Motor Impairments Are Early Sign of Juvenile Batten Disease, Study Finds

In most patients with juvenile Batten disease, motor impairments are already apparent at the time of diagnosis and are not related to vision loss, a study finds.

The findings of the study, “Motor function impairment is an early sign of CLN3 disease,” were published in Neurology.

Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, refers to a group of five childhood genetic neurodegenerative lysosomal storage disorders characterized by vision loss, lack of motor coordination, and impaired cognition.

Juvenile Batten disease, also known as CLN3 disease or juvenile neuronal ceroid lipofuscinosis (JNCL), is the most common type of NCL. JNCL is caused by a mutation in the CLN3 gene, which provides instructions to make a lysosomal protein called battenin, whose function is still poorly understood.

Vision loss is normally considered the earliest sign of the disease and, according to previous studies, precedes the onset of neurological decline by a few years, which may provide a window of opportunity for therapy.

“Recently, however, onset of vision loss was found to coincide with onset of cognitive decline, rather implying early brain involvement. This led us to hypothesize that motor function decline might also have its onset early in the disease course,” the investigators stated.

To test this hypothesis, researchers from the University of Groningen in the Netherlands used the six-minute walking test (6MWT) — a test that measures the distance a patient is able to cover in six minutes while walking on a flat and rigid surface — to assess the motor function of a group of children and adolescents with CLN3 disease.

The study involved 15 patients with CLN3 disease, as well as two control groups: one including 14 subjects who had visual impairments; another including 12 individuals who had visual impairments together with neurological deficits.

Based on 6MWT reference values obtained from healthy children, the investigators calculated 6MWT scores for children with CLN3, as well as for all individuals who had been included in the two disease control groups. Test results were correlated with patients’ age, as well as with scores from the Unified Batten Disease Rating Scale (UBDRS).

Results showed that 6MWT scores among children with CLN3 disease were already abnormal around the time of diagnosis (mean scores of −3.6 and −4.7 among children ages 7 and 8, respectively). The abnormally low 6MWT scores decreased even further among older children at later stages of the disease.

In addition, statistical analyses showed that 6MWT scores gradually worsened as children got older and UBDRS scores increased, confirming that motor impairments were correlated with disease progression.

Conversely, analyses showed that 6MWT scores tended to increase among children with visual impairments as they became older to a level similar to that of healthy children, confirming that vision loss per se does not cause motor impairments. On the other hand, the 6MWT scores decreased slightly among children with vision and neurological impairments, regardless of age.

“We show that motor decline has its onset early in the disease course of CLN3 disease, which is quantifiable using the 6MWT and cannot be explained by decreased visual acuity. We encourage using the 6MWT for CLN3 disease progression assessment in clinical follow-up and future therapeutic studies,” the scientists said.