Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by Enns et al., 2001).
Sialuria differs from the sialidoses (256550) in the accumulation and excretion of free sialic acid and normal (or increased) levels of neuraminidase activity. In the disorder originally described by Montreuil et al. (1968) and Fontaine et al. (1968) ... Sialuria differs from the sialidoses (256550) in the accumulation and excretion of free sialic acid and normal (or increased) levels of neuraminidase activity. In the disorder originally described by Montreuil et al. (1968) and Fontaine et al. (1968) and characterized by massive excretion of free sialic acid, Kamerling et al. (1979) implicated defective feedback inhibition of one of the enzymes involved in sialic acid synthesis. Wilcken et al. (1987) described a 2-year-old girl (A.W.) with moderate developmental delay, hepatosplenomegaly, slightly coarse facial features, a large tongue, macrocephaly, and massive urinary excretion of free sialic acid. At age 7 years, she had mild intellectual impairment, with fine-motor difficulty, but attended regular school (Don and Wilcken, 1991). Her growth was at the 10th percentile, and the organomegaly persisted. Seppala et al. (1989) indicated that only 3 bona fide cases appeared to have been discovered: the French case of Montreuil et al. (1968), the Australian case of Wilcken et al. (1987), and an American case studied by his coauthor Barsh. Seppala et al. (1989) studied the patient reported by Wilcken et al. (1987) and a 3-year-old boy who presented at 3 months of age with hepatosplenomegaly, coarse facies, and massive urinary excretion of free N-acetylneuraminic acid (NANA or NeuAc). Both patients had near normal growth and development, unlike patients with lysosomal storage of NANA. In sialuria fibroblasts, 88% of accumulated NANA was in the cytosolic fraction. From a study of cultured fibroblasts, Seppala et al. (1989) derived evidence that the metabolic defect consists of a loss in sensitivity of the rate-limiting enzyme in NANA synthesis, uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase; 603824), to feedback regulation by cytidine monophosphate (CMP)-NANA, as suggested by Thomas et al. (1985). This may be the first instance of a human disease due to defective allosteric inhibition, with apparent preservation of the mutant enzyme's active site. Thomas et al. (1989) demonstrated striking cellular differences between the original French sialuria patient and patients with infantile sialic acid storage disease (ISSD; 269920). Whereas phase microscopy and immunochemical studies showed abnormal storage within intracellular inclusions in ISSD cells, Thomas et al. (1989) found no morphologic evidence of storage within any subcellular organelle in the French sialuria cells. Moreover, comparative subcellular fractionation studies on gradients of colloidal silica showed the excess sialic acid in ISSD cells to be located within the light (buoyant) lysosomal fraction, whereas the excessive, free sialic acid in the sialuria cells was found in the cytoplasmic fraction with no increased storage within the lysosomal fractions. In fibroblasts cultured from the 3 known cases of sialuria, Seppala et al. (1991) found 70- to 200-fold increases in soluble sialic acid but normal concentrations of bound sialic acid. They found also that the total cellular content of soluble sialic acid was lowered 14 to 46% by cytidine feeding. They repeated their conclusion that the basic biochemical defect is a failure of CMP-N-acetylneuraminic acid to feedback-inhibit UDP-GlcNAc 2-epimerase. They noted that cells from both parents of 1 sialuria patient contained normal concentrations of free sialic acid, and the parental epimerase activity also responded normally to CMP-NeuAc. Leroy et al. (2001) reported a patient with sialuria who was heterozygous for a mutation in the epimerase gene (R266Q; 603824.0002). The same heterozygous mutation was detected in the patient's mother, who had similarly increased levels of free N-acetylneuraminic acid, thereby confirming the dominant mode of inheritance of this inborn error. Biochemical diagnosis of the proband was verified by the greatly increased levels of free N-acetylneuraminic acid in his cultured fibroblasts, the distribution of NeuAc mainly, (59%) in the cytoplasm, and by the complete failure of CMP-NeuAc to inhibit 2-epimerase activity in the mutant cells. The findings in this family call for expansion of the phenotype to include adults and for more extensive assaying of free NeuAc in the urine of children with mild developmental delay. The prevalence of sialuria is probably grossly underestimated. Enns et al. (2001) reported a longitudinal study of 1 of the original sialuria patients (J.C.) to age 11 years. Although he had coarse features and massive hepatomegaly, he showed normal growth and relatively normal development. Pulmonary function testing showed minimal small airway obstruction. At age 11 years, he developed intermittent abdominal pain and transient transaminase elevation above his baseline. Enns et al. (2001) suggested that sialuria should be considered in the differential diagnosis of a patient with a phenotype suggestive of mucopolysaccharidosis or oligosaccharidosis in the absence of developmental regression or prominent dysostosis multiplex.
