Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Mucolipidosis II alpha/beta and mucolipidosis III alpha/beta/gamma
- Updated 05.09.2024
- Released 02.01.1994
- Expires For CME 05.09.2027
Mucolipidosis II alpha/beta and mucolipidosis III alpha/beta/gamma
Introduction
Overview
Mucolipidosis II alpha/beta (I-cell disease) and mucolipidosis III alpha/beta (pseudo-Hurler polydystrophy) are caused by abnormal cellular lysosomal enzyme transport resulting from mutations in the GNPTAB gene, which encodes the alpha and beta subunits of N-acetylglucosamine-1-phosphotransferase. Mucolipidosis III can also be caused by mutations affecting the GNPTG gene.
N-acetylglucosamine-1-phosphotransferase is necessary for the synthesis of mannose-6-phosphate, which is essential for proper targeting of lysosomal enzymes to lysosomes. Mucolipidosis II alpha/beta has many features of Hurler syndrome but presents earlier and does not show mucopolysacchariduria. There is severe progressive psychomotor retardation, and death usually occurs in the first decade. Craniosynostosis and moyamoya syndrome have been observed in mucolipidosis II patients. Pseudo-Hurler polydystrophy is milder with more prolonged survival.
Key points
• Mucolipidosis II and III can be mild with little or no dysmorphic features, or severe with prominent dysmorphic features. | |
• Mucolipidosis II and III are caused by a deficiency of multiple lysosomal enzymes and the accumulation of their respective substrates. | |
• Hematopoietic stem cell transplantation is not recommended for mucolipidosis II. |
Historical note and terminology
In the mid-1960s a group of patients with clinical features intermediate between those found in the mucopolysaccharidoses and those in the sphingolipidoses was described. Because of the overlapping phenotypes and evidence of visceral storage of mucopolysaccharides, sphingolipids, and glycolipids, these patients were grouped under the generic term "genetic mucolipidosis" (81).
Among the eight distinct diseases included in this group of disorders were mucolipidosis II alpha/beta and mucolipidosis III alpha/beta. The former is often referred to as I-cell disease, whereas the latter is also known as pseudo-Hurler polydystrophy. Because both disorders can result from abnormalities affecting the same gene and also have many clinical, cellular, and biochemical features in common, they are considered together in this review.
Mucolipidosis II alpha/beta (I-cell disease) was first identified as a separate and distinct disorder in patients who had many of the clinical features of the Hurler syndrome but lacked the excessive mucopolysacchariduria expected in that disorder (45). Because of the striking cytoplasmic inclusions in their cultured fibroblasts, the disorder was given the designation "inclusion cell disease" (45), subsequently abbreviated to "I-cell disease" (46). Peripheral blood lymphocytes also show abnormal vacuoles in patients with I-cell disease (38).
May-Giemsa staining; x40 magnification. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21(18):6812. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness an...
Spranger and Wiedemann included this disorder in the group of diseases they called the mucolipidoses and designated it mucolipidosis II (81). This has been renamed mucolipidosis II alpha/beta (09).
In 1966, Maroteaux and Lamy described four patients with mild Hurler-like features that they classified "la pseudo-polydystrophie de Hurler" (53). They considered these patients to have the same disorder previously described as "a mucopolysaccharidosis defying classification" (55). Subsequently, this disorder was also placed in the mucolipidosis group and was given the designation mucolipidosis III alpha/beta (09). Support for this classification was provided by the discovery that cultured fibroblasts from these patients were characterized by the same "I-cell phenomenon" previously seen in mucolipidosis II patients (83).
Clinical manifestations
Presentation and course
• Mucolipidosis II alpha/beta (I-cell disease) is characterized by many of the clinical and radiologic findings found in the Hurler syndrome. | |
• Although apparently having the same cellular and biochemical alterations found in mucolipidosis II alpha/beta, mucolipidosis III alpha/beta is a much milder disorder. |
Mucolipidosis II alpha/beta (I-cell disease). Mucolipidosis II alpha/beta (I-cell disease) is characterized by many of the clinical and radiologic findings found in the Hurler syndrome (25; 42; 11). However, these patients lack the excessive mucopolysacchariduria found in the latter disorder. Generally, the clinical features are present, or become obvious, shortly after birth.
Birth weight and length are usually below normal for gestational age. Thoracic deformities, umbilical or inguinal hernias, and dislocations of the hips are often present soon after birth. Defective proximal tubular dysfunction was identified in a patient with mucolipidosis II (05). Both interfamilial and intrafamilial clinical variability has been reported (03).
Neonates have coarse facial features with puffy eyelids, prominent epicanthal folds, a flat nasal bridge, marked gingival hyperplasia, and macroglossia (74; 84). Patients usually have prominent abdomens with hepatomegaly and umbilical hernias. Splenomegaly, if present, is minimal. Cardiac abnormalities are often present (77).
Orofacial abnormalities include thickened lips, a hypoplastic midface, a high-arched palate, hypoplastic condyles, coronoid hyperplasia, macroglossia, gingival hyperplasia, thick dental follicles, dentigerous cysts, misshaped teeth, enamel defects, and open bite (15).
Skeletal abnormalities are usually present at an early age, including marked shortness of stature, cervical spinal stenosis, lumbar kyphosis and gibbus deformities, and restricted joint mobility. Growth is below normal and joint immobility becomes more severe with age. Claw-hand deformities are common. Generalized dysostosis multiplex is present from an early age (43). The skeletal disease is progressive and has many features of chronic hyperparathyroidism but with normal parathormone (14). Cervical spinal stenosis may induce spinal cord compression as early as 1 year of age (59). Airway problems and sleep-disordered breathing are very common (21; 68; 59).
Progressive psychomotor retardation is a characteristic feature of this disorder. A clinical study of 21 patients with mucolipidosis II suggested that motor development is generally more severely delayed than mental development (62).
Mixed hearing loss with both conductive and sensory (cochlear) components has been reported (33).
Patients who present a less severe phenotype than expected in classical mucolipidosis II have been categorized as "mucolipidosis intermediate," but these patients still manifest severe multisystemic symptoms (10; 01).
Mucolipidosis III alpha/beta. Although apparently having the same cellular and biochemical alterations found in mucolipidosis II alpha/beta, mucolipidosis III alpha/beta is a much milder disorder. The clinical findings in mucolipidosis III alpha/beta are characterized by a later onset (ie, 2 to 4 years of age) and a much more slowly progressive course (42; 93). As with mucolipidosis II alpha/beta patients, these individuals have many of the clinical features usually associated with disorders of mucopolysaccharide metabolism. In this case, however, the findings are those of the type found in the mild mucopolysaccharidoses, not the severe mucopolysaccharidoses seen in mucolipidosis II alpha/beta. Again, as with mucolipidosis II alpha/beta, these patients do not excrete increased amounts of the mucopolysaccharides. Overall, the clinical course of the disease is slowly progressive, with progressive destruction of the joints a major clinical problem.
