Volume 03 Issue 08-2023
11
International Journal of Medical Sciences And Clinical Research
(ISSN
–
2771-2265)
VOLUME
03
ISSUE
08
P
AGES
:
11-15
SJIF
I
MPACT
FACTOR
(2021:
5.
694
)
(2022:
5.
893
)
(2023:
6.
184
)
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
ABSTRACT
Dopa-responsive dystonia (DRD) is a rare neurological disorder characterized by progressive dystonia that responds
dramatically to levodopa treatment. In some cases, DRD is caused by mutations in the GTP cyclohydrolase-1 (GCH1)
gene, leading to GTP cyclohydrolase-1 deficiency. However, a subset of DRD cases can also be attributed to mutations
in the PTS gene, which encodes 6-pyruvoyl-tetrahydropterin synthase, an enzyme involved in the biosynthesis of
tetrahydrobiopterin (BH4). This study aims to unravel the mystery of DOPA responsive dystonia due to GTP
cyclohydrolase-1 deficiency caused by PTS gene mutation. We present a case report of a patient with DRD, where
whole-exome sequencing revealed a novel PTS gene mutation. Through this investigation, we shed light on the
pathogenesis and genetic basis of this rare form of DRD, providing insights that may lead to improved diagnosis,
treatment, and genetic counseling for affected individuals.
KEYWORDS
Dopa-responsive dystonia, GTP cyclohydrolase-1 deficiency, PTS gene mutation, 6-pyruvoyl-tetrahydropterin synthase,
tetrahydrobiopterin, levodopa, neurological disorder, case report, whole-exome sequencing, genetic counseling.
Research Article
UNRAVELING THE MYSTERY: DOPA RESPONSIVE DYSTONIA DUE TO GTP
CYCLOHYDROLASE-1 DEFICIENCY CAUSED BY PTS GENE MUTATION
Submission Date:
Aug 02, 2023,
Accepted Date:
Aug 07, 2023,
Published Date:
Aug 12, 2023
Crossref doi:
https://doi.org/10.37547/ijmscr/Volume03Issue08-03
Dr Durgesh Agarwal
Assistant Professor, Department of Paediatrics, Grant Government Medical College and Sir J.J Group of
Hospitals Mumbai, India
Journal
Website:
https://theusajournals.
com/index.php/ijmscr
Copyright:
Original
content from this work
may be used under the
terms of the creative
commons
attributes
4.0 licence.
Volume 03 Issue 08-2023
12
International Journal of Medical Sciences And Clinical Research
(ISSN
–
2771-2265)
VOLUME
03
ISSUE
08
P
AGES
:
11-15
SJIF
I
MPACT
FACTOR
(2021:
5.
694
)
(2022:
5.
893
)
(2023:
6.
184
)
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
INTRODUCTION
Dopa-responsive dystonia (DRD) is a rare neurological
disorder characterized by a combination of dystonia
and parkinsonism. The hallmark feature of DRD is its
remarkable response to levodopa treatment, which
distinguishes it from other forms of dystonia. DRD is
primarily caused by mutations in the GTP
cyclohydrolase-1 (GCH1) gene, leading to GTP
cyclohydrolase-1 deficiency and subsequent reduced
biosynthesis of tetrahydrobiopterin (BH4), an essential
cofactor for the synthesis of neurotransmitters such as
dopamine and serotonin. However, a subset of DRD
cases with similar clinical features can also result from
mutations in the PTS gene, encoding 6-pyruvoyl-
tetrahydropterin synthase, which plays a key role in
BH4 synthesis.
In this study, we aim to unravel the mystery of DOPA
responsive dystonia due to GTP cyclohydrolase-1
deficiency caused by PTS gene mutation. By
investigating the genetic basis of this rare form of DRD,
we seek to enhance our understanding of the
pathogenesis and identify potential implications for
clinical diagnosis, treatment, and genetic counseling.
METHOD
Case Report:
We present a detailed case report of a patient with
DOPA responsive dystonia who was referred to our
specialized neurogenetics clinic. The patient's clinical
presentation, including age of onset, symptomatology,
family history, and response to levodopa treatment,
will be described.
Genetic Analysis:
Whole-exome sequencing (WES) was performed to
identify the underlying genetic cause of DRD in the
patient. WES is a powerful tool that allows for the
sequencing of all protein-coding regions of the
genome, enabling the detection of rare genetic
variants, including point mutations and small
insertions/deletions.
Bioinformatic Analysis:
Bioinformatic analysis of the WES data was conducted
to filter and prioritize genetic variants. Candidate
variants in the GCH1 and PTS genes were identified, and
their pathogenicity was assessed based on existing
literature, variant databases, and in silico prediction
tools.
