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Batten disease

Batten disease is the common name for a family of severe and progressive neurological disorders (also known as neuronal ceroid lipofuscinoses - NCLs) that primarily affect children. Collectively, Batten disease is the most common inherited paediatric neurodegenerative disorder worldwide and the most common form of childhood dementia.

Batten disease is a genetic disease, caused by mutations in ceroid lipofuscinosis neuronal (CLN) genes. The different types of Batten disease are classified according to the defective CLN gene that is causing the disorder (eg. CLN1, CLN2, CLN3). It is also commonly described by reference to the child’s age when symptoms typically appear in that form of Batten disease (e.g. CLN2 disease is known as “late infantile Batten disease” and CLN3 disease is known as “juvenile Batten disease”). The most common forms of Batten disease in Australia are CLN3 disease and CLN2 disease.

Batten disease is classified as a ‘lysosomal storage disorder’. Lysosomes are tiny storage units within cells that break down cellular waste, such as proteins and carbohydrates. Mutations in CLN genes affect the normal activity of lysosomes, leading to a build-up of waste within cells and ultimately, cell death.

Approximately 1 in 100, 000 live births worldwide are affected by Batten disease. BDSRA Australia estimates that at any one time there are approximately 35 people living with a form of Batten disease in Australia, with an average of three to five new cases of Batten disease diagnosed each year in Australia.

Symptoms

Children with Batten disease are typically born healthy and develop normally, before they start to show disease symptoms. The age of symptom onset, range of symptoms and the rate of disease progression differ between the various forms of Batten disease. Affected children suffer progressive deterioration of brain and retinal cells, which result in a variety of severe symptoms and ultimately, premature death.

The most typical symptoms of Batten disease over time are:

- Visual impairment/blindness
- Early language delay
- Epilepsy (often with multiple seizure types, including generalised tonic-clonic, myoclonic, absence or focal seizures)
- Cognitive decline leading to childhood dementia
- Ataxia (including stumbling, falling, incoordination, slurred speech)
- Behavioural changes
- Sleep disturbance
- Psychiatric symptoms
- Extrapyramidal symptoms (spasms, restlessness, rigidity, tremors, jerky movements)
- Progressive motor decline and loss of the ability to walk, talk and communicate


Diagnosis

The diagnosis of Batten disease is typically based on assessment of early clinical symptoms, brain scans (including electroencephalography (EEG) and/or brain magnetic resonance imaging (MRI)) and biochemical testing for specific enzymes and/or genetic testing. Initially, Batten disease is frequently misdiagnosed as autism, epilepsy, developmental disorders and other syndromes.

It is important to get a diagnosis of Batten disease as early as possible. In the case of all types of Batten disease, early diagnosis allows for the prompt implementation of therapy and management strategies that help to prolong physical mobility, language and communication. It can also assist in obtaining access to essential financial and emotional support services and for family planning purposes. In the case of CLN2, early diagnosis can mean prompt access to enzyme replacement therapy.

Although NCLs are rare, they can often strike more than one person in families that carry the defective gene. Generally, a family can only be affected by one type of CLN disease.

Inheritance

Genes carry instructions for making proteins (e.g. enzymes). Generally, a person carries two copies of each gene. A child inherits one copy of a gene from its father and one copy of a gene from its mother.

Batten disease is a genetic disease, caused by mutations in CLN genes. Only one copy of a CLN gene is required in order for a cell to function normally. Carriers of one defective CLN gene are not affected by Batten disease, but they can pass the defective gene onto their children. A child will have Batten disease if it inherits two defective CLN genes - one from each parent.

This is represented as follows:

Genetics
This diagram illustrates the autosomal recessive inheritance pattern of Batten disease,
where both parents are ‘carriers’ of one copy of the defective CLN (ceroid lipofuscinosis neuronal) gene.


Where both parents carry one copy of the defective CLN gene, their children have:

Probability (Chance) Children Inherit:

One-in-four (25%)

Two copies of the defective CLN gene and, therefore, will be affected by Batten disease.

One-in-four (25%)

No copies of the defective CLN gene and, therefore, are unaffected.

One-in-two (50%)

One copy of the defective CLN gene and one copy of the healthy gene and, therefore, are a ‘carrier’ of Batten disease, but are unaffected by Batten disease.


Although Batten disease is rare, it can affect more than one child in families where both parents carry a defective CLN gene.

CLN1 disease, infantile

CLN1 disease, also known as “infantile Batten disease” is caused by mutations in the CLN1 gene. Mutations in the CLN1 gene result in deficiency of a lysosomal enzyme called palmitoyl-protein thioesterase 1 (PPT1).

CLN1 disease classically presents in the first year of life, with irritability, developmental arrest and rapid regression, slowing of head circumference growth rate, hypotonia, myoclonic seizures and progressive vision loss. Most affected children die in early to mid-childhood. Cases of late onset CLN1 disease (beginning around age 5 or 6) have also been reported.

CLN2 disease, late infantile

CLN2 disease, also known as “late infantile Batten disease”, is caused by mutations in the CLN2 gene. Mutations in the CLN2 gene result in deficiency of a lysosomal enzyme called tripeptidyl peptidase 1 (TPP1).


