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Mucolipidosis II

Synonyms: I-Cell Disease, Inclusion Cell Disease, ML II, Mucolipidosis II Alpha/Beta (ML II Alpha/Beta)

, MD, PhD, , MD, FACMG, and , PhD.

Author Information

Initial Posting: ; Last Update: May 10, 2012.

Estimated reading time: 28 minutes


Clinical characteristics.

Mucolipidosis II (ML II, I-cell disease) is a slowly progressive inborn error of metabolism with clinical onset at birth and fatal outcome most often in early childhood. Postnatal growth is limited and often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Already in infancy skeletal radiographs reveal dysostosis multiplex. All children appear to have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death.


Activity of nearly all lysosomal hydrolases is five- to 20-fold higher in plasma and other body fluids than in normal controls because of improper targeting of lysosomal acid hydrolases to lysosomes in ML II. Urinary excretion of oligosaccharides (OSs) is excessive. GNPTAB is the only gene in which pathogenic variants are known to cause ML II. Bidirectional sequencing of the entire GNPTAB coding region detects two pathogenic variants in more than 95% of persons with ML II.


Treatment of manifestations: “Low-impact” therapies to avoid joint and tendon strain, including aqua therapy, are usually well tolerated; cognitive stimulation through interactive programs; gingivectomy as needed for oral health; myringotomy tube placement as needed for recurrent ear infections.

Prevention of secondary complications: Because of concerns about airway management, surgical intervention should be avoided as much as possible and undertaken only in tertiary care settings.

Surveillance: Outpatient follow-up visits approximately every three months for infants and toddlers; outpatient visits approximately every six months for older children until cardiac and respiratory monitoring need to be more frequent.

Genetic counseling.

ML II is inherited in an autosomal recessive manner. At conception, each sib of an affected person has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

GeneReview Scope

Mucolipidosis II: Included Phenotypes
  • Pacman dysplasia

For synonyms and outdated names see Nomenclature.


Clinical Diagnosis

The following clinical features contribute to early diagnosis of mucolipidosis II (ML II) but are not by themselves diagnostic (Figure 1):

Figure 1. . 3.

Figure 1.

3.5-week-old boy with an older sib with ML II. Characteristic facial features and “crooked” lower left leg along with neurologic findings of hypotonia, weak cry, and reduced range of motion in the shoulders were consistent with ML II, (more...)

  • Perinatal onset
  • Small to low-normal anthropometric measurements for gestational age
  • Weak cry
  • Restricted range of motion in the shoulders
  • Generalized hypotonia
  • Full, round cheeks with flat face, shallow orbits, and depressed nasal bridge
  • Thick skin with wax-like texture. In neonates this is most evident in and around the earlobes.
  • Orthopedic findings that may include one or more of the following:
    • Thoracic deformity including kyphosis
    • Clubfeet
    • Deformed long bones (see Figure 1)
    • Dislocation of the hip(s)

In infancy, skeletal radiographs reveal the following (Figure 2):

Figure 2. . Outline of periosteal margins (also called “periosteal cloaking”), seen here in the humerus and forearm bones of a girl age eight months and often observed in infants with ML II.

Figure 2.

Outline of periosteal margins (also called “periosteal cloaking”), seen here in the humerus and forearm bones of a girl age eight months and often observed in infants with ML II. Not truly pathognomonic of ML II, this early and prominent (more...)

  • Dysostosis multiplex including the following [Spranger et al 2002]:
    • Diaphyseal widening and expansion of large and small tubular bones; shortened and undermodeled diaphyses; epiphyseal dysplasia and submetaphyseal overconstriction become apparent.
    • Shortening of the small tubular bones (more in the hands than feet) and gross delay in carpotarsal and epiphyseal ossification
    • Ribs that widen at or near the costochondral junctions and are narrower than normal in the dorsal juxtavertebral parts
    • Vertebral bodies with shortened anteroposterior diameter and anterosuperior hypoplasia, especially in the lower thoracic and upper-lumbar vertebrae; vertebral bodies taller posteriorly than anteriorly, often with concave anterior, superior, and inferior borders
    • Pelvic dysplasia with narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting acetabular roofs; coxa valga
    • Skull that is relatively normal; sella turcica becomes oblong only in long-term survivors.
  • In the most severely affected infants, transient signs reminiscent of rickets and osteopenia, and punctate calcifications in soft tissue (most frequently about the tarsal bones) are observed. The prenatally detected alveolomaxillar defect observed by Chen et al [2010], a transient finding, may have been an illustration of these perinatal features during pregnancy. In most infants, periosteal cloaking is observed around the diaphyses of the large long bones (see Figure 2); this transient phenomenon is rarely detectable after age one year.

