Neuronal ceroid lipofuscinosis 3

Alternate names

Juvenile neuronal ceroid lipofuscinosis; Vogt Spielmeyer disease; Spielmeyer Sjogren disease; CLN3 disease, juvenile

Definition

Neuronal ceroid lipofuscinosis 3 (CLN3-NCL) is a rare condition that affects the nervous system.

Onset

symptoms generally develop between age 4 and 8 years, although later onset cases have been reported.

Summary

• CLN3 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), which may also be collectively referred to as Batten disease.
• All these disorders affect the nervous system and typically cause worsening problems with vision, movement, and thinking ability. The different NCLs are distinguished by their genetic cause.
• Each disease type is given the designation "CLN," meaning ceroid lipofuscinosis, neuronal, and then a number to indicate its subtype.

Epidemiology

CLN3 disease is the most common type of NCL, but its exact prevalence is unknown; more than 400 cases have been described in the scientific literature. Collectively, all forms of NCL affect an estimated 1 in 100,000 individuals worldwide.

Cause

• CLN3 disease is caused by mutations in the CLN3 gene, which provides instructions for making a protein that is found in tissues throughout the body.
• The CLN3 protein is part of many compartments within cells, including lysosomes, which are cellular compartments that digest and recycle different types of molecules.
• However, the exact function of the CLN3 protein is unclear. Research has shown that this protein is involved in many cellular processes, but it is uncertain which of them is the primary role of the protein, or if these processes instead represent downstream effects.

Gene mutations

• It is unclear how mutations in the CLN3 gene lead to the characteristic features of CLN3 disease.
• One CLN3 gene mutation, found in the vast majority of cases, leads to the production of an abnormally short protein. As a result, the abnormal CLN3 protein is broken down or may interfere with normal cellular processes.
• Other mutations reduce the amount of normal protein or impair its function. It is not known how loss of this protein causes the signs and symptoms of CLN3 disease.
• CLN3 disease, like other NCLs, is characterized by the accumulation of proteins and other substances in lysosomes.
• These accumulations occur in cells throughout the body; however, nerve cells seem to be particularly vulnerable to their effects.
• The accumulations can cause cell damage leading to cell death.
• The progressive death of nerve cells in the brain and other tissues leads to the neurological signs and symptoms of CLN3 disease.
• However, it is unclear how mutations in the CLN3 gene are involved in the buildup of substances in lysosomes.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Affected people may experience rapidly progressive vision loss, developmental regression (loss of acquired milestones), cognitive decline, heart problems, seizures, speech disturbances, behavioral problems (including aggression), and movement abnormalities. Life expectancy generally ranges from the late teens to the 30's.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal electroretinogram
• Abnormal pyramidal sign
• Abnormality of extrapyramidal motor function
• Abnormality of visual evoked potentials
• Ataxia
• Behavioral abnormality(Behavioral changes)
• Bilateral tonic-clonic seizure(Grand mal seizures)
• Blindness
• Dementia(Dementia, progressive)
• EEG abnormality
• Focal-onset seizure(Seizure affecting one half of brain)
• Iris hypopigmentation(Light eye color)
• Motor deterioration(Progressive degeneration of movement)
• Neurological speech impairment(Speech disorder)
• Retinopathy(Noninflammatory retina disease)

Diagnosis

• The diagnosis of an NCL is increasingly based on assay of enzyme activity and molecular genetic testing.
• In unusual cases diagnosis relies on electron microscopy (EM) of biopsied tissues.
• The diagnostic testing strategy in a proband depends on the age of onset.

Treatment

• Treatment is currently symptomatic and palliative only.
• Seizures, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, depression and anxiety, spasticity, Parkinsonian symptoms, and dystonia can be effectively managed.
• Antiepileptic drugs (AEDs) should be selected with caution.
• Benzodiazepines may help control seizures, anxiety, and spasticity.
• Trihexyphenydate may improve dystonia and sialorrhea.
• Individuals with swallowing problems may benefit from placement of a gastric (G) tube.[1].