Mucolipidosis Ii Alpha/beta
A number sign (#) is used with this entry because of evidence that mucolipidosis II alpha/beta, also known as I-cell disease, is caused by homozygous or compound heterozygous mutation in the GNPTAB gene (607840).
Mucolipidosis III alpha/beta (252600), or pseudo-Hurler polydystrophy, is also caused by mutation in the GNPTAB gene.
A mucolipidosis variant called mucolipidosis III gamma (252605) is caused by mutations in the GNPTG gene (607838).
NomenclatureCathey et al. (2008) reported an updated nomenclature classification system for mucolipidosis II and III. ML II was renamed ML II alpha/beta; ML IIIA was renamed ML III alpha/beta; and ML IIIC was renamed ML III gamma.
DescriptionMucolipidosis type II alpha/beta is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. It is phenotypically more severe than the allelic disorder mucolipidosis type III alpha/beta (summary by Paik et al., 2005).
Clinical FeaturesMucolipidosis II is a Hurler (607014)-like condition with severe clinical and radiologic features, peculiar fibroblast inclusions, and no excessive mucopolysacchariduria. Congenital dislocation of the hip, thoracic deformities, hernia, and hyperplastic gums are evident soon after birth. Retarded psychomotor development, clear corneas, and restricted joint mobility are other features. Leroy et al. (1969) first described this condition and named it I-cell disease (for 'inclusion cell disease'). Abnormal inclusions were found in the fibroblasts of some heterozygotes. Both sexes were affected in early reports; sibs were affected in 2 families and the parents of 1 of the patients of Spranger and Wiedemann (1970) were first cousins.
Michels et al. (1982) pointed out that ML II should be added to the list of disorders that can show intrauterine fractures.
Beck et al. (1995) analyzed the inter- and intrafamilial variability in I-cell disease based on 9 patients. Although they all had disproportionate dwarfism, coarse facial features, and mental retardation, there was remarkable variability in age of onset, organ manifestation, and radiologic findings. Some had unusual clinical symptoms, including pericardial effusion and profound brain atrophy. Differences were seen even in 2 affected sibs: a brother survived to the age of 8 years, dying of bronchial pneumonia, whereas a sister died from cardiac failure at the age of 2 months, and another sister died at 29 days following a similar course.
Encarnacao et al. (2009) reported 9 unrelated patients with ML II alpha/beta. All had onset before 1 year of age, except 2 who had onset at 4 and 22 months, respectively. Clinical features included psychomotor retardation, coarse dysmorphic facial features, gingival hyperplasia, hip dysplasia, growth retardation, and restricted joint movement. Biochemical studies showed increased activity of several lysosomal enzymes in the serum and decreased activity of these enzymes in fibroblasts.
Biochemical FeaturesLeroy et al. (1972) found no accumulation of lipid in brain and viscera and no accumulation of mucopolysaccharide in these tissues or fibroblasts. For this reason they questioned the appropriation of the designation 'mucolipidosis.'
Deficiency of sialidase (neuraminidase) has been reported in cultured fibroblasts (Thomas et al., 1976) and in leukocytes (Strecker et al., 1976). Furthermore, a sialyl-hexasaccharide is excreted in the urine in considerable amounts (Strecker et al., 1976). Sialic acid levels were increased 3- to 4-fold in cultured ML II cells, but were normal in 9 other lysosomal diseases.
Vladutiu and Rattazzi (1975) found electrophoretic abnormality of lysosomal hydrolases excreted by cultured fibroblasts in I-cell disease and alteration of this mobility by treatment with neuraminidase. Presumably the higher electronegative charge of I-cell hydrolases at pH 6 resulted from sialic acid residues not present on enzyme excreted by normal cells.
Complementation studies suggested that ML II and ML III are determined by mutations at separate loci (Wright et al., 1979). However, by cell fusion studies, Honey et al. (1981) and Shows et al. (1982) demonstrated 2 ML II complementation groups and 3 ML III complementation groups. No complementation was observed between one of the ML II types and one of the ML III types.
Honey et al. (1981) found differing electrophoretic patterns of lysosomal enzymes in cases with the ML II phenotype, suggesting heterogeneity (at least 2 classes). In all cases of both ML II and ML III, deficiency has been found in only one enzyme, the GlcNAc-1-P transferase that attaches GlcNAc-1-P to mannose residues of multiple lysosomal enzymes. Defects in the diesterase that exposes the mannose-6-phosphate marker have not been identified (Sly, 1981). Different defects in the transferase have been found, e.g., an abnormality of the enzyme such that it does not recognize mannose as a substrate. The receptor for lysosomal enzyme necessary for transfer of enzymes to lysosomes is present in all tissues. No receptor-negative mutants had yet been recognized.