After infancy, skeletal radiographs reveal the following (Figure 3):

Figure 3. . Left wrist and forearm in a girl age five years with ML II.

Figure 3.

Left wrist and forearm in a girl age five years with ML II. Note small number and size of carpal bones, delayed skeletal age, tiny epiphyses, widening of the diaphyses of large and small long bones, shortening of the long bones, and proximal and distal (more...)

  • Large and small long bones. Short and wide diaphyses; often osteopenia and coarse trabeculation; sometimes osteolytic features; severely shortened and widened metacarpals that show proximal pointing; widened and short phalanges; tiny epiphyses and carpal bones caused by retarded ossification (see Figure 3). Disproportion of width and length of the small tubular hand bones worsens mainly in infancy and early childhood.
  • Ribs. Wide and undermineralized; anterior ends are splayed, paravertebral parts are overconstricted.
  • Spine. Most often the first and/or second lumbar vertebra show anterior-inferior hook configuration; concave anterior borders of all vertebrae.
  • Pelvis. Coarse bony trabeculation; hypoplastic and later dysplastic capital femoral epiphyses; punctate calcifications in lower pelvis may be present; relatively long pubic and ischial bones.
  • Skull. Normal sella turcica in early childhood, which becomes oblong in the rare, longer-surviving individual; the size of skull is proportional to stature; shallow orbits; absence of calvarial thickening.


Activity of lysosomal hydrolases. In ML II, the activity of nearly all lysosomal hydrolases is five- to 20-fold higher in plasma and other body fluids than in normal controls because the targeting molecule mannose-6-phosphate (M6P), which is required to direct acid hydrolases to lysosomes, cannot be added to the glycan part of these glycoproteins.

The following hydrolases are of most interest as their increased activity is relevant in the Differential Diagnosis of ML II:

  • β-D-hexosaminidase (EC
  • β-D-glucuronidase (EC
  • β-D-galactosidase (EC
  • α-L-fucosidase (EC

Note: In contrast to other storage disorders resulting from deficiency of a single lysosomal enzyme, ML II cannot be diagnosed by assay of acid hydrolases in leukocytes.

Urinary excretion of oligosaccharides (OSs) is excessive.

Note: (1) Normal values of urinary OSs depend on the method used; every test result must be accompanied by normal average value and range in the laboratory performing the test. (2) The elevation of urinary OSs is a nonspecific finding that serves as a screening test for the OSs provided that the thin-layer chromatographic technique used by the laboratory can reliably distinguish between the normal small OSs derived from breast milk and the larger abnormal OSs species associated with ML II. (3) Urinary excretion of glycosaminoglycans (GAGs) (i.e., acid mucopolysaccharides [AMPS]) is normal. Urinary excretion of GAGs is helpful in distinguishing between ML II and Hurler disease (mucopolysaccharidosis type 1) in the neonatal period when the clinical differences between the two disorders may not be obvious. A positive AMPS urinary test rules out ML II.

UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (GNPTAB) enzyme activity. Demonstration of nearly complete inactivity (<<1%) of the enzyme, UDP-N-acetylglucosamine: GNPTAB (EC encoded by GNPTAB, confirms the diagnosis of ML II. This analysis requires specific substrates, laboratory techniques, and experience.

Molecular Genetic Testing

Gene. To date, GNPTAB is the only gene in which pathogenic variants are known to cause ML II.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Mucolipidosis II

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
GNPTABTargeted analysis for pathogenic variantsc.3503_3504delTC 4
(see Table 2 [pdf], Table 3)
100% for the targeted variant
Sequence analysis 5Sequence variants>95% 6
Deletion/duplication analysis 7Partial- or whole-gene deletions or duplicationsUnknown 8
Uniparental disomyNot applicableUnknown; none reported 9

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Pathogenic variant attributed to a founder effect (see Prevalence)


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Bidirectional sequencing of the entire GNPTAB coding region detects two pathogenic variants in more than 95% of persons with ML II.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Few such pathogenic variants of GNPTAB have been reported; they may be rare. Otomo et al [2009] reported duplication of exon 2 in an individual with ML II. Cathey et al [2010] reported another as-yet undefined structural rearrangement of exon 13 in an affected person with a compound heterozygous genotype.


Uniparental disomy is theoretically possible but has not been reported as a cause of mucolipidosis II.

Interpretation of test results. In cases of apparent homozygosity for a single pathogenic variant, carrier status for each parent should be confirmed to determine if the child is a compound heterozygote for a deletion and the detected variant.