As originally defined, mucolipidosis III alpha/beta was considered to have the following major clinical features: mild Hurler-like phenotype, short stature, restricted joint mobility, skeletal changes, and mild mental retardation (93). A study of 12 patients with mucolipidosis III alpha/beta expanded the clinical spectrum to include progressive joint contractures, fine corneal opacities, valvular heart disease, a radiographic pattern of dysostosis multiplex, and unusual pelvic and vertebral changes (36; 94). Even patients with this milder form of the disease may present with complex orthopedic problems (26). Spinal cord compression may occur from cervical spinal canal stenosis (59).
Orofacial abnormalities include thickened lips, a hypoplastic midface, a high-arched palate, hypoplastic condyles, coronoid hyperplasia, macroglossia, gingival hyperplasia, thick dental follicles, dentigerous cysts, misshapen teeth, enamel defects, and open bite (15).
Most of the morbidity associated with mucolipidosis III alpha/beta is due to skeletal abnormalities. Growth failure and short stature are common. The initial complaint is often joint stiffness (90), which is followed by progressive restrictions of mobility of the hands, hips, elbows, and shoulders. Carpal tunnel syndrome is a common complication in these patients (96; 98; 35; 86), likely due to multifocal enlargement of peripheral nerves that is observed by ultrasound (58). One patient with carpal tunnel syndrome and insensitivity to pain had signs of self-mutilation of the distal phalanges of the digits of her hands (98).
In a series of 13 adult patients with mucolipidosis type III aged 18 to 68 years, only four patients had mild cognitive deficit whereas the others had normal cognitive function (64).
Mucolipidosis III gamma. Mucolipidosis III gamma is characterized by a progressive growth retardation in early childhood; joint stiffness and pain (shoulders, hips, and finger joints); gradual coarsening of facial features; and a slower progression, milder clinical course, and longer life expectancy than is seen with mucolipidosis type II and mucolipidosis type III alpha/beta. Cognitive function is normal or only slightly impaired. Retinitis pigmentosa has been reported (16).
-
Wide-angle fundus photography in man with mucolipidosis type III gamma
In this 47-year-old man with mucolipidosis type III gamma, there is blunting of the foveal contour and scattered pigmentary changes in the middle periphery in the form of discrete bone spicules and pigment clumping. (Source: de...
-
Wide-angel fundus autofluorescence in a man with mucolipidosis type III gamma (2)
In this 47-year-old man with mucolipidosis type III gamma, the center is well bounded. There is pathological patchy hypoautofluorescence in the middle periphery and more homogenous hyperautofluorescence peripherally. (Source: d...
-
Optical coherence tomography in man with mucolipidosis type III gamma
Extrafoveal scan of the right eye and foveal scan of the left eye in a 47-year-old man with mucolipidosis type III gamma show a mild epiretinal membrane with flattened foveal profile but without cystoid macular edema. (Source: ...
Prognosis and complications
Mucolipidosis II alpha/beta is associated with profound developmental impairment, but not with neurodegeneration and neurocognitive decline (01). The clinical course of mucolipidosis II alpha/beta patients is characterized by rapid clinical deterioration, with death usually occurring between the fifth and tenth year of life. The major causes of death are congestive heart failure and recurrent respiratory infections (97).
-
Motor function and verbal ability development in children with mucolipidosis II
Motor function and verbal abilities are presented based on the Bayley Scales of Infant and Toddler Development-III. The grey dashed line denotes the development of healthy children. Abbreviation: Aeqs, age-equivalent scores. (S...
Mucolipidosis III alpha/beta is a much milder disorder. Overall, the clinical course of the disease is slowly progressive, with progressive destruction of the joints a major clinical problem. The most detailed report of the clinical course of mucolipidosis III alpha/beta described three affected siblings who were 38, 61, and 86 years of age (91). Although the condition is compatible with a long life, physical abnormalities involving the hands, hips, elbows, shoulders, and spine resulted in serious complications in these patients.
Many individuals with mucolipidosis III gamma survive into early adulthood but ultimately succumb to cardiorespiratory insufficiency.
Clinical vignette
Case 1. Mucolipidosis II. A boy born to nonconsanguineous parents of German origin was evaluated at age 18 months because of delayed psychomotor development, coarse facies, restricted joint mobility, and claw-like hands (88). His older brother was healthy. Radiographs revealed a generalized bone dysplasia and an enlarged heart. Urinary mucopolysaccharide excretion was normal. At age 6 years, he had a Hurler-like appearance and short stature with a height of 90 cm (12 cm less than the third percentile). Developmental milestones were those of a 3.5-year-old child. Additional findings included mild corneal clouding, hepatomegaly (the liver was palpable 2 to 3 cm below the costal margin), marked joint contractures, and an umbilical hernia. By age 12 years, his condition had worsened. His height was 92 cm (46 cm less than the third percentile), and he exhibited radiologically severe dysostosis multiplex. He died at 14 years of age from cardiac failure.
Case 2. Mucolipidosis II. An 18-month-old boy was hospitalized for recurrent respiratory tract infections (52). He had been a high-risk preterm infant and subsequently manifested postnatal psychomotor retardation, language development retardation, intellectual disability, and abnormal facial features (ie, thick arched eyebrows, flat nose, swollen eyelids, exophthalmos, epicanthus, low-set ears, and short neck). X-ray showed multiple bone malformations (ie, small chest shape; short floating ribs; irregular bilateral proximal humerus; sharp and deep bilateral sciatic incisions; and small, shallow acetabula). Craniocerebral ultrasound showed bilateral ventricle widening. Brain MRI showed poor white matter development, small frontal and temporal lobes, wide extracerebral space, and a thin corpus callosum. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1284+1G> T and c.483delT) in the GNPTAB gene: c.1284+1G>T was inherited from his mother, and c.483delT is a de novo pathogenic variant that causes frameshift and premature termination (p.His162Ilefs∗51).
Case 3. Mucolipidosis II. An infant boy was the first child of nonconsanguineous healthy parents (30). He was delivered premature by cesarean section at 36 weeks because of little amniotic fluid. Birth weight was 2800 g (50th percentile) with a body length of 48 cm (50th percentile) and an occipitofrontal circumference of 32 cm (25th percentile). Examination revealed a prominent forehead, puffy eyelids, epicanthus, a flat nasal bridge, anteverted nostrils, gingival hyperplasia, macroglossia, thoracic deformity, a large inguinal hernia, and contractures of all large joints. Neonatal screening test results were normal.
The patient presented for evaluation at 6 months of age because of poor head control, leg weakness, hypotonia, and decreased muscle stretch reflexes. At 8 months of age, his motor development was significantly delayed, and he was still unable to raise his head, turn over, or sit. In addition, he showed worsened limb joint contractures, hypotonia, and rough skin. He had no hepatosplenomegaly.
Skeletal dysplasia was observed in x-rays and CT imaging. A cranial CT scan showed ventriculomegaly and abnormal skull development. Echocardiography revealed a patent foramen ovale with a normal ejection fraction.
A development screening test showed that the patient’s mental and motor development were significantly delayed. Standard biochemical testing of lysosomal enzyme activities, including arylsulfatase A and beta-glucuronidase, in this patient’s serum identified a more than 10-fold increase. Sanger sequencing of the GNPTAB gene identified compound heterozygous pathogenic mutations [c.673C > T in exon 7 and c.1090C > T in exon 9]; the loss-of-function mutations in both alleles predicted the manifestation of a severe phenotype of mucolipidosis II.