Thomas et al. (1982) reported studies of a patient with an atypical form of ML II and presented evidence that the patient was mosaic for 2 populations of cells, one with the I-cell mutation and one normal. They found no evidence of twin chimerism from genetic marker studies.
Okada et al. (1983) showed heterogeneity of ICD lines in the ability of sucrose loading in vitro to induce hydrolases. ML II illustrates nicely the principle that demonstration of an intermediate level of enzyme activity in heterozygotes is a valuable indicator that that enzyme is the site of the primary defect. Although the activity of lysosomal enzymes is low in cells of affected persons, normal levels are found in heterozygotes. (An exception to this statement is the report by Potier et al. (1979) who found intermediate levels of neuraminidase activity in obligatory heterozygotes.) On the other hand, the activity of GlcNAc-1-P transferase is intermediate in ML II heterozygotes (Shows, 1983).
Ben-Yoseph et al. (1987) found abnormally small N-acetylglucosamine 1-phosphotransferase enzyme in Golgi membranes from fibroblasts of patients with I-cell disease and classical pseudo-Hurler polydystrophy, which comprised 1 complementation group characterized by deficiency toward both artificial and natural acceptor substrates. The size of the enzyme varied from 151-174 kD, compared with the normal of 225-278 kD. The mutant enzyme from cell lines of patients with variant forms of pseudo-Hurler polydystrophy, which comprised another complementation group characterized by normal activity toward monosaccharide and oligosaccharide substrates, was significantly larger than the normal enzyme, ranging from 321-356 kD in 2 families and from 528-547 kD in a third family.
PathogenesisIn a review of genetic defects of intracellular membrane transport, Olkkonen and Ikonen (2000) referred to ML II as the prototypic genetic disorder affecting the machinery of protein sorting.
Wiesmann et al. (1971) concluded that the defect leads to leakage of lysosomal enzymes from the cell. Cultured fibroblasts showed low levels of 4 lysosomal enzymes whereas the level of these enzymes in the culture medium was high.
Hickman and Neufeld (1972) presented evidence for their hypothesis that the mutation in I-cell disease is in an enzyme which modifies several lysosomal enzymes to guarantee their recognition by cells and re-entry into cells from the intercellular space into which the enzymes have been secreted by the synthesizing cells. There was precedence for the idea that carbohydrate side chains of glycoproteins control entry of the proteins into liver cells (Morell et al., 1971). This hypothesis would explain why multiple enzymes are high in the medium in which I-cells are grown and low in the cells themselves. It was an alternative to the 'leaky lysosome' hypothesis of Wiesmann et al. (1971). The evidence presented by Hickman and Neufeld (1972) was of several types. For example, they found that alpha-1-iduronidase produced by I-cells did not 'correct' Hurler cells whereas semipurified iduronidase from urine and medium in which normal cells have grown does correct the metabolic defect of Hurler cells. The Neufeld hypothesis was an alternative to the Novikoff hypothesis which suggested that the acid hydrolases are packaged in the lysosomes directly after synthesis in the Golgi apparatus. This may indeed be true for some lysosomal enzymes because acid phosphatase and beta-glucosidase have normal activities in I cells.
Sly et al. (1977) presented evidence that lysosomal enzymes that are capable of being taken up by cells through pinocytosis (high uptake form of lysosomal enzymes) are phosphoglycoproteins. This is consistent with the destruction of uptake by treatment of the enzyme with periodate or with alkaline phosphatase. More specifically a phosphomonoester of mannose appears to be the recognition marker for many lysosomal enzymes.
Varki et al. (1981) showed that the basic defect in mucolipidoses II and III is in 1 of the 2 enzymes involved in generation of the phosphomannosyl residues on acid hydrolases that serve as specific recognition markers for targeting these enzymes to lysosomes. The first of these enzymes, N-acetylglucosamine-1-phosphotransferase (GNPTA; 607840), was deficient in 5 cases of I-cell disease and 10 cases of pseudo-Hurler polydystrophy. No enzyme activity was found in the first group; residual enzyme activity in the second group provides an explanation for the milder phenotype. These may be allelic disorders. Presumably a defect in the second enzyme involved in generating the phosphomannosyl residues, acetylglucosaminyl phosphodiesterase, could also lead to mucolipidosis. In the cases studied, the second enzyme was normal or elevated.
By the study of cell lines deficient in the mannose 6-phosphate receptor, Gabel et al. (1983) demonstrated that an alternative mechanism for delivery of acid hydrolases to lysosomal organelles exists in some cells. A succinct statement of the usual mechanism was given, and the review by Sly and Fischer (1982) was referenced.
