An international team of experts provided the latest evidence-based recommendations for the diagnosis, evaluation, management and treatment of neuronal ceroid lipofuscinosis type 2 (CLN2), a study reported.
The study, “Guidelines for the diagnosis, clinical evaluations, treatment and management of patients with CLN2 disease», Was published in the Orphanet Journal of Rare Diseases.
CLN2, also known as late infantile Batten disease, is a rare inherited neurodegenerative disease caused by a deficiency of the enzyme TPP1 due to mutations in the TPP1 uncomfortable.
Usually found in cellular structures called lysosomes, responsible for digesting and recycling molecules, TPP1 breaks down protein fragments. In the absence of this enzyme, proteins and fats called lipofuscins build up, especially in nerve cells, resulting in cell damage and death.
A diagnosis of CLN2 is often missed or delayed because of its rarity, but also because symptoms may be nonspecific, including vision loss, seizures, difficulty walking and maintaining balance, and delays in learning and language.
Although recommendations for the management of CLN2 disease are available, the methods used to make these recommendations have been limited. Thus, there is a need for additional independent guidelines on the diagnosis, clinical evaluations, treatment and management of the disease.
To fill this gap, a team of 21 international researchers from seven different specialties, including a patient advocate, came together to provide strong, evidence-based, expert-endorsed recommendations to meet the real need for timely identification, care and treatment. children with CLN2.
“The purpose of these guidelines is to provide comprehensive advice for the identification and clinical management of patients with CLN2, regardless of age and disease severity,” the team wrote.
CLN2 experts were identified based on the number of publications related to CLN2, those perceived as experts by families and advocates, and professionals considered experts by their peers and whose advice is most sought after to share. their knowledge of CLN2.
Two co-chairs were selected as well as a steering committee made up of experts from the United States, United Kingdom, Australia, Argentina, Brazil, Germany, Italy and Ghana. Specialists on the steering committee included pediatricians, pediatric neurologists, neurosurgeons, geneticists, physiotherapists, epileptologists, nurses and a patient advocate from the Batten Disease Research and Support Association (BDSRA).
A systematic review of the published evidence was conducted to develop key statements, which were discussed in a virtual online meeting and supported by an online questionnaire. Statements that reached consensus became guidelines for care.
The guidelines focused on 13 different clinical topics: general disease descriptions, diagnoses, disease management, treatments, assessments, social considerations, pain management, seizures, nutritional care, respiratory (lung) health, sleep and rest, end-of-life care. , and additional care considerations.
Regarding general descriptions of the disease, the team noted that there are several forms of CLN2, with the common form showing slow development followed by epilepsy of 2 to 4 years and a life expectancy of 6 years old in early adolescence. An atypical form occurs in about 13% of patients with late onset of symptoms, milder disease, sometimes without epilepsy or vision loss, and longer life expectancy. Symptoms of this atypical form appear as behavioral disturbances, movement disorders, and ataxia – problems with coordination or muscle control.
Clinicians should provide detailed diagnostic, biochemical and genetic information to all families.
Diagnosis of CLN2 in infancy would benefit from newborn screening programs, and infants with significant speech or motor delay, clumsiness and unprovoked seizures before the age of 4 years should be tested. The diagnosis can be confirmed by low levels of TPP1 enzyme activity and must be confirmed twice by identifying two pathogenic mutations in the TPP1 uncomfortable.
The management of CLN2 should be guided by the standards and guidelines of the International Childhood Palliative Care Network. All children suspected of CLN2 should be referred to a center specializing in the management of patients with NCL disorders. A physician should perform the first assessment with experience in treating the disease, supported by a local multidisciplinary team of nurses and therapists, dieticians, psychologists and counselors.
Emotional and psychological support to families should be offered by a health professional after diagnosis and be informed of relevant contacts of patient organizations.
The team recommended that a patient receive a basic initial assessment to monitor disease progression over time, which includes (if possible) an electroencephalogram (EEG), visual examination, epilepsy record, and medication use, as well as recording of MRI scans and cognitive tests. A physical exam should be done at each visit to assess general health, growth, vital signs, vision, seizure frequency and development.
Regarding treatment, a patient has been recommended to be prescribed long-term TPP1 enzyme replacement therapy with Brineura (cerliponase alfa), which slows the decline of motor and language function in CLN2, every two weeks in typical and atypical CLN2. Ideally, care will come from a team experienced in the management of CLN2 disease.
Additional care considerations found it essential to maintain a good quality of life for patients and their families through psychosocial support. Comprehensive patient and family centered care, which evolves as the disease progresses, should be implemented, with clinical visits tailored to individual needs.
Since CLN2 has a significant impact on families, the physician should be prepared for a family reaction after a diagnostic process that is often two years or more long. After the diagnosis, families should be provided with relevant information, resources, including contact details for patient advocacy groups, and be encouraged to ask questions. Genetic counseling should be offered, as should ongoing grief and bereavement support.
Due to their young age and lack of language skills, it is often difficult to distinguish between pain and other sources of discomfort, including fear, anxiety or boredom. Thus, patients should be carefully assessed for possible causes of pain and treated accordingly.
The team recommended that pain always be treated first or ruled out, with advice from movement disorders experts. In addition to available medications, positioning aids, weighted blankets, physiotherapy, and heat can help relieve pain.
Several types of seizures are observed in CLN2 disease, and management must minimize the impact on the well-being of the child, by promoting social interactions, mobility and prevention of falls. The management of epilepsy should use the most appropriate drugs for the CLN2 disease as well as awareness of anti-seizure drugs which may worsen symptoms.
Seizures in CLN2 children can be life threatening, and emergency plans for home and school seizures should be in place, including emergency medication.
Regarding nutritional management, swallowing difficulties often arise and worsen until food intake does not meet dietary needs. There is also a high risk of aspiration (food or liquid in the lungs). Caregivers need to know the correct food consistencies and know how to recognize the first signs of problems. Tube feeding should be considered if there is a risk of suffocation or an inability to meet nutritional needs.
To maintain respiratory health, since complications can quickly be life threatening in the later stages of CLN2 disease, vaccination against preventable diseases is recommended for the whole family. In addition, mobilization into age-appropriate positions and manual interventions to improve lung function as part of physiotherapy is recommended.
Insomnia and sleep disturbances are standard features in CLN2 patients and their caregivers and should be actively monitored by professionals. Sleep disturbances can interfere with seizure control and exacerbate behavior and cognitive impairment. Sleep tests may be needed to identify any treatable condition.
The main goal of end-of-life interventions is to relieve pain and distress. Where possible, palliative and home care services should be offered to support families and caregivers. In the later stages, the prevention of further complications such as ulcers, muscle atrophy and aspiration pneumonia should be emphasized.
“This manuscript provides strong evidence-based and consensus-based 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 that further research is needed to address current knowledge and evidence gaps, in particular the emergence and effect of new treatments.