Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of mucolipidosis II alpha/beta and mucolipidosis III alpha/beta, ML II, ML II alpha/beta, inclusion cell disease, ML III, ML III alpha/beta, mucolipidosis II alpha/beta, mucolipidosis III alpha/beta, I-cell disease, and pseudo-Hurler polydystrophy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Mucolipidosis II alpha/beta (I-cell disease) and mucolipidosis III alpha/beta (pseudo-Hurler polydystrophy) are caused by abnormal cellular lysosomal enzyme transport resulting from mutations in the GNPTAB gene, which encodes the alpha and beta subunits of N-acetylglucosamine-1-phosphotransferase. Mucolipidosis III can also be caused by mutations affecting the GNPTG gene.
N-acetylglucosamine-1-phosphotransferase is necessary for the synthesis of mannose-6-phosphate, which is essential for proper targeting of lysosomal enzymes to lysosomes. Mucolipidosis II alpha/beta has many features of Hurler syndrome, but presents earlier and does not show mucopolysacchariduria. There is severe progressive psychomotor retardation, and death usually occurs in the first decade. Craniosynostosis and moyamoya syndrome have been observed in mucolipidosis II patients. Pseudo-Hurler polydystrophy is milder with longer survival.
• Mucolipidosis can be severe or mild, with little or no dysmorphic features.
• The activity of multiple lysosomal enzyme is elevated in the plasma.
• The disease is caused by a deficiency of multiple lysosomal enzymes and the accumulation of their respective substrates.
• The phenotype is in fact a continuum and can even present with parkinsonism or masquerade as rickets.
• Hematopoietic stem cell transplantation is not recommended for mucolipidosis II.
In the mid-1960s a group of patients with clinical features intermediate between those found in the mucopolysaccharidoses and those in the sphingolipidoses were described. Because of the overlapping phenotypes and evidence of visceral storage of mucopolysaccharides, sphingolipids, and glycolipids, these patients were grouped together under the general classification of "genetic mucolipidosis" (60).
Among the 8 distinct diseases included in this group of disorders were mucolipidosis II alpha/beta and mucolipidosis III alpha/beta. The former is often referred to as I-cell disease, whereas the latter is also known as pseudo-Hurler polydystrophy. Because both of these disorders result from abnormalities affecting the same gene and also have many clinical, cellular, and biochemical features in common, they are considered together in this review.
Mucolipidosis II alpha/beta (I-cell disease) was first identified as a separate and distinct disorder in patients having many of the clinical features of the Hurler syndrome, but lacking the excessive mucopolysacchariduria expected in the disorder (32). The conclusion that these patients suffered from a heretofore unknown disorder was based on the finding of striking cytoplasmic inclusions in their cultured fibroblasts. Because of this finding, the disorder was given the designation "inclusion cell disease" (32), subsequently abbreviated to "I-cell disease" (33). Spranger and Wiedemann included this disorder in the group of diseases they called the mucolipidoses and designated it mucolipidosis II (60). This has been renamed mucolipidosis II alpha/beta (07).
In 1966, Maroteaux and Lamy described 4 patients with mild Hurler-like features that they classified "la pseudo-polydystrophie de Hurler" (39). They considered these patients to have the same disorder previously described as "a mucopolysaccharidosis defying classification" (40). Subsequently, this disorder was also placed in the mucolipidosis group and was given the designation mucolipidosis III alpha/beta (07). Support for this classification was provided by the discovery that cultured fibroblasts from these patients were characterized by the same "I-cell phenomenon" previously seen in mucolipidosis II patients (62).
Mucolipidosis II alpha/beta (I-cell disease) is characterized by many of the clinical and radiologic findings found in the Hurler syndrome (17; 29; 08). 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, hernia, and dislocations of the hips are often present soon after birth. Defective proximal tubular dysfunction was identified in a patient with mucolipidosis II (03).
Neonates have coarse facial features with puffy eyelids, prominent epicanthal folds, a flat nasal bridge, marked gingival hyperplasia (55; 63), and macroglossia. Patients usually have prominent abdomens with hepatomegaly and umbilical hernia. Splenomegaly, if present, is minimal. Cardiac abnormalities are often present (57). Marked shortness of stature, lumbar gibbus deformities, and restricted joint mobility are usually present at an early age.
