Batten Disease - Neuronal Ceroid Lipofuscinosis (NCL)

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What is Batten Disease?

Neuronal Ceroid Lipofuscinosis (NCL) is a rare and debilitating genetic disorder. NCLs are a group of disorders which are often collectively referred to as Batten disease. Batten disease primarily affects the nervous system and is characterized by seizures and a progressive loss in motor, language, visual, and cognitive skills. There are 14 different forms of Batten disease, which are numerically identified as CLN1, CLN2, etc.

Patients with Batten disease lack an enzyme that breaks down cellular waste in the body. This waste accumulates in cells throughout the body, with nerve cells being particularly affected by this build up, and leads to some of the symptoms described below.

Individuals with Batten disease are born healthy, often reaching expected developmental milestones in their first years. The signs and symptoms of Batten disease can vary greatly between individuals, though many of the forms have overlapping symptoms that impact patients in similar fashions.

Some children with Batten disease do not develop symptoms until later in childhood, after age 4, or even later into adulthood. These patients tend to have milder symptoms. Initial symptoms often include seizures and difficulty coordinating movements, the development of muscle twitches and vision loss. Patients’ motor skills, including sitting and walking, and speech development are also affected.

Currently, only treatment for CLN2 is available in the form of an enzyme replacement therapy, but there is much Hope on the horizon for some other types of Batten Disease with innovative treatments being studied in clinical trials.

The CLN1 gene, found on chromosome 1, is responsible for producing an enzyme called PPT1, which acts as a lysosomal enzyme. CLN1 disease is caused by a mutation in the PTT1 gene, which results in an enzyme deficiency, which allows for a buildup of lipids and proteins in the body’s cells.

There are two types of CLN1 disease: infantile onset, and juvenile onset. In the infantile form, symptoms appear before age 1 and progress rapidly. Most affected children die in early to mid-childhood. In the juvenile form, children may develop the disease after infancy, around age 5 or 6, and have a slower progression of symptoms. Children may live into their teenage years. Some children may not develop symptoms until adolescence, and may live into adulthood.

The CLN2 gene, found on chromosome 11, is responsible for producing an enzyme called TPP1, which acts as a lysosomal enzyme. CLN2 disease is caused by a mutation in the TPP1 gene, which results in an enzyme deficiency. In patients with CLN2, the TPP1 gene mutations greatly reduce or eliminate the production and activity of this enzyme. This results in cellular waste being stored in the body’s cells.

Like other Batten diseases, CLN2 is characterized by the accumulation of waste in cells throughout the body. Nerve cells are especially vulnerable to these effects. The progressive damage of nerve cells in the brain and other tissues cause the symptoms of CLN2 disease.

Children with CLN2 disease may have late-infantile onset or later-onset of the disease. In late-infantile onset, children typically begin to show symptoms around age 4-5; most die between 6-12 years. In later-onset, children may develop the disease later in childhood, around age 6-7, and may live into their teens.

In CLN3, the disease is caused by a mutation in the CLN3 gene, found on chromosome 16. This gene directs the production of battenin, a protein, found in the cell’s membrane. Children with CLN3 disease are missing a part of this gene, so the gene is unable to properly produce the protein.

Symptoms begin between age 4-7, often beginning with rapid vision loss, and other symptoms common with Batten diseases. Children with CLN3 disease die between ages 15-30.

CLN4 disease is also known as Kufs disease type B. A rare form of Batten, symptoms typically begin in early adulthood, around age 30. The disease relates to mutations in the DNAJC% gene, found on chromosome 20. Symptoms progress slowly, causing movement problems and early dementia. Life expectancy varies among individuals.
The CLN5 gene, located on chromosome 13, is a lysosomal protein, the function of which is unknown. CLN5 disease is caused by problems with this gene. Symptoms typically appear between 6-13 years; most children live into their late childhood or teens.
The CLN6 gene, found on chromosome 15, is responsible for directing the production of the protein CLN6, also called linclin, which is found in the cell’s membranes.
Mutations on the CLN7 gene, found on chromosome 4, cause CLN7 disease. This gene is responsible for producing the protein MFSD8. In patients with CLN7, these mutations greatly reduce or eliminate the production and activity of this protein. This results in cellular waste being stored in the body’s cells.

