Table 1 Clinical, imaging, and genetic features of patients with TUBG1 mutations

Mutation

c.202G > A; p.Asp68Asn

c1021C > T; p.Arg341Trp

c.1160 T > C; p.Leu387Pro

c.275A > G; p.Tyr92Cys

c.991A > C; p.Thr331Pro

c.63C > A; p.Phe21Leu

c.985G > T; p.Asp329Tyr

c.776C > T; p.Ser259Leu

c.776C > T; p.Ser259Leu

c.776C > T; p.Ser259Leu

c.776C > T; p.Ser259Leu

c.769A > T; p.Ile257Phe

c.776C > T; p.Ser259Leu

Mode of inheritance

De novo

De novo

De novo

De novo

Father’s DNA N/A

De novo

Father’s DNA N/A

De novo

De novo

Germline mosaicism in parent

Germline mosaicism in parent

De novo

De novo

Mutation effect

Aspartate to asparagine within a highly conserved residue in the GTP-binding pocket

Arginine to tryptophan within a highly conserved residue located in the C-terminal domain that is required for the dimerization of y-tubulin

Leucine to proline within a highly conserved residue within an α-helix located in the C-terminal domain

Tyrosine to cysteine within a highly conserved residue in the vicinity of the GTPase domain

Threonine to proline within a highly conserved residue in an α-helix within the γ-γ protein interaction domain located in the C-terminal domain

Phenylalanine to leucine within the GTPase domain

Aspartate to tyrosine within a highly conserved residue in the C-terminal domain. Located on the surface of the TUBG1 protein

Serine to leucine within a highly conserved residue located in the C-terminal domain

Serine to leucine within a highly conserved residue located in the C-terminal domain

Serine to leucine within a highly conserved residue located in the C-terminal domain

Serine to leucine within a highly conserved residue located in the C-terminal domain

Isoleucine to phenylalanine within a highly conserved residue located in the C-terminal domain

Serine to leucine within a highly conserved residue located in the C-terminal domain

Sex

F

M

F

M

F

M

M

F

F

F

M

M

F

Age at follow-up

10y

6mo

21y

18mo

31y

33y

21y

19mo

14y

11y 6mo

9y 6mo

15y

18mo

Head circumference

<−2.1 SD

<−1.9 SD

<−5.5 SD

<−4 SD

<−1 SD

57 cm

53.1 cm (<−2.6 SD)

<−3.5 SD

N/A

47.5 cm at 6y 6mo (<−3.3 SD)

N/A

51.3 cm at 13y (<− 2.5 SD)

N/A

Epileptic

No

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Seizure age of onset

–

< 1 h of life

Early-onset

N/A

Early-onset

36mo

N/A

–

6mo

4mo

N/A

3y 11mo

5mo

Type of seizures

–

Focal with secondary bilateral synchrony

N/A

Infantile spasms

N/A

Tonic-atonic-myoclonic

Partial complex; versive, myoclonic

–

Tonic-clonic

Generalized tonic-clonic

N/A

N/A

Focal, versive

Refractory epilepsy

–

No

Yes

Yes

Yes

N/A

Yes

–

N/A

N/A

N/A

N/A

No

Motor dysfunction

No

Mild axial hypotonia; appendicular hypertonia

Spastic tetraplegia (bedridden)

Spastic tetraplegia (bedridden)

Moderate cerebral palsy

Spastic tetraplegia (walks with support)

Spastic tetraplegia

Delayed motor development

Unsteady gait

Spastic diplegia

N/A

N/A

Delayed motor development

ID

Moderate

Moderate global delay

Severe

Severe

Moderate

Severe

Severe

N/A

N/A

Moderate

Moderate

Moderate (FS IQ-score 44)

Severe

Speech and Language Development

Normal

Moderate global delay

N/A

N/A

N/A

Only sounds, no speech

Non-verbal

Delayed

Non-verbal

50 words

Non-verbal

5–6 word sentences

Non-verbal

Age at MRI

9y

13 days

N/A

N/A

N/A

36y

11y

1y 6mo

12mo

13y 7mo

2mo

6y

9y

Cortical dysgenesis (MRI)

Posterior predominant pachygyria, band heterotopia, nodular heterotopia

Reduced cortical sulci and gyri

Severe posterior predominant pachygyria/agyria (posterior agyria, frontal pachygyria), thick cortex

Severe posterior predominant pachygyria/agyria (posterior agyria, frontal pachygyria), thick cortex

Posterior pachygyria, moderate posterior subcortical band heterotopia

Posterior predominant pachygyria (posterior frontal lobe and parieto-occipital cortex)

Diffuse agyria

Posterior predominant pachygyria (mild over frontal lobes, moderate over posterior lobes), cortex 10-13 mm thick

Posterior predominant pachygyria, sparse cells over occipital lobes, cortex 13-15 mm thick

Posterior predominant pachygyria (mild over frontal lobe, moderate over temporal and occipital lobes), cortex 6-13 mm thick

Posterior predominant pachygyria (mild over frontal lobe, moderate over temporal and occipital lobes), cortex > 15 mm thick

Posterior predominant pachygyria (almost normal over frontal lobes, pachygyria over perisylvian and occipital lobes), cortex 6-10 mm thick

Posterior predominant pachygyria (mild over frontal lobe, moderate over temporal and occipital lobe, deep parietal lobe infolding)

Corpus callosum (MRI)

Normal-Thick

Normal

Thin

Thick, dysmorphic

Thick, dysmorphic

Normal

Thin

Normal

Normal

Normal

Thin

Normal

Thin

Other MRI Findings

–

General paucity of white matter, small cerebellum, dilated lateral ventricles, small lentiform nuclei, small thalami, posterior limbs of internal capsule lacking myelination

Mildly enlarged lateral ventricles, mildly reduced white matter

Mildly enlarged lateral ventricles, severely reduced white matter

–

Enlarged perivascular spaces, enlarged posterior horns of lateral ventricles, hippocampal malrotation

Severely enlarged lateral ventricles, severely reduced white matter, dysplastic basal ganglia, hypoplastic brainstem, hypoplastic vermis

Mildly enlarged lateral ventricles, mildly reduced white matter

Mildly enlarged lateral ventricles, mildly reduced white matter

Enlarged posterior horns of lateral ventricles

Mildly enlarged lateral ventricles

Mildly enlarged posterior horns of lateral ventricles, mildly reduced white matter

Mildly enlarged lateral ventricles, mildly reduced white matter, dysplastic basal ganglia