Skeletal abnormalities include shortening and anterior beaking of vertebral bodies, widening of the ribs, and shortening of the long bones (08). Growth is below normal and joint immobility becomes more severe with age. Claw-hand deformities and lumbar kyphosis are common. Generalized dysostosis multiplex is present from an early age (30). Cellular alterations associated with the bone abnormalities differ with age (50; 49) and may look radiologically like rickets (35). It should be noted, however, that both interfamilial and intrafamilial clinical variability has been reported (01). The skeletal disease is progressive and has many features of chronic hyperparathyroidism, but with normal parathormone (11). Consequently, airway problems and sleep-disordered breathing are very common (13).
Progressive psychomotor retardation is a characteristic feature of this disorder. A clinical study of 21 mucolipidosis II patients suggested that motor development is generally more severely retarded than mental development (45). Conductive hearing impairment, associated with the cochlear component, has also been found in many patients (23). Although magnetic resonance studies have demonstrated ventriculomegaly associated with frontal lobe atrophy and bifrontal leukomalacia in 1 mucolipidosis II alpha/beta patient (05), its relationship to this disease is uncertain. Delayed myelination was observed on sequential brain MRI testing, which was confirmed by neuropathological examination (61). Craniosynostosis and Moyamoya syndrome have been observed in patients with mucolipidosis II (09; 12).
Although having the same cellular and biochemical alterations found in mucolipidosis II alpha/beta, mucolipidosis III alpha/beta is a much milder disorder. In contrast to the former, 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 (29; 70). 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.
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 (70). In a study of 12 patients considered to have mucolipidosis III alpha/beta, Kelly and colleagues further defined the major clinical findings in this disorder (25). In addition to the findings originally described, they added progressive joint contractures, fine corneal opacities, valvular heart disease, the radiographic pattern of dysostosis multiplex, and unusual pelvic and vertebral changes. MRI studies of the hips in siblings with mucolipidosis III alpha/beta have shown alterations in signal intensity (71). Even patients with this milder form of the disease may present with complex orthopaedic problems (18).
The initial complaint of individuals with mucolipidosis III alpha/beta is often joint stiffness (67). Progressive restrictions of mobility of the hands, hips, elbows, and shoulders are commonly encountered in this disorder. The carpal tunnel syndrome frequently occurs in these patients (73). At least 1 patient with the carpal tunnel syndrome and insensitivity to pain had self-mutilation of the distal phalanges of the digits of her hands (75). The common nerve entrapment is likely due to peripheral nerves multifocal enlargement in mucolipidosis type III that is observed by ultrasound (43). The use of the turnover palmaris brevis flap in conjunction with internal neurolysis has been reported to have alleviated symptoms in 1 patient (24). In a series of 13 adult patients with mucolipidosis type III aged 18 to 68 years, only 4 patients had mild cognitive deficit whereas the others had normal cognitive function (47). Most of the morbidity was due to skeletal abnormalities. Growth failure and short stature are common. Overall, the clinical course of the disease is slowly progressive, with progressive destruction of the joints a major clinical problem.
The clinical course of mucolipidosis II alpha/beta patients is characterized by rapid deterioration, with death usually occurring between the 5th and 10th year of life. The major causes of death are congestive heart failure and recurrent respiratory infections, perhaps secondary to cellular changes found in the tissues of these patients (74).
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. In the most detailed report of the clinical course of mucolipidosis III alpha/beta, Umehara and associates described 3 affected siblings who were 38, 61, and 86 years of age (68). 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. Subclinical abnormalities of the central nervous system have also been documented in t2 mucolipidosis III alpha/beta patients. These findings included abnormal central motor functions in both patients and central somatosensory system involvement in 1 of them (66).
The male patient was born to nonconsanguineous parents of German origin; his older brother was healthy. At 18 months of age, he was presented at a children’s hospital because of coarse facies, restricted joint mobility, claw-like hands, and delayed psychomotor development. Radiographs revealed a generalized bone dysplasia and enlarged heart. The urinary mucopolysaccharide excretion was normal. At 6 years of age, he had a Hurler-like appearance and short stature with a height of 90 cm, ie, 12 cm < 3 percentile. Marked joint contractures and an umbilical hernia were present. The liver was palpable 2 to 3 cm below the costal margin, and developmental milestones were those of a 3.5-year-old child. There was a mild corneal clouding. At 12 years of age, his condition had worsened. Patient's height was 92 cm, ie 46 cm < 3rd percentile, and he exhibited radiologically severe dysostosis multiplex. He died at 14 years of age from cardiac failure (65).
