Neuraminidase Deficiency

A number sign (#) is used with this entry because of evidence that sialidosis types I and II are caused by homozygous or compound heterozygous mutation in the gene encoding neuraminidase (NEU1; 608272) on chromosome 6p21.

Description

Sialidosis is an autosomal recessive disorder characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. Common to the sialidoses is the accumulation and/or excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins (summary by Lowden and O'Brien, 1979). The sialidoses are distinct from the sialurias in which there is storage and excretion of 'free' sialic acid, rather than 'bound' sialic acid; neuraminidase activity in sialuria is normal or elevated. Salla disease (604369) is a form of 'free' sialic acid disease.

Classification

Lowden and O'Brien (1979) provided a logical nosology of neuraminidase deficiency into sialidosis type I and type II. Type I is the milder form, also known as the 'normosomatic' type or the cherry red spot-myoclonus syndrome. Sialidosis type II is the more severe form with an earlier onset, and is also known as the 'dysmorphic' type. Type II has been subdivided into juvenile and infantile forms. Other terms for sialidosis type II are mucolipidosis I and lipomucopolysaccharidosis.

Clinical Features

Sialidosis Type II

Sialidosis was first recognized as a distinct entity by Spranger et al. (1968), who termed it a 'lipomucopolysaccharidosis.' They described a patient, who was later confirmed to have neuraminidase deficiency (see Spranger et al., 1977), who presented at age 12 years with neurologic abnormalities, including muscular hypotonia and hypotrophy, ataxia, myoclonus, and seizures. Other features included coarse facies, short trunk, barrel chest, spinal deformity, inner ear hearing loss, cherry red spot, and an IQ of 45. Spranger et al. (1977) reported that this patient had a progressive neurodegenerative course and died at age 21 years; a picture of this patient at age 19 years was provided by Spranger and Cantz (1978). Berard-Badier et al. (1970) reported an affected female with onset of muscular hypotonia and hypotrophy, myoclonus, and a cerebellar syndrome at age 14 years. She had short stature, Hurler-like facies, a barrel chest, thoracic kyphosis, hepatosplenomegaly, cherry red spot, corneal opacities, and an IQ of 50.

Spranger and Wiedemann (1970) used the designation 'mucolipidosis I' for the same disorder. They reported 2 affected patients, but Spranger et al. (1977) reported that these patients, as well as patients described by Pincus et al. (1967) and Sanfilippo et al. (1962), were later found to have mannosidosis (248500). However, Spranger et al. (1977) suggested that the patients reported by Orii et al. (1972) and Yamamoto et al. (1974) may be cases of mucolipidosis I.

Spranger et al. (1977) reported an affected male. Thoracic deformity was noted at 18 months. At 4 years, he was short with relatively long limbs, had coarse facies, pectus carinatum, exaggerated thoracic kyphosis, and a waddling gait. He spoke only a few words. At age 6 years, a degenerative neuropathy was evidenced by muscle wasting, loss of strength, hypotonia, and choreoathetoid movements. By age 12 he was unable to walk and developed myoclonus and seizures. Inner ear hearing loss and corneal opacities were also present. Radiographic studies showed a generalized osteopenia and distinct features of dysostosis multiplex with vertebral abnormalities, but there were no contractures. A cherry red spot was present. The bone marrow contained large foam cells with vacuoles of different sizes, and sural nerve biopsy showed myelin degeneration. Excessive amounts of sialic acid-rich compounds were found in cultured fibroblasts and urine, and there was a severe deficiency of neuraminidase activity, suggesting a catabolic defect. Spranger et al. (1977) suggested that the neuraminidase deficiency was due to an underlying genetic defect.

Kelly and Graetz (1977) studied an 8-month-old female with coarse facies and hepatosplenomegaly from birth. Growth proceeded at an accelerated rate and mental development was normal. Dysostosis multiplex developed radiographically. Cytoplasmic inclusions consistent with lysosomal storage were found in many tissues by electron microscopy. Fibroblasts showed a specific deficiency of neuraminidase and a 6-fold increase in intracellular bound sialic acid. An unidentified macromolecular compound rich in sialic acid was excreted in the urine. Kelly and Graetz (1977) noted that the disorder in this patient was quite different phenotypically and biochemically from mucolipidoses II (I-cell disease; 252500) and III (252600).