To elucidate the molecular mechanism for defective allosteric regulation of UDP-GlcNAc 2-epimerase in sialuria, Seppala et al. (1999) cloned and sequenced the human cDNA encoding the epimerase and determined the mutations in 3 sialuria patients. They identified 3 ... To elucidate the molecular mechanism for defective allosteric regulation of UDP-GlcNAc 2-epimerase in sialuria, Seppala et al. (1999) cloned and sequenced the human cDNA encoding the epimerase and determined the mutations in 3 sialuria patients. They identified 3 heterozygous mutations, arg266 to trp (603824.0001), arg266 to gln (603824.0002), and arg263 to leu (603824.0003), which indicated that the allosteric site of the epimerase resides in the region of codons 263 to 266. The heterozygous nature of the mutant allele in all 3 patients demonstrated dominant inheritance of sialuria, i.e., heterozygosity for a mutation in the allosteric site is sufficient to cause the disorder. One of the 3 patients, A.W., had been described by Wilcken et al. (1987). The other 2 patients were those reported by Weiss et al. (1989) and Gahl et al., 1996 and by Krasnewich et al., 1993.
The diagnosis of sialuria may be suspected in infants or young children with the following:...
DiagnosisClinical DiagnosisThe diagnosis of sialuria may be suspected in infants or young children with the following:Mild facial coarsening Hypotonia Equivocal developmental delay Frequent upper respiratory infections Note: The likelihood of sialuria is increased after exclusion of more prevalent disorders that share laboratory results rather than clinical features. See Differential Diagnosis.TestingConstitutive overproduction of free sialic acid is the metabolic defect of sialuria [Seppala et al 1999, Huizing 2005]. The sialic acids, a group of negatively charged sugars, are acetyl derivatives of the nine-carbon 3-deoxy-5-amino sugar acid called neuraminic acid. The sialic acid relevant here is N-acetyl-neuraminic acid (NANA).Free sialic acid levels. Assay of free sialic acid in the urine requires expertise either in the spectrophotometric or the fluorometric thiobarbituric acid assay or in thin-layer chromatography; other methods may fail to detect mild-to-moderate elevation of free sialic acid. The biochemical detection method of Cardo et al [1985] is adequate for assay of free and bound sialic acid in urine and whole-cell homogenates [Leroy et al 2001]. Laboratory methodology for the assay of free sialic acid has been reviewed [Gopaul & Crook 2006].Provided that the free sialic acid storage disorders can be ruled out, the finding of excessive excretion of free sialic acid (elevated over 100-fold) in the urine suggests the diagnosis of sialuria.Note: (1) In the spectrophotometric method, other substances may either decrease or increase the absorbance and thus lead to spurious results. (2) High-performance liquid chromatography and proton nuclear magnetic resonance spectroscopy (1H-NMR) may be helpful in sorting out relevant differential diagnoses [Seppala et al 1999, Engelke et al 2004, Valianpour et al 2004].The combination of one- and two-dimensional correlation spectroscopy (COSY):Identifies a specific 1H-NMR spectrum for urinary N-acetyl-neuraminic acid in sialuria, which can be distinguished from the spectrum associated with Salla disease [Engelke et al 2004]; Distinguishes bound sialic acid from free sialic acid and hence distinguishes sialidosis from sialuria. Cytoplasmic localization of free sialic acid. Establishing that the intracellular distribution of free sialic acid is cytoplasmic instead of lysosomal confirms the diagnosis. In sialuria, subcellular fractionation fails to find evidence of lysosomal accumulation of sialic acid, which is characteristic of free sialic acid storage disorders [Aula & Gahl 2001]. Electron microscopic study of parenchymal cells or cultured fibroblasts shows no damage to the lysosomes, in spite of the high levels of free sialic acid found in the cytoplasm. Assay of UDP-GlcNAc 2-epimerase activity. Assay of UDP-GlcNAc 2-epimerase enzyme activity in the presence and in the absence of 100-µmol/L cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac) confirms the diagnosis. The activity of the wild-type enzyme is inhibited 95% by CMP-Neu5Ac, whereas the enzymatic activity of the mutant protein is barely, if at all, diminished by the natural inhibitor. These studies must be performed in a specialized laboratory. Oligosaccharides. The urinary excretion of oligosaccharides is normal. Molecular Genetic TestingGene. GNE is the only gene in which mutations are known to cause sialuria. