psychomotor delay, spastic paraplegia, and mild mental retardation. One patient also had visual deterioration due to optic atrophy. None had corneal or retinal abnormalities.[ncbi.nlm.nih.gov]
  • Six new chapters cover congenital myasthenic syndromes, hereditary spastic paraplegia, ion channel disorders, the phakomatoses, beta-galactosidase deficiency, and prion diseases.[books.google.com]
Myoclonic Jerking
  • Random multifocal myoclonic jerks had diffuse EEG correlates [Figure 1]. Attenuation of visual evoked potentials was noted. Brain magnetic resonance imaging revealed mild diffuse atrophy with a thin corpus callosum [Figure 2].[neurologyindia.com]
Learning Difficulties
  • They are predisposed to mild learning difficulties and valvular heart disease, but death from heart disease is rare.[symptoma.com]
Involuntary Movements
  • Abstract A 36-year-old man with mucolipidosis type III alpha/beta presented with hypoactivity, mutism, muscle rigidity, and involuntary movement.[ncbi.nlm.nih.gov]

Workup

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.

Treatment

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].

Prognosis

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.

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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].

Summary

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.

Patient Information

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.

References

Article

  1. Wraith JE. Mucopolysaccharidoses and mucolipidoses. Handb Clin Neurol. 2013; 113:1723-1729.
  2. d'Azzo A, Machado E, Annunziata I. Pathogenesis, Emerging therapeutic targets and Treatment in Sialidosis. Expert Opin Orphan Drugs. 2015; 3(5):491-504.
  3. Cathey SS, Kudo M, Tiede S, et al. Molecular order in mucolipidosis II and III nomenclature. Am J Med Genet A. 2008; 146a(4):512-513.
  4. Bach G. Mucolipidosis type IV. Mol Genet Metab. 2001; 73(3):197-203.
  5. Wakabayashi K, Gustafson AM, Sidransky E, Goldin E. Mucolipidosis type IV: an update. Mol Genet Metab. 2011; 104(3):206-213.
  6. Langereis EJ, Wagemans T, Kulik W, et al. A Multiplex Assay for the Diagnosis of Mucopolysaccharidoses and Mucolipidoses. PLoS One. 2015; 10(9):e0138622.
  7. Xia B, Asif G, Arthur L, et al. Oligosaccharide analysis in urine by maldi-tof mass spectrometry for the diagnosis of lysosomal storage diseases. Clin Chem. 2013; 59(9):1357-1368.
  8. Fuller M, Tucker JN, Lang DL, et al. Screening patients referred to a metabolic clinic for lysosomal storage disorders. J Med Genet. 2011; 48(6):422-425.
  9. Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, von Figura K, Schmidt B. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim Biophys Acta. 2009; 1793(4):710-725.
  10. Hetherington C, Harris NJ, Smith TW. Orthopaedic management in four cases of mucolipidosis type III. J R Soc Med. 1999; 92(5):244-246.
  11. Grewal S, Shapiro E, Braunlin E, et al. Continued neurocognitive development and prevention of cardiopulmonary complications after successful BMT for I-cell disease: a long-term follow-up report. Bone Marrow Transplant. 2003; 32(9):957-960.
  12. Lund TC, Cathey SS, Miller WP, et al. Outcomes after hematopoietic stem cell transplantation for children with I-cell disease. Biol Blood Marrow Transplant. 2014; 20(11):1847-1851.
  13. Liu L, Lee WS, Doray B, Kornfeld S. Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy. Mol Ther Methods Clin Dev. 2017; 5:59-65.
  14. Yogalingam G, Bonten EJ, van de Vlekkert D, et al. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Dev Cell. 2008; 15(1):74-86.
  15. Venugopal B, Mesires NT, Kennedy JC, et al. Chaperone-mediated autophagy is defective in mucolipidosis type IV. J Cell Physiol. 2009; 219(2):344-353.
  16. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999; 105(1-2):151-156.
  17. Meikle PJ, Grasby DJ, Dean CJ, et al. Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006; 88(4):307-314.
  18. Edelmann L, Dong J, Desnick RJ, Kornreich R. Carrier screening for mucolipidosis type IV in the American Ashkenazi Jewish population. Am J Hum Genet. 2002; 70(4):1023-1027.

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Last updated: 2019-07-11 22:11