Brineura May Stop Progression in Typical, Atypical CLN2
Brineura (cerliponase alfa) stabilized the progression of neuronal ceroid lipofuscinosis type 2 (CLN2) — a type of Batten disease — in a small group of people in Columbia, including those with an atypical onset that occurs later in childhood.
Those results come from a small case series, “Real world effectiveness of cerliponase alfa in classical and atypical patients. A case series,” which was published in the journal Molecular Genetics and Metabolism Reports.
Due to mutations in the TPP1 gene, which leads to TPP1 enzyme deficiency, a loss of muscle coordination (ataxia) and seizures are the first symptoms of CLN2, also called late infantile Batten disease, that usually appear from ages 2 to 4.
In some cases, known as atypical CLN2, symptoms appear later in childhood, and include seizures, language difficulties, and behavioral problems.
Brineura is an enzyme replacement therapy (ERT) designed to replace the missing TPP1 enzyme, aiming to slow ataxia and other symptoms.
This study, conducted by researchers based at the Fundación Hospital Pediátrico la Misericordia (HOMI) in Colombia, described the presentation of CLN2 in eight patients, as well as the impact of Brineura on the course and progression of the disease for two years.
The team collected data on disease onset and treatment from medical records, and follow-up assessments included the CLN2 Clinical Rating Scale (motor, language), Weill Cornell scale (swallowing, walking, motor function, and language), and the Hamburg scale (motor, language, and visual). With all scales, higher scores indicated better outcomes.
Of those selected, typical CLN2 occurred in three participants, with a median onset age of 52 months (4.3 years), a median time from symptoms onset to diagnosis of six months, time between diagnosis to beginning treatment of four months, and 16 months treatment time.
In contrast, five were atypical CLN2 patients, with a median age of onset of 139 months (11.6 years), a median time from symptoms onset to diagnosis of two years, time between diagnosis to initiation of treatment of 13 months, and eight months treatment time. A novel TPP mutation was found in two atypical patients.
Two atypical patients were siblings, with one receiving a diagnosis while asymptomatic because of the history of the older sibling.
On the first visit to the clinic, seizures were observed in seven of eight patients, six with language difficulties, four with developmental problems, and three with ataxia and movement disorders. Six participants had an affected relative.
Before ERT, three of eight patients developed ataxia, three developed movement disorders, and two regressed in their language development.
Among the three participants with typical CLN2, two developed ataxia, two developed movement disorders, and two patients showed developmental regression, and all had eye problems.
Among the five with atypical characteristics, one developed ataxia, one a movement disorder, and one vision alterations, while one patient remained asymptomatic. All patients had either undetectable or below-the-normal-range of TPP1 enzyme activity.
Anti-convulsive medications before ERT included valproic acid (6 of 8 patients), levetiracetam (2 of 8), clobazam (3 of 8), oxcarbazepine (1 of 8), and lamotrigine (1 of 8).
All patients received 300 mg of Brineura infused directly into the fluid surrounding the brain every 15 days. After ERT, there was a reduction in valproic acid use in atypical patients (3 of 5 patients vs. 1 of 5) but increased use of levetiracetam (1 of 5 vs. 2 of 5) and clobazam (none vs. 1 of 5). For those with typical characteristics, medications remained constant.
Functional scores for all assessments analyzed before and after treatment did not show statistically significant differences in both typical and atypical participants.
However, there was no evidence of disease progression during follow-up, as defined by a two-point decline in the CLN2, Hamburg, and Weill Cornell scales for both typical and atypical patients. There were no serious adverse side effects reported for all who participated.
“These data support stabilization in the progression of the disease in both, the atypical and classical phenotypes [characteristics], with an adequate safety profile that was similar to that reported in other studies,” the researchers wrote.
“Our study highlights the importance of early diagnosis and timely initiation of therapy, which is a feasible therapy, well tolerated by patients and accepted by caregivers in this country, generating a positive impact in the quality of life of CLN2 patients and on disease outcome,” they added.