Testing Strategy

To confirm/establish the diagnosis in a proband requires a combination of clinical evaluation and laboratory testing. The following order of diagnostic testing is recommended:


Identification of characteristic clinical and radiographic findings


Assay of oligosaccharides (OS) in urine


Assay of several acid hydrolases* in plasma; for example:

  • β-D-hexosaminidase (EC
  • β-D-glucuronidase (EC
  • β-D-galactosidase (EC
  • α-L-fucosidase (EC
  • Arylsulfatase A (EC
    Note: (1) In ML II specific activity of lysosomal hydrolases is normal in peripheral leukocytes and therefore is of no value for the diagnosis of ML II. (2) The specific activity of lysosomal hydrolases in leukocytes is of value for the differential diagnosis of other lysosomal storage disorders (see Differential Diagnosis).

Sequence analysis of GNPTAB


Deletion/duplication analysis of GNPTAB; appropriate when:

  • Only one clearly pathogenic alteration can be identified by sequencing in a proband who has been clinically/biochemically diagnosed; OR
  • A proband appears homozygous for a pathogenic alteration but only one parent is identified to be a carrier of the alteration.

Carrier testing for at-risk relatives relies on molecular genetic testing. Prior identification of the pathogenic variants in a proband is preferred; however, sequence analysis of the entire gene in both carrier parents can be used to try to identify both pathogenic alleles.

Note: Lysosomal enzymes are slightly more active in the sera of obligate heterozygotes; however, this finding cannot reliably identify heterozygous individuals.

Prognostication. Molecular genetic studies that reveal an obvious genotype-phenotype correlation support the clinical distinction between ML II and the allelic and clinically milder disorder ML III alpha/beta. Pathogenic variants that completely inactivate the specific phosphotransferase consistently result in ML II irrespective of their location within the gene. Pathogenic variants with less adverse effect on this enzyme activity usually result in ML III alpha/beta or occasionally in intermediate phenotypes that are currently the subject of detailed clinical study [Kudo et al 2006, Cathey et al 2010].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Mucolipidosis II (ML II) or I-cell disease is a slowly progressive inborn error of metabolism with clinical onset at birth and fatal outcome most often in early childhood [Cathey et al 2010]. The phenotype as described by system is summarized in this section.

Growth. Birth weight is low to borderline normal. Postnatal growth is limited and ceases during the second year of life. In the event that the diagnosis is not made early, the term “failure to thrive” is often applied. Measured length appears to “decrease” over time as hip and knee contractures worsen (see Figure 4). Head size remains proportional to body size.

Figure 4. . Profile view of a child age three years with ML II.

Figure 4.

Profile view of a child age three years with ML II. Growth ceased more than one year earlier. Note small orbits, proptotic eyes, full and prominent mouth caused by gingival hypertrophy, short and broad hands, stiffening of small hand joints, prominent (more...)

Craniofacial. The neonate with ML II has a flat face, depressed nasal bridge, and shallow orbits. The mouth is prominent. Coarsening of facial features is apparent from early infancy and gradually progresses (see Figure 5). Impressive gingival hypertrophy is apparent soon after birth and causes dental eruption to appear incomplete.

Figure 5. . Coarse facial features and gingival hypertrophy in a girl age five years with ML II.

Figure 5.

Coarse facial features and gingival hypertrophy in a girl age five years with ML II. Note thickened skin around the eyes, low nasal bridge, and widely-spaced and only partially erupted teeth.

The skin is thickened especially around the earlobes. Additional cutaneous findings include prominent periorbital tortuous veins and telangiectatic capillaries in the subcutis over the cheeks. Hair texture and color may be atypical for families of Northern European origin as the hair is fine in texture and in some instances white to golden in color, even in neonates.

Metopic prominence is observed in some children. Craniosynostosis is regularly suspected but not formally confirmed and, in some instances, has resulted in inappropriate cranial surgery.

Ophthalmologic. The epicanthal folds persist. If corneal haziness is present in the slightly proptotic eyes, it is mild and detectable only by slit lamp examination.

Audiologic. Episodes of otitis media occur frequently in nearly all children with ML II. Even when otitis media is treated promptly and adequately, conductive hearing loss is common; however, significant hearing impairment is rare. Sensorineural hearing loss is uncommon.

Respiratory. The voice is consistently hoarse.

Breathing remains noisy throughout life. The airways are narrow and subject to slowly progressive mucosal thickening and overall stiffening of the connective tissues. These factors also adversely affect the lung parenchyma. The gradual stiffening of the thoracic cage compounds the restrictive respiratory insufficiency.

