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Tubulinopathies Overview

Synonym: Tubulin-Related Cortical Dysgenesis

, MD, PhD and , MD.

Author Information

Initial Posting: .

Summary

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.

Definition

Tubulinopathies (or tubulin-related cortical dysgenesis), which are associated with a wide and overlapping range of brain malformations, are caused by mutation of one of seven genes encoding different isotypes of α-tubulin (TUBA1A or TUBA8), β-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB [TUBB5]), and γ-tubulin (TUBG1) (Table 1).

Lissencephaly ranges from a thickened cortex and complete absence of sulci (agyria) to a thickened cortex and a few, shallow sulci (pachygyria). Subcortical band heterotopia has also been reported [Bahi-Buisson et al 2008, Fallet-Bianco et al 2008, Morris-Rosendahl et al 2008, Kumar et al 2010, Sohal et al 2012, Okumura et al 2013, Bahi-Buisson et al 2014, Hikita et al 2014, Oegema et al 2015, Mutch et al 2016].

  • Classic lissencephaly is characterized by marked thickening of the cortex with a posterior to anterior gradient of severity (i.e., more severe involvement posteriorly [parietal and occipital lobes] than anteriorly [orbitofrontal and anterior temporal regions]). Most often cerebellar structure is normal and the basal ganglia appear normal except that the anterior limb of the internal capsule is usually not visible.
  • Lissencephaly with cerebellar hypoplasia. Some rare forms of lissencephaly are associated with a disproportionately small cerebellum.
  • Lissencephaly with agenesis of the corpus callosum. The corpus callosum in living individuals is commonly dysmorphic (missing rostrum plus flat genu and anterior body), hypoplastic, or partially absent. In contrast, all prenatally diagnosed cases show complete agenesis (See Figure 1 A-C and Figure 1 D-F).
  • Centrally predominant pachygyria is characterized by pachygyria involving the insula and the frontal, temporal, and parietal opercula [Bahi-Buisson et al 2008]. All have abnormalities of the basal ganglia that appear as large round structures in which the caudate, putamen, and globus pallidus are indistinguishable. Hypoplasia of the anterior limbs of the internal capsule is a major feature. Common findings are vermian hypoplasia and brain stem hypoplasia. The corpus callosum is commonly dysmorphic or hypoplastic; less frequently it is partially or completely absent (Figure 1 G-I).
Figure 1.

Figure 1.

Representative images of TUBA1A-related tubulinopathies A-C. Infant age four months with classic lissencephaly. Other features include dysmorphic corpus callosum, dysmorphic/ dysplasic internal capsules, and hypoplasia of the cerebellar vermis.

Polymicrogyria-like cortical dysplasia can be either predominantly central or generalized (Figure 1 J-L, Figure 2 A-F, Figure 3 D-I) [Jaglin et al 2009, Guerrini et al 2012, Romaniello et al 2012, Cushion et al 2013, Amrom et al 2014]. MRI reveals a "coarse" appearance with a thick cortex and irregular surfaces on both the pial and grey-white junction sides; however, the deep infolding that is one of the criteria for the diagnosis of polymicrogyria is absent.

Figure 2.

Figure 2.

Representative -mages of TUBB2B-related tubulinopathies A-C. Child age three years with generalized polymicrogyria. The cortex has a coarse appearance with excessively folded gyri (arrowheads in B). Polymicrogyria is associated with complete agenesis (more...)

Figure 3.

Figure 3.

Representatives images of TUBB3-related tubulinopathies A-C. Child age three years with generalized polymicrogyria. The cortex shows a coarse appearance, with excessively folded gyri (arrowhead in B). Associated malformations include complete agenesis (more...)

Note: Because TUBB2B-related polymicrogyria comprises unlayered polymicrogyria combined with neuronal overmigration and neuronal heterotopias more reminiscent of cobblestone lissencephaly than classic polymicrogyria [Jaglin et al 2009], Cushion et al [2013] proposed the concept of atypical polymicrogyria or polymicrogyria-like cortical dysplasia in the tubulinopathies.

Simplified gyral pattern is a milder cortical malformation in which cortex is of normal thickness, but gyri are rather broad and sulci are too shallow [Kumar et al 2010, Bahi-Buisson et al 2014].

Microlissencephaly refers to the most severe of the cortical dysplasias that combines extreme microcephaly and lissencephaly with hemispheres lacking primary fissures and olfactory sulci. Mainly diagnosed by prenatal MRI, findings at a median age of 25 weeks’ gestation include microcephaly, absent to poorly operculized cortex, virtually no visible gyration, severe cerebellar hypoplasia, absent or severely hypoplastic basal ganglia, and usually complete agenesis of the corpus callosum. Associated malformations include pontocerebellar hypoplasia [Fallet-Bianco et al 2008, Lecourtois et al 2010, Fallet-Bianco et al 2014].