Winter et al. (1980) described a man with sialidosis type II, born of consanguineous parents. At 9 months, he had Hurleroid features, progressive kyphosis, scoliosis, pectus carinatum, and a left inguinal hernia. Intelligence was impaired; although he attended regular school, he could not learn to read. Joint contractures, muscle wasting, visual impairment, coarsening of the facies, mental deterioration, and difficulties chewing and swallowing were progressive after age 12. At age 22, cherry red spots were visible but there was no corneal clouding. Hyperactive deep tendon reflexes, onset before age 1 year, and normal beta-galactosidase levels favored classification as infantile sialidosis type II, but survival to age 22 and the absence of hepatosplenomegaly favored the juvenile group. He had 4% sialidase activity in fibroblasts and increased urinary sialyloligosaccharides; the father had 50% sialidase activity in cultured fibroblasts. Glycosylated enzymes and proteins were abnormal in electrophoretic mobility, a characteristic that could be corrected with treatment with bacterial neuraminidase.

Laver et al. (1983) reported a case of the type II early infantile sialidosis with onset at birth and death at 4 months. The patient's fibroblasts showed neuraminidase deficiency, and reduced levels of enzyme activity were found in the lymphocytes of both parents. A previously born sister was apparently affected; born prematurely, she died 6 hours after birth and showed hepatosplenomegaly as well as foam cells in the placenta.

Paschke et al. (1986) described a severe form of infantile sialic acid storage disease with sialuria. Dyspnea due to laryngomalacia, pronounced hepatosplenomegaly, vacuolization of circulating lymphocytes, and death at age 21 months were described. The authors drew a parallel with the cases of Hancock et al. (1982), Gillan et al. (1984), Stevenson et al. (1983), and Tondeur et al. (1982). Neonatal onset and extensive abdominal ascites were described in the first 2 reports. Nakamura et al. (1992) described a female Japanese infant who had ascites, hepatosplenomegaly, and right inguinal hernia at birth.

Sialidosis Type I

Durand et al. (1977) reported 2 sibs with what they termed a 'mild' form of mucolipidosis I. Sialyl acid-rich oligosaccharides were isolated from the urine of both patients. Both sibs showed a progressive reduction of visual acuity, red-green blindness, bilateral cherry red spots, punctate opacities of the lens, and minimal neurologic symptoms. Morphologically, vacuolated lymphocytes, inclusions in fibroblasts, and inclusions and osmiophilic granules in Kupffer cells were found. Durand et al. (1977) suggested the term 'sialidosis.'

O'Brien (1977, 1978), Thomas et al. (1978), and Rapin et al. (1978) reported several young adults with cherry red spots, progressive myoclonus, progressive visual loss, and sialyloligosaccharides in the urine. Onset was usually in the second to third decades. Neuronal lipidosis and vacuolated Kupffer cells were found on tissue examination. The phenotype differed from that of other reported cases in that somatic and bony abnormalities were absent, intelligence was normal, and survival was longer. Thomas et al. (1979) reported 3 affected brothers born to consanguineous parents. In early adult life, the brothers developed ataxia, myoclonus, and progressive visual loss. Cherry red spots and cataracts were present. Biochemical studies showed a deficiency of sialidase activity. The authors noted that the affected patients had sialidosis type I.

Swallow et al. (1979) studied 2 brothers with progressive ataxia, intention myoclonus and visual failure starting early in the third decade of life. The parents were consanguineous. Both brothers had bilateral cherry red spots at the maculae and bilateral perinuclear cataracts. Their intelligence was preserved. Urine showed large amounts of sialated oligosaccharides, and cultured skin fibroblasts showed deficiency of neuraminidase. Six enzymes known to be glycoproteins were shown to have an aberrant electrophoretic mobility consistent with excessive amounts of sialic acid on the enzyme molecules.

Matsuo et al. (1983) described the cases of a 24-year-old girl and her 20-year-old brother. The activity of both alpha-neuraminidase and beta-galactosidase was reduced in leukocytes and cultured skin fibroblasts. The parents were first cousins. Both patients showed progressive generalized myoclonus, macular cherry red spots, moderate cerebellar ataxia, vertebral deformities, coarse facies, and cytoplasmic vacuolation of peripheral lymphocytes, bone marrow cells and conjunctival epithelial cells. Intellect was normal. Excretion of sialyloligosaccharides in the urine was 3 to 5 times normal.