Severe pulmonary hypertension (PH) has been more formally documented in a longer-surviving individual with ML II [Kovacevic et al 2011]. PH is probably the rule instead of the exception in individuals with ML II who survive into childhood. Excessive egress of lysosomal glycoproteins into the extracellular matrix (ECM) is likely the main cause of adverse and progressive interstitial lung disease, although storage of glycoprotein may contribute. Poor general health in these individuals often precludes invasive diagnostic procedures. Ultimately, cardiorespiratory failure that is refractory to treatment is the cause of death in most affected children.

Respiratory support is only infrequently required in newborns. Obstructive sleep apnea necessitates nighttime respiratory support in some children; a minority of longer-surviving children require persistent assisted ventilation. In these cases, invariably, respiratory support was initiated during treatment of an acute infection.

Cardiovascular. Cardiac involvement likely occurs in all children. Thickening and insufficiency of the mitral valve and (less frequently) the aortic valve are the most common findings. Right side and general ventricular hypertrophy and pulmonary artery hypertension have been reported but rarely objectively documented [Kovacevic et al 2011]. Slowly progressive valvular changes are common, but valvular deficiency not consistently observed. Rapidly progressive cardiomyopathy is not a common feature in ML II.

Gastrointestinal/feeding. Children with ML II are usually poor eaters. Their small size and paucity of physical movements (most never walk independently) are contributory reasons. However, a minority require placement of a gastrostomy tube for feeding. The abdomen is protuberant, although hepatomegaly is equivocal and splenomegaly rarely observed. Inguinal hernias are slightly more common than in the normal infant and occur equally in males and females. Umbilical hernias, a nearly constant finding, may gradually enlarge, but are not known to cause gastrointestinal complications and do not require surgical correction.

Skeletal/soft connective tissue. Orthopedic abnormalities, often noticed at birth, may include one or more of the following: thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s).

The range of motion of all major and small joints is significantly limited. Mobility of the shoulders is significantly reduced despite consistent axial and appendicular hypotonia. The wrists gradually lose range of motion, the hands and fingers broaden gradually after infancy and become progressively more stiff and fixed in volar claw-like flexion. They usually deviate from the appendicular axis.

Neuromotor development and intellect. Alertness is limited in some, but close to normal in most affected children. Children with ML II show affection, happiness, and displeasure as would any child [Cathey et al 2010].

Early motor milestones are significantly delayed: sitting upright with support is usually acquired around age one year; unassisted sitting may not be achieved until age two years. In the majority of affected children, unaided walking is never achieved. Onset of expressive language is late and limited to single words. Receptive communication is much better than expressive language but not age appropriate. Cognitive functioning, although obviously below normal for age, enables the child to understand, interact with, and enjoy the immediate environment.

Pre- and perinatal phenotype. Two clinical observations, probably interrelated, raise issues about the pre- and perinatal phenotype of ML II:

  • Pacman dysplasia [Wilcox et al 1998] is the controversial [Feingold 2006] term originally given to a presumed perinatal lethal skeletal dysplasia with epiphyseal stippling and osteoclastic overactivity observed in the late part of the second trimester of pregnancy. The diagnosis of ML II has been confirmed by molecular genetic testing in the surviving subsequent sib of the fourth fetus reported with this “lethal” condition [Miller et al 2003]. The skeletal dysplasia in the proband with so-called Pacman dysplasia represents the prenatal manifestation of ML II [Saul et al 2005]. The same mutant genotype was later detected in the tissues of the affected fetus. However, the lethal skeletal dysplasia at issue must be causally heterogeneous as GNPTAB sequencing of the parents of an unrelated fetus diagnosed with Pacman dysplasia [Wilcox et al 1998] did not reveal any pathogenic variants.
  • Newborns with severe ML II are known to have radiographic abnormalities of bone similar to those seen in hyperparathyroidism or rickets. Marked elevation of serum concentrations of parathormone and alkaline phosphatase has been documented in such infants [Unger et al 2005, Sathasivam et al 2006, Chen et al 2010, Ting et al 2011]. Radiographic findings in infants with ML II including the occasionally observed punctate ossifications, relative osteopenia, and early periosteal cloaking around diaphyses of long bones have been considered the consequences of probable transient hyperparathyroidism [Spranger et al 2002]. Neonatal hyperparathyroidism in ML II may be severe, is transient, and is probably secondary to impaired placental calcium transport, simulating a condition observed in the offspring of chronically hypocalcemic mothers [Sathasivam et al 2006].

Other. Nonimmune fetal hydrops resulting from ML II-causing pathogenic variants has rarely been reported.

