Types of Batten Disease

Batten disease, or Neuronal Ceroid Lipofuscinosis (NCL), has 13 known forms. Progressions of the different forms of the disease vary (the phenotype) based on the type of genetic mutation (the genotype) and other factors.  Each form is classified by the gene that causes the disorder. Each gene is called CLN (ceroid lipofuscinosis, neuronal) and given a different number designation as its subtype. The disorders generally include a combination of vision loss, epilepsy, and dementia.  For more information about genetic science and a glossary of terms the US National Human Genome Research Institute provides a useful .  We have collaborated with our scientific colleagues in the field of Batten disease to provide clinical summaries for as many forms of the disease as possible. We seek out and publish updated information on each type because we serve families impacted by all forms of the disease.

Clinical Summaries

Infantile onset and others

What is the cause?

The gene called CLN1 lies on chromosome 1. CLN1 disease is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the CLN1 gene, and both parents are unaffected carriers. The gene was discovered in 1995. CLN1 normally directs production of a lysosomal enzyme called Palmitoyl protein thioesterase 1 or PPT1. A deficiency of PPT1 results in abnormal storage of proteins and lipids in neurons and other cells and impaired cellular function. The cells cannot function as they should and symptoms develop.

How is it diagnosed?

The diagnosis is usually made by enzyme (PPT1) and genetic (CLN1) tests on blood samples. Occasionally a skin biopsy may be necessary. Granular osmiophilic deposits (GRODSs) are the characteristic storage body at the electron microscope level.

Does it have any alternative name?

CLN1 disease was first described in the 1970s in Finland and is sometimes called Haltia-Santavuori Disease, Infantile neuronal ceroid lipofuscinoses, or INCL.

How does the disease progress?

Genotype/phenotype correlations

Classical CLN1 disease, infantile

Babies are healthy and develop normally for the first few months of life. Towards the end of the first year, developmental progress starts to slow down. Infants may have difficulty sleeping through the night and may become more restless and irritable during the day. Some infants develop repetitive hand movements and fiddling. They often become floppy and developmental skills such as walking, standing and speech are lost.

Children become less able and increasingly dependent during the toddler years. By the age of 2 years, most will have epileptic seizures and jerks. Vision gets worse until they are no longer able to see. From about the age of three years, children are completely dependent, unable to play, feed themselves, sit independently or communicate. They may need a feeding tube and their arms and legs usually become stiff. Some children get frequent chest infections. Most affected children die in early to mid-childhood.

CLN1 disease, juvenile onset

Some children with CLN1 abnormalities develop the disease after infancy—around age 5 or 6—and have slower disease progression. Affected children may live into their teenage years. Others may not develop symptoms until adolescence and may live into adulthood. CLN1 disease, variant late infantile and adult types. A wide variety of age at symptom onset and disease progression is seen with mutations in CLN1.

Scientific Posters for CLN1

A New and Effective Target for Infantile Batten Disease
Shyng, Nelvagal, Dearborn, Cooper, & Sands

Gene Therapy for Infantile NCL
Gray & Rozenberg

Infantile Batten Disease- A Synaptic Study
Wishart

Late-infantile

What is the cause?

The gene called CLN2 lies on chromosome 11. CLN2 disease is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the CLN2 gene, and both parents are unaffected carriers. The gene was discovered in 1998. CLN2 normally directs production of a lysosomal enzyme called tripeptidyl peptidase1 or TPP1. A deficiency of TPP1 results in abnormal storage of proteins and lipids in neurons and other cells and impaired cellular function. The cells cannot function as they should and symptoms develop.

How is it diagnosed?

The diagnosis is usually made by enzyme (TPP1) and genetic (CLN2) tests on blood samples. Occasionally a skin biopsy may be necessary. Curvilinear bodies (CVB) are the characteristic storage body at the electron microscope level.

Does it have any alternative name?

CLN2 late infantile disease is sometimes called Jansky-Bielschowsky Disease or late infantile NCL (LINCL).

How does the disease progress?

Children are healthy and develop normally for the first few years of life. Towards the end of the second year, developmental progress may start to slow down. Some children are slow to talk. The first definite sign of the disease is usually epilepsy. Seizures may be drops, vacant spells or motor seizures with violent jerking of the limbs and loss of consciousness. Seizures may be controlled by medicines for several months but always recur, becoming difficult to control. Children tend to become unsteady on their feet with frequent falls and gradually skills such as walking, playing and speech are lost. Children become less able, and increasingly dependent. By 4-5 years the children usually have myoclonic jerks of their limbs and head nods. They may have difficulties sleeping and become distressed around this time, often for no obvious reason. Vision is gradually lost. By the age of 6 years, most will be completely dependent on families and careers for all of their daily needs. They may need a feeding tube and their arms and legs may become stiff. Some children get frequent chest infections. Death usually occurs between the ages of 6 and 12 years (but occasionally later).

CLN2 disease, later onset

Some children with CLN2 abnormalities develop the disease later in childhood —around age 6 or 7—and have slower disease progression. In later-onset CLN2 disease, loss of coordination (ataxia) may be the initial symptom. Affected children may live into their teenage years.

The TTP1 deficiency in atypical CLN2 can present as symptoms of ataxia and cerebellar atrophy but the individual does not necessarily develop seizures or vision loss. This example of atypical CLN2 is referred to as SCAR7, or spinocerebellar ataxia autosomal recessive 7.

Treatment

CLN2 is currently the only form of Batten disease that has an FDA approved treatment. The enzyme replacement therapy, Brineura® (cerliponase alfa), was created by BioMarin and was approved by the FDA in April 2017. It was approved to slow loss of ability to walk or crawl (ambulation) in symptomatic pediatric CLN2 Batten disease patients 3 years of age and older. It is available commercially through several hospitals across the U.S. For more information about this treatment visit https://www.brineura.com.

There are ongoing efforts for CLN2 treatments in both gene therapy and small molecule therapy. The work in scientific research for further treatments and a cure for all forms of Batten disease continues. If you would like to talk to us about ongoing research, please contact us at info@bdsra.org.

Juvenile

What is the cause?

The gene called CLN3 lies on chromosome 16 and was discovered in 1995. CLN3 disease is