Both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are autosomal recessive disorders. Evidence for this conclusion in mucolipidosis III alpha/beta is found in the results of a large family study by Kelly and colleagues (25). In 8 families affected with this disorder, the researchers found 4 affected sibling pairs, phenotypically normal parents, and both affected males (7) and females (5). There were also 18 normal siblings. Similar findings have been found in mucolipidosis II alpha/beta families.
It has been shown that both of these disorders are associated with a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase (GlcNAc-P-transferase) (21; 54). As expected for an autosomal recessive disorder, affected patients lack this enzyme, whereas the activity in their parents (obligate heterozygotes) is below the normal range (41). Evidence that the enzyme maldistribution in mucolipidosis II alpha/beta and mucolipidosis III alpha/beta might result from a lack of a recognition marker required for normal uptake and transport of enzymes to the lysosomal system was presented in 1972 (22). Subsequently, it was shown that lysosomal enzymes from normal cells do, in fact, have a recognition marker (mannose-6-phosphate) that facilitates the targeting of the enzymes to lysosomes (44; 20). The lack of the mannose-6-phosphate in mucolipidosis II alpha/beta and mucolipidosis III alpha/beta patients was subsequently shown to result from a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase (21; 54). Using the lysosomal enzyme arylsulfatase A as a model, the phosphotransferase recognizes a large part of the lysosomal enzyme, a key step in the process of adding the required mannose-6-phosphate marker (58).
As a result of the above abnormality, multiple lysosomal enzymes in mucolipidosis II alpha/beta and mucolipidosis III alpha/beta cells, lacking the recognition marker required for normal cellular uptake, leak into extracellular fluids. The deficiency of lysosomal enzymes within the lysosomes results in abnormal cellular accumulation of undigested substrates (46). This, in turn, leads to the clinical manifestations typical of lysosomal storage disorders. An abnormality of autophagy was suspected (26) and confirmed in a knock in mouse model of mucolipidosis II (28). Accumulation of substrates of enzymes that require mannose 6-phosphate targeting occurs in the brain and is associated with progressive neurodegeneration (28).
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 (76; 67; 70). GNPTAB missense mutations are present in protein domains that involve Golgi retention of GlcNAc-1-phosphotransferase and its ability to specifically recognize lysosomal hydrolases, respectively. Other missense mutations are in domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition (51) or cause misfolding of the protein and its retaining in the endoplasmic reticulum (69; 36). Mutations in this gene as well as in the GNPTG gene, which encodes the gamma subunit of GNPT, and in the NAGPA gene, were found in affected subjects of Asian and European descent but not in control subjects. However, the author did not measure the actual activity of the enzymes. The GNPTAB mutation c.3503_3504delTC has been detected among Israeli and Palestinian Arab-Muslim, Turkish, Canadian, Italian, Portuguese, Irish travelers and patients in the United States (10). These authors found that 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 (52).
Nonsynonymous coding variants in GNPTAB, GNPTG, and NAGPA may account as a risk factor for as much as 16% of persistent nonsyndromic stuttering cases (53). These variants are generally not found in mucolipidosis and exert a less deleterious effect on protein function (53).
As already noted, 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 (32; 62). Antibody studies have shown that these inclusions have the properties of secondary lysosomes (56). Investigations on cells from 3 siblings with mucolipidosis II alpha/beta demonstrated inclusion bodies with vesicles, granules, flocculent material, amorphous electron-dense globules, and myelin structures (27). Cells from these patients also have an unusual enzyme alteration, ie, 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, urine, etc. (34; 64).
As mentioned, both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are inherited as autosomal recessive disorders. Case reports of these disorders have appeared from all parts of the world, suggesting that these disorders occur in most, if not all, ethnic groups. Although the basic enzyme and associated biochemical alterations appear to be similar in both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta, a related disorder, mucolipidosis III gamma is caused by mutations in the GNPTG gene that encodes the gamma subunit of N-acetylglucosamine-1-phosphotransferase. The identification of a female cat having clinical, biochemical, and morphologic findings similar to humans with mucolipidosis II alpha/beta may provide additional insights into the basic alterations underlying this disorder (04).