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in SialuriaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityGNESequence analysisSequence variants 2 including any in the allosteric domain6/6 3, 4Clinical Sequence analysis of select exons 5Missense mutations in exons 4 and 5 only 66/6 3, 4Deletion / duplication analysis 7UnknownUnknown; none reported 81. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of 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.3. Total number of persons known to have been tested to date4. Six of the seven known persons with sialuria have been tested; all six had identifiable mutations in GNE [Ferreira et al 1999, Seppala et al 1999, Aula & Gahl 2001, Enns et al 2001, Leroy et al 2001, Huizing & Krasnewich 2009]. Mutations appear to reside exclusively in the short stretch of consecutive nucleotides that have an important role in the allosteric site (see Molecular Genetics). 5. Exons sequenced may vary by laboratory.6. Including the allosteric domain (see Molecular Genetics)7. 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.8. No deletions or duplications in GNE have been reported to cause sialuria.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. The following order of diagnostic testing is recommended, especially if more probable differential diagnoses have been ruled out:1.Assay of free sialic acid in urine 2.Sequence analysis of GNE with special attention for mutations in nucleotides that encode the allosteric site. Deletion/duplication analysis likely has limited clinical value. Deletion/duplication analysis is relevant only if no nucleotide change is detectable in or around the allosteric site in a patient who fulfills all clinical and biochemical criteria of the diagnosis of sialuria.Testing at-risk relatives of a proband to identify those who may be mildly affected requires prior identification of the disease-causing mutation in the family. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersIn contrast to the dominant gain-of-function effect of heterozygous mutations in the allosteric site observed in sialuria, homozygous or compound heterozygous GNE missense mutations are being recognized in adults with an autosomal recessive late-onset type myopathy that is distinct from sialuria (see Inclusion Body Myopathy 2). The GNE-related myopathies have been known by several descriptive terms including hereditary inclusion body myopathy (hIBM), hereditary IBM quadriceps sparing type or h-IBM2 (OMIM 600737), and distal myopathy with rimmed vacuoles (DMRV) or Nonaka myopathy (OMIM 605820). Initially described and delineated as separate myopathies based on muscle pathology, these entities are now known to represent various stages in the natural course of this one disorder [Tomimitsu et al 2004, Huizing 2005, Huizing & Krasnewich 2009]. Initially observed most frequently in various populations in the Middle East [Argov et al 2003], GNE-related myopathies more recently have been reported in Japan (Nonaka myopathy) [Kayashima et al 2002, Nishino et al 2002, Tomimitsu et al 2004] and in several groups of European origin [Broccolini et al 2002, Vasconcelos et al 2002]. Hereditary inclusion body myopathy (hIBM) begins in the young adult with gait difficulties resulting from compromised foot dorsiflexion. Muscle weakness, first apparent in the distal limb muscles, progresses in severity. In the early stages of the disorder the proximal limb muscles (quadriceps in the legs and deltoids, biceps, and triceps in the arms) appear to be spared. Weakness in these muscles appears in the later stages of the disorder. There is gradual reduction of muscle bulk in the limbs. Affected persons become wheelchair bound. Intellectual functioning, sensation, and coordination remain intact even when the myopathy becomes more widespread and severe. Diagnosis is based on the histopathologic findings of red rimmed vacuolar degeneration of muscle fibers; specific MRI T1 documentation of quadriceps sparing but fatty and fibrous replacement of the surrounding musculature; and molecular genetic testing. Creatine kinase (CK) in plasma may be mildly elevated in later clinical stages. Urinary excretion of sialic acid is normal [Argov & Mitrani-Rosenbaum 2008, Huizing & Krasnewich 2009]
A phenotypic definition or natural history of sialuria must remain preliminary as only seven affected persons have been reported [Ferreira et al 1999, Leroy et al 2001]. Signs and symptoms are mild and can be transient. ...