Harzer et al. (1986) described 2 unrelated patients, aged 38 and 21 years, with myoclonus epilepsy and cerebellar ataxia but without dysmorphic signs or dementia. Although other features were consistent with normomorphic sialidosis, normal amounts of sialyloligosaccharides were found in their urine. The younger patient showed cherry red spots in the fundi. The other patient had a brother with autopsy-proven neuronal storage disease compatible with sialidosis, and rectal biopsy showed lamellar inclusion bodies. Enzyme assay in cultured fibroblasts of both patients showed profound but incomplete deficiency of oligosaccharide sialidase activity and normal beta-galactosidase activity.

Young et al. (1987) reported a 12-year-old boy with coarse facies, cherry red spot, ataxia, myoclonus, and dysostosis multiplex. Action myoclonus, a disabling symptom in sialidosis, was successfully treated with 5-hydroxytryptophan as an 'add-on' to anticonvulsive therapy (Gascon et al., 1988). The dramatic response to 5-HTP, a serotonin precursor, coupled with the exacerbation with cyproheptadine, a weak serotonin antagonist, favored a role for serotonin deficiency in the pathogenesis of action myoclonus. The patient, a 14-year-old Saudi boy with unaffected consanguineous parents, had 2 affected sibs and 2 affected maternal uncles.

Canafoglia et al. (2014) reported 6 patients from 2 unrelated families with a mild form of late-onset sialidosis. All presented with slowly progressive cortical action myoclonus between ages 22 and 32 years. The movement disorder was initially characterized by repeated falls or hand tremor, and most patients eventually needed support for walking. All patients had completed secondary schooling and were employed. None had cherry red spots or retinal abnormalities on ophthalmologic examination, but 2 had cataracts. Two sibs had mild ataxia, and only 1 had a few seizures in childhood, which may have been unrelated. Additional unusual features included femoral head necrosis in 2 sibs and syringomyelia in 2 unrelated patients. Urinalysis showed mildly increased urinary sialic acid in only 2 patients. The diagnosis was confirmed genetically by exome sequencing. Canafoglia et al. (2014) noted the unusual phenotype in these patients, and suggested that individuals who present with isolated action myoclonus in adulthood should be tested for NEU1 mutations even in the absence of typical clinical and laboratory findings of sialidosis.

Diagnosis

Prenatal Diagnosis

Sasagasako et al. (1993) reported the prenatal diagnosis of congenital sialidosis in a 21-week-old male fetus by enzyme assay of cultured amniotic fluid cells. This was the second affected sib. The first had been found to have hydrops fetalis at the 33rd gestational week by ultrasonography. At birth, severe subcutaneous edema, pleural effusion, and ascites were found. The liver and spleen enlarged progressively, and death due to respiratory failure occurred at the age of 87 days. See also Sergi et al. (2001).

Heterogeneity

Hoogeveen et al. (1980) noted that there are 3 inherited diseases in which there is a deficiency of neuraminidase: sialidosis types I and II, both of which have isolated neuraminidase deficiency; mucolipidosis II (I-cell disease), in which neuraminidase is one of many lysosomal deficient lysosomal hydrolases; and a third entity in which there is a combined deficiency of neuraminidase and beta-galactosidase (256540). Using somatic cell hybridization and cocultivation, they concluded that at least 3 separate genes are involved, and that the disorder with combined beta-galactosidase and neuraminidase deficiency probably has a defect in posttranslational modification of these enzymes. No complementation was observed between sialidosis type I and type II, indicating that they are allelic disorders. The complementation analyses of Swallow et al. (1981) suggested the existence of the same 3 varieties of sialidosis.

Mapping

Oohira et al. (1985) observed a Japanese child, offspring of consanguineous parents, who had both sialidosis II and congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Chromosome analysis, including high resolution studies, showed no deletion or other abnormality. Neuraminidase activity was very low in the proband and at intermediate levels in both parents. A first cousin also had 21-hydroxylase deficiency. Haplotype analysis of the family suggested that human neuraminidase is linked to the MHC on chromosome 6.

Harada et al. (1987) further studied the patient reported by Oohira et al. (1985). They examined multiple genetic markers on 6p to investigate the possibility that a deletion in the HLA region had caused the combined deficiency of neuraminidase and 21-hydroxylase. By haplotype analysis of the proband and her parents, Harada et al. (1987) suggested that the neuraminidase gene is located between HLA-A and GLO.

Molecular Genetics

In 1 patient with sialidosis type I and in 2 patients with sialidosis type II, Bonten et al. (1996) identified mutations in the neuraminidase gene (608272.0001-608272.0003).

In 6 sialidosis patients, Pshezhetsky et al. (1997) identified 3 mutations in the sialidase gene.

