The University of Toledo Translation Journal of Medical Sciences
UTJMS 2023 July 06, 11(2):e1-e3 https://doi.org/10.46570/utjms.vol11-2023-551

Novel Gene Abnormality in Epilepsy with
Myoclonic-Atonic Seizures (Doose Syndrome)

Rayan Magsi1, MD, Casey Ryan2, MD, Ajaz Sheikh1, MD, Mariam Noor1, MD,
and Naeem Mahfooz1, MD

1Derpartment of Neurology, University of Toledo Medical Center, Toledo, OH, 43614, USA
2University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA

E-mail: rayan.magsi@utoledo.edu

Published: 06 July 2023

Abstract

Introduction:
Doose Syndrome is a myoclonic-atonic seizure disorder most prominent in the pediatric
population. Several common genetic mutations have been identified. However, SUOX gene
mutations have not yet been correlated with Doose Syndrome.
Case Report:
At the age of 5, the patient presented with absence seizures followed by the development of
generalized tonic-clonic and myoclonic-atonic seizures. She was diagnosed with Doose
Syndrome based on her clinical presentation and EEG findings. An MRI found an incidental
left choroidal fissure cyst. Multiple medical interventions failed to control seizures. To date,
the patient has shown partial response to clobazam (40 mg/day), phenobarbital (97.5 mg/day),
and a ketogenic diet.
Conclusion:
SUOX gene defects have been associated with isolated sulfite oxidase deficiency. However,
our patient did not have the typical presentation, progression, and symptomology of this
disorder. Instead, several possible sources for the seizures were identified; the mutation itself,
focal seizures originating from the brain lesion which then generalizes mimicking Doose
Syndrome, or a synergistic role between the cyst and genetic mutation.

Keywords: Epilepsy, Genetics, Doose Syndrome, Myoclonic-Atonic Seizures, Case Report

1. Introduction
Doose Syndrome is a myoclonic-atonic seizure disorder

most prominent in the pediatric population (1). The onset of
Doose usually occurs between 6 months and 6 years of age
with a peak at 2-4 years, effecting males more than females
(2:1), and associated with 2 to 5Hz generalized polyspike and
wave epileptiform activity on EEG (2). The syndrome
consists of multiple seizure types; myoclonic, astatic and
myoclonic-astatic (2). All these types may cause status
epilepticus (3). Outcomes range widely from intractability to
seizure freedom, from severe intellectual disability to normal
cognitive function, hyperactivity, and behavioral problems
(4). Approximately 35-40% of first-degree relatives of
patients also developed clinical seizures. In fact, 68% of

immediate and 80% of distant family members have
abnormal EEG findings (5, 6). Several common genetic
mutations have already been delineated in the literature
including SCN1A, SLC6A1, GABRG2 as well as some rarer
mutations like KCNA2, GABRB3, and CHD2 (1, 7, 8, 9, 10,
11). To the best of our knowledge, our patient’s
heterozygous genetic mutation in SUOX variant c.514A>G
(p.Thr172Ala) has not yet been correlated with Doose
Syndrome.

2. Case Presentation

Our patient was a developmentally normal 8-year-old female
with a medical history of attention deficit hyperactivity
disorder and family history of sudden unexpected death from

UTJMS 11(2):e1-e3 Magsi et al

epilepsy (paternal grandfather) who developed seizures at 5-
years-old. Her initial seizures involved staring and
subsequent fall to the ground. She was initially placed on
ethosuximide with concern for absence seizures. A month
later, she developed a new seizure described as “drop
attacks.” These were identified by a sudden elevation of the
arms immediately followed by falling to the ground and were
labelled as myoclonic-atonic seizures. She also manifested
intermittent generalized tonic-clonic seizures. Interictal EEG
showed generalized polyspikes and paroxysmal fast activity,
and ictal EEG showed generalized polyspikes and a wave
with evolution (Fig 1). Her brain MRI was normal except for
an incidental 14.3 mm left choroidal fissure cyst (Fig 2). The
patient’s dialeptic and generalized tonic-clonic seizures
improved with antiepileptic medications. Levetiracetam,
topiramate, and valproic acid were not tolerated because of
side effects. Lamotrigine and perampanel increased the
frequency of drop attacks, whereas zonisamide was
ineffective. The drop attacks showed partial response to
clobazam (40 mg/day), phenobarbital (97.5 mg/day), and a
ketogenic diet with a decrease in the number and frequency
of attacks though not complete resolution. A genetic panel
(INVITAETM) was performed and a heterozygous defect in
the SUOX gene, variant c.514A>G (p.Thr172Ala), was
discovered. To date, the drop attacks have persisted,
occurring approximately 2-5 times per day with each episode
lasting up to 2 seconds. This has resulted in several facial
injuries despite use of a helmet.