Natural HistoryA phenotypic definition or natural history of sialuria must remain preliminary as only seven affected persons have been reported [Ferreira et al 1999, Leroy et al 2001]. Signs and symptoms are mild and can be transient. Pregnancy is usually normal. Affected infants are rather small for gestational age. At birth, the OFC is normal; the facies appear rather flat and slightly coarse. Mild hepatomegaly occurs in the majority of children and prolonged neonatal jaundice can be observed. In early infancy, developmental delay is reported in most children and generalized hypotonia in some. Microcytic anemia in two infants was severe enough to require transfusion. Upper respiratory infections occur frequently into the second year of life, sometimes associated with gastroenteritis, dehydration, and transient failure to thrive. Signs of dysostosis multiplex appear to be transient, but skeletal development is delayed at least in early childhood. There are no signs of any progression of the disorder. Instead clinical expression appears to be limited to infancy or to early childhood at most.Developmental age or IQ is borderline low. Later in childhood, physical development is normal and intellectual development can be nearly normal. One child had febrile convulsions. In about half of the children who had seizures in childhood, the seizures were controlled with phenobarbital [Leroy et al 2001]. The phenotypic spectrum of sialuria is insufficiently known. Moreover, it may be either equivocally abnormal or indistinguishable from the normal variation in childhood development. It is likely that children with sialuria who have no significant medical problems in infancy and/or early childhood do not come to medical attention at all. The retrospective diagnosis of sialuria in the mother of a proband supports this contention [Leroy et al 2001]. Physically the proband and his affected mother are normal individuals. The mother is the only person in a sibship of six children who did not study beyond elementary school. Her affected son is physically similar to his two older unaffected brothers. He needs special support in regular classes. Hence it is probable, although not proven, that sialuria results in mild intellectual disability. Confirmation of this observation requires the study of more families.
The direct correlation of genotype and phenotype is significant:...
Genotype-Phenotype CorrelationsThe direct correlation of genotype and phenotype is significant:In sialuria. In all persons who have been tested, the missense pathogenic GNE mutation was detected in the putative allosteric site (codons 263 or 266). In hereditary inclusion body myopathy (hIBM). Homozygous or compound heterozygous GNE mutations are observed outside the allosteric site in the epimerase or the kinase domain [Kayashima et al 2002, Argov et al 2003, Huizing et al 2004, Tomimitsu et al 2004, Huizing 2005] (see Genetically Related Disorders).
The free sialic acid storage disorders including Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid [Aula & Gahl 2001]. The mildest phenotype is Salla disease, characterized by normal appearance and normal neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild to moderate motor and developmental delay, truncal ataxia, spasticity, athetosis, intellectual disability, and epileptic seizures [Varho et al 2000, Varho et al 2002]. The most severe phenotype, ISSD, has its onset in early infancy. Affected children have severe delay of development, coarse facial features, generalized hypotonia, hepatosplenomegaly, severe intellectual disability, and cardiomegaly. Death through clinical complications usually occurs before or in early childhood [Lemyre et al 1999]. ISSD is prominent among the metabolic causes of non-immune fatal hydrops fetalis (as a group ~1% of the total) [Bellini et al 2009] that represent a separate phenotypic expression among the free sialic acid storage disorders [Stone & Sidransky 1999]. ...