The patient underwent hematopoietic stem cell transplantation at 12 months of age. At 14 months of age, the parents felt that the patient's skin was less rough than before, and his muscle strength and joint range of motion were significantly improved.
Case 4. Mucolipidosis III. A 14-month-old girl was hospitalized for abnormal postnatal facial features (closed anterior fontanelle, prominent zygomatic process, long eyelashes, sparse hair, upturned nostrils, a sharp beak-like mouth, low-set ears, and short neck). The child had no abnormal birth history but developed multiple abnormalities, including psychomotor retardation, abnormal facial features, bilateral limb muscle hypotonia, and genital abnormalities. X-ray of the spine revealed multiple bone malformations (ie, slight scoliosis of the spine and slightly narrow vertebral ends of ribs, slight kyphosis at the junction of the thoracolumbar segment, short anterior and posterior diameters of some thoracolumbar vertebrae, beaked shape of the anterior edge of the vertebral bodies, and irregular acetabula and lower edge of iliac bones). Brain MRI showed poor white matter development, small frontal and temporal lobes, wide extracerebral space, and a thin corpus callosum. Genetic testing showed the presence of two compound heterozygous pathogenic variants (c.1364C> T and c.1284+1G> T) in the GNPTAB gene.
Biological basis
Etiology and pathogenesis
Both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are autosomal recessive disorders associated with a deficiency of UDP-N-acetylglucosamine-lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase (GlcNAc-P-transferase).
Lysosomal enzymes from normal cells have a recognition marker (mannose-6-phosphate) that facilitates the targeting of the enzymes to lysosomes, but this recognition is impaired or absent in mucolipidosis II and III, which in turn impairs the uptake and transport of enzymes to the lysosomal system.
Because cells lack the recognition marker required for normal lysosomal uptake, multiple lysosomal enzymes leak into extracellular fluids.
The deficiency of lysosomal enzymes within the lysosomes results in abnormal cellular accumulation of undigested substrates, which leads to the clinical manifestations typical of lysosomal storage disorders.
Both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta cells are characterized by a marked and generalized reduction in intracellular levels of numerous lysosomal enzymes, although they have greatly increased levels of extracellular concentrations of the same enzymes in culture media, plasma, and urine.
Both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are autosomal recessive disorders (36). In eight families with mucolipidosis III alpha/beta, phenotypically normal parents, there were four affected sibling pairs, affected males (seven) and females (five), and 18 normal siblings (36). Similar findings have been found in mucolipidosis II alpha/beta families.
Both of these disorders are associated with a deficiency of the UDP-N-acetylglucosamine-lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase (GlcNAc-1-phosphotransferase or GlcNAc-P-transferase; EC 2.7.8.17) (29; 72). As expected for an autosomal recessive disorder, affected patients have severely impaired enzyme activity, whereas their parents (obligate heterozygotes) have enzyme activity that is intermediate but below the normal range (56).
GlcNAc-1-phosphotransferase is an α2β2γ2 heterohexameric transmembrane enzyme. The site-1 protease cleaves inactive precursor proteins and releases catalytically active alpha and beta subunits.
In the cis-Golgi network, GlcNAc-1-phosphotransferase phosphorylates selected mannose residues on lysosomal enzymes.
Starting at the lower left of the illustration, in the cis-Golgi network, GlcNAc-1-phosphotransferase phosphorylates selected mannose residues on lysosomal enzymes. In the process uridine diphosphate (UDP) is converted to uridi...
In the process, uridine diphosphate is converted to uridine monophosphate. Then, in the trans-Golgi network, N-acetylglucosamine (GlcNAc) is removed by the uncovering enzyme (73; 93). The phosphorylated enzymes bind with a recognition marker, the mannose 6-phosphate (M6P) receptor, and are then internalized to the endosome and finally enter the lysosomes.
Although lysosomal enzymes from normal cells have a recognition marker (mannose-6-phosphate) that facilitates the targeting of the enzymes to lysosomes, this recognition is impaired or absent in mucolipidosis II and III, which in turn impairs uptake and transport of enzymes to the lysosomal system (31; 60; 28).
The lack of the mannose-6-phosphate in patients with mucolipidosis II alpha/beta and mucolipidosis III alpha/beta results from a deficiency of the UDP-N-acetylglucosamine-lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase (29; 72; 78).
Because cells lack the recognition marker required for normal lysosomal uptake, multiple lysosomal enzymes leak into extracellular fluids. The deficiency of lysosomal enzymes within the lysosomes results in abnormal cellular accumulation of undigested substrates, which leads to the clinical manifestations typical of lysosomal storage disorders (63). An abnormality of autophagy was suspected (39) and subsequently confirmed in a knock-in mouse model of mucolipidosis II (41). Accumulation of substrates of enzymes that require mannose 6-phosphate targeting occurs in the brain and is associated with progressive neurodegeneration (41).
Altered growth factor signaling contributes to the phenotypes associated with mucolipidosis II (02). Sortilin, a sorting receptor for hydrolases and transforming growth factor beta-related cytokines, is upregulated in mucolipidosis II fibroblasts. Sortilin upregulation in cells with lysosomal storage apparently helps maintain hydrolase sorting but suppresses transforming growth factor beta 1 (TGFβ1) secretion through increased lysosomal delivery. These findings link impaired lysosomal sorting and altered growth factor bioavailability.
Mucolipidosis II and III are caused by mutations in the GNPTAB and GNPTG genes encoding the alpha/beta and gamma subunits of the GlcNAc-1-phosphotransferase, respectively (99; 90; 93; 37; 16). GNPTAB missense mutations are present in protein domains that involve Golgi retention of GlcNAc-1-phosphotransferase and its ability to specifically recognize lysosomal hydrolases. Other missense mutations impair catalytic function and lysosomal enzyme recognition (69) or cause misfolding of the protein and its retaining in the endoplasmic reticulum (92; 49). The GNPTAB mutation c.3503_3504delTC has been detected in many ethnic groups, including Israelis, Palestinian Arab Muslims, Turks, Canadians, Italians, Portuguese, Irish, and Americans (13); it is part of a common haplotype and is around 2063 years old. Patients with mucolipidosis III C have frameshift mutations affecting the gamma-subunit and are now defined as having mucolipidosis III gamma (70; 16).
Nonsynonymous coding variants in GNPTAB, GNPTG, and NAGPA may account for as much as 16% of persistent nonsyndromic stuttering cases (71). These variants are generally not found among mucolipidosis cases and exert a less deleterious effect on protein function (71).
Cultured fibroblast cells from patients with both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are characterized by the presence of numerous cytoplasmic inclusions when examined by phase-contrast microscopy (45; 83). Antibody studies have shown that these inclusions have the properties of secondary lysosomes (75). Investigations on cells from three siblings with mucolipidosis II alpha/beta demonstrated inclusion bodies with vesicles, granules, flocculent material, amorphous electron-dense globules, and myelin structures (40). Cells from these patients also have a maldistribution of multiple lysosomal acid hydrolyses. Thus, both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta cells are characterized by a marked and generalized reduction in intracellular levels of numerous lysosomal enzymes, although they have greatly increased levels of extracellular concentrations of the same enzymes in culture media, plasma, and urine (47; 87).
