Sialidosis (Mucolipidosis I)

Sialidosis, also known as mucolipidosis type I (ML I), is a rare inherited lysosomal storage disease that has clinical and histologic findings similar to the mucopolysaccharidoses and the sphingolipidoses. In the late 1960s, a small number of patients with mild Hurlerlike facies, skeletal dysplasia, psychomotor retardation, and normal excretion of urinary mucopolysaccharides were reported. Initially classified as a lipomucopolysaccharidosis, this disease was later classified into the group of similar diseases now known as the mucolipidoses. Patients with ML I were subsequently found to have an isolated deficiency of alpha-N -acetyl neuraminidase (sialidase) in leukocytes and cultured fibroblasts and, thus, have increased amounts of sialyloligosaccharide in the urine. At least 40 disease-causing mutations in the neuraminidase 1 (NEU1) gene have been reported.

Because of the neuraminidase deficiency, ML I is now categorized with the sialidoses, a group of biochemically distinct disease entities due to an isolated neuraminidase deficiency. Although the names are synonymous, this chapter refers to ML I by the newer name, sialidosis.

Two major clinical phenotypes of sialidosis are recognized; they are distinguished by the presence or absence of dysmorphic features and other somatic changes. Patients with type I disease have been referred to as having "cherry-red spot-myoclonus" syndrome. These patients typically develop symptoms of myoclonic epilepsy, visual problems, and ataxia in the second or third decade of life. Macular cherry red spots are always present. The myoclonus is aggravated by smoking and menses, among other factors, and may become debilitating.

Myoclonic seizures are poorly controlled by the standard antiepileptics. Patients with the type II form of sialidosis have an earlier onset of symptoms and exhibit dysmorphic and somatic features that progressively worsen. Type II can be further divided into an infantile onset form and a more severe congenital onset form. The infantile form presents in the first year of life with the appearance of coarse, Hurlerlike facies; hepatomegaly; bony changes of dysostosis multiplex; and early developmental delay. The reported incidence of cherry-red spots is less than 75%, in contrast to the virtual 100% in patients with the type I form. The more severe congenital form of type II sialidosis has onset in utero and results in hydrops fetalis, hepatomegaly, and either still birth or death within a period of months.

Some patients have been described with a clinical phenotype consistent with type II sialidosis and a combined deficiency of neuraminidase and beta-galactosidase. However, the biochemical basis for the combined enzyme deficiency is a loss of a protective protein that interacts with both enzymes to produce catalytic activity. Hence, this is a genetically and biochemically distinct entity from sialidosis. Sialidosis should not be confused with disorders of free sialic acid storage, which are caused by a defect in the lysosomal transport of free sialic acid due to mutations in the AST (anion and sugar transporter) gene.

In lysosomal storage disorders, the deficiency of a specific lysosomal enzyme interrupts the normal catabolic pathway, resulting in the cellular accumulation of substrates ordinarily degraded by that enzyme. The specificity of these accumulated materials to the distinct enzyme defect is striking in the lysosomal disorders, and the accumulation then leads to abnormal cell architecture. Precisely how the changes in cellular structure due to storage translates into adverse effects on cell function remains enigmatic. Some evidence implicates neuraminidase in regulation of intracellular trafficking of the lysosomal LAMP-1 membrane protein; LAMP-1 may be instrumental in lysosomal exocytosis. Further research is needed to fully explain the role of neuraminidase in this process.[1, 2]

The clinical course of the disease depends on the associated effects of progressive storage in the organ systems where these substrates are highly concentrated. In sialidosis, the deficiency of lysosomal alpha-N -acetyl neuraminidase prevents the normal degradation of glycoproteins containing sialic acid residues. This results in intracellular storage of excess sialyloligosaccharides and is histologically observed as abnormal vacuolization of various cell types. Whereas bone marrow and circulating lymphocytes are highly vacuolated in type II sialidosis, these findings are conspicuously absent in type I disease. The organ systems mostly involved in sialidosis include the CNS, the skeletal system, and the reticuloendothelial system.