Previously used diagnostic testing. In the past, phase-contrast or electron microscopic (EM) demonstration of large amounts of dense cytoplasmic inclusions (I-cells) in cultured fibroblasts was used to help confirm the diagnosis of ML II and ML III alpha/beta. The activity of lysosomal enzymes is severely reduced in I-cells, but significantly increased in the corresponding culture media.

Note: In the mesenchymal cells in any tissue EM reveals large numbers of cytoplasmic vacuoles comprising swollen lysosomes bound by a unit membrane. The contents are pleomorphic, but not dense. This phenomenon is specific to ML II and ML III alpha/beta and is not observed in any lysosomal storage disorder.

Genotype-Phenotype Correlations

GNPTAB sequencing has been available since 2005; however, the overall results of several studies have confirmed that homozygous and compound heterozygous genotypes that produce no or nearly no functional GlcNAc-1-phosphotransferase activity (caused by premature translation termination and/or frameshift effects) result in the ML II phenotype. The combination of less “morbid” pathogenic variants, such as missense and most of the splice site variants that result in up to 10% of residual GlcNAc-1-phosphotransferase activity, often yield the more slowly evolving ML III alpha/beta phenotype with later clinical onset [Paik et al 2005, Tiede et al 2005, Bargal et al 2006, Kudo et al 2006, Encarnação et al 2009, Otomo et al 2009, Tappino et al 2009, Cathey et al 2010, David-Vizcarra et al 2010, Cury et al 2011].

Clearly some children have clinical phenotypes intermediate between the reference phenotypes delineated as ML II and ML III alpha/beta [Cathey et al 2008]. In the study of 61 probands with ML seven individuals had an intermediate phenotype that straddled some of the criteria set for either ML II or ML III [Cathey et al 2010]. Even while accounting for the inherent clinical variability within either reference phenotype, the phenotypic spectrum of ML is dichotomous rather than continuously variable. Hence the minority of intermediate phenotypes acquires more clinical and scientific interest. They form a heterogeneous group. In some instances compound heterozygosity for a pathogenic missense variant and a splice site variant is found. In others the intermediate phenotype is associated with parental consanguinity. In one family with five affected sibs, the intermediate phenotype was clearly correlated with a specific compound heterozygous mutant genotype [David-Vizcarra et al 2010].


I-cell disease. The finding by Jules Leroy and Robert DeMars by phase-contrast microscopy of large amounts of dark and dense granules filling almost the entire cytoplasm of cultured fibroblasts from skin biopsies of two unrelated children resulted in the use of the term “inclusion cells”, abbreviated as “I-cells.” Hence, the term “I-cell disease” was introduced (see Figure 6).

Figure 6. . Living culture of skin fibroblasts derived from a patient with ML III alpha/beta viewed by the contrast light microscope.

Figure 6.

Living culture of skin fibroblasts derived from a patient with ML III alpha/beta viewed by the contrast light microscope. There is no morphologic difference between the fibroblasts derived from individuals with Ml II and those with ML III. The cytoplasms (more...)

Mucolipidosis. The laboratory term I-cell disease has been largely replaced by the term mucolipidosis type II, introduced in 1970 by Spranger in an attempt to provide the first clinical classification of the group of metabolic disorders, clinically considered intermediate between the lipidoses and the mucopolysaccharidoses (storage disorders of glycosaminoglycans). Although mucolipidosis is a clinically useful designation, biochemists consider it a misnomer because “mucolipids” do not exist in nature.

The term mucolipidosis has been used in four different inborn errors of metabolism; only ML II and ML III alpha/beta are GNPTAB related.

Mucolipidosis I (also called sialidosis type II) and mucolipidosis IV are genetically distinct. The former may represent a differential diagnostic challenge in the neonate or infant with ML II; the latter does not.

Oligosaccharidoses. During the 1970s excessive urinary excretion of OSs was documented in most of the mucolipidoses; therefore, the term “oligosaccharidoses” and later the term “glycoproteinoses” has been substituted for the term mucolipidoses.

Mucolipidosis II, mucolipidosis III alpha/beta, and mucolipidosis III gamma. Because even the trivial name of the causal enzyme defect, UDPGlcNAc-phosphotransferase, is long, the current naming of ML II and ML III alpha/beta as UDP-GlcNAc 1-P-transferase deficiency disorders is cumbersome, but strictly the most correct one as it refers to the affected subunit(s) in the UDP-GlcNAc 1-phosphotransferase.

UPD-GlcNAc 1-P-transferase is encoded by two genes, GNPTAB and GNPTG:

  • Pathogenic variants in GNPTAB at chromosomal location 12q23.3 cause ML II and the allelic disorder ML III alpha/beta (pseudo-Hurler-polydystrophy).
  • Pathogenic variants in GNPTG located on 16p13.3 cause the variant ML III, designated ML III gamma [Cathey et al 2008].

