Adult-Onset Dystonia with Late-Onset Epilepsy in TUBB4A-Related Hypomyelinating Leukodystrophy-A New Intermediate Phenotype

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Letters to the Editor
Annals of Indian Academy of Neurology ¦ Volume 25 ¦ Issue 3 ¦ May-June 2022
562
Sir,
Leukodystrophies usually manifest as childhood‑onset
disorders; however, adult‑onset presentations are not rare.
Intriguingly, mutations of the TUBB4A gene are associated
with two apparently distinct syndromes—one presenting
as an adult‑onset genetic dystonia, while the other as a
childhood‑onset hypomyelinating disorder.[1,2] Herein, we
present a case of TUBB4Amutation demonstrating an atypical
phenotype, which indicates a clinico‑radiological intermediate
between the two syndromes. It also illustrates the importance
of regular follow‑up in such patients as they may accrue new
symptoms requiring adequate management.
A 61‑year‑old unmarried lady, without any known
comorbidities or any family history of seizures or movement
disorders, presented with gradually progressive dystonia, gait
impairment, dysarthria, and cognitive decline, along with
new onset seizure. Symptoms started about 20 years ago, in
the form of cervical dystonia (right torticollis) along with
tremulousness of the head, which was more pronounced during
any activity like nodding her head or looking to a particular
side. Later, it persisted even at rest and gradually progressed
over years to involve the limbs (which was noticed by her as
diculty in cooking and holding utensils with posturing of
limbs); however, she did not notice any sensory tricks. She
developed progressive gait unsteadiness and stiness for the
last 10 years and ultimately required aid for ambulation. This
was followed by dysarthria without any spasmodic dysphonia.
For the last 5 years, there has been progressive impairment of
attention, executive function, and memory reported as diculty
in keeping track of conversation, frequent diculty in recalling
recent events, and tendency to skip steps in performing an
activity, leading to errors. She developed two episodes of
new onset seizure (generalized tonic clonic convulsions) a
few days before her admission. On admission, her MoCA
score was 22; there was predominantly cervical dystonia
with dystonic head tremor, and spasticity and hyperreexia
in all four limbs [Video 1]. Ophthalmological evaluation and
other cranial nerves were essentially normal. Investigations
revealed normal blood parameters (including complete
blood count, erythrocyte sedimentation rate, urea, creatinine,
sodium, potassium, calcium, glucose, and liver and thyroid
function tests), parathormone, ceruloplasmin, and ferritin
values. Nerve conduction study and electroencephalography
were normal. Magnetic resonance imaging of the brain
revealed T2/uid‑attenuated inversion recovery sequence and
hyperintensity of subcortical white matter with diuse cortical
atrophy [Figure 1]. Considering genetic disorders such as
adult‑onset leukodystrophy, clinical exome sequencing was
performed, which revealed a heterozygous pathogenic variant
in exon 4 of the TUBB4A gene, c.286G>A(p.Gly96Arg).
She was treated symptomatically with levetiracetam (1500 mg),
trihexyphenidyl (8 mg), and baclofen (30 mg) and had
no further episodes of seizures with some reduction in
dystonia (especially in the limbs) and spasticity. The patient
is being followed up at the institute for the last 1 year,
and botulinum toxin therapy has not been tried as she had
responded to medications and was reluctant for botox therapy.