Differential DiagnosisIncreased Urinary and Intracellular Free Sialic Acid The free sialic acid storage disorders including Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid [Aula & Gahl 2001]. The mildest phenotype is Salla disease, characterized by normal appearance and normal neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild to moderate motor and developmental delay, truncal ataxia, spasticity, athetosis, intellectual disability, and epileptic seizures [Varho et al 2000, Varho et al 2002]. The most severe phenotype, ISSD, has its onset in early infancy. Affected children have severe delay of development, coarse facial features, generalized hypotonia, hepatosplenomegaly, severe intellectual disability, and cardiomegaly. Death through clinical complications usually occurs before or in early childhood [Lemyre et al 1999]. ISSD is prominent among the metabolic causes of non-immune fatal hydrops fetalis (as a group ~1% of the total) [Bellini et al 2009] that represent a separate phenotypic expression among the free sialic acid storage disorders [Stone & Sidransky 1999]. Free sialic acid storage disorders result from defective transport of free sialic acid out of lysosomes as a consequence of mutations in SLC17A5 encoding the lysosomal transport protein sialin [Verheijen et al 1999, Aula et al 2000, Aula et al 2002]. The diagnosis of the free sialic acid storage disorder is suggested by documentation of significantly elevated free (i.e., unconjugated) sialic acid in urine. In Salla disease, urinary excretion of free sialic acid is elevated, but only about one-tenth of that found in sialuria. The diagnosis, suspected by the clinical signs and by lysosomal damage detected by electron microscopic study of skin biopsy specimens, is formally established either by demonstrating lysosomal (rather than cytoplasmic) localization of elevated free sialic acid or identifying disease-causing mutations in SLC17A5. Homozygosity for the SLC17A5 missense mutation p.Arg39Cys results in the typical Finnish Salla disease phenotype of intermediate severity. Compound heterozygotes, who have one copy of this mutation, have a more severe phenotype that is clinically reminiscent of ISSD. Most individuals homozygous or compound heterozygous for other SLC17A5 mutations have either ISSD or more severe forms of Salla disease [Aula et al 2000, Varho et al 2002, Morse et al 2005]. Affected individuals of non-Finnish ancestry usually have clinical features that are more severe than “classic” Salla disease or ISSD [Biancheri et al 2002].Free sialic acid storage disease caused by homozygosity of the p.Lys136Glu mutant allele in SLC17A5 has also been reported in two sibs with early clinical onset, mild phenotype, and mild cerebral hypomyelination. The urinary excretion of free sialic acid was within normal limits, but free sialic acid concentration was elevated threefold in the cerebrospinal fluid (CSF) [Mochel et al 2009].Initial Clinical Features (Coarse Facies, Hypotonia, Hepatomegaly) Although mild, inconsistent, and transient, the initial clinical features make the differential diagnosis in infants and young children an interesting challenge. Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum from mild to severe. Affected persons are best described by the terms MPS I with severe, intermediate, or mild disease. Infants with severe MPS I (Hurler disease) have coarse facial features, stiff shoulder joints, and generalized hypotonia at birth. Further coarsening of the facial features occurs within the first two years. Corneal clouding and cardiac involvement, most often not clinically apparent in the first few years, are consistent in MPS I. Cardiac valve dysfunction may soon become apparent on echocardiogram. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is seen in all persons with severe MPS I [Spranger 2002]. Linear growth, often excessive between ages six and 18 months, ceases by age three years. Onset of symptoms of intermediate MPS I usually occurs between ages three and eight years and survival to adulthood is common. Persons with mild MPS I are often diagnosed after age 15 years and generally have normal intellect, normal stature, and a near-normal life span [Neufeld & Muenzer 2001, Spranger 2002]. The diagnosis of MPS I relies on the demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase in peripheral blood leukocytes or cultured fibroblasts. Glycosaminoglycan (GAG) (heparan and dermatan sulphate) urinary excretion is a useful preliminary test. IDUA is the only gene currently known to be associated with MPS I. Using sequence analysis and/or mutation analysis, it is possible to identify both IDUA mutations in 95% of persons with MPS I. MPS I is inherited in an autosomal recessive manner.Severe types of other, less prevalent mucopolysaccharidoses (MPS). Disorders specifically relevant are MPS VI (Maroteaux-Lamy disease) and MPS VII (Sly disease), which cannot be distinguished clinically from MPS I before age one to two years. In the former, cognitive functioning remains normal or near normal. The diagnosis is made by demonstration in peripheral leukocytes or cultured fibroblasts of significant deficiency of either N-acetylgalactosamine-4-sulphatase or β-D-glucuronidase, respectively. Free sialic acid is normal in urine, which typically has increased amounts of glycosaminoglycans as in MPS I.Oligosaccharidoses. The more slowly evolving oligosaccharidoses represent an alternate possibility. These disorders are characterized by oligosacchariduria and hence excessive excretion of bound sialic acid but no elevation of free sialic acid in the individual's urine. The abnormal features of sialuria are mild compared to those of the oligosaccharidoses: Sialidosis (mucolipidosis I). Only the initial stages of this rare childhood dysmorphic sialidosis caused by acid sialidase deficiency have features in common with sialuria [Thomas 2001, Leroy 2002a, Leroy 2002b]. GM1-gangliosidosis type 2. In this disorder caused by beta-D-galactosidase deficiency, neuromotor regression, skeletal dysostosis multiplex, and organomegaly are less pronounced than in the severe infantile GM1-gangliosidosis type 1, but physical and intellectual morbidity is more pronounced in either than in sialuria [Suzuki et al 2001]. Infantile type galactosialidosis. Associated with the combined deficiency of beta-D-galactosidase and acid sialidase, this disorder is caused by genetic defect of the lysosomal protective protein/cathepsin A (PPCA) [d'Azzo et al 2001]. Like GM1 gangliosidosis, it is a serious CNS and multiple-organ disease in which usually only mild dysostosis multiplex and organomegaly are observed. Pseudo-Hurler polydystrophy (mucolipidosis III alpha/beta ormucolipidosis III gamma) [Cathey et al 2008]. Clinically and etiologically closely related to I-cell disease (mucolipidosis II), pseudo-Hurler polydystrophy has its clinical onset after age two years. It is characterized by joint stiffness and by slowing of physical growth in addition to coarsening of facial features. In this disorder the glycans in lysosomal acid hydrolases are poorly phosphorylated by a mutant UDP-GlcNAc-1-phosphotransferase and, hence, are deficient in mannose-6-phosphate (M6P) markers, which are crucial for binding of the hydrolases to the M6P-receptors (MPRs) and for targeting them to lysosomes. Mucolipidosis III alpha/beta is caused by homozygous or compound heterozygous mutations in GNPTAB. Mucolipidosis III gamma is caused by homozygous or compound heterozygous mutations in GNPTG [Kornfeld & Sly 2002, Leroy 2002a, Cathey et al 2010]. Developmental delay. Assay of urinary sialic acid could become part of the metabolic screening in young children with mild hypotonia and developmental delay, sometimes complicated from early childhood by a mild seizure disorder. Sialuria may be considered a cause of borderline intellectual disability, usually considered to have a multifactorial explanation. 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).
