Tubulinopathies Overview

Clinical characteristics.

The tubulinopathies are a wide and overlapping range of brain malformations caused by mutation of one of seven genes encoding different isotypes of tubulin. Brain malformations include:

• A range of lissencephalies (classic lissencephaly, lissencephaly with cerebellar hypoplasia, lissencephaly with agenesis of the corpus callosum, and centrally predominant pachygyria),
• Polymicrogyria-like cortical dysplasia,
• Simplified gyral pattern, and
• Microlissencephaly often in combination with dysplastic basal ganglia, corpus callosum abnormalities, and hypoplasia or dysplasia of the brain stem and cerebellum.

Clinical features include motor and intellectual disabilities, epilepsy, and ocular findings of varying severity.

Diagnosis/testing.

The diagnosis of a tubulinopathy (regardless of the gene involved) is based on the presence of characteristic complex brain malformations. Establishing the genetic cause requires molecular genetic testing to identify a heterozygous pathogenic variant in one of six genes (TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB [TUBB5], or TUBG1) or biallelic pathogenic variants in TUBA8.

Genetic counseling.

Tubulinopathies caused by mutation of TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB (TUBB5), or TUBG1 are inherited in an autosomal dominant manner. Most often a de novo heterozygous pathogenic variant is causative; however, in some families the pathogenic variant is inherited from an affected parent. In contrast, autosomal recessive inheritance of a TUBA8-related tubulinopathy has been reported in only a few families.

Management.

Treatment of manifestations: Supportive care includes physical therapy to manage the complications of spasticity, occupational therapy, and speech therapy based on individual needs. Nutritional needs commonly require nasogastric tube feedings, followed eventually by gastrostomy tube placement. Seizures are treated with antiepileptic drugs (AEDs) based on the specific seizure type. Those with congenital fibrosis of the extraocular muscles may require nonsurgical and/or surgical treatment.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a tubulinopathy, the following are recommended:

• Pediatric neurology consultation including interpretation of MRI to provide as much prognostic information as possible; EEG if episodic clinical events of uncertain cause or suggestive of epilepsy are present
• Evaluations by a physical therapist, occupational therapist, speech therapist, and developmental specialist in infancy and the preschool years because of the high risk of gross and fine motor delays, delayed speech and language development, and intellectual disability
• Assessment of special educational needs
• In the context of gross and fine motor delays and multiple disabilities, evaluation of:
  • Growth, feeding, and nutrition
  • Respiratory status
• Ophthalmologic evaluation
• Nerve conduction study (NCS) if progressive neuropathy is suspected
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A pediatric neurologist with expertise in the management of children with multiple disabilities and medically refractory epilepsy is recommended for long-term management.

Supportive management, including an individualized therapy plan that includes physical therapy, occupational therapy, speech therapy, and vision therapy for oculomotor deficits and/or strabismus should begin at the time of diagnosis to ensure the best possible functionality and developmental outcome. Of note, it is appropriate to institute measures early on to manage potential complications of spasticity (i.e., joint contractures or reduced range of motion), which can increase the risk for decubitus ulcers as well as affect mobility and hygiene.

Failure to thrive in infants with the more severe brain malformations (i.e., lissencephaly, generalized polymicrogyria) is usually managed by nasogastric tube feedings, followed by gastrostomy tube placement as needed.

Antiepileptic drugs (AEDs) for seizures based on the specific epilepsy type are indicated. In general, seizures should be treated promptly by specialists, as poor seizure control frequently worsens feeding and increases both the likelihood that a gastrostomy tube will be needed and the risk for pneumonia.

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

For those with CFEOM, see detailed discussion of nonsurgical and surgical treatment (including extraocular muscle and/or ptosis surgery) in Congenital Fibrosis of the Extraocular Muscles.

For patients with severe cortical malformations (lissencephalies, polymicrogyria-like cortical dysplasia, microlissencephaly), it is usually appropriate to discuss the level of care to be provided in the event of a severe intercurrent illness.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search Clinical Trials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.