Clinical manifestations

Presentation and course

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 (21; 36; 09). 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 (04). Both interfamilial and intrafamilial clinical variability has been reported (02).

Neonates have coarse facial features with puffy eyelids, prominent epicanthal folds, a flat nasal bridge, marked gingival hyperplasia, and macroglossia (68; 78). Patients usually have prominent abdomens with hepatomegaly and umbilical hernias. Splenomegaly, if present, is minimal. Cardiac abnormalities are often present (71).

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 (37). The skeletal disease is progressive and has many features of chronic hyperparathyroidism but with normal parathormone (12). Cervical spinal stenosis may induce spinal cord compression as early as 1 year of age (52). Airway problems and sleep-disordered breathing are very common (17; 62; 52).

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 (55).

Mixed hearing loss with both conductive and sensory (cochlear) components has been reported (27).

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 (36; 87). 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 (87). 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 (30; 88). Even patients with this milder form of the disease may present with complex orthopedic problems (22). Spinal cord compression may occur from cervical spinal canal stenosis (52).

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 (84), 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 (90; 92; 29; 80), likely due to multifocal enlargement of peripheral nerves that is observed by ultrasound (51). 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 (92).

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 (57).

Prognosis and complications

The clinical course of mucolipidosis II alpha/beta patients is characterized by rapid 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 (91).

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 (85). 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.

Clinical vignette

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 (82). 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.

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 (30). 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 (30). 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) (25; 66). 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 (49).

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.

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 (67; 87). 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 (26; 53; 24).

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 (25; 66; 72).

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 (56). An abnormality of autophagy was suspected (33) and subsequently confirmed in a knock-in mouse model of mucolipidosis II (35). Accumulation of substrates of enzymes that require mannose 6-phosphate targeting occurs in the brain and is associated with progressive neurodegeneration (35).

Altered growth factor signaling contributes to the phenotypes associated with mucolipidosis II (01). 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 (93; 84; 87; 31). 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 (63) or cause misfolding of the protein and its retaining in the endoplasmic reticulum (86; 43). 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 (11); 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 (64).

Nonsynonymous coding variants in GNPTAB, GNPTG, and NAGPA may account for as much as 16% of persistent nonsyndromic stuttering cases (65). These variants are generally not found among mucolipidosis cases and exert a less deleterious effect on protein function (65).

Cultured fibroblast cells from both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta patients are characterized by the presence of numerous cytoplasmic inclusions when examined by phase-contrast microscopy (39; 77). Antibody studies have shown that these inclusions have the properties of secondary lysosomes (69). 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 (34). 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 (41; 81).

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 (32; 79). Such abnormalities affect the spine, causing cervical developmental stenosis and atlantoaxial instability (79). Bone remodeling is impaired in patients with GNPTAB-associated mucolipidosis III alpha/beta but not with GNPTG-associated mucolipidosis III gamma (14).

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 (05).

Epidemiology

Mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are rare inborn errors of metabolism (15). Cases have been reported from multiple countries, and there is no evidence of ethnic predilection.

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 (15). The median age of death was 1.8 years for mucolipidosis II alpha/beta and 33.0 years for mucolipidosis III alpha/beta (15). The most frequent causes of death in all forms of mucolipidosis were pulmonary or cardiac complications (15). 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 (28). Pathogenic variants were described in 388 patients (GNPTAB: 571, GNPTG 179) (15).

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 (59; 03). 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 Hurler patients, the distinction is best based on laboratory findings (89). In contrast to Hurler patients, who excrete excessive amounts of acid mucopolysaccharides, mucolipidosis II patients have normal or only slightly elevated levels of these compounds.

In contrast to mucolipidosis II alpha/beta, mucolipidosis III alpha/beta patients 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 mucolipidosis III alpha/beta patients 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 (07). Mildly affected mucolipidosis III alpha/beta siblings with isolated involvement of the hips and mild abnormalities of the spine have also been described (19).

Diagnostic workup

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 both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta patients 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 (50).

Mutations of the GNPTAB or GNPTG genes confirm the diagnosis, and genetic counseling should be offered (93). Methods for rapid and high-throughput diagnosis are based on either the fingerprint approach for screening urinary oligosaccharides using mass spectrometry (74) or identifying a reduction in the specific lysosomal enzyme protein in dried blood spots (20).

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, widening of the ribs, and shortening of the long bones (09). Gibbus deformities may develop, particularly in the lumbar spine (32).

Other common spinal abnormalities evident on imaging include cervical developmental stenosis and atlantoaxial instability (79).

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.

Cellular alterations associated with bone abnormalities differ with age (61; 60) and may look radiologically like rickets (42).

Although cranial magnetic resonance studies in patients with mucolipidosis II alpha/beta have demonstrated ventriculomegaly associated with frontal lobe atrophy and bifrontal leukomalacia in one patient with mucolipidosis II alpha/beta (06), its relationship to this disease is uncertain. Delayed myelination was observed on sequential brain MRI testing, which was confirmed by neuropathological examination (76). Craniosynostosis and moyamoya syndrome have been observed in patients with mucolipidosis II (10; 13).

In the absence of known risk, antenatal cases of mucolipidosis II may be incidentally identified using ultrasound in women with polyhydramnios (38).

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 (27; 83). 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 (27). In addition, some patients may have abnormal central motor function on magnetic cortical stimulation or abnormal central somatosensory function with somatosensory evoked potentials (83).

Management

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 (54). 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 (54).

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 (44; 54).

Gene therapy is not available for patients with mucolipidosis II or III (70). Although biochemical correction of mucolipidosis III alpha/beta by gene transfer has been reported in vitro, it remains an experimental procedure (18). 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 (47); 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) (23). Odontoid dysplasia may cause atlantoaxial instability, or dislocation can lead to severe neurologic sequelae or sudden death (85). Carpal tunnel syndrome is a common complication of mucolipidosis III alpha/beta, often requiring surgical management (23; 85).

Special considerations

Anesthesia

Laryngeal intubation may be technically difficult, and laryngeal mask airway may be used in critical events to transiently secure the airway (45; 16; 73). 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 (73).