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  • Updated 11.11.2020
  • Released 04.26.1994
  • Expires For CME 11.11.2023

Walker-Warburg syndrome

Introduction

This article includes discussion of Walker-Warburg syndrome, HARD±E syndrome, Warburg syndrome, cerebro-oculo-muscular syndrome, COMS, cerebro-ocular dysplasia-muscular dystrophy, COD-MDT, Fukuyama-type congenital muscular dystrophy, and muscle-eye-brain disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Walker-Warburg syndrome is the eponymous name of an autosomal recessive disorder that combines congenital hydrocephalus, eye abnormalities, especially retinal dysplasia, a peculiar type of lissencephaly known as cobblestone lissencephaly, and congenital muscular dystrophy. There is marked genetic heterogeneity. Defects in various (currently 14) genes encoding alpha dystroglycan glycosylation underlie approximately half of the cases of Walker-Warburg syndrome. The author reviews the present knowledge of Walker-Warburg syndrome.

Key points

• Walker-Warburg syndrome was once considered a rare syndrome encompassing a neuronal migration disorder, hydrocephalus and eye anomalies; it has evolved to become part of a spectrum of 3 disorders with the following characteristics:

• Neuronal migration disorder with cobblestone lissencephaly as its most typical expression.

• Eye anomalies affecting anterior and posterior parts of the eye.

• Congenital muscular dystrophy. Myopathy with decreased staining for alpha dystroglycan.

• Mutations in an increasing number of genes involved in alpha-dystroglycan glycosylation account for about half of cases.

Historical note and terminology

Walker-Warburg syndrome is named after the Danish ophthalmologist Mette Warburg and the American neuropathologist A. Earl Walker. These researchers pioneered detailed descriptions of the syndrome, with its highly characteristic ophthalmopathologic and neuropathologic components (67; 68; 69). Warburg suggested autosomal recessive inheritance (69).

The phenotype is reflected in the different names applied. By 1983, all components then known appeared in the mnemonic: HARD±E, denoting hydrocephalus, agyria, retinal dysplasia, with or without encephalocele (46), but the proposal was changed to Warburg syndrome in honor of Warburg's pioneering contribution (47). Dambska and colleagues drew attention to the peculiar pattern of seeming architectural chaos with loss of neocortical stratification (17). The neuromuscular component manifesting as congenital muscular dystrophy was recognized through the work of Dambska and colleagues and Towfighi and colleagues (17; 61). An official subclassification of lissencephaly types, types 1 and 2, was initiated by Dobyns and colleagues, where type 2 belonged to Warburg syndrome or cerebro-oculo-muscular syndrome and type 1 to the regular 4-layered type of lissencephaly, typically found in the chromosomal Miller-Dieker syndrome and the isolated Norman-Roberts syndrome, presently known as LIS1 mutations (19). They also proposed to change the name of the disorder once more, this time to Walker-Warburg syndrome in equal recognition of Walker's early neuropathologic contribution. Following a suggestion by Haltia (21), Dobyns proposed to change the name to cobblestone lissencephaly (20). It has become usual to refer to type 1 as classic lissencephaly and to type 2 as cobblestone complex. In classic lissencephaly, the neocortex is macroscopically smooth, whereas the neocortex in cobblestone complex is uneven.

Walker-Warburg syndrome in a newborn (lateral view of left insular region)
Notice the cobblestone-like irregularity of the surface. The insula itself is severely underdeveloped, with hypoplasia of the temporal lobe. (Contributed by Dr. Peter Barth.)

Also, the microscopic picture is highly typical, with absence of stratification, and the arrangement of neurons in perpendicular streaks and whorls, the latter often surrounding penetrating blood vessels.

Neocortex in Walker-Warburg syndrome (photomicrograph)
The cortex in Walker-Warburg syndrome typically features complete loss of laminar structure, with neurons appearing in clusters and vertical streaks, often grouped around penetrating leptomeningeal vessels. (Hematoxylin-eosin; ori...

Typically, the glia limitans is broken, causing leptomeningeal, neuronal, and glial heterotopia. Another aspect is a disorder of myelination that can also be observed on MRI.

By 1985, the main constituents of the syndrome were well established: (1) variable eye malformation with typical retinal dysplasia combined with anterior chamber abnormalities; (2) cobblestone lissencephaly, hydrocephalus, hypoplasia, and malformation of the cerebellum; (3) congenital muscular dystrophy; and (4) autosomal recessive inheritance.

Since the discovery of the role of deficient alpha dystroglycan glycosylation in muscle and brain pathology, Walker-Warburg syndrome has become part of a larger spectrum together known as dystroglycanopathies that also encompasses muscle-eye-brain disease and Fukuyama syndrome or Fukuyama cerebromuscular dystrophy (FCMD). Together these related autosomal recessive syndromes share essential clinical features as well as a common biochemical background.

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