Table 1.

Tubulinopathies: Molecular Genetics and Complex Cortical Malformations

GeneMOIComplex Cortical Malformations 1
CLPCDSGPMLISOtherReferences
TUBA1AAD37% 212% 34% 413% 5Lissencephaly w/cerebellar hypoplasia (15%)
Predominantly central pachygyria (30%) 6
Kumar et al [2010], Bahi-Buisson et al [2014]
TUBB2BAD87.5%30%9.4%Lissencephaly w/agenesis of the corpus callosum (3.1%)
Open-lip schizencephaly (1 person)
CFEOM3 (1 family) 7
See footnote 8
TUBB3AD90%10%1 case 9Brain stem & cerebellar vermian hypoplasia & basal ganglia dysmorphism
CFEOM3 10
Poirier et al [2010], Tischfield et al [2010]
TUBB (TUBB5)AD3 personsRange: SGP to focal polymicrogyria & microcephalyBreuss et al [2012]
TUBG1AD2/3 personsPredominantly posterior subcortical band heterotopia (1/3 persons)Poirier et al [2013a]
TUBA8AR2 related families 11Generalized polymicrogyria, dysplastic or absent corpus callosum, optic nerve hypoplasia, absence of sharp demarcation between the pons & medulla w/pontine bulge extending too far caudallyAbdollahi et al [2009]
TUBB2AAD2 personsDysmorphic corpus callosum, normal gyral pattern, & basal gangliaCushion et al [2014]

AD = autosomal dominant; AR = autosomal recessive; CFEOM3 = congenital fibrosis of the extraocular muscles; CL = classic lissencephaly; MLIS = microlissencephaly; MOI = mode of inheritance; PCD = polymicrogyria-like cortical dysplasia; SGP = simplified gyral pattern

1.

Genotype-phenotype correlations are limited, as phenotypes caused by mutation of any one of the genes commonly overlap.

2.

Recurrent pathogenic TUBA1A (NM_006009​.3) variants include c.1204C>T (p.Arg402Cys), c.1205G>A (p.Arg402His), and c.1265G>A (p.Arg422His) [Bahi-Buisson et al 2008, Kumar et al 2010].

3.

Variants are all unique and have not been identified in other TUBA1A-related cortical malformations.

4.

Simplified gyral pattern with focal atypical polymicrogyria [Jansen et al 2011, Cushion et al 2013, Poirier et al 2013b]

5.

Variants are widely distributed in the different domains of TUBA1A, without a reported hot spot.

6.

TUBA1A variant c.790C>T (p.Arg264Cys) accounts for 50% of variants, whereas the remaining 50% are not recurrent [Bahi-Buisson et al 2008, Bahi-Buisson et al 2014].

7.

The novel inherited TUBB2B pathogenic variant NM_178012​.4:c.1261G>A (p.Glu421Lys) has been observed in one family [Cederquist et al 2012].

8.
9.

At the extreme severe end of the spectrum, only one fetus was reported with microlissencephaly and corpus callosum agenesis, severe brain stem and cerebellar hypoplasia, and dysmorphic basal ganglia [Poirier et al 2010] (Figure 3 A-C).

10.
11.

A 14-base pair deletion was reported in the two related families.

Note: Mutation of TUBB4A is not responsible for cortical dysgenesis but rather for a spectrum of extrapyramidal movement abnormalities [Hamilton et al 2014] ranging from hypomyelinating leukoencephalopathy with atrophy of the basal ganglia and cerebellum (see Leukodystrophy Overview and Hereditary Ataxia Overview) to hereditary whispering dysphonia (see Dystonia Overview) [Lohmann et al 2013].

Clinical Features of the Tubulinopathies

The clinical features of the tubulinopathies include motor and intellectual disabilities, epilepsy, and ocular findings of varying severity.

Cognitive and motor impairments are present in almost all individuals with a tubulinopathy and are correlated with the severity of brain malformations.

  • Lissencephaly and generalized polymicrogyria-like cortical dysplasia: spastic tetraplegia and virtually no voluntary motor control and absent eye contact
  • Simplified gyral pattern: mild motor disability and intellectual disabilities

Although most affected individuals have severe to profound intellectual disability, a minority have less extensive cortical malformations that result in only moderate intellectual disability, and a few have limited malformations that allow near-normal development. In the latter, the cortical malformation is typically less severe and less extensive on MRI.

