New Guidelines Issued for CLN2 Diagnosis, Management

An international team of experts has provided the latest evidence-based recommendations for diagnosis, assessment, management, and treatment of neuronal ceroid lipofuscinosis type 2 (CLN2), a study reported. 

The study, “Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients,” was published in the Orphanet Journal of Rare Diseases.

CLN2, also known as late infantile Batten disease, is a rare, inherited neurodegenerative disorder caused by a deficiency in the TPP1 enzyme due to mutations in the TPP1 gene.

Typically found in cell structures known as lysosomes, which are responsible for digesting and recycling molecules, TPP1 breaks down protein fragments. In the absence of this enzyme, proteins and fats called lipofuscins accumulate, particularly in nerve cells, which leads to cell damage and death. 

A CLN2 diagnosis often is missed or delayed due to its rarity, but also because symptoms can be non-specific, including vision loss, seizures, difficulty walking and maintaining balance, as well as delays in learning and language. 

Although recommendations for managing CLN2 disease are available, the methods used to formulate these recommendations have been limited. Thus, there is a need for further independent guidance on diagnosis, clinical assessments, treatments, and disease management. 

To address this gap, a team of 21 international researchers from seven different specialties, including a patient advocate, came together to provide robust evidence-based, expert-agreed-upon recommendations to address the real need for timely identification, management, and treatment of children with CLN2.

“The purpose of these guidelines is to provide comprehensive guidance for the identification and clinical management of patients with CLN2, independent of age and disease severity,” the team wrote. 

CLN2 experts were identified based on the number of CLN2-related publications, those perceived as experts among families and advocates, and professionals seen as experts by their peers and whose advice is most called upon to share their knowledge about CLN2. 

Two co-chairs were selected along with a steering committee with experts from the U.S., U.K., Australia, Argentina, Brazil, Germany, Italy, and Ghana. Specialists within the steering committee included pediatricians, pediatric neurologists, neurosurgeons, geneticists, physiotherapists, epileptologists, nurses, and a patient advocate from the Batten Disease Support and Research Association (BDSRA).

A systematic review of published evidence was conducted to develop key statements, which were debated during a virtual online meeting and supported by an online questionnaire. Statements reaching a consensus became care guidelines. 

13 topics

The guidelines focused on 13 different clinical topics: general disease descriptions, diagnostics, disease management, treatments, assessments, social care considerations, pain management, seizures, nutritional care, respiratory (lung) health, sleep and rest, end-of-life care, and additional care considerations.

Regarding general disease descriptions, the team noted that multiple forms of CLN2 exist, with the common form showing slow development followed by epilepsy from ages 2 to 4, and a life expectancy from age 6 to the early teens. An atypical form occurs in about 13% of patients with later symptom onset, milder disease, sometimes without epilepsy or vision loss, and a longer life expectancy. Symptoms in this atypical form appear as behavioral disorders, movement disorders and ataxia — issues with muscle coordination or control.

Clinicians should provide all families with detailed diagnostic, biochemical, and genetic information.

Diagnosis of CLN2 during infancy would benefit from newborn screening programs, and infants with a significant speech or motor delay, clumsiness, and unprovoked seizures before the age of 4 should be tested. Diagnosis can be confirmed by low levels of TPP1 enzyme activity and should be double-confirmed by identifying two disease-causing mutations in the TPP1 gene. 

Management of CLN2 should be guided by the standards and guidelines from the International Children’s Palliative Care Network. All children with suspected CLN2 should be referred to a center with expertise in managing patients with NCL disorders. A physician should conduct the first assessment with experience in treating the condition, supported by a local multidisciplinary team of nurses and therapists, dieticians, psychologists, and counselors. 

Emotional and psychological support for families should be offered by a healthcare provider following diagnosis and be informed of relevant patient organization contacts.

The team recommended that a patient receive an initial baseline assessment to track disease progression over time, which includes (where possible) an electroencephalogram (EEG), visual exam, epilepsy record and medication use, and a record of MRI scans and cognitive tests. A physical examination should be conducted at every visit to assess general health, growth, vital signs, vision, frequency of seizures, and development. 

Regarding treatment, it was recommended a patient be prescribed long-term TPP1 enzyme replacement therapy with Brineura (cerliponase alfa), which slows the decline of motor and language function in CLN2, every other week in both typical and atypical CLN2. Ideally, the care will come from a team experienced in the management of CLN2 disease. 

Additional care considerations found it crucial to maintain a good quality of life, for the patients and their families, through psychosocial support. Comprehensive patient and family-centric care, which evolves as the disease progresses, should be put in place, with clinical visits tailored to meet the individual needs.

As CLN2 has a significant impact on families, the physician should be prepared for a reaction from the family after an often lengthy diagnostic process of two or more years. After diagnosis, families should receive relevant information, resources, including contact details from patient advocacy groups, and be encouraged to ask questions. Genetic counseling should be offered and so should ongoing grief and bereavement support.

Due to their young age and lack of language skills, it often is difficult to distinguish between pain and other sources of discomfort, including fear, anxiety, or boredom. Thus, patients need to be assessed carefully for possible causes of pain and treated accordingly. 

The team recommended pain always be treated first or ruled out, with advice from experts in movement disorders. Along with available medications, positioning aids, weighted blankets, physiotherapy, and heat may help to alleviate pain.

Multiple seizure types are seen in CLN2 disease, and management should minimize the impact on the child’s well-being, supporting social interactions, mobility, and fall prevention. Epilepsy management should use the most appropriate medications for CLN2 disease along with awareness of anti-epilepsy treatments that can worsen symptoms. 

Seizures in CLN2 children can be life-threatening, and emergency seizure plans for home and school should be put in place, including medications for emergency use. 

Regarding nutritional management, swallowing difficulties often arise and worsen until food intake fails to meet dietary requirements. There also is a high risk of aspiration (food or liquid in the lungs). Caregivers should know about appropriate food consistencies and how to recognize early signs of problems. Tube feeding should be considered if there is a risk of choking or an inability to meet nutritional requirements.

To maintain respiratory health, as complications may quickly become life-threatening in the latter stages of CLN2 disease, vaccinations against preventable diseases are recommended for the entire family. In addition, mobilization in age-appropriate positions and manual interventions to improve lung function within physiotherapy is recommended. 

Insomnia and sleep disturbances are standard features in CLN2 patients and their caregivers and should be actively monitored by professionals. Sleep disturbance can adversely affect seizure control and exacerbate behavior as well as cognitive impairments. Sleep tests may be needed to identify any treatable conditions. 

The primary goal of end-of-life interventions is to alleviate pain and distress. Wherever possible, hospice and home palliative care services should be offered to support families and caregivers. In the later stages, prevention of additional complications such as ulcers, muscle atrophy, and aspiration pneumonia should be emphasized. 

“This manuscript provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease,” the authors concluded. “It is [recognized] that the guidelines provided represent a point in time, and further research is required to address current knowledge and evidence gaps, especially the emergence and effect of new treatments.”