Figure: Typical CLN2 disease progression. This timeline indicates approximate ages of first clinical presentation of typical CLN2 disease symptoms. (Reproduced with permission of Dr Miriam Nickel, University Medical Centre Hamburg Eppendorf, 2019)

CLN2 disease classically presents with new onset seizures at 2-4 years of age, preceded by delayed language development. The onset of seizures is typically followed rapidly by progressive motor and language decline between the ages of 4 to 6 (see graph and corresponding table below), loss of ability to swallow and talk, myoclonic jerks, epilepsy, blindness by age 7 to 10 years, and childhood dementia. Children also often have sleep disturbance and behavioural symptoms. Untreated, most affected children die between the ages of 6-12 years. Find more information about CLN2 disease characteristics and progression in patients.


Graph: Longitudinal motor-language scores for the DEM-CHILD core cohort.
Data are cross-sectional summaries of disease severity for all patients in the DEM-CHILD core data cohort for whom longitudinal scoring data were available (n=41). Reproduced with permission from Nickel et al. (2018). 
Score Motor Language
3 Walks normally Normal
2 Frequent falls, obvious clumsiness Recognisably abnormal
1 No unaided walking or crawling Hardly understandable
0 Immobile, mostly bedridden Unintelligible or no language

Table: Motor and language scoring system used for assessing functional motor and language ability in patients with CLN2 disease (Steinfeld et al. (2002)).
Motor and language function rapidly declines in CLN2. Untreated, CLN2 disease has a largely predictable time-course with regards to loss of language and motor function. Following the onset of first symptoms at around 2 to 3 years of age, loss of motor and language skills is rapid, as indicated by the decline in combined motor and language scores (see accompanying table for scoring system).

Cases of atypical CLN2 disease, including later-onset CLN2 disease, have also been reported.

CLN2 disease may be suspected in a patient based on early clinical symptoms, EEG and/or MRI. It is diagnosed by genetic testing and/or a biochemical enzyme activity assay. Initially, it is commonly misdiagnosed as speech delay, autism, epilepsy and/or other developmental disorders.

The management of CLN2 disease is complex and patients generally require extensive multidisciplinary care to manage the different symptoms and rapid rate of functional decline. Maintaining function and optimising the quality of life for patients and their families are major management priorities, and co-ordinated involvement of both clinical and allied healthcare professionals is required. Such professionals may include physicians, nurses, therapists (physical, occupational and speech), dieticians, psychologists, social workers and counsellors working collaboratively to manage symptoms, minimise pain and suffering and provide emotional and spiritual support to patients and families. Find more information about the management of CLN2 disease.

There is no cure for CLN2 disease. A ground-breaking treatment for children with CLN2 was approved in Australia in 2018. This treatment, called cerliponase alfa (Brineura) is an enzyme replacement therapy that is infused directly into the brain of patients every two weeks. This treatment has been shown to substantially slow the progression of CLN2 disease, when compared with historical data of disease progression in untreated CLN2 patients (see Schulz et al. 2018).

Brineura was approved for therapeutic use in Australia in 2018 and included in the Federal Government’s Life-Saving Drugs Program in 2019. Guidelines on accessing cerliponase alfa are available via this link .

CLN3 disease, juvenile

CLN3 disease, also known as “juvenile Batten disease”, is the most common form of Batten disease worldwide. CLN3 disease is caused by mutations in the CLN3 gene. These mutations interfere with the production of an essential membrane-spanning (or ‘transmembrane’) protein called battenin.

CLN3 disease typically presents first with onset of central vision impairment around the age of 5 to 6 years, followed by behavioural and cognitive problems, progressive motor decline, slow movement, stiffness and loss of balance, sleep disturbance, speech and language problems, the onset of seizures and premature death, typically between the ages of 20 and 30.

Figure: Typical CLN3 disease progression. This timeline indicates approximate age range of first clinical presentation of typical CLN3 disease symptoms. Note, there is considerable variation in age at onset of symptoms in CLN3 disease, and not all symptoms are observed in all patients. This is an illustrative guide only. References: Ostergaard, J. (2016)  ,   von Tetzchner, S. et al (2019)   and Masten, M. et al. (2020)    .


The clinical course of CLN3 can also be broadly divided into four phases or stages, as described below (adapted from Kohlschütter, A. et al. 2019, Chapter 3 in von Tetzchner et al. (Eds.), 2019).



Phase Summary Description

1

Isolated visual failure
(4 to 8 years)

Following normal development, onset of vision problems occurs around 5 to 6 years of age, with progressive decay of the retina and changes to the macula. The macula is the spot of greatest visual acuity in the eye. Loss of vision tends to occur uniformly and rapidly in patients, resulting in legal blindness by around 10 years of age.

2

Emerging intellectual difficulties
(6 to 10 years)

During this phase, early signs of cognitive decline begin to emerge, with notable difficulties in thinking and talking. In some children, behavioural changes may start in parallel to the cognitive decline.

