Exploring pediatric lipofuscinoses in Latin America: insights from neurology

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Author: Joaquin A Pena MD

Neuronal ceroid lipofuscinoses (NCLs), a group of inherited neurodegenerative disorders, present unique challenges in pediatric neurology, particularly in Latin America. These conditions exhibit distinct clinical and genetic features in this region. In this blog entry, we explore the common presentations of NCLs, with a focus on CLN2, and emphasize the importance of increased awareness and improved diagnostic strategies.

Understanding NCLs

NCLs are characterized by the accumulation of autofluorescent lipopigments within lysosomes, resulting in progressive neurologic decline. These conditions typically manifest with seizures, visual impairment, motor and cognitive deterioration, and a shortened lifespan. Among the various forms of NCL, late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is particularly relevant due to the availability of targeted therapies.

Initial symptoms and phenotypic variability. In Latin American populations, the clinical presentation of CLN2 exhibits a spectrum of manifestations.

• Classic CLN2. Patients typically present with language regression (68%) and seizures (93%) around the age of 3 years. Other common initial symptoms include ataxia and developmental delay.
• Atypical CLN2. Atypical cases present with more diverse symptoms and later onset, commonly including seizures and language delay, occurring in 75% and 90% of cases, respectively. Atypical cases can also present with behavioral disorders, cognitive decline, and ataxia. The median age of symptom onset for atypical CLN2 is around 6 or 7 years.

Genetic landscape in Latin America. Genetic analysis has revealed several recurrent mutations in Latin American patients with NCLs.

• The most frequent is the c.827 A > T variant in the TPP1 gene, found in 17 of 72 alleles in a study, indicating a potential regional founder effect.
• Other common variants include c.622C > T (p.Arg208X) and the intronic variant c.887-10 A > G, associated with a higher frequency of atypical presentations.
• The p.Asp276Val variant is a regional-specific mutation in Latin America, underscoring the potential impact of targeted genetic testing in diagnosing NCLs in this region. These findings hold promise for enhanced patient outcomes and emphasize the potential of ongoing research and development in this field to revolutionize NCL diagnosis in Latin America.

Diagnostic and therapeutic implications

The variability in clinical presentation and the range of genetic mutations can complicate the diagnosis of NCLs. However, early identification is within our control and is crucial to timely treatment with cerliponase alfa, an enzyme replacement therapy, in the case of CLN2. This highlights the vital role of medical professionals in the early detection and management of these conditions, enabling us to make a significant impact on patient outcomes.

• Next-generation sequencing panels, including TPP1 and other relevant genes, can help confirm or exclude the diagnosis.
• Enzyme activity assays for TPP1 (CLN2), PPT1 (CLN1), and CTSD (CLN10) can help streamline the diagnosis, and dried blood spot testing facilitates rapid and cost-effective screening.
• A high index of suspicion, along with thorough clinical, neurophysiological, morphological, and genetic studies, is essential for the proper diagnosis of NCLs.

Conclusion

Pediatric NCLs in Latin America, particularly CLN2, present a complex landscape with classic and atypical presentations. Compared to other parts of the world, both qualitative and quantitative differences have been observed. Reports from Latin America highlight significant genetic heterogeneity, which includes novel mutations in the CLN1 and CLN2 genes. In contrast, international studies often describe common mutations that are specific to certain regions for similar NCL genes. The clinical presentations—such as seizures, developmental delays, and visual impairments—are generally comparable across different areas, with some exceptions. Additionally, diagnostic approaches in Latin America are increasingly incorporating genetic testing alongside clinical, neurophysiological, and pathological assessments. Conversely, studies from other regions tend to rely more consistently on advanced genetic and biochemical tests. The ongoing efforts to characterize novel mutations and refine diagnostic algorithms in this area are not only essential but also inspiring for continued advances in managing these rare yet devastating conditions. This potential for progress should motivate us all to contribute to the field of NCL research.

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