To establish the extent of disease in a person diagnosed with sialuria, the following evaluations are recommended, if they have not already been completed. Note: The priority of these recommendations depends on the signs observed in the patient and/or noted by the parents:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in a person diagnosed with sialuria, the following evaluations are recommended, if they have not already been completed. Note: The priority of these recommendations depends on the signs observed in the patient and/or noted by the parents:CBC with differential to evaluate for microcytic anemia Measurement of serum bilirubin concentration to evaluate for jaundice Skeletal survey to evaluate for dysostosis multiplex Developmental and neurologic assessment EEG when relevant Neuroimaging with the purpose of differentiating sialuria from neurodegenerative lysosomal storage disordersTreatment of ManifestationsPersons with sialuria need symptomatic and supportive management, including treatment of anemia, prolonged but mild jaundice, and convulsions. Barbiturates have been more effective in treating the occasional convulsion in early childhood than other antiepileptic drugs (AEDs).Affected individuals benefit from early developmental intervention and appropriate educational programs.Prevention of Secondary ComplicationsAppropriate antibiotics to prevent secondary bacterial super-infection in the upper/lower airways are indicated.SurveillanceThe following are appropriate:Clinical follow-up during and after infancy to confirm that CNS disease is not progressive (in contrast to free sialic acid storage disorders) and to document the gradual remission of signs and/or symptoms present in infancyFollow-up evaluations three to four times in infancy, twice in the second year of life, and once every subsequent year Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposesTherapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.See Molecular Genetic Pathogenesis for therapy trials in “knock-in” mice yielding preliminary data for future possible therapies in humans.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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. Sialuria: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGNE9p13.3Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinaseGNE homepage - Leiden Muscular Dystrophy pagesGNEData 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 Sialuria (View All in OMIM) View in own window 269921SIALURIA 603824UDP-N-ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASEMolecular Genetic PathogenesisSialuria. The basic metabolic defect in sialuria is failed allosteric feedback inhibition of the bifunctional UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase (EC 5.1.3.14) / N-acetylmannosamine (ManNAc) kinase (EC 2.7.1.60) (GNE/MNK), rate-limiting enzyme in the biosynthesis of sialic acid (Neu5Ac). The biologic inhibitory substance, CMP-Neu5Ac, the downstream product in this biosynthetic pathway, is formed in the cell nucleus per activation of Neu5Ac by CTP catalyzed by CMP-Neu5Ac synthase. It is subsequently transported into the Golgi apparatus assisted by a specific Golgi membrane protein. It serves in that location as a substrate for different sialyltransferases [Reinke et al 2009]. Feedback inhibition fails when CMP-sialic acid (CMP-neu5Ac) cannot bind to the small mutant allosteric site in GNE/MNK, itself a soluble protein of 722 amino acids found in the cytoplasm, mainly in the Golgi region, and also in the cell nucleus [Krause et al 2005] The allosteric site is still incompletely defined but comprises the consecutive amino acids 263 through 266 in the epimerase functional domain.In each person with sialuria, the GNE disease-causing DNA mutation was found to be a missense mutation in one of the two nearly adjacent codons in exon 5 (Table 2). In each person, it was found only in the heterozygous state [Ferreira et al 1999, Seppala et al 1999, Aula & Gahl 2001, Enns et al 2001, Leroy et al 2001, Huizing & Krasnewich 2009]. The detection of this molecular defect provided the initial information that identified the allosteric site in the GNE/MNK enzyme and explains the main aspects of the pathogenesis of sialuria. Moreover, the finding that the regulatory mutation in all persons with sialuria is heterozygous establishes the autosomal dominant mode of inheritance. The lack of feedback inhibition results in highly excessive production of free sialic acid and in its very elevated concentrations in the cellular cytoplasm, interstitial tissues, and body fluids, such as urine. Defective allosteric inhibition is not an exceptional cause of human metabolic disease. It has been shown recently also for the glutamate dehydrogenase gene in infants with hyperinsulinism and hyperammonemia (see Familial Hyperinsulinism).Normal allelic variants. GNE consists of 14 exons, 13 of which are located closely together, whereas the recently discovered additional exon of 90 base pairs, named A1, resides 20 kb upstream of exon 1 as outlined in the references in Reinke et al [2009]. Four different mRNA splice variants are transcribed from GNE, resulting