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  • Updated 10.31.2024
  • Released 04.07.1995
  • Expires For CME 10.31.2027

Pelizaeus-Merzbacher disease

Introduction

Overview

Pelizaeus-Merzbacher disease is an X-linked recessive leukodystrophy caused by pathogenic variants in the proteolipid protein 1 (PLP1) gene. It typically presents in the first year of life with congenital hypotonia, nystagmus, and ataxia. There are a few different forms of Pelizaeus-Merzbacher disease, depending on the type of genetic variant. They range on a clinical spectrum of disease from the severe connatal form to an uncomplicated spastic paraparesis syndrome. In this article, the authors describe the clinical features, pathophysiology, differential diagnosis, diagnostic workup, and management of Pelizaeus-Merzbacher disease and its various forms. Understanding disease pathology and improving the diagnosis rate is increasingly vital as therapeutic options are in development and clinical trials.

Key points

• Pelizaeus-Merzbacher disease is caused by a variety of mutations in the PLP1 gene that lead to oligodendrocyte dysfunction and a reduction or absence of myelin in the central nervous system.

• The clinical presentation is on a spectrum, from the severe connatal form to an uncomplicated spastic paraparesis syndrome.

• Common clinical manifestations include nystagmus, hypotonia, ataxia, stridor, and, eventually, spastic paraplegia.

• As Pelizaeus-Merzbacher disease has X-linked inheritance, males are affected, and females are rarely symptomatic.

• MRI shows diffuse and symmetric T2 hyperintensity of the white matter in the cerebrum and cerebellum, but diagnosis is confirmed with genetic testing of the PLP1 gene.

• Treatment is mostly symptomatic, but emerging therapies are being investigated.

Historical note and terminology

Pelizaeus-Merzbacher disease has historically been subdivided into clinical variants based on the age of onset and severity of clinical signs. "Classical" Pelizaeus-Merzbacher disease is the most common presentation and was first described by Dr. Friederich Pelizaeus (41). He discovered the disease when he encountered a family of several males with nystagmus, spastic paraparesis, ataxia, and developmental delay. A few years later, Ludwig Merzbacher, a pathologist, described the X-linked recessive inheritance pattern of Pelizaeus-Merzbacher disease (31). The "connatal" form of Pelizaeus-Merzbacher disease was described later and denotes clinically evident onset within the first few weeks of life and a more severe syndrome (46). Seitelberger also described a “transitional” form of Pelizaeus-Merzbacher disease that was intermediate in clinical severity between connatal and classical disease (47). In 1964, Zeman and colleagues pointed out that Pelizaeus-Merzbacher disease is a dysmyelinating, rather than a demyelinating, entity and stressed the importance of clinical observation and the familial nature of the disorder rather than strict pathological criteria to define the condition (67). They also hypothesized that the defect in Pelizaeus-Merzbacher disease affected a myelin proteolipid. Saugier-Veber and colleagues discovered that some families with X-linked spastic paraparesis have PLP1 mutations (44). It must be noted that the phenotypes of Pelizaeus-Merzbacher disease and X-linked spastic paraparesis syndrome overlap.

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