DiagnosisClinical DiagnosisThe following clinical features contribute to early diagnosis of mucolipidosis II (ML II) but are not by themselves diagnostic (Figure 1):FigureFigure 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 (more...)Perinatal onsetSmall to low-normal anthropometric measurements for gestational ageWeak cryRestricted range of motion in the shouldersGeneralized hypotoniaFull, round cheeks with flat face, shallow orbits, and depressed nasal bridgeThick 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 kyphosisClubfeetDeformed long bones (see Figure 1)Dislocation of the hip(s)In infancy, skeletal radiographs reveal the following (Figure 2):FigureFigure 2. Outline of periosteal margins (also called “periosteal cloaking”), seen here in the humerus and forearm bones of an 8-month-old girl 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 ossificationRibs that widen at or near the costochondral junctions and are narrower than normal in the dorsal juxtavertebral partsVertebral 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 bordersPelvic dysplasia with narrow basilar portions of the ilia and relatively long pubic and ischial bones; slanting acetabular roofs; coxa valgaSkull 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):FigureFigure 3. Left wrist and forearm in 5-year-old girl 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.TestingActivity 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 3.2.1.52)β-D-glucuronidase (EC 3.2.1.31)β-D-galactosidase (EC 3.2.1.23)α-L-fucosidase (EC 3.2.1.51) 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 2.7.8.17) encoded by GNPTAB, confirms the diagnosis of ML II. This analysis requires specific substrates, laboratory techniques, and experience. Molecular Genetic TestingGene. To date, GNPTAB is the only gene in which mutations are known to cause ML II.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Mucolipidosis IIView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityGNPTABTargeted mutation analysisc.3503_3504delTC 2(see Table 2 [pdf], Table 3)100% for the targeted mutationClinical Sequence analysisSequence variants 3>95% 4Deletion / duplication analysis 5Partial- or whole-gene deletions or duplicationsUnknown 6Uniparental disomyNot applicableUnknown; none reported 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutation attributed to a founder effect (see Prevalence).3. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.4. Bidirectional sequencing of the entire GNPTAB coding region detects two alleles with disease-causing mutations in more than 95% of persons with ML II. 5. 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.6. Few such mutations 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.7. Uniparental disomy is theoretically possible but has not been reported as a cause of mucolipidosis II.Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.In cases of apparent homozygosity for a single pathogenic allelic 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.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband requires a combination of clinical evaluation and laboratory testing. The following order of diagnostic testing is recommended:1.Identification of characteristic clinical and radiographic findings2.Assay of oligosaccharides (OS) in urine3.Assay of several acid hydrolases in plasma; for example:β-D-hexosaminidase (EC 3.2.1.52)β-D-glucuronidase (EC 3.2.1.31)β-D-galactosidase (EC 3.2.1.23)α-L-fucosidase (EC 3.2.1.51)Arylsulfatase A (EC 3.1.6.1)
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).4.Sequence analysis of GNPTAB5.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; ORA 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 mutations in a proband is preferred; however, sequence analysis of the entire gene in both carrier parents can be used to try to identify both disease-causing 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. Mutations that completely inactivate the specific phosphotransferase consistently result in ML II irrespective of their location within the gene. Mutations 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 disease-causing mutations in the family.Genetically Related (Allelic) DisordersMucolipidosis III alpha/beta (pseudo-Hurler polydystrophy) is allelic with ML II. Its clinical onset is later, the course considerably slower, and the life expectancy in the absence of complications much longer. The phenotypic spectrum of individuals with GNPTAB mutations is dichotomous rather than continuously variable, as has been confirmed by the several studies on genotype-phenotype correlation made possible by mutation screening (see Genotype-Phenotype Correlations). Mucolipidosis alpha/beta intermediate (ML II/III alpha/beta). Genotypes associated with phenotypes intermediate to both ML II and ML III alpha/beta have been identified, even when the inherent clinical variability of ML II and ML III are taken into account [Cathey et al 2010] (see Genotype-Phenotype Correlations). Pacman dysplasia, once thought to be a distinct perinatal lethal skeletal dysplasia, is now known to be the prenatal manifestation of ML II [Saul et al 2005] (see Clinical Description, Pre- and perinatal phenotype).Mucolipidosis III gamma. To date, not a single individual with a true ML II phenotype with either a homozygous or compound heterozygous GNPTG mutant genotype has been observed or reported.}

Natural HistoryMucolipidosis 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.FigureFigure 4. Profile view of 3-year-old 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 abdomen (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.FigureFigure 5. Coarse facial features and gingival hypertrophy in 5-year old girl 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 mutations.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 mutations 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 CorrelationsGNPTAB 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” mutations, such as missense and most of the splice-site mutations 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, Encarnaçao 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 missense mutation and a splice-site mutation is found. In others the intermediate phenotype is associated with parental consanguinity. In one family with five affected siblings, the intermediate phenotype was clearly correlated with a specific compound heterozygous mutant genotype [David-Vizcarra et al 2010].

Differential DiagnosisLysosomal Storage DiseaseFindings 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisIn 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 functionPulmonary 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 examinationHearing screenDevelopmental assessment to help establish appropriate expectations for the child’s developmental progressGenetics consultationTreatment of ManifestationsSupportive 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 ComplicationsBecause 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.SurveillanceInfants 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementSince 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 InvestigationTreatment 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 ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGNPTAB12q23​.2N-acetylglucosamine-1-phosphotransferase subunits alpha/betaGNPTAB homepage - Mendelian genesGNPTABData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Mucolipidosis II (View All in OMIM) View in own window 252500MUCOLIPIDOSIS II ALPHA/BETA 607840N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE, ALPHA/BETA SUBUNITS; GNPTABMolecular Genetic PathogenesisIf 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 mutations 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 mutations 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 2.7.8.17). 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. Mutations 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.Normal allelic variants. 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. Pathologic allelic variants. Several dozens of mutations are known. Types of pathologic variants include missense, nonsense, and splice-site mutations, as well as small insertions and deletions that result in a shift of the proper reading frame. See Table 2 (pdf). Either type of mutation combined with a splice-site or missense mutation 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 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.3503_3504delTC ^{1p.Leu1168Glnfs*5NM_024312​.4
NP_077288​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Mutation 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 mutations 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.}