Walker–Warburg Syndrome

Overview

Walker–Warburg syndrome (WWS) is a rare and severe congenital disorder classified as a type of autosomal recessive muscular dystrophy. It is characterized by a combination of muscular, brain, and eye abnormalities that are present from birth. Infants with WWS typically have profound developmental delays, brain malformations such as lissencephaly (smooth brain), hydrocephalus, and structural eye defects. The syndrome represents the most severe end of the spectrum of congenital muscular dystrophies with brain and eye involvement, often resulting in death during infancy or early childhood.

Causes

Walker–Warburg syndrome is caused by mutations in genes involved in the glycosylation of alpha-dystroglycan, a protein crucial for muscle, brain, and eye development. These genes include, but are not limited to, POMT1, POMT2, FKTN, FKRP, ISPD, and PMM2. These mutations impair the proper formation and function of the dystroglycan complex, leading to widespread structural abnormalities in the brain, muscles, and eyes.

The condition is inherited in an autosomal recessive pattern, meaning that an affected individual must inherit two defective copies of the gene—one from each parent. Parents of an affected child are typically carriers and do not show symptoms.

Symptoms

The symptoms of Walker–Warburg syndrome are typically apparent at birth and may include a wide range of physical and neurological abnormalities. Common signs and symptoms include:

• Muscle hypotonia: Marked muscle weakness and poor muscle tone (floppiness) from infancy.

• Brain malformations: These may include lissencephaly (smooth brain surface), hydrocephalus (excess cerebrospinal fluid), cerebellar hypoplasia, and agenesis of the corpus callosum.

• Seizures: Often occur early in life due to brain structural defects.

• Developmental delay: Severe delay or absence of milestones like sitting, walking, or speaking.

• Eye abnormalities: These may include microphthalmia (small eyes), cataracts, retinal dysplasia, and optic nerve hypoplasia, potentially leading to blindness.

• Facial dysmorphism: Features may include a prominent forehead, flat nasal bridge, and small jaw.

• Feeding difficulties: Due to poor muscle control and neurological impairment.

Diagnosis

Diagnosing Walker–Warburg syndrome involves a combination of clinical evaluation, imaging studies, and genetic testing. Diagnostic steps may include:

• Clinical examination: Identification of physical abnormalities, hypotonia, and delayed milestones.

• Brain imaging: MRI or CT scans reveal characteristic malformations such as lissencephaly, hydrocephalus, or cerebellar hypoplasia.

• Ophthalmologic evaluation: Detailed eye examinations to assess structural anomalies.

• Muscle biopsy: May show reduced or abnormal glycosylation of alpha-dystroglycan.

• Genetic testing: Confirms mutations in the causative genes and can help with family planning and carrier detection.

Treatment

There is no cure for Walker–Warburg syndrome, and treatment focuses on supportive care to manage symptoms and improve comfort. A multidisciplinary approach is often required, including the following interventions:

• Neurological care: Management of seizures with anticonvulsants and monitoring of hydrocephalus, which may require surgical intervention (e.g., ventriculoperitoneal shunt).

• Nutritional support: Specialized feeding techniques or gastrostomy tube placement to address feeding difficulties and prevent malnutrition.

• Physical and occupational therapy: Aimed at improving comfort and preventing contractures, though developmental gains are typically limited.

• Vision support: Visual aids or interventions based on the severity of eye involvement.

• Palliative care: Emphasizes quality of life and comfort, often coordinated with hospice services for terminal care.

Prognosis

The prognosis for Walker–Warburg syndrome is very poor. Most affected infants do not survive beyond the first few years of life, often due to respiratory failure, infections, or severe neurological complications. Developmental progress is minimal or absent, and affected children are typically non-verbal and non-ambulatory. Because the condition is inherited, genetic counseling is strongly recommended for affected families to understand recurrence risks in future pregnancies and explore options such as prenatal testing or preimplantation genetic diagnosis.