Epilepsy varies significantly among affected individuals and is not necessarily determined by the severity of the cortical malformation, the gene involved, or the causative pathogenic variant. However:

  • Early epileptic encephalopathy (with or without infantile spasms) is common in lissencephaly and generalized polymicrogyria-like cortical dysplasia.
  • Seizures are usually present in fewer than 30% of individuals with a simplified gyral pattern with the exception of the two with pathogenic variants in TUBB2A who had infantile spasms with hypsarrhythmia (i.e., West syndrome) [Cushion et al 2014].

Additional findings

  • Facial diplegia and strabismus suggestive of pseudobulbar palsy are often observed in central pachygyria and polymicrogyria-like cortical dysplasia [Bahi-Buisson et al 2008].
  • Congenital fibrosis of the extraocular muscles (CFEOM) is observed with specific TUBB3 pathogenic variants and one specific TUBB2B pathogenic variant (p.Glu421Lys) (see Congenital Fibrosis of the Extraocular Muscles).
  • The combination of hypoplastic to absent olfactory bulbs (Kallmann syndrome), CFEOM, and facial weakness are seen in TUBB3 p.Glu410Lys (c.1228G>A) syndrome [Chew et al 2013].
  • The progressive sensorimotor polyneuropathy observed with specific TUBB3 and TUBB2 pathogenic variants [Tischfield et al 2010] is sometimes associated with wrist and finger contractures [Cederquist et al 2012].
  • Optic nerve hypoplasia is one of the hallmarks of TUBA8 pathogenic variants [Abdollahi et al 2009].
  • Congenital microcephaly, observed in more than 75% of individuals with TUBA1A-, TUBA8-, TUBB2B-, TUBB-, and TUBG1-related tubulinopathies, is not reported in TUBB2A-related tubulinopathies.
  • Individuals with the milder forms of tubulinopathies survive into adulthood, while those with the most severe forms may die at a young age as a result of complications such as seizures or pneumonia.

Differential Diagnosis of Tubulinopathies

Table 2.

Differential Diagnosis of Tubulinopathies

GeneDisorder (OMIM) 1MOI
Lissencephaly-pachygyria spectrum of cortical malformation 2
LIS1 (PAFAH1B1)LIS1-associated lissencephaly/subcortical band heterotopiaAD 3
Classic and atypical lissencephaly syndromes 4
LIS1 (PAFAH1B1), YWHAE 5Miller-Dieker lissencephaly syndrome (247200)AD
DCXDCX-related disordersXL
DYNC1H1See footnote 6 (600112)AD
ARXX-linked lissencephaly 2 (300215)XL
RELNLissencephaly 2 (257320)AR
VLDLRVLDLR-associated cerebellar hypoplasiaAR
Cobblestone cortical malformation (lissencephaly) syndromes 4
ADGRG1 (GPR56)PolymicrogyriaAR
~6 genesWalker-Warburg syndromeAR
~14 genesMuscle-eye-brain diseaseAR
FKTNFukuyama congenital muscular dystrophyAR
Polymicrogyria-like cortical dysplasia
NDE1Lissencephaly 4 (614019)AR
WDR62Primary autosomal recessive microcephaly 2 (604317)AR
DYNC1H1 6See footnote 6 (600112)AD
ACTBBaraitser-Winter cerebrofrontofacial (BWCFF) syndromeAD 7
ACTG1
Polymicrogyria 8
KIF5CComplex cortical dysplasia with other brain malformations 2 (615282)AD
EOMES (TBR2)See OMIM 604615AR
Microlissencephaly
NDE1Lissencephaly 4 (614019)AR
WDR62Primary autosomal recessive microcephaly 2 (604317)AR
KATNB1Lissencephaly 6 with microcephaly (616212)AR
Microcephaly with cortical malformations
KIF2AComplex cortical dysplasia with other brain malformations 3 (615411)AD
1.

Disorders are linked to corresponding GeneReview if available. If not, a link to OMIM is included.

2.

Lissencephaly-pachygyria spectrum of cortical malformation is characterized by smooth cortex with simplified gyration appearance. Lissencephaly refers to a brain without sulci. Pachygyria (focal or diffuse) is a mild expression of lissencephaly in which sulci are shallow and reduced in number.

3.

To date, most reported pathogenic variants have been de novo.

4.

The cobblestone cortical malformation (lissencephaly) syndromes (Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy) differ clinically in a number of ways, including the frequent presence of hydrocephalus, dysmyelination, dysplasic cerebellum and brain stem hypoplasia, multiple different eye anomalies, and congenital muscular dystrophy manifest by hypotonia and elevated serum creatine kinase concentrations.

5.

