Leukodystrophies in Children: Diagnosis, Care, and Treatment

Abstract

Leukodystrophies are a group of genetically determined disorders that affect development or maintenance of central nervous system myelin. Leukodystrophies have an incidence of at least 1 in 4700 live births and significant morbidity and elevated risk of early death. This report includes a discussion of the types of leukodystrophies; their prevalence, clinical presentation, symptoms, and diagnosis; and current and future treatments. Leukodystrophies can present at any age from infancy to adulthood, with variability in disease progression and clinical presentation, ranging from developmental delay to seizures to spasticity. Diagnosis is based on a combination of history, examination, and radiologic and laboratory findings, including genetic testing. Although there are few cures, there are significant opportunities for care and improvements in patient wellbeing. Rapid advances in imaging and diagnosis, the emergence of and requirement for timely treatments, and the addition of leukodystrophy screening to newborn screening, make an understanding of the leukodystrophies necessary for pediatricians and other care providers for children.The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

Characterization of MRI White Matter Signal Abnormalities in the Pediatric Population

“…Pairwise comparison showed significant age differences between patients with autoimmune disorders and those with non-genetic hypoxic and ischemic insults, infectious white matter damage, and leukodystrophies. These findings were driven by the predominance of adolescent-onset MS patients in the autoimmune group [21][22][23], and the predominance of perinatal insults, congenital infections, and leukodystrophies with early symptom-onset [24] in the other groups. There were no gender related differences.…”

Case Report: A Novel EIF2B3 Pathogenic Variant in Central Nervous System Hypomyelination/Vanishing White Matter

“…In the past, the diagnosis of leukodystrophies relies mostly on the clinical course and brain imaging. Brain MRI is a crucial diagnostic step and helps determine the subgroup of leukodystrophies; however, the characteristics of brain MRI may not be able to distinguish specific leukodystrophies (Bonkowsky et al, 2021). The recent rapid development of next-generation sequencing facilitates the diagnosis of rare inherited leukodystrophies.…”

“…Inherited leukodystrophies (Bonkowsky et al, 2021) are a group of largely heterogeneous genetic disorders affecting brain myelin (Vanderver et al, 2015). Although individually rare, inherited leukodystrophies are collectively common with an estimated incidence of 1 in 4,700 live births (Soderholm et al, 2020).…”

“…In pediatric population, inherited leukodystrophies cause significant morbidity and mortality, with a mortality rate of 34% and an average age at death of 8.2 years (Bonkowsky et al, 2010). Leukodystrophies can present at any age, ranging from infancy to adulthood (Bonkowsky et al, 2021). Disease progression rate and severity vary, even among affected individuals within the same family.…”

An update on the diagnosis and treatment of adrenoleukodystrophy

“…In a recent study from Japan, consisting of 99 patients who received HSCT between 1988 and 2015, the 5-year survival rate was 90% and the 10-year survival rate was 80.3%, a reduced conditioning regimen with fludarabine, melphalan, and low dose total body irradiation provided the best outcomes [36]. Data from 51 tertiary care hospitals in the United States showed that the average age at diagnosis was 6.2 years and the average time to HSCT averaged 97 days following index MRI [37]. In a case report, it was demonstrated that even with low donor chimerism (<10%), 7 years after an unrelated cord blood transplantation, the patient's neurological symptoms and brain MRI remained stable, indicating that a small number of donor cells may be enough to prevent progression in ALD [38].…”