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

• DES (Dysequilibrium Syndrome)
• Non-Progressive Cerebellar Disorder with Mental Retardation 
• VLDLR-Associated Cerebellar Hypoplasia (VLDLRCH)

What is Dysequilibrium Syndrome? (Definition/Background Information)

• Dysequilibrium Syndrome (DES) is a non-progressive cerebellar disorder characterized by ataxia associated with an intellectual disability, delayed ambulation and cerebellar hypoplasia
• To date, more than 50 individuals have been reported in the world literature
• Dysequilibrium Syndrome can be classified into subtypes, based on the causal gene mutation(s): 
  • Type 1 (CAMRQ1), VLDLR
  • 2 (CAMRQ2), CA8
  • 3 (CAMRQ3) WDR81
  • 4 (CAMRQ4) ATP8A2
• VLDLR encodes the very low density lipoprotein receptor (VLDLR) which is involved in neuronal migration in the cerebral cortex and cerebellum
• CA8 encodes a carbonic-anhydrase related protein, whose biological function is not yet fully understood. The function of WDR81 is still unknown
• ATP8A2 encodes an ATPase which is mainly expressed in brain tissue, with the highest levels found in the cerebellum, and that may be critical for the developmental processes of the central nervous system
• Dysequilibrium Syndrome is inherited in an autosomal recessive manner

(Source: Dysequilibrium Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Dysequilibrium Syndrome? (Age and Sex Distribution)

• Dysequilibrium Syndrome is a rare congenital disorder, with over 50 cases described in the medical literature
• The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Dysequilibrium Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Dysequilibrium Syndrome can be inherited

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 Dysequilibrium Syndrome? (Etiology)

Dysequilibrium Syndrome can be caused by mutations in the VLDLR, CA8, WDR81 or ATP8A2 genes.

• The disorder can be classified into subtypes, based on the causal gene mutation(s): 
  • Type 1 (CAMRQ1), caused by VLDLR gene mutation(s). This gene codes for very low density lipoprotein receptor, which is involved in neuronal migration in the cerebral cortex and cerebellum
  • 2 (CAMRQ2), caused by CA8 gene mutation(s). This gene codes for carbonic-anhydrase related protein, whose biological function is not yet fully understood
  • 3 (CAMRQ3), caused by WDR81 gene mutation(s), whose function is unknown
  • 4 (CAMRQ4), caused by ATP8A2 gene mutation(s). This gene encodes an ATPase which is mainly expressed in brain tissue, with the highest levels found in the cerebellum, and that may be critical for the developmental processes of the central nervous system
• Dysequilibrium Syndrome is inherited in an autosomal recessive manner

(Source: Dysequilibrium Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Dysequilibrium Syndrome?

The signs and symptoms of Dysequilibrium Syndrome vary, but may include the following:

Very frequently present symptoms in 80-99% of the cases:

• Ataxia
• Gait disturbance
• Hyperreflexia
• Intellectual disability
• Muscular hypotonia

Frequently present symptoms in 30-79% of the cases:

• Cerebral palsy
• Seizures
• Skeletal muscle atrophy
• Strabismus

Occasionally present symptoms in 5-29% of the cases:

• Abnormality of vision
• Cataract

Additionally, the following signs and symptoms may be present:

• Abnormality of metabolism/homeostasis
• Broad-based gait
• Cerebellar atrophy
• Cerebellar hypoplasia
• Cortical gyral simplification
• Delayed speech and language development
• Dysarthria
• Dysdiadochokinesis
• Dysmetria
• Gaze-evoked nystagmus
• Generalized hypotonia
• Hypoplasia of the brainstem
• Intention tremor
• Pachygyria
• Pes planus
• Poor speech
• Truncal ataxia

(Source: Dysequilibrium Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Dysequilibrium Syndrome Diagnosed?

Dysequilibrium Syndrome is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary

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 Dysequilibrium Syndrome?

The complications of Dysequilibrium Syndrome may include:

• Speech impediment
• Vision problems
• Hearing impairment
• Falls and injury due to seizures
• Respiratory difficulties
• Inability to lead an independent life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Dysequilibrium Syndrome Treated?

There is no cure for Dysequilibrium Syndrome, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops.

How can Dysequilibrium Syndrome be Prevented?

Dysequilibrium Syndrome may not be preventable, since it is a genetic disorder.

• 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

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Dysequilibrium Syndrome? (Outcomes/Resolutions)

• The prognosis of Dysequilibrium Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Dysequilibrium Syndrome:

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

http://www.dovemed.com/diseases-conditions/rare-disorders/