TUBB4A (cytogenetic location: 19p13.3) (tubulin beta‑4A gene)
encodes a brain‑specic member of beta‑tubulin family, highly
expressed in the cerebellum, putamen, and white matter.[1]
Mutations of the TUBB4A, on the one end of the spectrum, are
associated with adult‑onset genetic dystonia without signicant
MRI changes (DYT 4, MIM #128101).[1,3] At the other end, it
is associated with hypomyelinating leukodystrophy‑6 (MIM
#612438) or hypomyelination with atrophy of the basal ganglia
and cerebellum (H‑ABC) with clinical and radiological traits
of hypomyelination, cerebellar atrophy, and progressive
atrophy of the neostriatum (caudate and putamen), which
Adult-Onset Dystonia with Late-Onset Epilepsy in
TUBB4A-Related Hypomyelinating Leukodystrophy—A New
Intermediate Phenotype
Figure 1: Hypomyelination with cerebellar and cortical atrophy. Magnetic
resonance imaging of brain—axial T2-weighted (a), T2 fluid-attenuated
inversion recovery (b), T1-weighted (c), and sagittal T2-weighted
(d) images: showing symmetrical white matter signal intensity
changes—hyperintense on T2/FLAIR (arrows) and isointense on T1,
with cerebellar and cortical atrophy
d
c
b
a

Letters to the Editor
Annals of Indian Academy of Neurology ¦ Volume 25 ¦ Issue 3 ¦ May-June 2022 563
Contd...
Table 1: Studies elaborating prominent clinical radiological and genetic features of TUBB4A disease spectrum
Name of study Total number of
patients
Clinico-radiological profile Mutation
Movement disorder Other neurological
findings
Other system
findings
Radiology
1) Erro R, et al. H‑ABC
syndrome and DYT4:
Variable expressivity or
pleiotropy of TUBB4
mutations (2015)[6]
04 (age of onset
rst decade of life)
Generalized dystonia, ataxia.
Bulbar involvement leading
to aphonia and swallowing
diculty.
Spasticity, non‑development
of communication skills with
preserved comprehension.
Hypomyelination of cerebellum
with atrophy of basal ganglia
except two cases: One did not
show hypomyelination and the
other did not show basal ganglia
atrophy.
One previously described and
two novel mutations (c.941C
>T; p.Ala314Val and c.900G
>T; p.Met300Ile) in the exon 4
of the gene.
Whispering dysphonia in one
patient.
Oculogyric crises
2) Hamilton EM, et al.
Hypomyelination with
atrophy of the basal ganglia
and cerebellum: Further
delineation of the phenotype
and genotype‑phenotype
correlation. (2014)[7]
42 (median age
of onset was 6
months, (range
birth–3 years))
Dystonia, choreoathetosis
(rarely)
Developmental delay,
nystagmus, loss of speech
from median age 7 years.
Most patients unable to
ambulate by the second
decade. Ryles tube feeding
required in 58% of patients.
Absent or disappearing
putamen, variable cerebellar
atrophy, and highly
variable cerebral atrophy.
Hypomyelination, agenesis of
corpus callosum.
25 patients, a heterozygous
c.745G >A TUBB4A mutation
was identied. Thirteen other
TUBB4A mutations were
identied in 17 patients always
in the heterozygous state.
3) Blumkin L, et al.
Expansion of the spectrum of
TUBB4A‑related disorders:
A new phenotype associated
with a novel mutation in the
TUBB4A gene. (2014)[8]
01 Segmental dystonia. Slowly progressive spastic
paraparesis.
Intellectual disability
Permanent, incomplete
myelination associated with
progressive cerebellar atrophy
Novel E410K de novo
heterozygous mutation in the
TUBB4A gene
Whispering dystonia: Present.
4) Lohmann K,
et al. Whispering
dysphonia (DYT4 dystonia)
is caused by a mutation in
the TUBB4 gene. (2013)[3]
Whispering dysphonia:
Present. Focal or generalized
dystonia.
. Distinctive
facies and
body habitus.
Disease‑causing gene was
mapped to a 23cM region on
chromosome 19p13.3‑p13.2
Missense variant in the
TUBB4 (tubulin beta‑4;
Arg2Gly).
5) Simons C, et al. A de novo
mutation in the β‑tubulin
gene TUBB4A results in
the leukoencephalopathy
hypomyelination with
atrophy of the basal ganglia
and cerebellum. (2013)[9]
11 (9 months to
4.5 years: age of
onset)
Hemidystonia. Ataxia
with gait progressively
deteriorating in all cases
Motor delayed
developmental milestones.
