What are the other Names for this Condition? (Also known as/Synonyms)

• Cherry-Red Spot Myoclonus Syndrome
• Mucolipidosis Type 1
• Neuraminidase Deficiency (Sialidosis)

What is Sialidosis? (Definition/Background Information)

• Sialidosis is a rare, inherited genetic disorder that is caused by mutation in the NEU1 gene. Mutations in this gene are inherited in an autosomal recessive manner
• It is classified into 2 types, namely type I and type II, depending on the age of presentation of symptoms and their severity:
  • Sialidosis Type I: Also known as the Cherry-Red Spot Myoclonus Syndrome, it is the less severe form, mostly affecting the eye. The age of onset is typically in the teens or later
  • Sialidosis Type II: It is the more severe form, presenting characteristic facial features. It is further divided into 3 subtypes
• Sialidosis Type II subtypes:
  • Sialidosis, congenital type: It is the most severe form and the symptoms are observed in the developing fetus
  • Sialidosis, infantile type: It is a moderately severe form, with symptom-onset occurring in the first year after birth of the child
  • Sialidosis, juvenile type: It is the least severe subtype, with symptoms presenting in late childhood
• The characteristic symptoms of type I Sialidosis include abnormal gait, reduced vision acuity, muscle twitches, lack of coordination, and seizures
• The more severe type II form can lead to fluid accumulation in the fetal abdomen, present coarse facial features (such as a large head, thickened skin, widely-spaced teeth), enlarged spleen and liver, bone abnormalities, and early developmental delays. The congenital form of Type II Sialidosis presents the most severe symptoms, followed by the infantile and juvenile forms
• In order to diagnose the disorder, the healthcare provider may perform a thorough physical examination, assess the symptoms, and evaluate family and individual medical history. Further, diagnostic tests, such as imaging studies for detecting bone deformities, microscopic analyses of tissues, and confirmatory genetic testing, may be performed
• The potential complications of Type I Sialidosis are progressive deterioration of vision and loss of mobility. Type II complications may be fatal and can include progressive deterioration in vision, severe bone deformities, and stillbirths
• Treatment for Sialidosis is generally supportive, and is tailored to making the affected individual as comfortable as possible. Medication to control seizures may be necessary, in some cases
• The prognosis of Sialidosis depends on the type of the disorder. Whereas the type I form is not reported to affect life expectancy, the type II form is known to be fatal; most individuals succumb to the disorder, before they reach 20 years of age

Who gets Sialidosis? (Age and Sex Distribution)

• Sialidosis is very rare congenital disorder; the exact prevalence of the disorder is unknown
• No racial or sexual predilection is reported in its occurrence
• However, the type I form of Sialidosis is more common in individuals of Italian heritages

What are the Risk Factors for Sialidosis? (Predisposing Factors)

• Sialidosis is an inherited genetic disorder. Therefore, having a family history of the disorder is a major risk factor for being born/diagnosed with the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Sialidosis? (Etiology)

Sialidosis is a genetic disorder caused by mutation(s) in the NEU1 gene that is located on chromosome 6.

• Under normal circumstances, the NEU1 gene codes for an enzyme called neuraminidase. There are 3 types of neuraminidases, which are localized in the plasma membrane, cytoplasm, and lysosomes
• The NEU1 gene codes for the enzyme that removes sialic acid (also known as neuraminic acid) from carbohydrate-protein complexes in the lysosomes, facilitating cellular recycling
• When there is a mutation in the NEU1 gene, it results in the accumulation of sialic acid containing complexes, such as lipomucopolysaccharides, inside the lysosomes. Since lysosomes are the sites of cellular waste recycling, the mutation interferes with the process, causing the observed symptoms of Sialidosis

Sialidosis is classified into 2 major subtypes:

• Sialidosis Type I: The mutation in the NEU1 gene allows some residual neuraminidase activity, making this type ‘less severe’
• Sialidosis Type II: In this type, the neuraminidase activity is highly-reduced or non-existent, and therefore, the symptoms are severe. Depending on the age of onset, and severity of symptoms, this form is divided into 3 subtypes
  • Sialidosis, congenital type: It is the most severe form and the manifestation occurs during gestation (in-utero) and/or shortly after birth
  • Sialidosis, infantile type: It is less severe than the congenital subtype, and the disease-onset takes place during the first year after birth
  • Sialidosis, juvenile type: It is the least severe of the type II form; disease-onset occurs in late childhood

The disorder is inherited in an autosomal recessive pattern. In this pattern of inheritance, an individual must have both copies of the causative gene to be defective in all his/her cells for the disorder to manifest itself. Both parents are carriers of the disorder and are typically symptom less.

