identify patterns of disease presentation, TTP1 enzyme activity, and genetic findings to help diagnose the condition when suspected.
The study included 30 people from various counties in South America. The median age of onset was 6, ranging from 1 to 41 years. In this group, nine patients (30%) had affected siblings.
The first reported symptoms were seizures occurring in 14 patients (47%), followed by speech alterations in six (20%), behavioral abnormalities in two patients (7%), cognitive impairment was found in two patients (7%), one reported visual alterations (3%), and another visual hallucinations (3%).
Of 29 participants with a recorded age at first symptom onset, 12 (41%) experienced at least one additional symptom within a year. Eight of these patients (27%) had seizures as the first symptom. When two symptoms arose simultaneously, cognitive decline (67%) and language difficulties (50%) occurred most often.
The symptoms that motivated parents to seek medical help were seizures in 22 of 30 participants (73%), followed by movement disorders that included muscle spasms, decreased body movement, and frequent falls, as well as behavioral abnormalities, cognitive difficulties, language and visual impairment.
“Of note, seizure onset was the symptom that led the majority of the families to seek medical care, while more subtle symptoms such as behavioural or cognitive changes were not enough for the families in this study to seek medical attention in the early phases of the disease,” the researchers wrote.
Abnormal electroencephalogram — a brain activity test — was found in 18 participants (60%).
All participants were tested for TPP1 activity in either dried blood spots (57%), white blood cells (40%), or in one case, saliva. Reduced TPP1 enzyme activity was confirmed in 28 patients (93%), with eight patients showing no enzyme activity.
The diagnoses were confirmed by genetic mutation analysis and additional TPP1 enzymatic activity tests. One patient was confirmed by metabolites profile analysis.
Two mutations were found most frequently in this population — 887-10A to G and 1048C to T. (Of note, A refers to adenine, T to thymine, C is cytosine, and G stands for guanine, the four building blocks of DNA).
“The [887-10A to G] mutation was first described in CLN2 disease in Portugal, and the authors proposed that the mutant protein might retain some residual activity, leading to a late-onset and delayed progressive form of CLN2,” the researchers wrote.
Three previously unknown mutations also were detected — 1226G to A, 1343C to A, and 1552-1G to A. The “impact of these mutations on TPP1 structure, activity and [symptoms] remains to be determined,” the researchers wrote.
“Data from this cohort of Latin American patients with atypical CLN2 show that potential differences between atypical and classical phenotypes include a later onset of disease, and that motor manifestations may not be so common as the first symptoms,” the researchers wrote.
“In light of the availability of specific therapy that may alter disease progression, these findings strengthen the importance of clinical suspicion and investigation of CLN2 even in patients above the classical age of the disease onset who present mainly with seizures but also language or behaviour abnormalities,” they added.