Bonten et al. (2000) reported 8 novel mutations in the neuraminidase gene of 11 sialidosis patients with various degrees of disease penetrance. In general, there was a close correlation between the residual activity of the mutant enzymes and the clinical severity of disease. Patients with the severe infantile type II disease had catalytically inactive enzymes that were not present in lysosomes, whereas patients with a type I disease had some residual activity.

In 2 Japanese sialidosis patients, Itoh et al. (2002) identified 3 novel missense mutations in the NEU1 gene.

Pattison et al. (2004) identified 5 novel mutations in a mutation screen of 4 unrelated sialidosis patients. Four were missense and 1 nonsense. One mutation exerted its pathologic effect by this perturbing substrate binding, while 2 others appeared to impair the folding of the sialidase enzyme.

Cytogenetics

Uhl et al. (2002) identified an 11-kb deletion encompassing the entire coding and promoter regions of the NEU1 gene in 2 Turkish patients with sialidosis. Both patients died shortly after birth. The deletion caused fusion of exon 10 of the CTL4 gene (606107), which is located 851 bp centromeric from NEU1, with the 3-prime UTR of NEU1. The expected CTL4/NEU1 fusion transcript was observed in one patient, but the other patient expressed an alternatively spliced CTL4 transcript that retained intron 9 and terminated transcription before the fusion site.

Pathogenesis

Neu1 -/- mice show features of human sialidosis and develop a pronounced, age-dependent splenomegaly characterized by elevated numbers of hematopoietic progenitor cells (de Geest et al., 2002) (see ANIMAL MODEL). Yogalingam et al. (2008) found that Neu1 -/- mouse hematopoietic cells carried an oversialylated form of Lamp1 (153330), and they showed that Lamp1, but not other lysosomal membrane proteins, was an endogenous Neu1 substrate. Oversialylated Lamp1 accumulated at the plasma membrane of Neu1 -/- macrophages, and this accumulation was associated with enhanced Ca(2+)-dependent exocytosis of lysosomal hydrolases. Yogalingam et al. (2008) also observed enhanced exocytosis of catalytically active neutral serine hydrolases into the extracellular space of Neu1 -/- bone marrow, as well as inactivation of serine protease inhibitors. The resulting increased extracellular protease activity caused premature degradation of Vcam1 (192225), leading to depletion of bone marrow hematopoietic progenitor cells and their appearance in peripheral blood. Yogalingam et al. (2008) found that fibroblasts from 2 patients with type II sialidosis showed increased plasma membrane LAMP1 compared with normal fibroblasts. In contrast, fibroblasts from a patient with type I sialidosis exhibited a more normal LAMP1 distribution. The culture medium of type II sialidosis fibroblasts also showed elevated alpha-mannosidase activity (see 609458), suggesting increased lysosomal exocytosis. Yogalingam et al. (2008) suggested that deregulation of lysosomal exocytosis may underlie some phenotypic abnormalities of sialidosis.

Population Genetics

Lowden and O'Brien (1979) pointed out that sialidosis type I seems to be particularly frequent in Italians, and type II frequent in Japanese.

Animal Model

In the mouse, the naturally occurring inbred strain SM/J shows a number of phenotypic abnormalities attributable to reduced neuraminidase activity. The mice were originally characterized by their altered sialylation of several lysosomal glycoproteins. The defect was linked to the Neu1 gene on mouse chromosome 17, which was mapped by linkage analysis to the H-2 locus. Rottier et al. (1998) showed that SM/J mice have a leu209-to-ile (L209I) amino acid substitution in the Neu1 protein that is responsible for the partial deficiency of lysosomal neuraminidase.

In humans, primary or secondary deficiency of neuraminidase leads to 2 clinically similar neurodegenerative lysosomal storage disorders: sialidosis and galactosialidosis. De Geest et al. (2002) generated Neu1 -/- mice; these animals developed clinical abnormalities reminiscent of early-onset sialidosis in children, including severe nephropathy, progressive edema, splenomegaly, kyphosis, and urinary excretion of sialylated oligosaccharides. Although the sialidosis mouse model shares clinical and histopathologic features with galactosialidosis mice (Zhou et al., 1995) and patients, some phenotypic abnormalities seemed specific for sialidosis mice. These included progressive deformity of the spine, high incidence of premature death, age-related extramedullary hematopoiesis, and lack of early degeneration of cerebellar Purkinje cells. The differences and similarities identified in these sialidosis and galactosialidosis mice may help to increase understanding of the pathophysiology of these diseases in children and to identify more targeted therapies for each of these diseases.