Developmental delays begin to appear in the first few years of a child’s life, with seizures and other symptoms beginning between ages 3-7. Affected children often experience a rapid progression of symptoms between 9-11. Children typically live until their late childhood or teenage years.

Mutations in the CLN8 gene cause CLN8 disease. The CLN8 gene provides instructions for producing a protein. While the function of this protein is not well understood, it plays a role in moving materials in and out of a cell structure called the endoplasmic reticulum, which is involved in protein production, processing, and transporting to different parts of the cell.

Symptoms often begin between 5-10 years and include seizures and cognitive decline. A very rare form of this disorder is sometimes called Northern Epilepsy syndrome, because of its prevalence among certain families in an area of Finland.

Children with late-variant onset of CLN8 begin to show symptoms between ages 2-7. Symptoms common with Batten diseases are likewise present in CLN8. Affected children develop treatment-resistant epilepsy and a progressive loss of cognitive skills, and the ability to walk or stand unassisted. Life expectancy varies, and some children live into their teens.

In CLN9 disease, the underlying genetic cause is unknown. Symptoms common with Batten disease generally develop in early childhood, around age 4.
CLN10 is caused by a mutation in the CTSD gene, found on chromosome 11, which produces a protein called cathespin D. Cathespin D is responsible for breaking apart other proteins in the lysosome. In patients with CLN10, the gene mutations greatly reduce or eliminate the production and activity of this enzyme, which results in cellular waste being stored in the body’s cells.

Though CLN10 disease can occur later in childhood or adulthood, symptoms are often seen soon after birth, with some children having microcephaly, an abnormally small sized head, with reduced brain size.

In the congenital form, seizures can occur after birth. Though, these are hard to differentiate from normal baby movements. Babies may die shortly after birth, or within the first few weeks of life. In the late-infantile form, affected children show a later onset of symptoms, and a slower progression of the disease. Affected children often die in early childhood.

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Batten Disease Quick Stats

13

Types of CLN Disorders

1

FDA Approved Therapy (for CLN2)

4

of 7 eligible CLN2 Patients in Canada Currently Receiving Treatment

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"Knowing there are other families across Canada that are going through this and are receiving this life-saving treatment – it makes me happy for them, but it makes me very sad for us. We want the same opportunity for our child to grow, and play, and laugh. And live."Meet Charleigh, who was recently diagnosed with CLN2 in BC. She's one of only 13 patients in Canada. Other children across the country have started receiving access to a life-saving treatment, but time is rapidly running out for Charleigh to be approved for the same treatment.Please watch and share. This story is too heartbreaking to scroll past, and watching, sharing, and commenting will help save this little girl's life. We will be working hard to help this beautiful little girl and her family before time runs out, and will update you as things progress. In the meantime, for more information about CLN2, please visit www.theisaacfoundation.com/batten.#Hope

Posted by The Isaac Foundation's Project One Million on Wednesday, June 12, 2019
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What Causes Batten Disease?

Batten disease is a genetic disorder that impacts the function of cells. It is a lysosomal storage disorder. Lysosomes are responsible for breaking down of waste in the cells of the body. Patients with Batten disease have genes that have been mutated and that mutated gene type represents the form of Batten disease an individual patient has. The mutated gene impacts leads to a lack of protein necessary for successful breakdown of cellular waste, causing that waste to build up in the neurons (brain cells) and other cells, leading to progressive and devastating symptoms in sufferers.


Genetic Condition Caused By Enzyme Deficiency

Batten disease is an inherited genetic disorder, and is a type of lysosomal storage disease, that affects cells in the brain. It is caused by a mutation in the CLN gene, which results in an enzyme deficiency. These genes provides instructions for producing an enzymes. In patients with Batten disease, the CLN gene mutations greatly reduce or eliminate the production and activity of this enzyme. This results in cellular waste being stored in the body’s cells. 

Lack of Enzyme Leads to Progressive Symptoms

Batten disease is characterized by the accumulation of waste in cells throughout the body. Nerve cells are especially vulnerable to these effects. The progressive damage of nerve cells in the brain and other tissues cause the symptoms of Batten disease. 

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Symptoms of Batten Disease

Symptoms of Batten Disease are often not present at birth; children with the disease are often born healthy and develop normally until symptoms begin to appear. Children may begin to show symptoms at different ages, depending on the form of the disease. Children with infantile and late-infantile forms often show symptoms earlier than age 1. For others, symptoms begin between age 2-4, or further into childhood.