Accumulation of storage materials in chondrocytes affects primary bone formation and causes severe skeletal manifestations because it disturbs the normal systemic endochondral and membranous bone growth after birth; these abnormalities are collectively known as dysostosis multiplex (38; 85). Such abnormalities affect the spine, causing cervical developmental stenosis and atlantoaxial instability (85). Bone remodeling is impaired in patients with GNPTAB-associated mucolipidosis III alpha/beta but not with GNPTG-associated mucolipidosis III gamma (18).
Such disorders may also occur in animals that might be used as models for human disease. For example, a female cat has been identified with clinical, biochemical, and morphologic findings similar to humans with mucolipidosis II alpha/beta (06).
Epidemiology
Mucolipidosis II alpha/beta and mucolipidosis III alpha/beta/gamma are rare inborn errors of metabolism (19). Cases of mucolipidosis II alpha/beta and mucolipidosis III alpha/beta have been reported from multiple countries, and there is no evidence of ethnic predilection. Mucolipidosis type III gamma has most often been observed in the Middle East.
In a systematic review of 843 patients, the median age at diagnosis was 0.7 years for mucolipidosis II alpha/beta and 9.0 years for mucolipidosis III alpha/beta (19). The median age of death was 1.8 years for mucolipidosis II alpha/beta and 33.0 years for mucolipidosis III alpha/beta (19). The most frequent causes of death in all forms of mucolipidosis were pulmonary or cardiac complications (19). The most well-documented cardiac manifestation is the thickening and insufficiency of mitral and aortic valves, but there are very few reports concerning myocardial involvement (34). Pathogenic variants were described in 388 patients (GNPTAB: 571, GNPTG 179) (19).
Prevention
Couples at risk for the birth of children with either mucolipidosis II alpha/beta or mucolipidosis III alpha/beta are almost always identified with the diagnosis in a previously affected child. If it is established that the patient in question is affected by one of these disorders, proper genetic counseling should be provided to the parents, siblings, and other close relatives.
As these are recessive disorders, there is a 25% chance of an affected child at each subsequent pregnancy of parents who already have an affected child. Other family members should be aware that they are at risk only if both they and their spouse are carriers for the disorder. Measurement of N-Acetylglucosamine-1-phosphotransferase can identify carriers of these disorders. Finally, at-risk couples should be advised of the possibility of prenatal diagnosis (65; 04). Preimplantation genetic diagnosis should also apply to both disorders.
Differential diagnosis
Confusing conditions
Mucolipidosis II alpha/beta, the more severe of these two disorders, is most likely to be confused with one of the severe forms of the mucopolysaccharidoses, such as Hurler syndrome. Generally, these patients present within the first year of life with obvious signs of a "lysosomal storage disorder." Although an earlier onset of symptoms and a more rapid decline might permit the clinical differentiation of mucolipidosis II alpha/beta from patients with Hurler syndrome, the distinction is best based on laboratory findings (95). In contrast to patients with Hurler syndrome, who excrete excessive amounts of acid mucopolysaccharides, patients with mucolipidosis II have normal or only slightly elevated levels of these compounds.
In contrast to mucolipidosis II alpha/beta, patients with mucolipidosis III alpha/beta usually have a much milder presentation. In many cases, the initial complaint, often before 5 years of age, results from the early onset of stiffness of the joints. Because of the presence of progressive joint stiffness, these patients are often evaluated for rheumatoid arthritis. In a report of three patients with mucolipidosis III alpha/beta referred to a pediatric rheumatology clinic, one had initially been diagnosed as having juvenile rheumatoid arthritis, the second was suspected of having scleroderma, and the third Hurler syndrome (08). Mildly affected mucolipidosis III alpha/beta siblings with isolated involvement of the hips and mild abnormalities of the spine have also been described (23).
Diagnostic workup
• Because the clinical findings in both the severe and the mild forms of these disorders often overlap with those seen in various forms of the mucopolysaccharidoses, laboratory confirmation is necessary. | |
• If a patient has greatly elevated levels of one or more lysosomal enzymes in plasma, examination of cultured skin fibroblasts by phase-contrast microscopy will establish the presence of inclusions (I-cells) in affected patients. | |
• The most direct biochemical means of confirming the presence of mucolipidosis is based on measuring the activity of UDP-N-acetylglucosamine-lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the actual enzyme responsible for these disorders. | |
• Although each of these laboratory procedures is valuable for establishing the diagnosis of either mucolipidosis II alpha/beta or mucolipidosis III alpha/beta, they usually cannot distinguish between the two forms of the disease; the conclusion that a patient suffers from either the severe (mucolipidosis II alpha/beta) form or the mild (mucolipidosis III alpha/beta) form of the disorder is usually based on the clinical findings. |
Laboratory studies. The clinical findings in both the severe and the mild forms of these disorders often overlap with those seen in various forms of the mucopolysaccharidoses. For this reason, the measurement of urinary levels of acid mucopolysaccharides serves to help distinguish mucolipidosis patients, who lack marked elevations, from mucopolysaccharidoses patients, who usually excrete excessive amounts of these compounds.
A second and more useful screening test for either of these two forms of mucolipidosis is based on the measurement of one or more lysosomal enzymes in plasma. Due to the extracellular leakage of lysosomal enzymes, these patients have greatly elevated levels (10 to 20 times normal) many lysosomal enzymes in plasma or serum. The measurement of hexosaminidase A (typically used for screening for Tay-Sachs disease carriers) provides a readily available screening test for either mucolipidosis II alpha/beta or mucolipidosis III alpha/beta. The presence of greatly elevated levels (between 10 and 20 times normal) of this enzyme is good evidence for these disorders.
If a patient has greatly elevated levels of one or more lysosomal enzymes in plasma, examination of cultured skin fibroblasts by phase-contrast microscopy will establish the presence of inclusions (I-cells) in affected patients. Cultured fibroblasts from patients with both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are also characterized by decreased levels (approximately 15% to 30% of normal) of most lysosomal enzymes.
The most direct biochemical means of confirming the presence of mucolipidosis is based on measuring the activity of UDP-N-acetylglucosamine-lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the actual enzyme responsible for these disorders.
A single-chain antibody fragment against Man6P allows the specific, rapid, and convenient detection of Man6P-containing proteins, which in the case of mucolipidosis II and III are absent (57).
A multiplex tandem mass spectrometry enzymatic activity assay for the screening and diagnosis of mucolipidosis type II and III in dried blood spots is being developed (32).
Mutations of the GNPTAB or GNPTG genes confirm the diagnosis, and genetic counseling should be offered (99). Methods for rapid and high-throughput diagnosis are based on either the fingerprint approach for screening urinary oligosaccharides using mass spectrometry (80) or identifying a reduction in the specific lysosomal enzyme protein in dried blood spots (24).
Although each of these laboratory procedures is valuable for establishing the diagnosis of either mucolipidosis II alpha/beta or mucolipidosis III alpha/beta, they usually cannot distinguish between the two forms of the disease; the conclusion that a patient suffers from either the severe form (mucolipidosis II alpha/beta) or the mild form (mucolipidosis III alpha/beta) of the disorder is usually based on the clinical findings.