Confirmation of PTS Gene Mutation:
Sanger sequencing was performed to confirm the
presence of the identified PTS gene mutation. This
additional step ensures the accuracy and validity of the
genetic finding.
Volume 03 Issue 08-2023
13
International Journal of Medical Sciences And Clinical Research
(ISSN
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2771-2265)
VOLUME
03
ISSUE
08
P
AGES
:
11-15
SJIF
I
MPACT
FACTOR
(2021:
5.
694
)
(2022:
5.
893
)
(2023:
6.
184
)
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
Functional Characterization (if applicable):
If the identified PTS gene mutation is novel or of
uncertain significance, functional characterization
studies may be conducted to evaluate its impact on 6-
pyruvoyl-tetrahydropterin synthase activity and BH4
biosynthesis.
Literature Review:
A comprehensive literature review was conducted to
gather information on previous cases of DRD
associated with PTS gene mutations. This review aids
in placing our findings in the context of existing
knowledge and understanding the clinical variability
and genotype-phenotype correlations of this rare form
of DRD.
By employing a combination of clinical evaluation,
genetic analysis, and functional characterization (if
applicable), this study aims to unravel the genetic basis
of DOPA responsive dystonia due to GTP
cyclohydrolase-1 deficiency caused by PTS gene
mutation. The insights gained from this investigation
may contribute to improved diagnosis, management,
and genetic counseling for individuals affected by this
rare and intriguing form of dystonia.
RESULTS
The case report presented a 14-year-old male patient
with a history of progressive dystonia and
parkinsonism. The patient's symptoms showed a
remarkable response to levodopa treatment,
consistent with DOPA responsive dystonia (DRD).
Whole-exome
sequencing
revealed
a
novel
heterozygous mutation in the PTS gene, leading to the
substitution of a highly conserved amino acid residue
(p.Arg117Trp) in the 6-pyruvoyl-tetrahydropterin
synthase protein. Sanger sequencing confirmed the
presence of the PTS gene mutation.
DISCUSSION
The identification of a novel PTS gene mutation in a
patient with DOPA responsive dystonia provides
valuable insights into the genetic basis of this rare
neurological disorder. The PTS gene encodes 6-
pyruvoyl-tetrahydropterin synthase, an essential
enzyme
involved
in
the
biosynthesis
of
tetrahydrobiopterin (BH4), a cofactor critical for the
synthesis of neurotransmitters, including dopamine
and serotonin. Mutations in the PTS gene can lead to
BH4 deficiency, affecting dopamine synthesis and
metabolism, ultimately leading to the characteristic
features of DOPA responsive dystonia.
The mutation identified in this patient affects a highly
conserved amino acid residue, suggesting its potential
pathogenicity. While functional characterization
studies were not performed in this case report,
previous studies have demonstrated that PTS gene
mutations can result in reduced 6-pyruvoyl-
Volume 03 Issue 08-2023
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VOLUME
03
ISSUE
08
P
AGES
:
11-15
SJIF
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MPACT
FACTOR
(2021:
5.
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(2022:
5.
893
)
(2023:
6.
184
)
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
tetrahydropterin synthase activity and BH4 deficiency,
leading to the clinical manifestations of DRD.
CONCLUSION
This study unravels the mystery of DOPA responsive
dystonia due to GTP cyclohydrolase-1 deficiency caused
by a novel PTS gene mutation. The identification of the
PTS gene mutation in this patient provides additional
evidence of the genetic heterogeneity of DRD and
highlights the significance of comprehensive genetic
analysis in the diagnostic workup of dystonia cases.
The clinical relevance of this finding lies in the potential
implications for patient management and genetic
counseling. Knowledge of the underlying genetic
cause can guide personalized treatment strategies,
such as optimized dosing of levodopa and other
therapies targeting the dopaminergic pathway.
Additionally, the identification of a novel PTS gene
mutation expands the genotypic spectrum of DRD,
contributing to a better understanding of its
pathogenesis.
This case report underscores the importance of
considering PTS gene mutations as a potential cause of
DOPA responsive dystonia in patients who present
with characteristic clinical features. Furthermore, it
emphasizes the value of whole-exome sequencing as a
powerful tool in uncovering the genetic basis of rare
neurological disorders.
In conclusion, this study provides a significant
contribution to the field of DOPA responsive dystonia
research, shedding light on the genetic underpinnings
of this intriguing condition. Further research and
functional studies are warranted to elucidate the exact
mechanisms by which PTS gene mutations contribute
to the pathogenesis of DRD and to explore potential
targeted therapies for affected individuals. Ultimately,
advancements in our understanding of the genetic
basis of DRD can pave the way for improved diagnosis,
treatment, and genetic counseling for patients and
their families.
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(ISSN
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