Frequency

International

Sialidosis is a rare disorder that has no racial predilection. Very little population data are available, but a study from the Netherlands reported a frequency of approximately 1 case in 2,175,000 live births.[3] However, this rate may not apply to all populations, some of which could have a higher incidence; moreover, missed clinical recognition is an important factor when newborn screening is not an option.

Mortality/Morbidity

In the type II infantile form, death usually occurs by the second decade of life, but survival into the early third decade of life has been reported. In the type II congenital form, infants are delivered either stillborn or they die within the first 2 years of life. In type I adult form, patients usually do not die from the disease but they experience decreased visual acuity, and myoclonus often interferes with walking.

Race

Sialidosis is panracial.

Sex

Sialidosis is inherited as an autosomal recessive trait. Both sexes are affected with equal frequency.

Age

In the infantile form, onset of symptoms occurs in infants aged 0-12 months. In the congenital form, development of symptoms occurs in utero, and symptoms are present at birth. In the adult form, the cherry-red spot may develop in the second decade of life, with myoclonus and ataxia developing later.

In patients with type II infantile onset, psychomotor retardation and neurologic deterioration is progressive, and death from cardiorespiratory complications usually occurs by the second decade of life.

Care must be taken to educate families about the genetic basis of this disorder, including recurrence risks, identification of carriers, and the availability of prenatal diagnosis for future at-risk pregnancies.

In general, sialidosis is a heterogenous disorder with a wide spectrum of variability in disease manifestation.

Patients with the type II infantile form may be normal or almost normal in appearance at birth. Coarse facial features, developmental delay, and hepatosplenomegaly may develop within the first year of life.

Although not as severe as the Hurler phenotype, similar-appearing coarse features, hepatosplenomegaly, and skeletal abnormalities (dysostosis multiplex) become more pronounced with time. Short stature may also progressively develop.

The extent of neurologic progression varies, but macrocephaly, hypotonia, nystagmus, visual impairment, and myoclonic seizures are known to develop. Cherry-red spots appear with age in most patients. As the neurologic picture progresses, these patients become nonambulatory and are unable to care for themselves.

In the congenital form, hepatosplenomegaly, ascites, and hydrops fetalis are noted at birth, and the infant may be stillborn. In those who survive postnatally, the course is rapidly progressive.

Nephrosis has been reported in some patients; these patients may comprise a subgroup of the infantile form.

Patients with the adult form of the disease first report visual impairment due to color blindness or night blindness. Cherry-red spots are present in virtually all such patients. Myoclonus, which can be disabling, and ataxia develop later.

Neurologic findings of sialidosis include the following:

• Developmental delay or mental retardation

• Visual impairment or loss of visual acuity

• Hypotonia

• Myoclonus

• Nystagmus, ataxia, and seizures (have been reported)

Coarse facial features include the following:

• High forehead, puffy eyelids, epicanthal folds

• Flat nasal bridge, anteverted nares, long philtrum

• Gingival hypertrophy, macroglossia

Skeletal abnormalities include the following:

• Lumbar gibbus deformity and kyphoscoliosis

• Joint stiffness and contractures (may develop)

Ophthalmologic findings include cherry-red macula, corneal opacities, lens opacities, and lamellar cataracts. Abdominal findings include hepatosplenomegaly in patients with the type II form as a result of visceral storage. Findings in the congenital form include hydrops fetalis, neonatal ascites, hepatosplenomegaly, and inguinal hernia.

Sialidosis is an autosomal recessive disorder caused by an isolated deficiency of the enzyme, alpha-N -acetyl neuraminidase (also called sialidase). Three distinct human neuraminidases are known and are specifically localized to the cytosol, plasma membrane, and lysosome. The lysosomal enzyme is selectively deficient in human sialidosis. The lysosomal neuraminidase gene maps to chromosome 6p21 and has been cloned. Various enzyme-inactivating mutations have been identified in patients with sialidosis.