Couples at risk for the birth of infants affected with either mucolipidosis II alpha/beta or mucolipidosis III alpha/beta are almost always identified as the result of the diagnosis of a previously affected child. For this reason, it is important that any patient with some or all of the clinical features of mucolipidosis II alpha/beta or mucolipidosis III alpha/beta be worked up in such a manner as to confirm or rule out this possibility. If it is established that the patient in question is affected with 1 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 members of the family 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, couples at risk should be advised of the possibility of prenatal diagnosis (48; 02). It is possible that, in the absence of known risk, mucolipidosis II can be diagnosed using ultrasound (31). Preimplantation genetic diagnosis should also be applicable to both disorders.
Mucolipidosis II alpha/beta, the more severe of these 2 disorders, is most likely to be confused with 1 of the severe forms of the mucopolysaccharidoses, eg, the Hurler syndrome. Generally, these patients will present within the first year of life with obvious signs of some form of "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. 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 an 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 3 mucolipidosis III alpha/beta patients referred to a pediatric rheumatology clinic, 1 had initially been diagnosed as having juvenile rheumatoid arthritis, the second was suspected of having scleroderma, and the third Hurler syndrome (06). Mildly affected mucolipidosis III alpha/beta siblings with isolated involvement of the hips and mild abnormalities of the spine have also been described (15). The differentiation of mucolipidosis and related disorders from the mucopolysaccharidoses has been reviewed (72).
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 the 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 2 forms of mucolipidosis is based on the measurement of 1 or more lysosomal enzymes in plasma. Due to the leakage of cellular enzymes, these patients are characterized by greatly elevated levels (10 to 20 times normal) of a large number of lysosomal enzymes in plasma or serum. The measurement of hexosaminidase A 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 between 10 and 20 times normal levels of this enzyme is good evidence for these disorders.
Once a patient is shown to have elevated levels of 1 or more lysosomal enzymes in plasma, examination of cultured skin fibroblast 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 the measurement of the UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the actual enzyme responsible for these disorders. Finally, it should be noted that 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 2 forms of the disease; the conclusion that a patient suffers from either the severe (mucolipidosis II alpha/beta) form or the mild (mucolipidosis III alpha/beta) form of the disorder is usually based on the clinical findings. A single-chain antibody fragment against Man6P has been demonstrated to allow the specific, rapid, and convenient detection of Man6P-containing proteins, which in the case of mucolipidosis II and III is absent (42). Mutations of the GNPTAB or GNPTG genes confirm the diagnosis, and genetic counseling should be offered (Tappino et al 2009; 76). Methods for rapid and high-throughput diagnosis are based on either the fingerprint approach for the screening of urinary oligosaccharides using mass spectrometry (59) or identifying reduction in the specific lysosomal enzyme protein in dried blood spots (16).
As both mucolipidosis II alpha/beta and mucolipidosis III alpha/beta are inherited disorders, the establishment of a firm diagnosis, confirmed by the laboratory procedures outlined previously, is an important aspect of the management of these disorders. Once the diagnosis is confirmed and the clinical distinction between the 2 types is established, the family can be counseled as to the prognosis, inheritance, recurrence risks, etc. 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. Because of the progressive nature of these disorders, the expected future course of the disease process should be reviewed with the patient and family. Of particular concern is odontoid dysplasia resulting in atlantoaxial instability or dislocation that can lead to severe neurologic sequelae or sudden death (68). These authors recommend that attention be paid to the possibility of these complications from an early stage of the illness (68). The use of nasal continuous positive airway pressure has been shown to lessen morbidity and improve the quality of life in at least 1 patient with mucolipidosis II alpha/beta. Laryngeal intubation may be technically difficult, and laryngeal mask airway may be used in critical events to transiently secure the airway (38). Carpal tunnel syndrome has also been found to be a common complication of mucolipidosis III alpha/beta (19; 68). Haddad and associates have described their assessment protocol, physiotherapy, operative regime, and functional review of this complication in patients suffering from either one of the mucopolysaccharidoses or mucolipidoses III alpha/beta (19).
Although biochemical correction of mucolipidosis III alpha/beta in vitro by gene transfer has been reported (14), it remains an experimental procedure at this time. A review of 22 patients who underwent hematopoietic stem cell transplantation concluded that, unlike in mucopolysaccharidosis I (Hurler disease), this procedure is not effective in mucolipidosis II (37).
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.See Profile
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