Gillespie syndrome

Overview

Gillespie syndrome is a very rare genetic disorder characterized by a unique combination of partial aniridia (absence or underdevelopment of the iris), intellectual disability, and cerebellar ataxia (poor muscle coordination due to cerebellum dysfunction). First described by Fred Gillespie in 1965, the syndrome affects both ocular and neurological systems and typically presents in infancy or early childhood. Its rarity and overlapping features with other conditions can make diagnosis challenging, but the presence of partial aniridia is a distinguishing hallmark.

Causes

Gillespie syndrome is caused by mutations in the ITPR1 gene, which encodes a receptor involved in calcium signaling in cells. This gene plays a critical role in cerebellar function and eye development. The condition can be inherited in either an autosomal dominant or autosomal recessive pattern, depending on the specific mutation. Most reported cases are due to de novo mutations, meaning they arise spontaneously and are not inherited from the parents.

Symptoms

The clinical features of Gillespie syndrome typically involve a triad of signs affecting the eyes, brain, and cognitive development:

Ocular Symptoms:

• Partial aniridia: The iris is partially formed, with scalloped or irregular edges (a key distinguishing feature)

• Nystagmus: Involuntary eye movements

• Reduced visual acuity

• Photophobia: Sensitivity to light

Neurological and Developmental Symptoms:

• Cerebellar ataxia: Impaired coordination, unsteady gait, balance issues

• Hypotonia: Decreased muscle tone, especially in infancy

• Delayed motor milestones: Such as sitting, standing, or walking

• Intellectual disability: Ranges from mild to moderate

Not all individuals have the full triad, and severity can vary among patients.

Diagnosis

Diagnosis of Gillespie syndrome involves a combination of clinical evaluation, eye examination, and genetic testing:

• Ophthalmologic examination: Confirms partial aniridia with typical iris scalloping

• Neurological evaluation: Identifies cerebellar signs such as ataxia and hypotonia

• Developmental assessment: Detects cognitive or motor delays

• Brain imaging (MRI): Often shows cerebellar hypoplasia or atrophy

• Genetic testing: Detects pathogenic variants in the ITPR1 gene

Differential diagnoses include other causes of aniridia, such as WAGR syndrome or isolated congenital aniridia, but these lack the cerebellar and intellectual involvement seen in Gillespie syndrome.

Treatment

There is no cure for Gillespie syndrome, and treatment is supportive, aimed at managing symptoms and improving quality of life. A multidisciplinary approach is often required:

• Vision care: Regular eye exams, corrective lenses, and support for low vision

• Physical therapy: To improve motor coordination and muscle strength

• Occupational therapy: To assist with daily activities and fine motor skills

• Speech and language therapy: If speech development is delayed

• Educational support: Special education programs tailored to the child’s learning needs

• Genetic counseling: For families planning future pregnancies

Prognosis

The prognosis for individuals with Gillespie syndrome depends on the severity of neurological and cognitive involvement. While the condition is non-progressive, meaning it does not worsen over time, affected individuals may require lifelong support for intellectual and motor difficulties. Life expectancy is generally normal, and with early intervention and supportive care, many individuals can lead fulfilling lives. Regular follow-up with a multidisciplinary team is essential to monitor and address evolving needs.