3. Discussion
As discussed in the Introduction, many different genetic

mutations have been linked to the propensity to develop
Doose Syndrome. However, the SUOX mutation, with a
heterozygous mutation in exon 6, c.514A>G (p.Thr172Ala),
as discovered in our patient, has never been associated with
this condition. The SUOX gene encodes sulfate oxidase,
which is required for the metabolism of sulfur-containing
amino acids methionine and cysteine (12). Deficiency of the
SUOX gene can cause isolated sulfite oxidase deficiency
(ISOD), a rare and often fatal disorder present in neonates
that can cause intractable seizures, rapidly progressive
encephalopathy, feeding difficulties, microcephaly, profound
intellectual disability, and lens subluxation (12). A late-onset
presentation of ISOD also exists, but usually manifests from
the age of 6 to 18 months (12). Our patient manifested
seizures at the later age of 5 years and did not have other
accompanying symptoms. In fact, ISOD MRI findings
usually demonstrate a loss of gray-white matter
differentiation and the presence of edema in the cerebral
cortex and basal ganglia, while our patient’s only finding
was a left mesial temporal choroidal fissure cyst (12). A
review of 47 cases revealed that most if not all ISOD cases
have significantly debilitating symptoms as described above
(17). Combined with the fact that ISOD is an autosomal

recessive condition, the odds that our patient has ISOD is
minimal. The condition was therefore ruled out clinically and
no further workup was performed.

The above evidence prompted us to rule out ISOD
clinically. Instead, electro-clinical findings indicated Doose
Syndrome as the possible diagnosis. Her semiology, age, and
EEG findings are all consistent with the condition – the
seizures typically present with quick, jerky movements often
followed by a myoclonic drop from 7 months to 6 years of
age (12). In fact, it has been theorized that Doose Syndrome
seizures start focally due to a symptomatic cause (including
genetic or structural defect) and then generalizes for
unknown reasons (12). Our patient’s genetic mutation and
temporal structural defect may have a synergistic role in the
development of myoclonic-atonic seizures, which
strengthens our claim. However, many cases of Doose
Syndrome have MRI images without abnormal findings
whereas other studies have demonstrated that it is possible
for brain lesions to rarely mimic myotonic-atonic seizures (3,
13). Overall, the role of the choroidal cyst in pathology is
unclear.

The approach in identifying and evaluating a case of
Doose Syndrome should include an EEG and a baseline MRI
(4). A long-term EEG may be used to confirm seizures or
elucidate their type while a routine EEG may be used to
confirm seizure freedom (4). Some suggest a metabolic panel
to rule out other differentials (4). Other experts recommend
neuropsychological testing at least once before the start of
school and then yearly onwards because of the spectrum of
developmental delays these patients may face (4). Several
different treatment strategies for Doose Syndrome have been
elucidated, the most effective of which is a ketogenic diet (3,
14, 16). Some studies suggest Levetiracetam and zonisamide
as effective therapy while others recommend valproic acid,
clobazam or clonazepam as first line (12, 16). Ethosuximide
has been suggested as second line therapy while partial
effectiveness of corticosteroids have also been identified (3,
4).

A zonisamide trial was ineffective at reducing drop
attacks while levetiracetam and valproic acid were not
tolerated due to gastrointestinal side effects. Lamotrigine and
topiramate have also been identified as successful therapies
but were unsuccessful in our patient (4, 17). Implementation
of a ketogenic diet in conjugate with clobazam and
phenobarbital demonstrated partial response with a decrease
in frequency of drop attacks. The regimen was chosen
because of the effectiveness of the ketogenic diet and the
failure of other known effective therapies. If our patient
continues to have refractory seizures, we will consider
implantation of a vagus nerve stimulator or corpus
callosotomy which are known, last line treatments (4).

UTJMS 11(2):e1-e3 Magsi et al

4. Conclusion

This case report is on an 8-year-old female who presents
with multiple types of seizures. Genetic testing found a
SUOX gene mutation which has not been previously
correlated with Doose Syndrome to the best of our
knowledge. The mutation might potentially be pathogenic to
our patient’s condition, but further studies are needed to
establish the link between SUOX mutation and Doose
Syndrome.

Conflicts of Interest:
Authors declare no conflicts of interest

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