Elsevier

Revue Neurologique

Volume 176, Issues 1–2, January–February 2020, Pages 10-19
Revue Neurologique

Mini Review
Neuropediatrics
Leukodystrophies and genetic leukoencephalopathies in children

https://doi.org/10.1016/j.neurol.2019.04.003Get rights and content

Abstract

Leukodystrophies and genetic leukoencephalopathies are a large group of genetic disorders affecting central nervous system white matter. They can begin at any age, however this study focuses on disorders beginning in childhood and adolescence. We discuss the recent definitions, classifications, and classic syndromes, as well as genetic progress in the field through the identification of new genes and several new genetic syndromes.

Introduction

Leukodystrophies (LD) and genetic leukoencephalopathies (LE) are heterogeneous orphan genetic diseases affecting mainly the CNS (central nervous system) white matter (WM). The incidence is rare, estimated between 1 per 50,000 and 1 per 7,600, respectively [1], [2], [3]. The inheritance mode depends on genetic etiology and can be autosomal recessive or dominant, X-kinked or mitochondrial. The predominant symptoms in these disorders are due to axonal suffering, leading to central motor symptoms associated, to a lesser extent, with cognitive and behavioral symptoms.

In the 1980s, LD were defined as progressive genetic disorders primarily affecting CNS myelin. Genetic LE were then defined as disorders predominantly affecting CNS WM, which do not require the primary abnormality of myelin or glial cells as the main mechanism [4], [5], [6].

The identification of LD was initially based on neuropathology, biochemical, and enzymatic markers. Much progress in diagnosis was made with the development of MRI in the 2000s. New syndromic entities were classified on clinical, electrophysiological, and radiological criteria. The MRI description of WM permitted the distinction of hypomyelination, when the disorder interferes with myelin formation, from demyelination, when a normal myelin is secondarily destroyed, including vacuolization, when cavitation appears in WM [7], [8], [9].

To date, this classification may be based on the cellular pathology mechanism [10], [11] or on the pathological pattern observed on MRI (hypo- or demyelination, WM swelling and/or myelin vacuolization, or leuko-vasculopathy). Many genes lead to a broad spectrum of phenotypes starting from infancy to adulthood. Diagnosis is difficult in several situations, as many genetic disorders other than primary CNS myelin diseases begin in infancy and may interfere with the myelination program. This can lead to severe hypomyelination, while disorders expressed after the active phase of myelination, including primary CNS myelin diseases, can induce an axonal degenerative disease without MRI abnormalities. The etiological approach is based on a combination of criteria using inheritance mode, age at first symptoms, neurological and extra-neurological symptoms, electrophysiology, brain MRI, and MR spectroscopy (MRS) [7], [12]. This approach combined with DNA high-throughput sequencing have led to the identification of new genetic disorders in the last two decades, although a genetic diagnosis remains unknown for a certain number of patients [9].

Section snippets

Recent definitions

A Delphi consensus of experts in 2015 redefined LD as “heritable disorders affecting CNS WM with or without peripheral nervous system (PNS) involvement, with primary myelin sheath or glial cell abnormalities,” whereas genetic LE were defined as heritable “disorders with significant, if not primary, WM abnormalities with strong evidence for a genetic primary neuronal, vascular, or systemic involvement” [10], [12]. This excludes acquired disorders affecting WM: non-genetic vascular,

Clinical aspects

LD in children mainly affects the motor system leading to delayed motor development or motor regression. Acute worsening occurs with certain LD, mainly with intercurrent illness. Motor symptoms include spasticity, dystonia, choreo-athetosis, tremor, cerebellar, or proprioceptive ataxia. Other neurological symptoms associated are autonomic dysfunction, macro/microcephaly, nystagmus, cranial nerves involvement, seizures, schooling regression, cognitive or neurobehavioral abnormalities.

Classification of leukodystrophies

In this section the primary classic and more recent LD are reported and classified, without exhaustively listing all genetic or metabolic disorders affecting WM [10]. The LD are classified using the primary MRI pattern for a practical clinical approach: hypomyelination, demyelination, myelin vacuolization and/or WM swelling, and leuko-vasculopathies.

Conclusion

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of CNS disorders with variable clinical manifestations and pathological mechanisms. There is still no consensus on definitions. In parallel to classic LD, identification of genes involved in other specific syndromes and new genetic entities are emerging in step with advances in DNA sequencing technologies.

Disclosure of interest

The authors declare that they have no competing interest.

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