Kornfeld (1986) reviewed the 'trafficking of lysosomal enzymes in normal and disease states.' He gave a table of 6 types of lysosomal storage diseases, with examples: those in which no immunologically detectable enzyme is produced (includes conditions with grossly abnormal structural genes); those in which a catalytically inactive polypeptide is synthesized (includes mutations affecting stability or transport of the polypeptide); those in which a catalytically active enzyme is synthesized but not segregated into lysosomes; those in which a catalytically active enzyme is synthesized but is unstable in prelysosomal or lysosomal compartments; those in which an activator protein of a lipid-degrading hydrolase is missing, e.g., 249900; and those in which lysosomal enzyme deficiencies result from intoxication by an inhibitor of a lysosomal enzyme. Kornfeld (1986) provided a graphic diagram of the pathway of lysosomal enzyme targeting to lysosomes. See 154570 for a further illustration of the elucidation of lysosomal enzyme trafficking by study of another 'experiment of nature.' Herzog et al. (1987) found that thyroglobulin (188450) carries the lysosomal recognition marker mannose-6-phosphate. This finding is consistent with the fact that the ultimate destination of TG is the lysosomal compartment, where thyroid hormones are released by proteolytic degradation. However, the thyroglobulin is first exported to the thyroid follicle and then recaptured for the release of thyroid hormone.
DiagnosisVidgoff et al. (1982) studied a population isolate with several couples at risk for ICD and concluded that carriers can be identified by serum levels of beta-D-hexosaminidase B (Vidgoff and Buist, 1977).
Prenatal Diagnosis
Ben-Yoseph et al. (1988) demonstrated the usefulness of specific enzyme diagnosis on the basis of chorion villus samples.
Differential Diagnosis
Saul et al. (2005) reported a female sib of a male fetus that had previously been diagnosed with Pacman dysplasia (167220) by Miller et al. (2003). She had a clinical course and biochemical, cytologic, and radiographic features consistent with the diagnosis of ML II. Saul et al. (2005) suggested that what is called Pacman dysplasia may represent a prenatal manifestation of ML II. Wilcox et al. (2005) argued that Pacman dysplasia is distinct from ML II, but that radiographic and morphologic criteria cannot be used to distinguish between them. In order to make a definitive diagnosis, pathologic material must be examined for lysosomal storage or enzyme assays must be performed.
MappingVidgoff et al. (1982) found possible linkage of ML II to MN (111300) with a lod score of 1.3. Mueller et al. (1987) determined the chromosome assignment of the structural gene altered in the common forms of ML II and ML III, designated GNPTA, by linkage analysis, somatic cell hybrids, and gene dosage. Linkage data with ML II families indicated that the ML II locus is located between GC (139200) and MNS (111300). The combined data indicated that GNPTA maps to 4q21-q23.
Canfield et al. (1998) stated that the GNPTA gene maps to chromosome 12p.
Molecular GeneticsCanfield et al. (1998) found that in 4 of 4 patients with mucolipidosis II, the GNPTA transcript was absent. In 2 of 2 patients with mucolipidosis IIIA, the GNPTA transcript was present but greatly reduced. In all ML II and ML III patients examined, GNPTAG (607838) was present at normal levels.
In 3 unrelated Korean girls with type II mucolipidosis characterized by a decelerating growth pattern from infancy and cardiac abnormalities, Paik et al. (2005) identified compound heterozygosity for 5 different mutations in the GNPTAB gene (607840.0003-607840.0007).
In 6 patients with clinically and biochemically diagnosed mucolipidosis II, Tiede et al. (2005) identified homozygosity or compound heterozygosity for 7 mutations in the GNPTAB gene, all resulting in premature translational termination (e.g., 607840.0010).
Bargal et al. (2006) studied GNPTAB mutations in 24 patients. They suggested that there is a clinical continuum between ML III and ML II, and that the classification of these diseases should be based on the age of onset, clinical symptoms, and severity.
Genotype/Phenotype CorrelationsOtomo et al. (2009) identified 18 GNPTAB mutations, including 14 novel mutations, among 25 unrelated Japanese patients with ML II and 15 Japanese patients with ML III. The most common mutations were R1189X (607840.0004), which was found in 41% of alleles, and F374L (607840.0015), which was found in 10% of alleles. Homozygotes or compound heterozygotes of nonsense and frameshift mutations contributed to the more severe phenotype. In all, 73 GNPTAB mutations were detected in the 80 alleles. In a review of the reported clinical features, most ML II patients had impairment in standing alone, walking without support, and speaking single words compared to those with ML III. The frequencies of heart murmur, inguinal hernia, and hepatomegaly and/or splenomegaly did not differ between ML II and III patients.
Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly Portuguese patients with ML II. Eight of 9 patients had a nonsense or frameshift mutation, the most common being a 2-bp deletion (607840.0011) that was found in 45% of the mutant alleles; one patient was homozygous for a missense mutation. Three additional patients with a less severe phenotype consistent with ML III had missense mutations. Encarnacao et al. (2009) concluded that patients with ML II alpha/beta are almost all associated with the presence of nonsense or frameshift mutations in homozygosity, whereas the presence of at least 1 mild mutation in the GNPTAB gene is associated with ML III alpha/beta.
Population GeneticsIn the French-Canadian population of the Saguenay-Lac-Saint-Jean region of Quebec province, De Braekeleer (1991) estimated the prevalence at birth of ML II to be 1/6,184, giving a carrier frequency of 1/39.
In 27 parents of 16 deceased French Canadian children with ML II, Plante et al. (2008) identified a 2-bp deletion (3503delTC; 607840.0011) in the GNPTAB gene. All parents carried the mutation in the heterozygous state, indicating that the children were likely homozygous. Genealogic data showed 6 founders (3 couples) with a high probability of having introduced the mutation in the population; all originated from France and were married in the Quebec region in the second half of the 17th century.
By haplotype analysis of 44 carriers of the 3503delTC mutation from various populations, Coutinho et al. (2011) found that 59 (97%) of 61 mutant chromosomes shared a common haplotype covering 4 of the 5 polymorphic markers analyzed, indicating a strong founder effect. The 2 remaining chromosomes, both from Italian patients, differed by alleles only at 1 marker. A common haplotype encompassing the 3503delTC mutation was shared by individuals of Italian, Arab-Muslim, Turkish, Argentinian, Brazilian, Irish Traveller, Portuguese, and Canadian origin. The mutation was estimated to have occurred about 2,063 years ago, most likely in a peri-Mediterranean region.
Animal ModelBosshard et al. (1996) described spontaneous mucolipidosis in a cat, which they suggested might be useful in the study of human I-cell disease. The cat showed facial dysmorphism, large paws in relation to body size, dysostosis multiplex, and poor growth, as well as leukocytes and cultured fibroblasts which had the appearance of inclusion cells (I-cells). Activities of a set of lysosomal hydrolases were abnormally low in fibroblasts and excessive in blood plasma. Radiologic findings in the same cat by Hubler et al. (1996) revealed a severely deformed spinal column, bilateral hip luxation with hip dysplasia, an abnormally shaped skull and generalized decreased bone opacity.
Mazrier et al. (2003) described the inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II. They found that the activities of 3 lysosomal enzymes were high in serum but low in cultured fibroblasts that contained inclusion bodies (I-cells), reflecting the unique enzyme defect in ML II. Serum lysosomal enzyme activities of adult obligate carriers were intermediate between normal and affected values. Clinical features in affected kittens were observed from birth and included failure to thrive, behavioral dullness, facial dysmorphia, and ataxia. Radiologic lesions included metaphyseal flaring, radial bowing, joint laxity, and vertebral fusion. In contrast to human ML II, diffuse retinal degeneration leading to blindness by 4 months of age was seen in affected kittens. All clinical signs were progressive and euthanasia or death invariably occurred within the first few days to 7 months of life, often due to upper respiratory disease or cardiac failure.
In an N-ethyl-N-nitrosourea mutagenesis screen, Paton et al. (2014) identified a line of mice with a novel mutation, termed Nymphe (nym), that caused growth retardation and ataxic gate. They identified the nym mutation as a c.2601T-A transversion in exon 13 of the Gnptab gene, resulting in a tyr867-to-ter (Y867X) substitution in the Gnptab preprotein prior to the cleavage signal between the alpha and beta subunits. The mutation resulted in a truncated alpha subunit, complete lack of the beta subunit, and retention of the alpha subunit in the endoplasmic reticulum. Whereas nym/+ mice appeared normal, nym/nym mutants had facial and skeletal abnormalities from birth, reduced fertility, progressive ataxia and motor incoordination, and elevated mortality. Nym/nym serum had abnormally high activity of lysosomal hydrolases, and tissues showed inclusion bodies indicative of lysosomal storage. Nym/nym brain showed atrophy, with progressive loss of cerebellar Purkinje cells. Paton et al. (2014) concluded that the nym mutation produces a mouse model that recapitulates the human pathology of mucolipidosis II.