Age, type of symptoms at disease onset predict progression in metachromatic leukodystrophy

Earlier age at disease onset and the presence of motor symptoms at disease onset predicted more rapid progression in patients with metachromatic leukodystrophy, according to study findings published in Neurology.

The study included the largest natural history cohort of patients with metachromatic leukodystrophy to date, according to the researchers.

“The course of [metachromatic leukodystrophy] is neurodegenerative, with developmental stagnation, followed by the loss of abilities in motor function, language and cognition,” Christiane Kehrer, MD, of the department of pediatric neurology and developmental medicine at the University Children’s Hospital in Tübingen, Germany and colleagues wrote. “Different forms are described according to age at onset and used in clinical trials.”

Researchers describe forms of metachromatic leukodystrophy according to age, Kehrer and colleagues noted, including late infantile (with symptom onset typically before 2.5 years of age), juvenile (with symptom onset between 2.5 and 16 years of age) and adult subtypes. Disease onset is usually described in regard to gait disturbances that are present; other symptoms may include behavioral issues and decreasing performance in school. The latter issue may precede first abnormalities in gross motor function by years, particularly in later-onset forms of the disease, the researchers wrote.

As a result, Kehrer and colleagues conducted the present study “to understand whether it is exclusively age at onset, or also the type of first symptoms, which predicts the course of disease in metachromatic leukodystrophy.”

Kehrer and colleagues examined clinical, genetic and biochemical parameters of patients with late infantile (n = 35), early juvenile (n = 18), late juvenile (n = 38) and adult onset (n = 6) metachromatic leukodystrophy. Researchers recruited all 97 patients (girls, n = 51) from LEUKONET, a network that researches leukodystrophies and is funded by Germany’s Federal Ministry of Education and Research. They categorized patients as having motor symptoms, cognitive symptoms or a combination of both symptoms at time of disease onset.

Researchers measured decline in motor function, loss of motor and language capabilities and dysphagia/tube feeding.

Children who had late infantile or early juvenile onset disease had either motor symptoms exclusively (late infantile, 91%; early juvenile, 61%) or a combination of motor and cognitive symptoms (late infantile, 9%; early juvenile, 39%). More than half of patients with late juvenile onset (61%) had exclusively cognitive symptoms at disease onset; only 13% presented with motor symptoms and 26% presented with a combination of both types of symptoms. In the adult onset cohort, the division of symptoms at disease onset was split evenly across the motor only, motor and cognitive and cognitive only subgroups (n = 2 for each group).

Both the late infantile and early juvenile onset groups experienced more rapid progression and significantly different courses of disease compared with the late juvenile and adult onset groups (P < .005). The late infantile group, followed by the early juvenile group, demonstrated the most severe disease progression. Disease progression was similarly rapid in both groups, but specific elements of the disease differed for certain endpoints, such as onset to swallowing issues (P = .032) and onset to loss of expressive language (P = .034).

“In addition to age at onset, the type of first symptoms predicts the rate of disease progression in [metachromatic leukodystrophy]. These findings are important for counseling and therapy,” the researchers wrote. “This study provides Class II evidence that, in patients with [metachromatic leukodystrophy], age at onset and the type of first symptoms predict the rate of disease progression.”

References:

Kehrer C et al. Neurology. 2020;doi:10.1212/WNL.0000000000011047.

German leukodystrophy network. http://www.leukonet.de/10/?L=1. Accessed Oct. 26, 2020.