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. Pelizaeus-Merzbacher disease (PMD) is a demyelinating disorder of the CNS belonging to the group of hypomyelinating leukodystrophies. The disease was named in honor of Friederich Pelizaeus, a German physician, and Ludwig Merzbacher, a German pathologist. Pelizaeus discovered PMD in 1885 when he came across a family that had several male individuals with nystagmus, spastic paresis, ataxia, and developmental delay. Twenty-five years later, Merzbacher proved that the mode of inheritance of PMD was X-linked recessive. PMD occurs due to several types of mutations at the level of proteolipid protein 1 (PLP1) gene, leading to varying clinical pictures in terms of severity. The different forms of PMD, resulting from different mutations, exist on a clinical spectrum ranging between the most severe, the connatal form and spastic paraplegia type 2 (SPG2), the mildest version, with the classic form falling in between the others. SPG2 is further classified into complicated and pure types, the details of which will be explained throughout the review. PLP-1 null syndrome is a mild version of PMD described as a separate entity since its causative mutation leads to peripheral nervous system demyelination, unlike typical PMD. Since there are several types of hypomyelinating leukodystrophies (HLD) apart from PMD, PMD was classified as prototypic HLD type 1 (HLD1) to distinguish it from others that might be presenting with very similar pictures. Another disease, known as Pelizaeus-Merzbacher-Like disease (PMLD), was classified as HLD2. It is described as a separate entity from PMD due to a mutation at the level of a different gene, GJC2. This review will shed light on PMD; however, given the proximity of their clinical presentations, differentiating points will be mentioned.

Pelizaeus-Merzbacher disease (PMD) is X-linked hypomyelinating leukodystrophy caused by mutations of the PLP1 gene, which codes the proteolipid protein 1. The result of mutations is abnormal myelination - hypomyelination and dysmyelination of cerebral white matter, and in some form of the disease hypomyelinating peripheral neuropathy. DNA samples from 68 patients suspected of PMD due to the clinical course and hypomyelination at magnetic resonance imaging (MRI) were analyzed. Medical history and detailed clinical course of PMD patients were also analyzed. Different mutations of the PLP1 gene were detected in 14 boys from 11 families (~20%). Amongst the molecularly confirmed patients, 13 presented classical PMD forms but clinical phenotypes varied in the severity even amongst siblings. One patient presented a severe connatal form. One mother, obligate carrier, presented complicated SPG2 (spastic paraparesis). There was no phenotype-genotype correlation in our material. In many cases PMD was suspected with a delay of many years, sometimes only after birth of another affected child in the family. Pelizaeus-Merzbacher disease was most frequently misdiagnosed as cerebral palsy.

Pelizaeus-Merzbacher disease is an infrequent hypomyelinating disorder caused by alterations in the PLP1 gene, which leads to a fault in the axonal myelination of the oligodendrocytes in the central nervous system. Two forms have been reported, according to the severity of the presentation: connatal and classic. It is characterised by neonatal hypotonia, delayed psychomotor development, progressive spasticity predominantly in the lower limbs and nystagmus, with pyramidal and extrapyramidal signs and symptoms; the connatal form is far more severe. Magnetic resonance imaging shows diffuse hypomyelinating leukoencephalopathy, evoked potentials are usually altered and confirmation is obtained through a molecular study of the PLP1 gene. We present the cases of five paediatric patients, four of whom had the classic form and one with the connatal form. The clinical characteristics and complementary studies are described, and a concise review of the literature is carried out. This disease has a progressive and almost unvarying course, which is the clinical key to be able to differentiate it from other entities such as infantile cerebral palsy, peripheral neuropathies or multiple sclerosis, among others, in addition to the characteristic neuroimaging findings. It is necessary to suspect this diagnosis and confirm alterations in the PLP1 gene with the aim of obtaining a real incidence of this entity, which is probably underestimated, like other leukodystrophies. Clinica y diagnostico de la enfermedad de Pelizaeus-Merzbacher: descripcion de cinco casos. Introduccion. La enfermedad de Pelizaeus-Merzbacher es un trastorno hipomielinizante raro debido a alteraciones en el gen PLP1, que lleva a un fallo de la mielinizacion axonal de los oligodendrocitos en el sistema nervioso central. Existen dos formas descritas segun la gravedad de su presentacion: connatal y clasica. Se caracteriza por hipotonia neonatal, retraso del desarrollo psicomotor, espasticidad progresiva de predominio en los miembros inferiores y nistagmo, con signos y sintomas piramidales y extrapiramidales, y la forma connatal es mucho mas grave. La resonancia magnetica muestra leucoencefalopatia hipomielinizante difusa, los potenciales evocados usualmente se alteran y la confirmacion se realiza mediante estudio molecular del gen PLP1. Casos clinicos. Se presentan cinco pacientes pediatricos afectados, cuatro con la forma clasica y uno con la forma connatal; se describen las caracteristicas clinicas, los estudios complementarios y se realiza una revision concisa de la bibliografia. Conclusion. Esta enfermedad tiene una evolucion progresiva y casi invariable, lo cual es la clave clinica para diferenciarla de otras entidades como la paralisis cerebral infantil, neuropatias perifericas, esclerosis multiple, entre otras, ademas de los hallazgos caracteristicos en las neuroimagenes. Es necesario sospechar este diagnostico y confirmar alteraciones en el gen PLP1 con el fin de obtener una incidencia real de esta entidad, probablemente subestimada, como otras leucodistrofias.