Worldwide, it has been reported that the initial clinical manifestations in CLN6 disease occur between 2 and 4 years of age 20, however in this investigation, the cases analyzed trended towards the older end of this range with regards to symptom onset (3.9 ± 0.6), with a range between 3 and 5 years of age. This may be due to the small number of cases studied, or possibly to certain variations in the clinical course of the disease linked to this causative mutation as has previously been reported for Costa Rican patients 27. The age of diagnosis in this study was an average of seven years. This could be due in part to the challenges associated with diagnosis of a complex rare disease in a locality with limited utilization of genetic testing. In this patient cohort, females outnumbered males 2:1. This level of sex disparity has not been reported in clinical literature and is likely due to the small sample size. Differences in severity between the sexes have been documented for some forms of NCL, with more aggressive forms commonly reported in female patients, however this was not recapitulated in our study 35,36.
The genetic alterations identified in the study population, pointedly the Costa Rican mutation and the substitution polymorphism in intron 2, have been previously reported 11,29. This substitution polymorphism has also been described in Argentinian populations 10,11. In the Costa Rican Batten disease population, the homozygous mutation and the presence of the polymorphism suggests that the polymorphism and the damaging mutation are inherited as a haplotype. Thus, unlike many other NCL mutations, the Costa Rican c.214G > T mutation has been associated with the founder effect 27,37. It is important to mention, that despite not having carried out multi-generation genealogical studies, the presence of the specific haplotype in all study samples, the absence of consanguinity registered in medical records and the varied geographical locations where study subjects were born and live, supports this local founder effect for this allele. It has been suggested that this founder effect was introduced in the initial pool of genes from the time of the Spanish and Portuguese colonization. This hypothesis has been mentioned in other medical conditions described in our country such as Wilson´s Disease 38,39.
The main signs and symptoms observed in study participants generally agree with what has been reported worldwide for CLN6 patients, where visual loss, the presence of rapid and involuntary muscle movements, seizures, ataxia, and mental and motor deterioration are the most frequent findings described 23,24. Specifically, the published literature establishes that motor regression constitutes one of the first clinical manifestations 22, an aspect confirmed in our study subjects, where gait disturbances were near constant findings in the initial stages of the disease.
Where neuroimaging studies were available, cortical and / or subcortical atrophy were common findings, as has been consistently reported in NCLs 22,24−26. Regarding imaging modalities, magnetic resonance imaging (MRI) had limited availability in Costa Rica over the study period; many patient records thus only had computed tomography (CT) scans. Likewise, ERG equipment was not operational for the duration of the study period and ERG data is available for only three patients in the study. In the majority of the analyzed cases, deterioration was reported in both the ophthalmological evaluation and in the visual evoked potentials (defective macular light reflection, optic disc pallor, attenuation of retinal vessels, pigmentary retinal changes, macular degeneration and optic atrophy); all of these findings are congruent with what has been described previously in medical literature 40. These changes can occur even before the onset of vision loss, which was documented in the present investigation. In this study, similar to what has been reported worldwide, substantial disease progression was observed when comparing the initial clinical manifestations reported in medical records with the findings of the most recent neurological examination 41,42.
Current therapeutic options in this disease include symptom management for: seizures, sleep problems, extrapyramidal symptoms, behavior problems, anxiety and psychosis. Seizures in NCLs are often refractory to treatment and require the prescription of multiple antiseizure medications such as sodium valproate, lamotrigine, topiramate, levetiracetam, carbamazepine, and benzodiazepine derivatives 43,44. There were no major differences regarding the main antiseizure medications prescribed when compared to other countries, and possible variations would be due mainly to the availability of the medication in the country and in the social security health care system (CCSS).
Regarding the study participant in whom the c.214G > T Costa Rican mutation was not identified, it is possible that mutations in other NCL genes could be responsible for their symptoms, as has been documented in other Costa Rican patients 27,29. It is worth noting that this was the only patient that presented with a normal ophthalmic evaluation and normal visual evoked potential at diagnosis, demonstrative of some disparity in their disease presentation. Additionally, while vast majority of Costa Rican patients with NCL are treated in the HNN, the possibility (although low) of patients in other regional or private healthcare centers cannot be disregarded.