from alternative splicing of the exons A1, 1, and 2. Exon 1 is a non-coding exon. Hence, two of the splice variants encode a protein of 722 amino acids, hGNE1, as reported for the originally characterized GNE/MNK protein and referred to in most molecular biology studies. Pathologic allelic variants. In all persons with sialuria, one of three single missense mutations, p.Arg263Leu, p.Arg266Gln, or p.Arg266Trp, was found in only a single GNE allele (located in exon 5 and the epimerase domain of GNE/MNK) and associated with highly excessive urinary excretion of free sialic acid. This strongly suggested that the corresponding group of amino acids represents the allosteric site of the enzyme for retroinhibition by CMP-Neu5Ac acid binding [Seppala et al 1999]. In contrast to the sialic acid storage disorders, the clinical consequence has been mild and not associated with lysosomal retention of free sialic acid or by other histologically demonstrable cellular damage. The finding in the symptom-free mother of one of the probands confirms the mild clinical effect and proves the autosomal dominant inheritance of the disorder. Note: Homozygous or compound heterozygous mutations in either the epimerase domain or the kinase domain are associated with adult-onset autosomal recessive hereditary inclusion body myopathy (hIBM). See Genetically Related Disorders. Table 2. Selected GNE Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences c.788G>Tp.Arg263LeuNM_005476.4 1NP_005467.1c.797G>Ap.Arg266Glnc. 796C>Tp.Arg266TrpSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. The codon numbers correspond to reference sequence NP_005467.1 (sometimes referred to isoform 2), which contains a different 5' terminal exon compared to transcript variant 1, resulting in translation initiation from an in-frame downstream AUG and an isoform (2) with a shorter N-terminus compared to isoform 1. See Entrez Gene www.ncbi.nlm.nih.gov/gene/10020.Normal gene product. Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase (GNE) (EC 5.1.3.14)/ N-acetylmannosamine (ManNAc) kinase (MNK) (EC 2.7.1.60), a protein of 722 amino acids is a bifunctional enzyme that catalyzes the first rate-limiting step and the second step in the biosynthetic pathway of sialic acid [Seppala et al 1999, Aula & Gahl 2001, Huizing & Krasnewich 2009]. The first of these steps is inhibited by feedback from CMP-neu5Ac. The epimerase activity domain is found in the amino-terminal portion of the protein (amino acids 1 to ~378) and the kinase domain is found in the carboxy-terminal half (amino acids ~410 to 722) [Seppala et al 1999, Huizing 2005]. The allosteric site resides in exon 5 within the epimerase domain. The active site in either enzyme domain is still to be determined. GNE/MNK is a major determinant of cell surface glycoconjugate sialylation and a critical regulator of the function of specific cell-surface adhesion molecules. Bound N-acetyl-neuraminic acid (NANA) is widely distributed in normal tissues and is a constituent of glycoproteins and complex lipids such as gangliosides. In N-linked glycoproteins, NANA is consistently the terminal sugar in the oligosaccharide tree [Huizing & Krasnewich 2009]. Human GNE (GNE/MNK) exists in three different isoforms — hGNE1, hGNE2, and hGNE3 — the latter two possessing extended or deleted N-terminal regions, respectively. The isoform hGNE1 is ubiquitously expressed, most intensively in liver and placenta. Lower concentrations are detectable in muscle, brain, kidney, and pancreas [Reinke et al 2009 and references therein].It is of interest that as a monomer GNE/MNK has no catalytic activity. It requires di- and even multimerization of the nascent polypeptides in order to become fully active as a bifunctional enzyme [Huizing & Krasnewich 2009, Reinke et al 2009]. Abnormal gene product. Mutations appear to reside exclusively in the short stretch of consecutive nucleotides in GNE that encodes the amino acids 263 to 266, which have an important role in the allosteric site of the gene product, UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase (GNE/MNK). Of note, the borders of the putative allosteric site have not yet been determined [Huizing 2005]. The activity of the bifunctional and rate-limiting GNE enzyme is normal in sialuria fibroblasts, but no longer subject to retro-inhibition by the end-product CMP-sialic acid, when one and only one of the two GNE alleles has a missense mutation in the putative allosteric site in and probably near codons 263 and 266. Hence, there is significant and steady overproduction and vastly excessive urinary excretion of free sialic acid (neu5Ac). The apparently rare individuals with sialuria have a clinically mild disorder. Nevertheless, a mutation resulting in an allosteric autosomal dominant metabolic defect is of considerable importance in the study of the various physiologic roles of free sialic acid and of sialylation in tissues. Moreover, the metabolic trait has been shown to be important in the production of biologic molecules with therapeutic potential and in testing the feasibility of silencing mutation effects by RNA interference. Click here for additional information.