Inherited white matter disorders: Hypomyelination (myelin disorders).

Abstract

Hypomyelinating leukodystrophies are a subset of genetic white matter diseases characterized by insufficient myelin deposition during development. MRI patterns are used to identify hypomyelinating disorders, and genetic testing is used to determine the causal genes implicated in individual disease forms. Clinical course can range from severe, with patients manifesting neurologic symptoms in infancy or early childhood, to mild, with onset in adolescence or adulthood. This chapter discusses the most common hypomyelinating leukodystrophies, including X-linked Pelizaeus-Merzbacher disease and other PLP1-related disorders, autosomal recessive Pelizaeus-Merzbacher-like disease, and POLR3-related leukodystrophy. PLP1-related disorders are caused by hemizygous pathogenic variants in the proteolipid protein 1 (PLP1) gene, and encompass classic Pelizaeus-Merzbacher disease, the severe connatal form, PLP1-null syndrome, spastic paraplegia type 2, and hypomyelination of early myelinating structures. Pelizaeus-Merzbacher-like disease presents a similar clinical picture to Pelizaeus-Merzbacher disease, however, it is caused by biallelic pathogenic variants in the GJC2 gene, which encodes for the gap junction protein Connexin-47. POLR3-related leukodystrophy, or 4H leukodystrophy (hypomyelination, hypodontia, and hypogonadotropic hypogonadism), is caused by biallelic pathogenic variants in genes encoding specific subunits of the transcription enzyme RNA polymerase III. In this chapter, the clinical features, disease pathophysiology and genetics, imaging patterns, as well as supportive and future therapies are discussed for each disorder.