Case of the Week
Section Editors: Matylda Machnowska1 and Anvita Pauranik2
1University of Toronto, Toronto, Ontario, Canada
2BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
Sign up to receive an email alert when a new Case of the Week is posted.
August 18, 2022
Tubulinopathy
- Background:
- Tubulins are a component of microtubules, which are critical to the processes of mitosis, axon navigation, and neuron migration, all key factors in brain development.
- Mutations in tubulin genes can alter the normal function and structure of microtubules, leading to complex congenital and nonprogressive disorders of brain development characterized by severe brain malformations.
- Disorders caused by mutations in the tubulin gene family are recognized as tubulinopathies. They have an overlapping range of brain malformations caused by mutation of 1 of 7 genes encoding different isotypes of α-tubulin (TUBA1A or TUBA8), β-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB [TUBB5]), and γ-tubulin (TUBG1).
- Clinical Presentation:
-
Patients have a high prevalence of seizures during infancy.
-
Gross motor delays associated with axial hypotonia, sensorimotor polyneuropathy, and intellectual disability can be seen.
-
Ocular findings of varying severity can be seen.
-
- Key Diagnostic Features:
-
Tubulinopathy results in multiple malformations including basal ganglia dysmorphism with fused striatum (pathognomonic association that occurs in 75% of cases), dysgenesis/absence of various parts of the internal capsule (most commonly the anterior limb), and cortical malformations. There is also a high association with ventriculomegaly, a small or absent corpus callosum, small pons, abnormal gyral and sulcal patterns (termed “dysgyria”), and cerebellar hypoplasia or dysplasia.
- Common cortical malformation patterns include microlissencephaly, agyria-pachygyria, central pachygyria, polymicrogyrialike cortical dysplasia, and simplified gyral pattern. Impaired axonal pathfinding leads to anomalies of white matter pathways and anomalies of cranial nerves.
-
- Differential Diagnoses:
- Lissencephaly type I - subcortical band heterotopia spectrum: Results from any 1 of at least 5 mutations—(a) isolated: without a known genetic defect, (b) PAFAH1B1 (LIS1) gene mutation-isolated (LIS1)/Miller-Dieker syndrome, (c) doublecortin (DCX) gene mutation, (d) XLAG, or (e) RELN
- Hourglass or figure-8 appearance of brain with thickened cortex
- Subcortical heterotopia is usually diffuse and symmetric but sometimes has anterior-posterior predilection, which suggests specific underlying genetic abnormality; anterior predilection suggests mutations of DCX; posterior predilection suggests mutations of LIS1
- Lissencephaly type II (cobblestone lissencephaly): Reduction in normal sulcation, bumpy cortical surface, and congenital muscular dystrophy; 3 most commonly included syndromes are:
- Walker-Warburg syndrome: Hydrocephalus, cobblestone cortex, complete absence of cerebral and cerebellar myelin, cerebellar polymicrogyria, pontine and cerebellar vermian hypoplasia
- Fukuyama congenital muscular dystrophy: Cerebral and cerebellar polymicrogyria, type II lissencephaly, white matter changes; cerebellar dysplasia, retinal dysplasia, and gyral malformations are not commonly appreciated as in Walker-Warburg syndrome.
- Muscle-eye-brain disease: Congenital muscular dystrophy with associated progressive eye and brain abnormalities
- Polymicrogyrialike cortical dysplasia: Baraitser-Winter syndrome - Pachygyria, subcortical band heterotopia, and hippocampal malformations are seen.
- Classic basal ganglia dysmorphism with fused striatum and dysgenesis/absence of various parts of the internal capsule, which is a pathognomonic feature of tubulinopathy, is absent in all these differentials listed above.
- Lissencephaly type I - subcortical band heterotopia spectrum: Results from any 1 of at least 5 mutations—(a) isolated: without a known genetic defect, (b) PAFAH1B1 (LIS1) gene mutation-isolated (LIS1)/Miller-Dieker syndrome, (c) doublecortin (DCX) gene mutation, (d) XLAG, or (e) RELN
-
Treatment:
- Treatment of manifestations
- Seizures are treated with antiepileptic drugs (AEDs) based on the specific seizure type.
- Supportive care includes physical therapy to manage the complications of spasticity, occupational therapy, and speech therapy based on individual needs.
- Those with congenital fibrosis of the extraocular muscles may require nonsurgical and/or surgical treatment.
Current Issue
Case Collections