The variability of disease manifestation due to this enzyme deficiency, as evidenced by the 3 disease subtypes, has indicated a potential genotype-phenotype correlation. Research has shown that the type of gene mutation affects not only enzyme activity but also whether the enzyme localizes to the lysosome. Preliminary studies indicate that both of these properties have positively correlated with the clinical subtype of sialidosis.[4] However, the wide variability of clinical presentation in these patients cannot be fully explained by alpha-N -acetyl neuraminidase mutations. Therefore, other environmental or genetic factors probably account for the varying degrees of disease severity.

More than 40 mutations in the NEU1 gene have been described. Most are missense mutations, but deletions and insertions have also been described. In multiple small studies, sequencing identified all mutations in the NEU1 gene.[5, 6, 7]

As with any progressive neurologic disease, patients with sialidosis are at risk for recurrent infections and aspiration pneumonia. Renal involvement has been reported in a few cases of sialidosis and has been thought to be a result of generalized visceral storage.

Although no reports have been described in sialidosis, atlantoaxial instability may develop because of abnormally shaped cervical vertebrae. If this occurs, patients should be observed and eventually surgically stabilized to avoid the risk of spinal cord injury.

Definitive diagnosis of sialidosis is made by demonstrating a deficiency of alpha-N -acetyl neuraminidase activity, which can be measured in amniocytes, leukocytes, and cultured fibroblasts. The finding of pathologic mutations in NEU1 is an alternate method to diagnose this disease and offers the ability for reliable detection of heterozygous carriers for genetic counseling of family members. Detection of an abnormal pattern of urinary oligosaccharides can be used as an initial screening test.

The characteristic bone changes are similar to but not as severe as those observed in the mucopolysaccharidoses. The classic radiographic finding is dysostosis multiplex. This may be observed as anterior beaking of the vertebral bodies, widening of the ribs, hypoplastic ilia, and expanded metacarpal and phalangeal shafts. Radiographs obtained early in the course of the disease may reveal only stippling of the epiphyses.

The literature has described 4 cases of femur head necrosis, which might be an early manifestation of late-onset sialidosis.[8]

Renal function evaluation and serial urinary protein evaluation are indicated.

Cytoplasmic vacuolation of varying degrees has been observed and reported in peripheral lymphocytes, bone marrow cells, conjunctival epithelium, Kupffer cells, hepatocytes, tissue fibroblasts, nerve biopsy specimens, myenteric plexus neurons, and brain biopsy material. Using electron microscopy, membrane-bound vacuoles containing flocculent or reticulogranular material have been described.[9]

Treatment options for sialidosis remain limited and are primarily directed at supportive care and symptomatic relief. Efforts should be made to maximize overall health maintenance, providing adequate nutrition and seizure control if necessary. Myoclonic seizures often prove difficult to treat with anticonvulsant medication. Recent in vitro studies suggest a therapeutic role for a combination of a specific immunosuppressant and a proteosomal inhibitor in enhancing mutant enzyme activity.[10]

In the absence of gene replacement therapy, the present holy grail of treatment for sialidosis is enzyme replacement therapy (ERT). Thus far, attempts at ERT have been made only in animal models, with limited success.[11]

Consultation with a geneticist is indicated for initial evaluation and diagnosis and to provide genetic counseling to affected families regarding recurrence risks and the availability of prenatal diagnosis of future offspring.

Consultation with a neurologist is indicated for initial evaluation of psychomotor delay and follow-up care as the disease progresses and for anticonvulsant therapy if seizures develop.

Consultation with an ophthalmologist is indicated. The presence of cherry-red maculae, corneal clouding, or both may aid in the diagnosis of sialidosis.

Serial urinary protein evaluation and periodic renal function assessment are indicated in patients with sialidosis.

No specific pharmacologic therapy is available at this time.