MRI suggestive of
hypomyelination with basal
ganglia atrophy.
Heterozygous de novo mutation
in TUBB4A was identied in
all aected individuals: 745G
>A (g. 6495765C >T)
Dysarthria causing
communication diculty
with preserved language and
cognitive domains

Letters to the Editor
Annals of Indian Academy of Neurology ¦ Volume 25 ¦ Issue 3 ¦ May-June 2022
564
Table 1: Contd...
Name of study Total number of
patients
Clinico-radiological profile Mutation
Movement disorder Other neurological
findings
Other system
findings
Radiology
6) Wilcox RA, et al.
Whispering dysphonia in an
Australian family (DYT4):
A clinical and genetic
reappraisal. (2011)[10]
One family with
nine aected
members.
Isolated spasmodic dysphonia
(whispering dysphonia) often
with mild craniocervical
dystonia to severe generalized
dystonia. Extrusional tongue
dystonia and a unique “hobby
horse gait.”
Missense (c.2297C >G;
p.T766R) and a splice‑site
mutation (IVS5 + 1G >T) were
identied.
7) Lu Y, Ondo Y, Shimojima
K, Osaka H, Yamamoto T.
A novel TUBB4A mutation
G96R identied in a patient
with hypomyelinating
leukodystrophy onset beyond
adolescence. (2017)[5]
01 (onset after age
of 17)
Ataxia, dystonia without
dysphonia
MRI ndings suggestive of
hypomyelination of cerebellum,
without signicant basal ganglia
atrophy.
TUBB4A: c. 86G >A [p.Gly (G)
96Arg (R)] was detected in
the conserved region (de novo
mutation).
8) Tonduti D,
TUBB4A‑related
hypomyelinating
leukodystrophy: New
insights from a series of
12 patients. (2016).[2]
12 patients (disease
onset at a mean age
of 19 months (range
3 months–5 years).
Dystonia, 2 had a severe
hypokinetic‑rigid syndrome,
1 manifested only postural
tremor.
Motor delayed
developmental milestones.
Dysarthria/anarthria, spastic
diplegia with cerebellar
signs, spastic paraplegia,
ataxia, spastic tetraparesis.
1 had
hypodontia and
1 manifested
type 1 diabetes
mellitus.
White matter hypomyelination,
while cerebellar atrophy. 1
image showed “globular”
appearance of the basal ganglia
because the anterior limb
of internal capsule was not
recognizable on FLAIR
1) 6 carried the mutation
c.731G >T (p.Gly244Val)
2) 1 showed the nucleotide
change c. 1163T >C leading
to the amino acid change
Met388Thr.
3) Novel mutations—c. 544C
>A (p.Pro182Thr), c. 533C
>T (p.Thr178Met), c. 731G
>A (p.Gly244Asp) missense
mutation

Letters to the Editor
Annals of Indian Academy of Neurology ¦ Volume 25 ¦ Issue 3 ¦ May-June 2022 565
usually presents in children.[2,4] Our patient was unique
in terms of age of disease onset and temporal prole of
symptomatology. Her onset of symptoms was in the fth
decade, when she initially had dystonia and was in the DYT4
range of the spectrum, although without typical “whispering
dysphonia.” After she developed ataxia, spasticity, cognitive
impairment, and eventually, seizures, and her MRI being
suggestive of hypomyelination, she manifested features in
the H‑ABC range of the spectrum. Previously, the same
mutation [c.286G>A(p.Gly96Arg)] was demonstrated in a
Japanese patient with hypomyelinating leukodystrophy, whose
symptoms started in the second decade with spasticity and
dystonia.[5] An overview of the various studies on TUBB4A
mutation disease spectrum with their prominent clinical
ndings is given in Table 1. Notably, our patient had a much
later onset and, additionally, developed seizures. One patient
of spasmodic dysphonia and oromandibular dystonia and
dyskinesia with p.Ala271Thr variant of TUBB4A had onset at
60 years.[3] However, there was no history of ataxia or seizures.