3

Increasing medical problems
(9 to 14 years)

Onset of epilepsy (seizures) is typical in this phase, with tonic clonic (or ‘grand mal’) type seizures most common and first occurring around 10 years of age. Behavioural changes such as mood and emotional instability, obsessive-compulsive-like behaviour and aggression become more noticeable, along with sleep disturbance and a noticeable decrease in motor abilities.

4

Multiple function loss
(15+ years)

In this phase, verbal communication for patients becomes increasingly difficult. While language comprehension appears to persist longer, expressive speech becomes more simple in content, contains many repetitive elements and may include apparently meaningless words and phrases. Major motor problems begin to develop with Parkinson-like movements, decreased bodily movement, stiffness of muscles, stooped posture and shuffling gait. Patients may become wheelchair bound around, on average, 16 years of age (although this varies widely and may occur anywhere between 11 to 26 years). Dementia symptoms become more severe and include decline in memory, attention, emotional control and general reasoning abilities. Behavioural, psychological and psychiatric symptoms are common in this phase, including aggression, anxiety, depression and hallucinations.


Given that vision impairment is typically the first clinical symptom in CLN3 disease, ophthalmologists may be the first to suspect or recognise CLN3 disease based on characteristic changes to the eye and retina. Once CLN3 is suspected based on the initial clinical symptoms, the first diagnostic test may be the microscopic examination of a routine blood smear to detect the presence of characteristic vacuoles (or large white holes) in white blood cells called lymphocytes. Diagnosis is confirmed with genetic testing. Due to general lack of awareness of CLN3 disease (and other forms of Batten disease) among clinicians, reaching a diagnosis can often take a number of years following the onset of symptoms.

There is no cure or treatment for CLN3 disease. The management of CLN3 is complex and patients generally require extensive multidisciplinary care to manage the different symptoms including vision loss, cognitive decline, language and communicative decline and motor impairment. Maintaining function and optimising the quality of life for patients and their families are major management priorities, and co-ordinated involvement of both clinical and allied healthcare professionals is required. Such professionals may include physicians, nurses, therapists (physical, occupational and speech), dieticians, psychologists, social workers and counsellors working collaboratively to manage symptoms, minimise pain and suffering and provide emotional and spiritual support to patients and families.

Other forms of Batten disease

Find information on other, rarer forms of Batten disease, including information on CLN 1 disease, juvenile onset; CLN 2 disease, later-onset; CLN 4 disease, adult onset (also known as Kufs disease); CLN5 disease, CLN 6 disease, CLN7 disease, CLN8 disease, and CLN10 disease.

A cure?

There is no known cure for any form of Batten disease. Globally, research on Batten disease and the development of novel treatments are accelerating at an unprecedented rate. Treatments including gene therapy, stem cell therapy, small molecule therapy and neuroprotection are currently being investigated.

A ground-breaking treatment for children with CLN2 (Brineura) was approved in Australia in 2018. This treatment has been shown to substantially slow the progression of CLN2 disease. Gene therapies and therapeutic drug candidates are currently being investigated in pre-clinical and/or clinical trial settings for a number of forms of Batten disease.

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More information

General information

Fact sheet

A downloadable fact sheet on all forms of Batten disease, including the rarer forms.
Acknowledgement of and thanks to the National Institute of Neurological Disorders and Stroke (USA) for permitting the reproduction of this fact sheet.

Therapeutic avenues

An overview of promising therapeutic avenues for Batten disease, including current FDA-approved clinical trials and prospective future treatments. See Johnson et al. (2019) 

CLN2 disease

Disease characteristics

For information about disease characteristics and progression in typical CLN2 disease (untreated) see: Nickel et al., (2018)     and   Steinfeld, R. et al., (2002) 

Disease management

For information about the management of CLN2 disease see: Williams et al., (2017)

Enzyme replacement therapy study for treatment of CLN2 disease

The clinical trial study for intraventricular cerliponase alfa (Brineura), an enzyme-replacement therapy for treatment of CLN2 disease – see Schulz A., et al. (2018)

A story of the development of cerliponase alfa.

Behind the scenes of the first therapy approved to treat the underlying cause of CLN2, a form of Batten disease.

About CLN2 disease brochure

A printable brochure about CLN2 disease is available for download  .

Acknowledgement and thanks to BioMarin Pharmaceuticals Australia Pty Ltd for permitting the reproduction of this fact sheet.

About CLN2 disease

Help is available to understand CLN2 disease and care strategies is available at this site, www.cln2family.com/en-au/

CLN3 disease

Comprehensive resource

For a comprehensive resource on CLN3 disease based on worldwide research see, Juvenile Neuronal Ceroid Lipofuscinosis, Childhood Dementia and Education: Intervention, education and learning strategies in a lifetime perspective (2019) von Tetzchner, S, et al. (Eds.). This downloadable textbook describes the developmental course of CLN3 disease and provides practical information for parents, educators and support staff.


Disease characteristics

For information about disease characteristics and progression in typical CLN3 disease see Ostergaard, J. (2016)  ,   von Tetzchner, S. et al (2019)   and Masten, M. et al. (2020)    .