Radiology studies. Skeletal abnormalities on imaging studies include shortening and anterior beaking of vertebral bodies, kyphosis, widening of the ribs, and shortening of the long bones (11; 30). Gibbus deformities may develop, particularly in the lumbar spine (38).
The anteroposterior diameters of the vertebral bodies are reduced. Ossification of the anterior upper border of the lumbar vertebral bodies is also reduced. There is already a mild gibbus deformity at the vertebral L2 body. (So...
Other common spinal abnormalities evident on imaging include cervical developmental stenosis and atlantoaxial instability (85; 01).
-
Cerebellum and vermis atrophy and cervical spinal stenosis in child with mucolipidosis II (sagittal T2 MRI)
Atrophy of the top part of the cerebellum and vermis and cervical spinal canal stenosis in an 11.2-year-old girl with mucolipidosis II (mucolipidosis intermediate). (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestation...
-
Cervical spinal canal stenosis in child with mucolipidosis II (sagittal T1 MRI)
Sagittal T1-weighted MRI sequence shows cervical spinal canal stenosis in a 3.3-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analys...
-
Cervical spinal canal stenosis in child with mucolipidosis II (transverse T2 MRI)
Transverse T2-weighted MRI sequence shows cervical spinal canal stenosis in a 3.3-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective anal...
-
Cervical spinal canal stenosis in child with mucolipidosis II (sagittal T2 MRI)
Sagittal T2-weighted MRI sequence shows cervical spinal canal stenosis in a 3.3-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analys...
-
Pre- and postoperative MRI and x-rays in mucolipidosis III alpha/beta with cervical myelopathy
T2-weighted sagittal images (top row) and plain lateral radiographs (bottom row) of a 38-year-old woman with mucolipidosis III alpha/beta. Her symptoms include clumsiness and gait disturbance. Preoperative images are on the lef...
The pelvic bones are often abnormally shaped, with flared iliac wings and with a hypoplastic basis of the os ilium; the acetabula are frequently shallow and dysplastic. In addition, ossification abnormalities may involve the proximal femoral head and greater trochanter.
-
Ossification abnormalities of the proximal femoral head and greater trochanter in mucolipidosis III alpha/beta
On the left, an anterior-posterior x-ray of hemipelvis of an 8-year-old healthy control is shown. On the center and right images, ossification abnormalities (indicated by a white arrow) of the proximal femoral head are observed...
Cellular alterations associated with bone abnormalities differ with age (67; 66) and may look radiologically like rickets (48).
Cranial CT and MRI studies in patients with mucolipidosis II alpha/beta have demonstrated ventriculomegaly associated with frontal lobe atrophy and bifrontal leukomalacia in mucolipidosis II alpha/beta (07; 01; 30). Delayed myelination was observed on sequential brain MRI testing, which was confirmed by neuropathological examination (82). Craniosynostosis and moyamoya syndrome have been observed in patients with mucolipidosis II (12; 17). Atrophy of the cerebellum and vermis may be present (01).
-
White matter signal changes in child with mucolipidosis II (transverse T2 MRI) (1)
Transverse T2-weighted MRI sequence shows white matter signal changes in an 11.2-year-old girl with mucolipidosis II (mucolipidosis intermediate). (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis...
-
White matter signal changes in child with mucolipidosis II (sagittal FLAIR MRI) (1)
Sagittal FLAIR MRI sequence shows white matter signal changes in an 11.2-year-old girl with mucolipidosis II (mucolipidosis intermediate). (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II...
-
White matter signal changes in child with mucolipidosis II (transverse FLAIR MRI)
Transverse FLAIR MRI sequence shows white matter signal changes in a 2.4-year-old girl with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of ...
-
White matter signal changes in child with mucolipidosis II (transverse T2 MRI) (2)
Transverse T2-weighted MRI sequence shows white matter signal changes in a 2.4-year-old girl with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analys...
-
White matter signal changes in child with mucolipidosis II (sagittal FLAIR MRI) (2)
Sagittal FLAIR MRI sequence shows white matter signal changes in a 3.2-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of lon...
In the absence of known risk, antenatal cases of mucolipidosis II may be incidentally identified using ultrasound in women with polyhydramnios (44).
Electrophysiological studies. Electrophysiological techniques may detect and localize minimal neurologic lesions in severe lysosomal disorders like mucolipidosis II alpha/beta and mild lysosomal disorders like mucolipidosis III alpha/beta (33; 89). Auditory brainstem response studies in patients with mucolipidosis II alpha/beta may show prolonged latency of wave I, a normal I-V interpeak latency, and an elevated threshold of wave V, reflecting conductive hearing impairment; in addition, a steep intensity-latency curve may reflect cochlear hearing impairment (33). In addition, some patients may have abnormal central motor function on magnetic cortical stimulation or abnormal central somatosensory function with somatosensory evoked potentials (89).
Management
• No specific therapy has been developed for either mucolipidosis II alpha/beta or mucolipidosis III alpha/beta. |
Once the diagnosis is confirmed and the clinical distinction between the two types is established, the family can be counseled, with a discussion of the prognosis, inheritance, recurrence risks, management, and potential complications. Because of the progressive nature of these disorders, the expected future course of the disease process should be reviewed with the patient and family. The risk of a future affected child by the same parents (25% for each subsequent pregnancy) should be reviewed, including, if desired, various options such as prenatal diagnosis.
There are no ongoing clinical trials or preclinical work with enzyme replacement therapy for mucolipidosis II or III (61). Prospects for enzyme replacement therapy in mucolipidosis II and III are complicated because multiple hydrolases are deficient within lysosomes and because some of the pathology is caused by hypersecretion of enzymes into the extracellular space, a molecular consequence that could not be addressed by enzyme replacement therapy (61).
A review of 22 patients who underwent hematopoietic stem cell transplantation concluded that, unlike in mucopolysaccharidosis I (Hurler disease), this procedure is ineffective in mucolipidosis II, even when performed at a young age (50; 61).
Gene therapy is not available for patients with mucolipidosis II or III (76). Although biochemical correction of mucolipidosis III alpha/beta by gene transfer has been reported in vitro, it remains an experimental procedure (22). Being explored is the possibility of an innovative therapeutic strategy for mucolipidosis II alpha/beta based on the use of antisense oligonucleotides able to induce the skipping of GNPTAB exon 19, which harbors the most common disease-causing mutation, c.3503_3504del (54); although specific antisense oligonucleotides can modulate RNA splicing, the utility of this strategy remains unproven.
Some complications require specific management, including many associated with skeletal involvement (eg, avascular necrosis, odontoid dysplasia, and carpal tunnel syndrome) (27). Odontoid dysplasia may cause atlantoaxial instability, or dislocation can lead to severe neurologic sequelae or sudden death (91). Carpal tunnel syndrome is a common complication of mucolipidosis III alpha/beta, often requiring surgical management (27; 91).
Special considerations
Anesthesia
Laryngeal intubation may be technically difficult, and laryngeal mask airway may be used in critical events to transiently secure the airway (51; 20; 79). Ideally, especially with mucolipidosis II alpha/beta and pediatric mucolipidosis III alpha/beta cases, these complex children should undergo elective anesthesia delivered by an experienced pediatric anesthesiologist in an appropriate tertiary center with on-site pediatric ENT and critical care support (79).
