Sign Up for a Free Account
  • Updated 04.14.2024
  • Released 04.26.1994
  • Expires For CME 04.14.2027

Walker-Warburg syndrome



Walker-Warburg syndrome is a rare autosomal recessive disorder and the most severe presentation in the dystroglycanopathy spectrum. It combines congenital hydrocephalus; lissencephaly with cobblestone malformation; eye abnormalities, especially retinal dysplasia; and congenital muscular dystrophy. Walker-Warburg syndrome is genetic heterogeneous, with 14 genes identified to date. Gene functions converge on glycosylation of alpha-dystroglycan, a component of the dystrophin-glycoprotein complex mediating important interactions between cells and the extracellular matrix. The authors review the present knowledge of Walker-Warburg syndrome.

Key points

• Walker-Warburg syndrome is part of a spectrum of presentations within dystroglycanopathies. It is closely related to muscle-eye-brain disease and Fukuyama-type congenital muscular dystrophy as they all share many characteristics.

• Neuronal migration disorder with cobblestone malformation is the most typical expression.

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

• Congenital muscular dystrophy with decreased staining for alpha dystroglycan glycosylation is a shared characteristic.

• Mutations in a number of genes involved in alpha-dystroglycan glycosylation account for more than 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 (60; 62). Warburg suggested autosomal recessive inheritance (62).

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 (42), but the proposal was changed to Warburg syndrome in honor of Warburg's pioneering contribution (43). Dambska and colleagues drew attention to the peculiar pattern of seeming architectural chaos with loss of neocortical stratification (15). The neuromuscular component manifesting as congenital muscular dystrophy was recognized through the work of Dambska and colleagues and Towfighi and colleagues (15; 55). 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 (16). 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 (18), Dobyns proposed to change the name to cobblestone lissencephaly (17). Thus, this malformation is referred to as either type 2 lissencephaly or cobblestone lissencephaly in the literature. The most recent classification guidelines for cortical malformations have coined the term “cobblestone malformation,” which is applicable to both cases with smooth or undersulcated brain with thin cortex in Walker-Warburg syndrome and cases with pachygyria and thicker cortex (50). These nomenclature changes reflect a better understanding of the shared neuronal migration deficits found in the cortex leading to different presentations based on severity. In classic lissencephaly, the neocortex is macroscopically smooth, whereas the neocortex in cobblestone malformation is “bumpy” and uneven, resembling the eponymous cobblestone.

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.)

Histological studies of postmortem tissue show that cortical lamination is severely disrupted, with neurons sometimes arranged in columns and whorls often surrounding penetrating vasculature.

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, and there are gaps in the pial basement membrane causing leptomeningeal, neuronal, and glial heterotopias.

Despite the nomenclature changes, the main constituents of the syndrome have been well established since the 1980s: (1) variable eye malformations with typical retinal dysplasia combined with anterior chamber abnormalities; (2) cobblestone malformation, hydrocephalus, hypoplasia, and malformation of the cerebellum; (3) congenital muscular dystrophy; and (4) autosomal recessive inheritance.

As gene discovery has progressed, revealing variable phenotypic presentations among mutations in the same gene, Walker-Warburg syndrome has become part of a spectrum of disorders with shared disruptions in alpha-dystroglycan glycosylation, termed “dystroglycanopathies.” Other dystroglycanopathies affecting the brain and eye are muscle-eye-brain disease and Fukuyama congenital muscular dystrophy. Additional less severe presentations include limb-girdle muscular dystrophy with or without intellectual disability.

This is an article preview.
Start a Free Account
to access the full version.

  • Nearly 3,000 illustrations, including video clips of neurologic disorders.

  • Every article is reviewed by our esteemed Editorial Board for accuracy and currency.

  • Full spectrum of neurology in 1,200 comprehensive articles.

  • Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660



ISSN: 2831-9125