What are the Signs and Symptoms of Sialidosis?

The signs and symptoms of Sialidosis include:

Type I Sialidosis signs and symptoms:

• Cherry-red spot in the eye
• Deterioration in vision acuity
• Color blindness
• Compromised night vision
• Gait problems, problems with walking
• Loss of muscle tone
• Myoclonus (jerky movements of the joints, like seizures)
• Joint stiffness
• Ataxia (loss of balance) or uncoordinated movements
• Tremors
• Seizures

Type II Sialidosis signs and symptoms: Congenital, infantile, and juvenile types

Congenital Sialidosis:

• Hydrops fetalis, or swelling of the fetal body before birth
• Ascitis, or fluid build-up in the abdomen
• Inguinal hernia, or protrusion of tissue through the abdominal wall
• Enlarged liver and enlarged spleen
• Severe bone deformities (dysostosis multiplex) such as:
  • Structural defect in the vertebrae, such as anterior beaking
  • Widened ribs
  • Incomplete development of hip bones
  • Expanded finger and toe bones (metacarpal, meta-tarsal and phalangeal bones)
• Coarse facial features, including
  • Large head, flat face
  • Wide-set eyes, puffy eyelids
  • Short nose, flared and upward tilted nostrils
  • Thick gums
  • Large and thick tongue
  • Protruding forehead

Infantile Sialidosis:

• Dysostosis multiplex or bone deformities
• Enlarged liver and spleen
• Coarse facial features (as above)
• Short stature
• Developmental delays
• Intellectual disability
• Hearing loss
• Cherry-red spots in the eyes
• Nystagmus, or abnormal movements of the eyeballs
• Progression into myoclonus (jerky movements)
• Widely-spaced teeth and protruding/overgrown gums

Juvenile Sialidosis:

• Milder form of coarse facial features
• Bone deformities less severe than congenital or infantile subtypes
• Cherry-red spots in the eyes
• Myoclonus
• Intellectual impairment
• Skin marked by dark-red spots (angiokeratoma)

How is Sialidosis Diagnosed?

A healthcare professional may employ the following tests, in order to arrive at an accurate diagnosis of Sialidosis:

• Physical examination and analysis of family medical history; assessment of symptoms
• Urine test for checking abnormal mucopolysaccharides (a screening test)
• Imaging tests, such as X-rays and ultrasound, to check for bone deformities
• Evaluating neuraminidase activity in white blood cells and cultured fibroblasts. In case of suspicion of Sialidosis during pregnancy, fetal cells circulating in amniotic fluid may be determined
• Genetic testing for confirmation of mutation in NEU1 gene
• For differentiating between type I and type II disease, microscopic analysis or histology of various cells types (nerve cells, lymphocytes, liver cells) to check for vacuolization (empty spaces inside cells). This feature is absent in type I disease

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Sialidosis?

Some potential complications of Sialidosis include:

Type I Sialidosis:

• Progressive deterioration in vision, with impaired color and/or night vision
• Myoclonus may interfere with walking, sitting, or standing. Eventually, the individual may become immobile, necessitating the requirement of a wheelchair

Type II Sialidosis:

• Congenital form of Sialidosis:
  • Still births
  • Death following birth or within the next 2 years
• Infantile form of Sialidosis:
  • Bony deformities
  • Visual impairment
  • Death may occur within 20 years of life

How is Sialidosis Treated?

Treatment for Sialidosis is geared predominantly toward keeping the affected individuals comfortable, since there is no cure for the disorder. The options generally involve providing good nutrition, use of seizure control medicines, and symptomatic treatment.

How can Sialidosis be Prevented?

Sialidosis is a genetic condition, and therefore, there are no guidelines or specific methods currently available towards its prevention.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Sialidosis
• Regular medical screening at periodic intervals with tests and physical examinations are strongly recommended.

What is the prognosis of Sialidosis? (Outcomes/Resolutions)

The prognosis of Sialidosis is dependent on whether the individual is having either the type I or type II form of the disorder.

• Type I Sialidosis: The intellectual development and longevity is unaffected in those with type I form of Sialidosis. However, quality of life is often affected owing to vision impairment and reduced mobility
• Type II Sialidosis:
  • The congenital form of type II Sialidosis is the most severe form. It results in either stillbirths, or death before the child reaches 2 years of age
  • Most individuals with the infantile form are reported to die before they reach age 20 years
  • The longevity of those with the juvenile form is dictated by the kind and severity of symptoms

Additional and Relevant Useful Information for Sialidosis:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/congenital-genetic-disorders/