Common symptoms for most forms of Batten include seizures, vision loss, abnormal movements, the loss of previously acquired skills, and dementia. The progressive nature of Batten disease leads to the worsening of symptoms over time. These symptoms are described in greater detail below.

Until recently, management of symptoms was the only course of care for patients. In 2017, the first ever treatment for CLN2 was approved by the FDA and the European Commission. More information on this treatment can be found in our TREATMENT section.

Vision Problems

Affected children often experience a gradual onset of vision loss. This can eventually lead to blindness.

Seizures

The gradual onset of worsening seizures is one of the most common early symptoms of Batten. For children with CLN2, for example, seizures often begin to appear between age 2-4. Seizures tend to be the first symptom which brings a child to medical attention.

Speech and Language

Children diagnosed with Batten often have a history of language delay. Children who may have been previously developing normally can suddenly exhibit language delays or repetitive speech.

Intellectual Disability

Because Batten primarily affects nerve cells, patients develop a progressive intellectual disability, which also leads to behavioural challenges. Early signs of Batten may be subtle behavioural or personality changes, slow learning, or regression. The progressive loss of intellectual abilities leads to dementia.

Motor Skills and Mobility

Children with Batten disease experience difficulties with sitting and walking. Children often exhibit clumsiness, involuntary movements, and slow movement. Because of mobility loss, patients often eventually require the use of a wheelchair.

Severely Shortened Lifespan in Infants

Without treatment, the lifespan of patients with Batten disease is severely shortened. The increased risk of early death is depending on the form of the disease, and age of the child at disease onset. Children with infantile Batten disease often die in early childhood, others typically do not survive past their teens, and those with later-onset forms may live into their teens or early adulthood. It is imperative that patients have access to life-sustaining treatment as soon as possible after diagnosis, to help slow down the progression of life-threatening symptoms.

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Talk to a Batten Mom or Dad

If you would like to talk directly with other parents of patients with Batten disease in Canada, please fill out your information and one or more will contact you as soon as possible.  When things get stressful and tough, sometimes it helps to speak with someone in similar circumstances, fighting the same battle that you are.

At the same time, sometimes it’s just nice to connect! Whatever the reason, if you’d like to talk with a “Batten Mom or Dad,” we’ll connect you right away.

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Emerging and Exciting New Treatments

Up until recently, no treatments have existed to specifically treat Batten disease. The management of symptoms was the only course of care for patients – anti-convulsants; behavioural and speech therapies; and vitamin therapies.

In recent years, however, new treatments have started to emerge. These promising treatments, including Enzyme Replacement Therapies and Gene Therapies, provide hope to patients and their families.


Hope for CLN2 Patients and Their Families

In April 2017, the first ever treatment for CLN2 was approved by the U.S. Food and Drug Administration. Brineura, manufactured by BioMarin, was passed through the approval process in both the US and Europe because of the tremendous unmet need the treatment provided patients. It is currently pending approval through Health Canada.

This enzyme replacement therapy (ERT) is the first to be directly administered into the brain’s fluid, treating the underlying cause of CLN2 disease by helping to replace the TPP1 enzyme that is deficient in patients.

Jump To Biomarin’s Brineura Information Page

Gene Therapy for CLN6 – A Curative Solution?

In research labs around the world, there are numerous Gene Therapy projects in progress. These therapies are being investigated in the lab setting for their potential to act as curative solutions to genetic diseases.

Currently, a clinical trial for Batten CLN6 Gene Therapy is under way at Nationwide Children’s Hospital, in Columbus, Ohio. As there is currently no specific treatment approved to treat CLN6, this trial could potentially serve a tremendous unmet need for individuals with CLN6.

