International Experts Develop Guidelines for CLN1 Management

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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An international team of experts has developed a set of consensus-based, family-informed recommendations for the diagnosis and best care management of neuronal ceroid lipofuscinosis type 1 (CLN1) disease.

The guidelines were outlined in a report, “Management of CLN1 Disease: International Clinical Consensus,” published in the journal Pediatric Neurology.

Originally called infantile Batten disease, CLN1 disease is a rare, inherited neurodegenerative disorder caused by a deficiency in the PPT1 enzyme due to mutations in the CLN1 gene. PPT1 deficiency leads to the toxic accumulation of lipofuscins, made up of fats and proteins, inside cells’ recycling centers.

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A CLN1 diagnosis often is missed or delayed due to its rarity, but also because symptoms overlap with those of other conditions. Clinical features include developmental delay, cognitive and motor decline, vision loss, seizures, and difficulty walking and maintaining balance.

“In the classic form of CLN1 disease, symptoms begin during infancy; additional [forms] have been observed with late infantile, juvenile, and adult onset,” the researchers wrote.

Currently, no disease-modifying therapies are available for the disease, and there are no specific clinical management guidelines or consensus statements.

As such, “families affected by CLN1 disease led an international initiative to develop a clinical care consensus statement based on the guidance of clinicians, researchers, and patient advocates who have direct experience with the care of patients with CLN1 disease,” the researchers wrote.

This family-clinician partnership was created by Taylor’s Tale, a nonprofit rare disease patient advocacy group.

A systematic review of published evidence was conducted to develop key statements, which were debated during a meeting and supported by expert- and caregiver-specific online questionnaires.

The expert-specific survey was completed by 15 experts from seven countries on four continents. These included 10 pediatric neurologists, a neuropsychologist, a metabolic specialist, a developmental physical therapist, a hospice nurse, and a social worker. The caregiver-specific survey was completed by 39 primary caregivers from six countries.

Statements reaching a consensus became care guidelines.

Key topics

The report focused on 14 key topics: clinical spectrum; early diagnosis; disease management; seizures; movement disorders; cognitive impairment; vision problems; physical, occupational, and speech therapy; nutritional, gastrointestinal, respiratory, and anesthesia management; sleep disturbances; pain and distress; mood and behavioral symptoms; end-of-life care; and family support.

Regarding clinical spectrum, the panel agreed that the disease varies by age at onset, order of symptom onset, rate of disease progression, and life expectancy. Therefore, it is key to determine the specific form to predict clinical course, prognosis, and care needs and subsequently tailor disease management.

The infantile form typically develops between 6 and 18 months, the late infantile form between 18 months and 4 years, the juvenile form after 4 years and up to early adolescence, and the adult form during late adolescence or adulthood.

Based on caregivers’ responses, the infantile form is the most common (51%), followed by the late infantile and juvenile forms (both accounting for about 20% of cases). In general, the later the age at symptom onset, the slower the disease progression.

In addition, early diagnosis “is critical for providing optimal symptom management, minimizing complications, and connecting families to appropriate psychosocial support and genetic counseling,” the team wrote.

CLN1 disease should be considered in young children older than 6 months with developmental stabilization or regression, slowed head growth, and/or newly occurring treatment-resistant seizures, as well as in school-age children with some combination of visual loss, dementia, or seizures.

While the adult form is “incredibly rare,” adults experiencing progressive visual, cognitive, motor, and/or behavior abnormalities should be tested for CLN1 disease.

According to caregivers, the first symptoms that most often prompted medical attention included motor delay or decline (36%), vision decline (22%), learning delay or decline (14%), and seizures (14%).

Diagnosis can be confirmed through genetic tests looking for disease-causing mutations in the CLN1 gene and/or by PPT1 enzymatic testing.

Management of CLN1 disease should focus on minimizing symptoms and maximizing quality of life for the patient and family. Symptom management can include “a broad range of strategies: pharmacologic and nonpharmacologic therapies, nutrition, psychosocial and school support, palliative care, and hospice support,” the researchers wrote.

As such, ongoing management often involves a multidisciplinary clinical team, in which regular communication and coordination of care is critical, they added.

Most (72%) caregivers believed that the interventions they used helped improve their child’s quality of life. Most common interventions included anti-seizure medications, physical therapy, massage, home/school modifications, and dietary changes.

Regarding seizures, which may become less problematic over time, the panel recommended the prescription of optimal anti-seizure medication based on seizure type and exploration of nonpharmacological approaches, such as ketogenic diet.

Given that seizures may never be completely eliminated, a balance between seizure reduction and side effects of anti-seizure medication should be attempted.

Physicians should determine whether movement problems are intrinsic to the disease or therapy’s side effects and then focus treatment on those causing functional impairments.

Experts recommended that occupational, physical, and speech therapy be initiated early in the disease course, and swallowing dysfunction and risk of aspiration (food or liquid going into the lungs) be assessed as motor function declines.

Motor and vision problems were ranked by caregivers as the symptoms with the greatest unmet need for therapeutic intervention. Still, they considered that physical therapy and occupational therapy were the most effective ways to manage CLN1 disease symptoms, after anti-seizure treatments.

“Everything in their short life should make them as happy and comfortable as possible. When vision goes, play more music and let them listen to their favorite movies. Ask yourself, ‘Will I regret not doing this’ and do it,” caregivers said.

Patients should also be provided with “nutritional supports, modified diets, and/or alternate routes of feeding as needed,” the team wrote.

Caregivers should follow recommended vaccination schedules for their affected child to reduce lung infections and promote positive sleep hygiene practices to manage their child’s sleep disturbances, which, according to caregivers, affect nearly all (91%) CLN1 patients.

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“Some caregivers reported that pediatric palliative care options are not readily available in many locations and hospice providers are largely inexperienced with pediatric cases,” the team wrote, adding that there is a need for additional support “to make families more comfortable when things get difficult.”

Moreover, “goals and strategies should be re-evaluated over time and adapted to patients’ current needs, with a primary aim of optimizing patient and family quality of life,” the experts wrote.

This also includes providing community/psychosocial support to families, particularly siblings, whose needs “may be overlooked due to the pressing needs of the patient with CLN1 disease,” they added.

According to the caregivers, having help from family/friends (18%) or respite/other caregivers (16%) can make the biggest difference, as well as connecting via social media (14%), and outside support groups (11%), among other support strategies.