Pacman dysplasia, once thought to be a distinct perinatal lethal skeletal dysplasia, is now known to represent in most of the reported instances the prenatal manifestation of ML II [Saul et al 2005].


The few estimates of the prevalence of ML II confirm that it is rare. Estimates include the following:

If these findings reflect a global prevalence ranging between 2.5x10-6 and 1.10-5, the overall carrier rate ranges between 1:158 and 1:316.

ML II has been reported from nearly all parts of the world. Parental consanguinity is more common in most reports of cohorts of affected individuals.

An unusually high prevalence of ML II in 1:6184 live births with an estimated carrier rate of 1:39 was found in the northeastern region of the province of Quebec, Canada [Plante et al 2008]. In this region ML II in several large pedigrees has been attributed to a founder effect as only one GNPTAB pathogenic variant (c.3503_3504delTC) has been detected in all obligate carriers. The variant was introduced into that part of Canada in the 17th century by immigrants from France and Scotland.

Differential Diagnosis

Lysosomal Storage Disease

Findings in mucolipidosis II (ML II) overlap those observed in the more prevalent Hurler disease (mucopolysaccharidosis type I H). Compared to ML II, MPS I is associated with more signs of storage on physical examination and less severe dysostosis multiplex on radiographs. Biochemical testing distinguishes the two conditions unequivocally.

Other disorders to consider in the differential diagnoses in infants, also distinguishable by biochemical testing, include:

  • GM1-gangliosidosis type 1 (more hepatomegaly; sole deficiency of β-D-galactosidase deficiency in leukocytes and plasma). The features of dysostosis multiplex in early infancy and childhood in ML II are indistinguishable from the radiographic abnormalities in the skeleton of the neonate with GM1-gangliosidosis type 1 [Spranger et al 2002].
  • Infantile galactosialidosis (storage phenomena less pronounced than in GM1-gangliosidosis but more than in ML II); absence of acid sialidase and of β-D-galactosidase activity in leukocytes in addition to cathepsin A deficiency in leukocytes and cultured fibroblasts. This clinical type of galactosialidosis may present as congenital nonimmune hydrops fetalis more often than has been observed in ML II.
  • Infantile sialidosis, formerly called sialidosis type II or mucolipidosis I, may present as congenital nonimmune hydrops fetalis. Only acid sialidase is deficient in this disorder. Barring the few instances with a rapidly evolving glomerular nephropathy and early fatal outcome, infants with this form of sialidosis have a more chronic disorder with moderate organomegaly, dysostosis multiplex that is milder than that of ML II [Spranger et al 2002], and minimal limitation of joint mobility. Growth and cognitive development are considerably less impaired than in children with ML II.
  • Infantile free sialic acid storage disease (ISSD) (excessive amounts of free sialic acid in urine). Infantile SSD is characterized by less facial dysmorphism and much less dysostosis multiplex than ML II. However neuromotor development in ISSD is barely present and intellectual disability is more pronounced.


Evaluations Following Initial Diagnosis

In order to establish the extent of disease in a child diagnosed with mucolipidosis II (ML II), the following evaluations are recommended:

  • Radiographic skeletal survey, if not performed or incomplete in the diagnostic evaluation. Such survey in early infancy is important for comparison with similar radiographs in the third year of life.
  • Cardiac evaluation with echocardiography to assess valve thickening and ventricular size and function
  • Pulmonary radiographs; an important means of monitoring interstitial lung disease in any serious intrathoracic airway infection. Chest CT may better show fibrotic changes in the lungs. It is doubtful that the child with ML II can cooperate sufficiently to achieve reliable pulmonary function tests, by which the restrictive respiratory deficiency could be documented more objectively.
  • Baseline ophthalmologic examination
  • Hearing screen
  • Developmental assessment to help establish appropriate expectations for the child’s developmental progress
  • Clinical genetics consultation

Treatment of Manifestations

Supportive and symptomatic management is indicated.

Joint. No measures are effective in treating the progressive limitation of motion in large and small joints. The classic physiotherapeutic early intervention programs that are often beneficial in children with developmental delay, neuromotor delay, or cerebral palsy cannot be recommended unequivocally in ML II because of the following:

  • Stretching exercises are ineffective and painful.
  • The unknowing therapist may inflict damage to the surrounding joint capsule and adjacent tendons and cause subsequent soft tissue calcification.

Therapies that are “low impact” in regard to joint and tendon strain, including short sessions of aqua therapy, are usually well tolerated.