Therefore, this patient represents a new phenotype associated
with TUBB4A mutation, as a hypomyelinating leukodystrophy
with very late age of onset, starting as dystonia, progressing
over decades, and finally manifesting seizures, thus
highlighting the role of thorough investigation and long‑term
follow‑up in such patients.
Declaration of patient consent
Written informed consent was duly obtained.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conicts of interest.
Peyalee Sarkar, Adreesh Mukherjee, Sumanta Sarkar, Raju Agrawal,
Souvik Dubey, Alak Pandit
Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education
and Research, Kolkata, West Bengal, India
Address for correspondence: Dr. Adreesh Mukherjee,
2-B, Surja Kumar Chatterjee Street, Kolkata, West Bengal, India.
E-mail: adreesh03@yahoo.co.in
RefeRences
1. Hersheson J, Mencacci NE, Davis M, MacDonald N, Trabzuni D,
Ryten M, et al. Mutations in the autoregulatory domain of β‑tubulin 4a
cause hereditary dystonia. Ann Neurol 2013;73:546‑53.
2. Tonduti D, Aiello C, Renaldo F, Dorboz I, Saaman S, Rodriguez D,
et al. TUBB4A‑related hypomyelinating leukodystrophy: New
insights from a series of 12 patients. Eur J Paediatr Neurol
2016;20:323‑30.
3. Lohmann K, Wilcox RA, Winkler S, Ramirez A, Rakovic A, Park J‑S,
et al. Whispering dysphonia (DYT4 dystonia) is caused by a mutation
in the TUBB4 gene. Ann Neurol 2013;73:537‑45.
4. Ferreira C, Poretti A, Cohen J, Hamosh A, Naidu S. Novel
TUBB4A mutations and expansion of the neuroimaging phenotype
of hypomyelination with atrophy of the basal ganglia and
cerebellum (H‑ABC). Am J Med Genet A 2014;164:1802‑7.
5. Lu Y, Ondo Y, Shimojima K, Osaka H, Yamamoto T. A novel
TUBB4A mutation G96R identied in a patient with hypomyelinating
leukodystrophy onset beyond adolescence. Hum Genome Var
2017;4:17035.
6. Erro R, Hersheson J, Ganos C, Mencacci NE, Stamelou M, Batla A,
et al. H‑ABC syndrome and DYT4: Variable expressivity or pleiotropy
of TUBB4 mutations? Mov Disord 2015;30:828‑33.
7. Hamilton EM, Polder E, Vanderver A, Naidu S, Schimann R, Fisher K,
et al. Hypomyelination with atrophy of the basal ganglia and cerebellum:
Further delineation of the phenotype and genotype‑phenotype
correlation. Brain 2014;137:1921‑30.
8. Blumkin L, Halevy A, Ben‑Ami‑Raichman D, Dahari D, Haviv A,
Sarit C, et al. Expansion of the spectrum of TUBB4A‑related disorders:
a new phenotype associated with a novel mutation in the TUBB4A
gene. Neurogenetics 2014;15:107‑13. doi: 10.1007/s10048‑014‑0392‑
2. Erratum in: Neurogenetics 2014;15:115.
9. Simons C, Wolf NI, McNeil N, Caldovic L, Devaney JM, Takanohashi A,
et al. A de novo mutation in the β‑tubulin gene TUBB4A results in the
leukoencephalopathy hypomyelination with atrophy of the basal ganglia
and cerebellum. Am J Hum Genet 2013;92:767‑73.
10. Wilcox RA, Winkler S, Lohmann K, Klein C. Whispering dysphonia in
an Australian family (DYT4): A clinical and genetic reappraisal. Mov
Disord 2011;26:2404‑8.
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DOI: 10.4103/aian.aian_952_21
Submitted: 31‑Oct‑2021 Revised: 02‑Jan‑2022 Accepted: 14‑Jan‑2022
Published: 20‑Apr‑2022
Video available on: www.annalsoan.org
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