Media
References
- 01
- Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12(12):4114. PMID 37373807
- 02
- Barnes JW, Aarnio-Peterson M, Norris J, Haskins M, Flanagan-Steet H, Steet R. Upregulation of sortilin, a lysosomal sorting receptor, corresponds with reduced bioavailability of latent TGFβ in mucolipidosis II cells. Biomolecules 2020;10(5):670. PMID 32357547
- 03
- Beck M, Barone R, Hoffmann R, et al. Inter- and intrafamilial variability in mucolipidosis II (I-cell disease). Clin Genet 1995;47:191-9. PMID 7628121
- 04
- Besley GT, Broadhead DM, Nevin NC, Nevin J, Dornan JC. Prenatal diagnosis of mucolipidosis II by early amniocentesis. Lancet 1990;335:1164-5. PMID 1971899
- 05
- Bocca G, Monnens LA. Defective proximal tubular function in a patient with I-cell disease. Pediatr Nephrol 2003;18:830-2. PMID 12811655
- 06
- Bosshard NU, Hubler M, Arnold S, et al. Spontaneous mucolipidosis in a cat: an animal model of human I-cell disease. Veterinary Pathol 1996;33:1-13. PMID 8826001
- 07
- Breningstall GN, Tubman DE. Magnetic resonance imaging in a patient with I-cell disease. Clin Neurol Neurosurg 1994;96:161-3. PMID 7924082
- 08
- Brik R, Mandel H, Aizin A, et al. Mucolipidosis III presenting as a rheumatological disorder. J Rheumatol 1993;20:133-6. PMID 8441145
- 09
- Cathey SS, Kudo M, Tiede S, et al. Molecular order of mucolipidosis II and III nomenclature. Am J Med Genet 2008;146A:512-3. PMID 18203164
- 10
- Cathey SS, Leroy JG, Wood T, et al. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet 2010;47(1):38-48. PMID 19617216
- 11
- Ceroni JRM, Spolador GM, Bermeo DS, et al. Clinical and radiological findings in Brazilian patients with mucolipidosis types II/III. Skeletal Radiol 2019;48(8):1201-7. PMID 30712120
- 12
- Chittem L, Bhattacharjee S, Ranganath P. Craniosynostosis in a child with I-cell disease: The need for genetic analysis before contemplating surgery in craniosynostosis. J Pediatr Neurosci 2014;9(1):33-5. PMID 24891900
- 13
- Coutinho MF, Encarnacao M, Gomes R, et al. Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity. Clin Genet 2011;80(3):273-80. PMID 20880125
- 14
- David-Vizcarra G, Briody J, Ault J, et al. The natural history and osteodystrophy of mucolipidosis types II and III. J Paediatr Child Health 2010;46(6):316-22. PMID 20367762
- 15
- de Bode CJ, Dogterom EJ, Rozeboom AV, et al. Orofacial abnormalities in mucopolysaccharidosis and mucolipidosis type II and III: a systematic review. JIMD Rep 2022;63(6):621-9. PMID 36341168
- 16
- De Geer K, Mascianica K, Naess K, Sardh E, Lindstrand A, Björck E. Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report. BMC Ophthalmol 2023;23(1):394. PMID 37752499
- 17
- de Guzman P, Hamilton M, Khan A, Eesa M, Kirton A. Moyamoya syndrome associated with mucolipidosis-II. Can J Neurol Sci 2014;41(4):522-4. PMID 24878482
- 18
- Di Lorenzo G, Westermann LM, Yorgan TA, et al. Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III. Genet Med 2021;23(12):2369-77. PMID 34341521
- 19
- Dogterom EJ, Wagenmakers MA, Wilke M, et al. Mucolipidosis type II and type III: a systematic review of 843 published cases. Genet Med 2021;23(11):2047-56. PMID 34172897
- 20
- Dohrmann T, Muschol NM, Sehner S, et al. Airway management and perioperative adverse events in children with mucopolysaccharidoses and mucolipidoses: a retrospective cohort study. Paediatr Anaesth 2020;30(2):181-90. PMID 31834659
- 21
- Edmiston R, Wilkinson S, Jones S, Tylee K, Broomfield A, Bruce IA. I-Cell disease (mucolipidosis II): a case series from a tertiary paediatric centre reviewing the airway and respiratory consequences of the disease. JIMD Rep 2019;45:1-8. PMID 30209781
- 22
- Fowler ML, Fan YS, Mueller OT, Henry WM, Shows TB. Correction of mucolipidosis III in vitro by gene transfer. Genomics 1993;18:236-43. PMID 8288225
- 23
- Freisinger P, Padovani JC, Maroteaux P. An atypical form of mucolipidosis III. J Med Genet 1992;29:834-6. PMID 1453439
- 24
- 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):422-5. PMID 21415080
- 25
- Gungor N, Coskun T, Akcoren Z, Caglar M. I-cell disease. A case report and review of the literature. Turk J Pediatr 1994;36:145-52. PMID 8016916
- 26
- Haddad FS, Hill RA, Vellodi A. Orthopaedic manifestations of mucolipidosis III: an illustrative case. J Pediatr Orthop B 2000;9:58-61. PMID 10647114
- 27
- Haddad FS, Jones DH, Vellodi A, Kane N, Pitt MC. Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses. J Bone Surg Br 1997;79(4):576-82. PMID 9250742
- 28
- Hasilik A, Neufeld EF. Biosynthesis of lysosomal enzymes in fibroblasts: II phosphorylation of mannose residue. J Biol Chem 1980;255:4946-50. PMID 6989822
- 29
- Hasilik A, Waheed A, Von Figura K. Enzymatic phosphorylation of lysosomal enzymes in the presence of UDP-N-acetylglucosamine. Absence of the activity in I-cell fibroblasts. Biochem Biophys Res Commun 1981;98:761-7. PMID 6452876
- 30
- He SJ, Li DJ, Lv WQ, et al. Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations. Front Pediatr 2023;11:1199489. PMID 37484777
- 31
- Hickman S, Neufeld EF. A hypothesis for I-cell disease: defective hydrolases that do not enter lysosomes. Biochem Biophys Res Commun 1972;49:922-9. PMID 4345092
- 32
- Hong X, Pollard L, He M, Gelb MH, Wood TC. Multiplex tandem mass spectrometry enzymatic activity assay for the screening and diagnosis of mucolipidosis type II and III. Mol Genet Metab Rep 2023;35:100978. PMID 37275682
- 33
- Ichiyama T, Hayashi T, Matsuo K. Hearing impairment in two boys with I-cell disease. Brain Dev 1991;13:363-5. PMID 1785662
- 34
- Kashihara S, Ohtani K, Sato T, Nishizaki A, et al. A rare manifestation of right ventricular dysfunction in an adult patient with mucolipidosis type III α/β. Can J Cardiol 2020;36(12):1978.e1-3. PMID 32818557
- 35
- Kelly MB, Bosmans L, Gault D. Use of the palmaris brevis flap for preventing recurrent median nerve compression in mucolipidosis. J Hand Surg Br 1999;24:300-2. PMID 10433441
- 36
- Kelly TE, Thomas GH, Taylor HA, et al. Mucolipidosis III (pseudo-Hurler polydystrophy): clinical and laboratory studies in a series of 12 patients. Johns Hopkins Med J 1975;137:156-75. PMID 810612
- 37
- Khan MA, Zubaida B, Karim N, Cheema HA, Naeem M. Identification of two novel variants in GNPTAB underlying mucolipidosis II in a Pakistani family. J Pediatr Endocrinol Metab 2020;33(5):647-651. PMID 32238606
- 38
- Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21(18):6812. PMID 32957425
- 39
- Kobayashi H, Takahashi-Fujigasaki J, Fukuda T, et al. Pathology of the first autopsy case diagnosed as mucolipidosis type III α/β suggesting autophagic dysfunction. Mol Genet Metab 2011;102(2):170-5. PMID 21051253
- 40
- Koga M, Ishihara T, Hoshii Y, Uchino F, Matsuo K, Yamashita Y. Histochemical and ultrastructural studies of inclusion bodies found in tissues from three siblings with I-cell disease. Pathol Int 1994;44:223-9. PMID 8025664
- 41
- Kollmann K, Damme M, Markmann S, et al. Lysosomal dysfunction causes neurodegeneration in mucolipidosis II 'knock-in' mice. Brain 2012;135(Pt 9):2661-75. PMID 22961545
- 42
- Kornfeld S, Sly WS. I-cell disease and pseudo-Hurler polydystrophy: disorders of lysosomal enzyme phosphorylation and localization. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 7th ed. New York: McGraw-Hill, 1995:2495-508.