Cognitive. Intellectual impairment in ML II is rarely severe. It is often milder than the adverse impression created by the significantly impaired development of speech: any well-adapted program of cognitive stimulation such as interactive play is recommended, such as a stimulation program that favors alertness, imitative skills, ambition, and even some active motion. Occupational and speech therapy are important, the former being the more effective of the two.

Dental. Severe gingival thickening can compromise routine dental cleaning. Mouth pain, infections, and even abscesses have been successfully treated with gingivectomy in some patients (see Prevention of Secondary Complications).

Otic. Myringotomy tube placement for recurrent ear infections is common but should not be considered a routine procedure because of the unique airway issues and hence risk associated with anesthesia (see Prevention of Secondary Complications).

Prevention of Secondary Complications

Because of concerns about airway management, surgical intervention should be avoided as much as possible and undertaken only in tertiary care settings with pediatric anesthesiologists and intensive care. Children with ML II are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a much smaller endotracheal tube than for age- and size-matched children is necessary. Poor compliance of the thoracic cage and the progressively sclerotic lung parenchyma further complicate airway management. Extubation may also be challenging in ML II.


Infants and toddlers with ML II and their families benefit from outpatient follow-up visits approximately every three months. Subsequently throughout early childhood, two outpatient visits per year may be adequate until cardiac and respiratory monitoring need to be more frequent.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Since individuals with ML II do not survive into adulthood, there have not been any reports of affected individuals who have become pregnant.

In women who have a fetus diagnosed prenatally with ML II, the fetus should be carefully monitored for intrauterine growth retardation and skeletal changes such as extraosseous calcifications and/or osteolytic lesions. Ultrasound abnormalities are not present in all affected pregnancies.

Therapies Under Investigation

Treatment of ML II by bone marrow transplantation or hematopoietic stem cell transplantation has been attempted in a few affected toddler-age children without any significant therapeutic result. Information on the outcome of recent transplantations in a few young children is not yet available.

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mucolipidosis II (ML II) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutated allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected person has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Individuals with ML II do not reproduce.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Reliable identification of carrier status requires molecular genetic testing.

Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family. Carrier testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variants have been identified in the family, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for ML II are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Advocate for Glycoprotein Storage Diseases (ISMRD)
    3921 Country Club Drive
    Lakewood CA 90712
  • National MPS Society
    PO Box 14686
    Durham NC 27709-4686
    Phone: 877-677-1001 (toll-free); 919-806-0101
    Fax: 919-806-2055
  • Society for Mucopolysaccharide Diseases (MPS)
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: 0345 389 9901

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Mucolipidosis II: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Mucolipidosis II (View All in OMIM)


Molecular Genetic Pathogenesis

If inactivation of the GlcNAc-phosphotransferase enzyme (encoded by GNPTAB [alpha/beta] is complete the addition of the common M6P moiety to lysosomal acid hydrolases is completely precluded, thereby preventing proper binding to specific M6P receptors in the trans-Golgi network. This precludes receptor-mediated transport of the lysosomal enzyme to the lysosomal compartment. Hence, the mutant hydrolases leave the cells and appear in excessive amounts in the cell culture media or in the patient’s body fluids. Once outside, these enzymes are unable to reenter normal fibroblasts (and are sometimes referred to as “low-uptake” lysosomal enzymes). In contrast, normal mature hydrolases are phosphoglycoproteins (also known as “high-uptake” lysosomal enzymes) and can enter any type of cultured fibroblast by pinocytosis, including “I-cells” [Kudo et al 2006, Cathey et al 2010].

N-linked glycosylation of lysosomal hydrolases occurs in the endocytoplasmic reticulum (ER), which is the site of the stepwise buildup of OSs and of their subsequent en bloc transfer from the dolicholpyrophosphoryl-OS-precursor carrier to some of the asparagine residues in the nascent hydrolase proteins.

As the newly formed glycoproteins traverse the Golgi cisterns, sequential enzymatic modification of the N-linked OSs occurs along two different pathways: one pathway modifies the N-linked OSs into complex-type glycan sidechains, whereas the other (quantitatively the more important pathway at least in mesenchymal tissues) converts the precursor glycans into oligomannosyl-type OS side-chains. Only specific phosphorylation is adversely affected by biallelic inactivating GNPTAB variants at a late step in this synthetic pathway (see following paragraph). Phosphorylation of the oligomannosyl glycans is completely absent in (and is the metabolic cause of) ML II, whereas a significant decrease of this phosphorylation manifests clinically as ML III alpha/beta. Formation of the M6P recognition marker in lysosomal hydrolases does not occur in ML II and is very deficient in ML III alpha/beta. Biallelic variants in GNPTG have not yet been found to cause ML II. However, significant inactivation of the gamma subunit in the heterohexameric GlcNAc-phosphotransferase causes ML III gamma, a disorder that is clinically nearly or totally indistinguishable from ML III alpha/beta.