Jump To Clinical Trial Information Jump To Amicus Therapeutics’ Batten Disease Program
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" Access to treatment takes the gut wrenching horror of this disease away because it makes a future for him something that IS attainable. It means that this disease doesn’t have to dictate his life expectancy. It gives us the gift to celebrate his birthdays, not fear them."
Leah Brochu - Mother of a child with CLN2 Batten Disease
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Access to Treatment in Canada

 Reimbursement of Treatments for Rare Diseases in Canada – A Long and Arduous Process

From an access standpoint, there is no reason for delay, and no reason why patients who need access can’t receive it soon after regulatory approval from Health Canada.  Patients suffering from these rare and progressive diseases don’t have the luxury of time on their side, and the current process is long and arduous. Companies and governments can and should help patients now while these processes play out, and I remain hopeful that true collaboration with all stakeholders can take place. Andrew McFadyen, Executive Director, The Isaac Foundation 

Unfortunately, any approval by Health Canada for treatments for a Rare Disease doesn’t mean that patients can begin receiving therapy immediately.  Canada’s lack of an Orphan Drug Plan, coupled with the bureaucratic approval process that differs in individual provinces, often leaves patients lacking the treatment they desperately need.  The reason?  While Health Canada may approve a treatment for use, it’s still up to individual provinces to decide whether they will pay for the treatment or not.  The process to decide whether to cover such treatments is long and arduous, beginning with a review by CADTH (Canadian Agency for Drugs and Technology in Health).  This review can take 6-12 months, at which point a recommendation will be rendered to either list the drug on provincial drug plans, list the drug with conditions (such as a decrease in price from the manufacturer or restrictions on which portion of the patient population can access the drug), or do not list at all.

If a drug receives a positive recommendation, the file then moves to the pCPA (Pan-Canadian Pharmaceutical Alliance) for bulk pricing negotiations.  In this stage, negotiators assigned to represent all prices open discussions with the company in an attempt to come to terms on the cost.  Because rare disease drugs are often some of the most expensive in the world, these negotiations take a very long time – anywhere from 6-18 months.  If negotiations result in a deal, provinces can then decide to accept the deal and begin delivering the drug to patients on their drug plan.  Occasionally, no deal is able to be struck between pCPA and the company, and the drug remains difficult or impossible to secure for patients in need.

While these processes undergo their reviews, Physicians with patients suffering from a rare disease may fill out a request for reimbursement application and submit it to the provincial Ministry of Health.  From there, the application is reviewed and a decision to cover the cost of treatment is either approved or, in most cases, denied.  Most reasons governments provide for denial are due to a lack of evidence of the benefits these treatments provide patients, especially while the CADTH reviews are in place.  In many provinces, policies are in place that prevent these decisions from being rendered until the above reviews have been completed.  Companies can work directly with governments to see how drugs can be accessed while reviews are taking place, and they are often encouraged to show a willingness to help provide access for their patient population by drugs on a compassionate use basis.

Bureaucratic Path to Reimbursement – Information and Estimated Timelines 

Bureaucratic Path to Reimbursement Could Take 18-24 Months Longer



STEP 1 - Approval By Health Canada

A company submits their drug to Health Canada for review and approval for use in Canada.  Many reviews for rare disease drugs are considered a “priority” review because of the potential impact the therapy could have on patients.

STEP 2 - Submission and Review to the Common Drug Review (CDR)

The Common Drug Review  is a “process for conducting objective, rigorous reviews of the clinical, cost-effectiveness, and patient evidence for drugs.”  The CDR completes their review and recommends to provinces whether a drug should be reimbursed or not.

STEP 3 - Negotiations Begin With the Pan-Canadian Pricing Alliance (pCPA)

The Pan-Canadian Pricing Alliance works to capitalize “on the combined ‘buying power’ of drug plans across multiple provinces and territories” to bring the cost of expensive treatments down. If a drug receives a recommendation at CDR to continue to the pCPA negotiation process, negotiations could take 12-18 months. 



6

Months Estimated for Health Canada Review

6

Months Estimated to CADTH process

12

Months Estimated to Negotiate Price through pCPA

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Support for Accessing Treatment in Canada

If you would like assistance obtaining any available treatment in Canada or help navigating and finding clinical trials, please don’t hesitate to contact us and we will do whatever we can to assist.

We can join you for a meeting with your Member of the Provincial Parliament (MPP) or  Member of the Legislature (MLA) and work closely with them to ensure reimbursement for treatment is forthcoming.  We can also help you connect with other families undertaking the same processes, connect with the pharmaceutical companies on your behalf, and come meet with you in your home province to help support you in any way necessary.

Whatever we can do to help, we’ll be here.

If you would rather connect with us via social media, please find us on the links below:

 

Batten Disease in Canada


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