- 43
- Lai LM, Lachman RS. Early characteristic radiographic changes in mucolipidosis II. Pediatr Radiol 2016;46(12):1713-20. PMID 27525427
- 44
- Lees C, Homfray T, Nicolaides KH. Prenatal ultrasound diagnosis of Leroy I cell disease. Ultrasound Obstet Gynecol 2001;18(3):275-6. PMID 11555461
- 45
- Leroy JG, De Mars RI. Mutant enzymatic and cytological phenotypes in cultured human fibroblasts. Science 1967;157:804-6. PMID 17842782
- 46
- Leroy JG, Spranger JW, Feingold M, Opitz JM, Crocker AC. I-cell disease: a clinical picture. J Pediatr 1971;79:360-5. PMID 4327936
- 47
- Lightbody J, Weissman U, Hadorn B, Herschkowitz N. I-cell disease: multiple lysosomal-enzyme defect. Lancet 1971;i:451. PMID 4100420
- 48
- Lin MH, Pitukcheewanont P. Mucolipidosis type II (I-cell disease) masquerading as rickets: two case reports and review of literature. J Pediatr Endocrinol Metab 2012;25(1-2):191-5. PMID 22570975
- 49
- Ludwig NF, Velho RV, Sperb-Ludwig F, et al. GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms. Int J Biochem Cell Biol 2017;92:90-4. PMID 28918368
- 50
- 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):1847-51. PMID 25016194
- 51
- Mallen J, Highstein M, Smith L, Cheng J. Airway management considerations in children with I-cell disease. Int J Pediatr Otorhinolaryngol 2015;79(5):760-2. PMID 25818347
- 52
- Mao SJ, Zu YM, Dai YL, Zou CC. Case report: mucolipidosis II and III alpha/beta caused by pathogenic variants in the GNPTAB gene [mucolipidosis]. Front Pediatr 2022;10:852701. PMID 35463894
- 53
- Maroteaux P, Lamy M. La pseudo-polydystrophie de Hurler. Presse Med 1966;74:2889-92. PMID 4958870
- 54
- Matos L, Vilela R, Rocha M, et al. Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for mucolipidosis II: validation at RNA level. Hum Gene Ther 2020;31(13-14):775-83. PMID 32283951
- 55
- McKusick VA, Kaplan D, Wise D, et al. The genetic mucopolysaccharidoses. Medicine 1965;44:445-83. PMID 4221470
- 56
- Mueller OT, Little LE, Miller AL, et al. I-cell disease and pseudo-Hurler polydystrophy: heterozygote detection and characteristics of the altered N-acetylglucosamine-phosphotransferase in genetic variants. Clin Chim Acta 1985;150:175. PMID 2998644
- 57
- Muller-Loennies S, Galliciotti G, Kollmann K, Glatzel M, Braulke T. A novel single-chain antibody fragment for detection of mannose 6-phosphate-containing proteins: application in mucolipidosis type II patients and mice. Am J Pathol 2010;177(1):240-7. PMID 20472886
- 58
- Mulroy E, Chancellor AM, Pelosi L. Peripheral nerve ultrasound findings in mucolipidosis type 3. Neuroradiology 2018;60(2):207-9. PMID 29218369
- 59
- Nakaoka S, Kondo H, Matsuoka K, et al. Mucolipidosis II and III with neurological symptoms due to spinal cord compression. Brain Dev 2021;43(8):867-72. PMID 33965289
- 60
- Natowicz MR, Chi MM, Lowry OH, Sly WS. Enzymatic identification of mannose 6-phosphate on the recognition marker for receptor-mediated pinocytosis of b-glucuronidase by human fibroblasts. Proc Natl Acad Sci U S A 1979;76:4322-6. PMID 291966
- 61
- Naumchik BM, Gupta A, Flanagan-Steet H, et al. The role of hematopoietic cell transplant in the glycoprotein diseases. Cells 2020;9(6):1411. PMID 32517081
- 62
- Okada S, Owada M, Sakiyama T, et al. I-cell disease: clinical studies of 21 Japanese cases. Clin Genet 1985;28:207-15. PMID 2998652
- 63
- Otomo T, Higaki K, Nanba E, Ozono K, Sakai N. Lysosomal storage causes cellular dysfunction in mucolipidosis II skin fibroblasts. J Biol Chem 2011;286(40):35283-90. PMID 21846724
- 64
- Oussoren E, van Eerd D, Murphy E, et al. Mucolipidosis type III, a series of adult patients. J Inherit Metab Dis 2018;41(5):839-48. PMID 29704188
- 65
- Parvathy MR, Mitchell DA, Ben-Yoseph Y. Prenatal diagnosis of I-cell disease in the first and second trimesters. Am J Med Sci 1989;297:361-4. PMID 2544090
- 66
- Pazzaglia UE, Beluffi G, Castello A, Coci A, Zatti G. Bone changes of mucolipidosis II at different ages. Postmortem study of three cases. Clin Orthop 1992;276:283-90. PMID 1537168
- 67
- Pazzaglia UE, Beluffi G, Danesino C, Frediani PV, Pagani G, Zatti G. Neonatal mucolipidosis 2. The spontaneous evolution of early bone lesions and the effect of vitamin D treatment. Report of two cases. Pediatr Radiol 1989;20:80-4. PMID 2602022
- 68
- Poore TS, Prager J, Weinman JP, Larson A, Houin P. Tracheal and lower airway changes in a patient with mucolipidosis type II. Pediatr Pulmonol 2020;55(7):1843-5. PMID 32270604
- 69
- Qian Y, van Meel E, Flanagan-Steet H, Yox A, Steet R, Kornfeld S. Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition. J Biol Chem 2015;290(5):3045-56. PMID 25505245
- 70
- Raas-Rothschild A, Cormier-Daire V, Bao M, et al. Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC). J Clin Invest 2000;105:673-81. PMID 10712439
- 71
- Raza MH, Domingues CE, Webster R, et al. Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes. Eur J Hum Genet 2016;24(4):529-34. PMID 26130485
- 72
- Reitman ML, Varki A, Kornfeld S. Fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy are deficient in UDP-N-acetylglucosamine:glycoprotein-N-acetylglucosaminyl-phosphotransferase activity. J Clin Invest 1981;67:1574-9. PMID 6262380
- 73
- Rohrer J, Kornfeld R. Lysosomal hydrolase mannose 6-phosphate uncovering enzyme resides in the trans-Golgi network. Mol Biol Cell 2001;12(6):1623-31. PMID 11408573
- 74