As currently defined, Miller-Dieker syndrome is associated with deletions that include both LIS1 (official symbol PAFAH1B1) and YWHAE (a region of ~1.3 Mb harboring many genes) in 17p13.3 [Pilz et al 1998, Cardoso et al 2003].

6.

Mutation of DYNC1H1 is associated with isolated polymicrogyria, nodular heterotopia, hypoplasia of the corpus callosum, abnormally shaped basal ganglia, and in some cases, evidence of peripheral neuropathy [Poirier et al 2013a]. See Charcot-Marie-Tooth Hereditary Neuropathy Overview.

7.

To date, all affected individuals have had a de novo heterozygous gain-of-function variant in either ACTB or ACTG1 [Verloes et al 2015].

8.

Polymicrogyria is defined by an excessive number of small and infolded gyri separated by shallow sulci that give the cortical surface a lumpy appearance. Although polymicrogyria is often secondary to abnormal post-migrational development attributable to environmental causes, genetic causes are also recognized. See Polymicrogyria Overview.

Establishing a Diagnosis of a Type of Tubulinopathy

The diagnosis of a tubulinopathy (regardless of the gene involved) is established in a proband with complex cortical malformation that combines the range of cortical malformations discussed in Definition and summarized in Table 1.

Molecular Genetic Testing

One genetic testing strategy is serial single-gene molecular genetic testing based on clinical findings and neuroimaging findings:

  • Lissencephalies and microlissencephalies. TUBA1A, preferentially the pathogenic variants NM_006009.3:c.1204C>T(p.Arg402Cys) or c.1205G>A (p.Arg402His)
  • Polymicrogyria-like cortical dysplasia. TUBA1A NM_006009.3:c.790C>T (p.Arg264Cys), TUBB2B, TUBB3, and TUBG1

An alternative genetic testing strategy is use of a multigene panel that includes these seven genes (Table 1) and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here

Genetic Counseling

Mode of Inheritance

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.

Note: Autosomal recessive inheritance of TUBA8-related tubulinopathy has been reported in two families to date [Abdollahi et al 2009].

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic pathogenic variants in genes encoding tubulin [Jamuar & Walsh 2014, Zillhardt et al 2016].

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents: if a parent of the proband has the pathogenic variant, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband is low. Likewise, if the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of germline mosaicism. Maternal germline mosaicism has been reported in two families with multiple affected offspring [Poirier et al 2013a, Zillhardt et al 2016].

Offspring of a proband. Each child of an individual with a tubulinopathy has a 50% chance of inheriting the pathogenic variant.

Other family members

  • The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be at risk.
  • The risk to other family members appears to be low given that most probands with an autosomal dominant tubulinopathy have the disorder as a result of a de novo pathogenic variant.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected and to their parents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the tubulinopathy-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for tubulinopathy are possible.

Management

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 www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • American Epilepsy Society (AES)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

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Chapter Notes

Author Notes

Nadia Bahi-Buisson is a pediatric neurologist specializing in cortical malformations and fetal neurology. Her research at Imagine Institute focuses on the genetic and pathophysiologic bases of cortical malformations. She follows more than 100 patients with diffuse cortical malformations, and has consulted on more than 500 such cases. Mara Cavallin is a pediatric neurologist and PhD student in the research group led by Nadia Bahi-Buisson. She works on genetic and pathophysiologic bases of cortical malformations and Aicardi syndrome. She is engaged in collecting clinical and genetic data on individuals with cortical malformations; her research goal is the identification of new genes involved in classic and variant lissencephalies, polymicrogyria, and heterotopia, with a special focus on Aicardi syndrome. Dr Bahi-Buisson is involved in the European consortium on cortical malformations. This work is performed in collaboration with Chérif Beldjord, MD, PhD (director of the Laboratory of Biochemical Genetics - Cochin-Port-Royal).

Acknowledgments

  • Catherine Fallet Bianco and Annie Laquerriere for sharing their fetal cases and for their helpful discussion of fetal brain tubulinopathies
  • Chérif Beldjord, Aurelie Toussaint, and Nathalie Carion for their help in the screening of tubulin genes for diagnosis -- from Sanger sequencing to the recent development of NGS panel screening
  • Jamel Chelly and Karine Poirier, who allowed the author to collaborate on the identification of tubulin genes and to define/refine the associated phenotypes; and who have contributed through constructive discussion to the understanding of the pathophysiology of tubulinopathies
  • Sophie Thomas and Stanislas Lyonnet (Imagine Institute), for welcoming the authors to the Laboratory of Embryology and Genetics of Congenital Malformations and supporting their continued work in the identification of genes associated with cortical malformations

Revision History

  • 24 March 2016 (bp) Review posted live
  • 7 July 2015 (nbb) Original submission
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