Neuronal ceroid lipofuscinosis 2

Other Names: CLN2; Jansky-Bielschowsky disease; CLN2 disease, late infantile (subtype); CLN2 disease, juvenile (subtype) Neuronal ceroid lipofuscinosis 2 (CLN2) is a type of neuronal ceroid lipofuscinosis (NCL), a group of severe diseases that affect the nervous system. Symptoms of the CLN2 generally develop between ages two and four years, although later onset cases have been reported. Children with CLN2 may experience speech delay, seizures that do not respond to medications, loss of muscle coordination (ataxia), muscle twitches (myoclonus), loss of vision, developmental delay, and intellectual disability. Symptoms of CLN2 worsen as the child gets older (progressive).

Cause

Mutations in the TPP1 gene cause CLN2 disease. The TPP1 gene provides instructions for producing an enzyme called tripeptidyl peptidase 1. This enzyme is found in cell structures called [[]]lysosomes, which digest and recycle different types of molecules. Tripeptidyl peptidase 1 breaks down protein fragments, known as peptides, into their individual building blocks (amino acids).

Mutations in the TPP1 gene greatly reduce or eliminate the production or activity of the tripeptidyl peptidase 1 enzyme. A reduction in functional enzyme results in the incomplete breakdown of certain peptides. CLN2 disease, like other NCLs, is characterized by the accumulation of proteins or peptides 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 signs and symptoms of CLN2 disease.

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.

Epidemiology

In the Newfoundland province of Canada, the incidence of CLN2 disease is estimated to be 9 in 100,000 births. The incidence of the condition outside of this population is unknown. More than 300 cases worldwide have been described in the scientific literature

signs and symptoms

The signs and symptoms of this condition typically begin between ages 2 and 4. The initial features usually include recurrent seizures (epilepsy) and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects motor skills, such as sitting and walking, and speech development. This condition also causes the loss of previously acquired skills (developmental regression), intellectual disability that gradually gets worse, and behavioral problems. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens.

Diagnosis

Diagnosis of Jansky–Bielschowsky disease is increasingly based on assay of enzyme activity and molecular genetic testing. Thirteen pathogenic candidate genes—PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2 GRN, KCTD7—are associated with the development of the disease. Patients with Jansky–Bielschowsky disease typically have up to 50% reduced lysosomal enzymes, and thus an enzyme activity assay is a quick and easy diagnostic test.

Vision impairment is an early symptom of Jansky–Bielschowsky disease, and so an eye exam is another common diagnostic tool. During the eye exam, loss of cells within the eye would indicate the presence of the disease however more tests are needed for a complete diagnosis. Other common diagnostic tests include:

Blood or urine test: Elevated levels of the chemical dolichol found in the urine is typical of individuals with the disease, as well as the presence of vacuolated lymphocytes in the blood. Skin or tissue sampling: Microscopy of skin could be used to observe lipopigment aggregation.

CT scan or MRI: Visualization of the brain would be able to detect areas of cerebral atrophy.

Treatment

Although there is no medication that can currently cure CLN2, in the Spring of 2017 both the United States Food and Drug Administration (FDA) and the European Commission approved the use of cerliponase alfa(brand name: Brineura) for children with CLN2. In clinical studies, cerliponase alfa was shown to slow down the progression of the disease.In addition, other medications and therapies can help relieve some of the symptoms of CLN2.