- Sabbia T, Bovone S, Camera A, Balbi P, Camera G. Gingival hypertrophy in I-cell disease (mucolipidosis II). A report of 2 nonfamilial cases. II. Minerva-Stomatol 1993;42:63-7. PMID 8510621
- 75
- Sandoval IV, Chen JW, Yuan L, August JT. Lysosomal integral membrane glycoproteins are expressed at high levels in the inclusion bodies of I-cell disease fibroblasts. Arch Biochem Biophys 1989;271:157-67. PMID 2540710
- 76
- Santos HS, Poletto E, Schuh R, Matte U, Baldo G. Genome editing in mucopolysaccharidoses and mucolipidoses. Prog Mol Biol Transl Sci 2021;182:327-51. PMID 34175047
- 77
- Satoh Y, Sakamoto K, Fujibayashi Y, et al. Cardiac involvement in mucolipidosis: importance of non-invasive studies for detection of cardiac abnormalities. Jpn Heart J 1983;24:149. PMID 6854951
- 78
- Schierau A, Dietz F, Lange H, Schestag F, Parastar A, Gieselmann V. Interaction of arylsulfatase A with UDP-N-acetylglucosamine:lysosomal enzyme-N-acetylglucosamine-1-phosphotransferase. J Biol Chem 1999;274:3651-8. PMID 9920914
- 79
- Scott-Warren VL, Walker R. Perioperative management of patients with Mucolipidosis II and III: Lessons from a case series. Paediatr Anaesth 2021;31(3):260-7. PMID 33247997
- 80
- Sowell J, Wood T. Towards a selected reaction monitoring mass spectrometry fingerprint approach for the screening of oligosaccharidoses. Anal Chim Acta 2011;686(1-2):102-6. PMID 21237314
- 81
- Spranger JW, Wiedemann HR. The genetic mucolipidosis. Diagnosis and differential diagnosis. Humangenetik 1970;9:113-39. PMID 4246487
- 82
- Takanashi J, Hayashi M, Yuasa S, Satoh H, Terada H. Hypoyelination in I-cell disease; MRI, MR spectroscopy and neuropathological correlation. Brain Dev 2012;34(9):780-3. PMID 22269149
- 83
- Taylor HA, Thomas GH, Miller CS, Kelly TE, Siggers D. Mucolipidosis III: cytological and ultrastructural observations in cultured fibroblasts cells. Clin Genet 1973;4:388-97. PMID 4201594
- 84
- Taylor NG, Shuff RY. I-Cell disease: an unusual cause of gingival enlargement. Br Dent J 1994;176:106-8. PMID 7598997
- 85
- Terai H, Tamai K, Hoshino M, et al. Clinical outcomes of laminoplasty for patients with lysosomal storage disease including mucopolysaccharidosis and mucolipidoses: a retrospective cohort study. Orphanet J Rare Dis 2021;16(1):401. PMID 34583711
- 86
- Thirache C, Gaume M, Gitiaux C, Salon A, Dana C, Pannier S. Carpal tunnel syndrome and finger deformities in children with mucopolysaccharidoses and mucolipidoses: a retrospective review of 52 patients. J Hand Surg Eur Vol 2022;47(5):469-74. PMID 34851776
- 87
- Thomas GH, Taylor HA, Reynolds LW, Miller CS. Mucolipidosis III (pseudo-Hurler polydystrophy). Multiple lysosomal enzyme abnormalities in serum and cultured fibroblast cells. Pediat Res 1973;7:751-6. PMID 4200718
- 88
- Tiede S, Cantz M, Spranger J, Braulke T. Missense mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG. Hum Mutat 2006;27(8):830-1. PMID 16835905
- 89
- Toscano E, Perretti A, Balbi P, Silvestro E, Andria G, Parenti G. Detection of subclinical central nervous system abnormalities in two patients with mucolipidosis III by the use of motor and somatosensory evoked potentials. Neuropediatrics 1998;29:40-2. PMID 9553948
- 90
- Tuysuz B, Kasapcopur O, Alkaya DU, Sahin S, Sozeri B, Yesil G. Mucolipidosis type III gamma: three novel mutation and genotype-phenotype study in eleven patients. Gene 2018;642:398-407. PMID 29170090
- 91
- Umehara F, Matsumoto W, Kuriyama M, Sukegawa K, Gasa S, Osame M. Mucolipidosis III (pseudo-Hurler polydystrophy); clinical studies in aged patients in one family. J Neurol Sci 1997;146(2):167-72. PMID 9077513
- 92
- van Meel E, Kornfeld S. Mucolipidosis III GNPTG missense mutations cause misfolding of the gamma subunit of GlcNAc-1-phosphotransferase. Hum Mutat 2016;37(7):623-6. PMID 27038293
- 93
- Velho RV, Harms FL, Danyukova T, et al. The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: update on GNPTAB and GNPTG mutations. Hum Mutat 2019;40(7):842-64. PMID 30882951
- 94
- Wihlborg CE, Babyn PS, Clarke JT. MRI appearances of hip abnormalities, type III. Pediatr Radiol 2000;30:262-4. PMID 10789907
- 95
- Wraith JE. Mucopolysaccharidoses and mucolipidoses. Handb Clin Neurol 2013;113:1723-9. PMID 23622395
- 96
- Wraith JE, Alani SM. Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders. Arch Dis Child 1990;65:962-3. PMID 2121106
- 97
- Yuasa Y, Yoshinaga M, Kitahara T, Miyata K, Shimozono I, Yoshida H. A case of I-cell disease. Acta Paediatr Jpn 1990;32:670-4. PMID 1707208
- 98
- Zammarchi E, Savelli A, Donati MA, Pasquini E. Self mutilation in a patient with mucolipidosis III. Pediatr Neurol 1994;11:68-70. PMID 7986298
- 99
- Zarghooni M, Dittakavi SS. Molecular analysis of cell lines from patients with mucolipidosis II and mucolipidosis III. Am J Med Genet A 2009;149A(12):2753-61. PMID 19938078
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile
Former Authors
- George H Thomas PhD
- Raphael Schiffmann MD
Patient Profile
- Age range of presentation
-
- 0 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- heredity typical
- autosomal recessive
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Lipid storage disorder, unspecified: E75.6
- ICD-11
-
- Mucolipidosis: 5C56.20
- Other specified inborn errors of lipid metabolism: 5C52.Y
- OMIM
-
- Mucolipidosis II alpha/beta: #252500
- Mucolipidosis III alpha/beta: #252600
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-