Normal formation of the M6P glycan marker is a two-step process. The first step is catalyzed by UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (trivial name GlcNAc-phosphotransferase GNPTAB) (EC This enzyme is also known as N-acetylglucosamine-1-phosphotransferase subunits alpha/beta and is encoded by GNPTAB. Inactivity or deficiency of this enzyme causes ML II and ML III alpha/beta, respectively. The second step, which is not affected in persons with ML II or III alpha/beta, involves the action of N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase, which removes the blocking N-acetylglucosamine (GlcNAc) residue from the phosphorylated oligomannosyl type glycan, thereby exposing the M6P recognition marker. Pathogenic variants that inactivate the N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase have not been reported to date in either ML II or ML III alpha/beta.

Gene structure. GNPTAB, located on chromosome 12q23.3, has 21 exons and spans 85 kb of genomic DNA. GNPTAB encodes the alpha and beta subunits of the oligomeric human GNPTAB in a single 6.2-kb alpha/beta transcript. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Several dozen pathogenic variants are known.

Types of pathogenic variants include missense, nonsense, and splice-site variants, as well as small insertions and deletions that result in a shift of the proper reading frame. See Table 2 (pdf).

Either type of pathogenic variant combined with a splice site or missense variant can be found in individuals with ML II. To date, no larger-scale rearrangements have been reported. To date, only a couple of larger intragenic rearrangements have been encountered in GNPTAB; no larger deletions or duplications of regions of the genome surrounding GNPTAB and GNPTG are known.

Table 3.

Selected GNPTAB Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.3503_3504delTC 1p.Leu1168GlnfsTer5NM_024312​.4

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Pathogenic variant attributed to a founder effect (see Prevalence)

Normal gene product. GNPTAB encodes the alpha and beta subunits of the oligomeric human GNPTAB in a single 6.2-kb alpha/beta transcript.

The subunit structure of the human GNPTAB enzyme is a 540-kd hexameric complex of three subunits that are disulfide-linked homodimers. The alpha and beta subunits are encoded by GNPTAB and synthesized as a 190-kd precursor protein. The gamma subunit is encoded by GNPTG. Hence the hexameric enzyme complex may be symbolized as α2β2γ2 [Kudo et al 2005, Tiede et al 2005, Kudo et al 2006].

Following translation, the alpha/beta precursor polypeptide undergoes proteolytic cleavage at the lysine (residue 928) – aspartic acid (residue 929) peptide bond. Recently it has been shown that this bond is released enzymatically by site-1 protease (S1P). S1P-deficient cells failed to activate the alpha/beta precursor and exhibited the I-cell phenotype in vitro [Marschner et al 2011]. The N-terminal alpha subunit, the larger of the two, consists of 928 amino acids. The beta subunit, the C-terminal part of the precursor, contains 328 amino acids. The 1256-amino acid precursor protein has a predicted molecular mass of 144 kd, two transmembrane domains, and 19 potential glycosylation sites [Kudo et al 2005, Tiede et al 2005, Kudo et al 2006]. In a recent study of ML II and ML III alpha/beta fibroblast (I-cell) strains, the use of anti-peptide antibodies against the alpha and beta subunits showed that pathogenic variants in the gamma subunit adversely affected the assembly and intracellular distribution of the former subunits [Zarghooni & Dittakavi 2009].

Abnormal gene product. See Molecular Genetic Pathogenesis.


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Suggested Reading

  • Gissen P, Maher ER. Cargos and genes: insights into vesicular transport from inherited human disease. J Med Genet. 2007;44:545–55. [PMC free article: PMC2597945] [PubMed: 17526798]
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  • Lachmann R. Treatments for lysosomal storage disorders (2010). Biochem Soc Trans. 2010;38:1465–8. [PubMed: 21118108]
  • Leroy JG. Oligosaccharidoses, disorders allied to the oligosaccharides. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics. 5 ed. Philadelphia, PA: Churchill Livingstone; 2007:2413-48.

Chapter Notes

Revision History

  • 10 May 2012 (me) Comprehensive update posted live
  • 7 July 2009 (cd) Revision: deletion/duplication analysis available clinically for GNPTAB
  • 26 August 2008 (me) Review posted live
  • 11 March 2008 (jgl) Original submission
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