The researchers pointed out that blood film microscopy (where a blood drop is analyzed under microscope) is a fast, accessible, and sensitive screening test for diagnosis, which otherwise can often be delayed or mistaken in children with the disease.
The study, “Juvenile Batten Disease (CLN3): Detailed Ocular Phenotype, Novel Observations, Delayed Diagnosis, Masquerades, and Prospects for Therapy,” was published in the journal Ophthalmology Retina.
Juvenile Batten disease, like other forms of Batten disease, is characterized by the toxic accumulation of lipofuscins (deposits of fats and proteins) inside lysosomes — cellular compartments responsible for breaking down waste. This buildup is particularly harmful to brain cells, leading to nerve cell damage and death.
The juvenile form of this disease is caused by mutations in the CLN3 gene, which provides instructions to produce battenin, a protein present at the membrane of lysosomes but whose function is still unknown.
Symptoms usually arise in early childhood and include vision loss, cognitive impairment, behavioral problems, progressive motor function decline, and seizures. Gradual vision loss is the first symptom in 80% of the cases, appearing at age five on average.
“Although timely diagnosis of [juvenile Batten disease] is often challenging, given the rapidly progressive and unfavorable prognosis of the disease, early diagnosis is important both to provide timely clinical management and support and to facilitate access to novel therapeutic interventions at the early disease stages,” the researchers wrote.
Juvenile Batten can be challenging to diagnose since many of its symptoms, including those related to vision, overlap with symptoms of other diseases. This results in delayed or mistaken diagnosis in a considerable number of cases.
Its diagnosis is confirmed by the detection of vacuoles (or cavities) inside lymphocytes (a type of white blood cell) using blood film microscopy, along with genetic testing for CLN3 disease-causing mutations.
In cases where the presence of vacuoles is uncertain, or a more detailed cellular analysis is needed, the blood sample can be further analyzed by electron microscopy to confirm the presence of lysosomal fingerprint-like structures.
In the study, a team or British researchers set out to better characterize early vision-related symptoms of juvenile Batten disease and propose an algorithm for early diagnosis.
To do that, the team retrospectively analyzed the clinical data of eight children (five girls and three boys) who were diagnosed with juvenile Batten at the Moorfields Eye Hospital, in London.
Results showed that the first symptoms appeared when the children were from 3 to 7 years of age, but they were diagnosed with juvenile Batten 1.5 to five years later (mean of 2.9 years later).
At the time of their referral to Moorsfields, the presumed diagnoses were Stargardt disease (one child), severe retinal dystrophy (three children), and unexplained visual loss (four children). After their first appointments, the children were diagnosed with juvenile Batten disease within six to 18 weeks.
All children had a history of rapid vision loss over a period of one to eight months. Seven of them (88%) showed bilateral (on both eyes) bull’s-eye maculopathy, six (75%) displayed eccentric fixation/“overlooking,” five (63%) had structural abnormalities in the retina, and four (50%) showed signs of retinal photoreceptor dysfunction (poor response to a light stimulus).
Also, neurologic or cognitive symptoms — including changes in behavior, mood, balance, or memory — were present in six children (75%).
Blood film microscopy detected vacuoles inside the lymphocytes of all the children. Samples of seven were also analyzed by electron microscopy, showing the presence of fingerprint-like structures. Genetic tests confirmed that they all carried CLN3 disease-causing mutations.
“We suggest that a child with bilateral rapidly progressive vision loss, with or without cognitive/behavioral problems at presentation, should have [blood film microscopy] to detect the presence of vacuolated lymphocytes, which can act as a sensitive screening test (all patients with CLN3 disease will test positive), followed by electron microscopy for [fingerprint-like structures],” the researchers wrote, adding that the diagnosis should subsequently be confirmed by genetic tests.