Epilepsy diagnosis ❚
Case notes
Epilepsy: when family history holds the
key to diagnosis
Baba M Aji MRCP, Philip Milburn-McNulty MRCP, Andrew J Larner MD, MRCP
There may be many causes of epileptic seizures, so thorough clinical history taking and
examination to determine the seizure semiology is paramount. In this article, the authors
describe a patient with new-onset seizures whose family history proved pivotal to
targeted genetic testing and appropriate antiepileptic drug therapy.
E
pileptic seizures may
take many different forms,
and there may
be many causes
of epileptic seizures. Clinical history taking and
examination aim to characterise
seizure semiology in order to
determine appropriate investigations and treatment. As epilepsy
syndromes may now sometimes be
defined by their underlying
genetic mutations, a thorough
family history may also be a crucial
supplement to generic clinical
skills. We present a patient in
whom not only clinical phenotype
but also family history were critical
to appropriate investigation.
Rather than a dry academic exercise, this genetic characterisation
may have important implications
for the avoidance of inappropriate
investigation and antiepileptic
drug treatment, as well as having
ramifications for the wider family.
Presentation
A 22-year-old man, born to consanguineous (first cousin) parents,
was admitted in status epilepticus
following a minor head injury.
There was no prior history of seizures. He was stabilised in an
intensive therapy unit with sodium
valproate 1g twice a day. He then
complained of visual symptoms
with blurring in his left eye, as well
as occasional flashing lights and
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colourful vision lasting a few seconds. These were thought to be
seizures of occipital lobe origin.
Examination showed a left homonymous hemianopia. Magnetic resonance imaging (MRI) of the
brain showed an area of increased
signal in the right occipital lobe
without enhancement, which at
the time was thought to represent
brain contusion. Electroencephalography (EEG) showed diffuse
slowing of background rhythms
(in the theta/delta range, with no
alpha rhythm) consistent with a
diffuse encephalopathy. Brief cognitive testing with the Six-item
Cognitive Impairment Test (6CIT)
scored 8/28, suggesting some mild
cognitive impairment.
Family history was significant.
Two of the patient’s cousins, also
children of consanguineous parents, had died in status epilepticus
more than 10 years earlier. One
had sensorineural hearing loss
and developed blackouts from
about the age of eight years, progressing to refractory myoclonus
epilepsy leading to death at age 17
years. As a mitochondrial disorder
was suspected clinically, muscle
biopsy had been performed, which
showed significant numbers of
cytochrome c oxidase (COX) negative fibres; real-time polymerase
chain reaction showed that these
harboured high levels of mitochondrial DNA (mtDNA) deletions. This cousin’s eldest sister
presented with a very similar
disorder characterised by refractory progressive myoclonus epilepsy from which she died at age
32 years. Her muscle biopsy also
showed occasional COX negative
fibres. Their father had an undefined optic neuropathy.
In light of the patient’s clinical
phenotype and the family history,
both suggestive of a mitochondrial
disorder with an autosomal pattern
of disease inheritance, genetic testing was undertaken targeting the
nuclear-encoded gene polymerase
gamma (POLG) on chromosome
15q25, which encodes the catalytic
subunit of the mtDNA. Genetic
testing showed a homozygous point
mutation (p.Ala467Thr) in the
POLG gene, hence establishing the
diagnosis of POLG-related mitochondrial disease.
In light of this genetic diagnosis, specific recommendations
were made to both the patient and
his family members. The latter
have been offered referral to
genetic counselling services when
required; currently no other family members are known to be
affected. Since POLG-related
mitochondrial disease may be associated with adverse reactions to
sodium valproate, the patient’s
antiepileptic drug treatment
was switched to levetiracetam.
Despite this he has had further
hospital admissions with seizures.
He also developed jaundice with
elevated liver-related blood tests.
Ultrasound showed a diffusely
Progress in Neurology and Psychiatry September/October 2016
11
Case notes ❚ Epilepsy diagnosis
hyperechoic liver consistent with
fatty infiltration.
Discussion
Using the terminology suggested
in the revision of the classification
of epilepsies developed by the
International League Against Epilepsy,1 there are a number of epilepsy syndromes that may be
termed genetic epilepsies. These
continue to increase in number as
new associations between genetic
mutations and epilepsy syndromes
are characterised.2 Diagnosis of
genetic epilepsy syndromes may be
facilitated by the additional clinical features observed along with
the seizure disorder (eg dementia).3 In the present case, the clinical features and the family history
were indicative of a mitochondrial
disorder, hence prompting targeted genetic testing and thus
avoiding the requirement to
undertake invasive investigation
with a muscle biopsy.
Mutations in the POLG gene,
over 150 of which have been
described to date, have been associated with a broad spectrum of
clinical phenotypes characterised
by progressive neurological disorder, often commencing in the
teenage years. Inheritance is more
often recessive than dominant.
Presentations range from childhood onset Alpers–Huttenlocher
syndrome to adult-onset sensory
ataxic neuropathy dysarthria and
ophthalmoplegia (SANDO).4–9
Epilepsy is a common presentation of POLG mutations.6,7 In the
majority of patients there is an
occipital EEG focus, causing occipital seizures, which are characterised by flickering coloured lights,
often persistent for long periods of
time; in addition there may also be
nystagmus, metamorphopsias and
ictal visual loss. Brain MRI may
show high signal lesions in the
occipital cortex. In retrospect, the
occipital high signal seen on our
patient’s MRI scan was probably
due to continuous epileptic activity, reflecting the underlying
disease rather than a consequence
of trauma.
Episodes of status epilepticus
are common in POLG-related
mitochondrial disease and often
have a fatal outcome despite intensive treatment. Liver failure associated with the use of sodium
valproate is also recorded.5,6 The
factors underlying phenotypic heterogeneity associated with POLG
mutations are unknown, although
in patients with the p.Ala467Thr
mutation the clinical presentation
has been noted to be similar in siblings (as in our patient’s cousins),
suggesting a genetic basis.8 The
finding of significant variations in
mtDNA in different p.Ala467Thr-­
associated POLG phenotypes suggests downstream molecular defects
caused by the point mutation.9
In summary, in addition to
careful characterisation of seizure
semiology, obtaining a detailed
family history may be critical to the
diagnosis of epilepsy syndromes,
with implications for targeted
genetic testing and the avoidance
of inappropriate investigations
and certain antiepileptic drugs.
Acknowledgement
The authors would like to thank to
Dr T.P. Enevoldson for sharing
information on the family history.
Declaration of interests
No conflicts of interest were
declared.
Dr Aji is a Consultant Neurologist,
Dr Milburn-McNulty is a Specialist
Registrar in Neurology and Dr Larner
is a Consultant Neurologist, all at
the Walton Centre for Neurology and
Neurosurgery, Liverpool.
References
1. Berg AT, Berkovic SF, Brodie MJ, et al. Revised
terminology and concepts for organization
of seizures and epilepsies: report of the ILAE
Commission on Classification and Terminology,
2005–2009. Epilepsia 2010;51:676–85.
2. Avanzini G, Noebels JL, eds. Genetics of
epilepsy and genetic epilepsies (Mariani Foun­
dation Paediatric Neurology 20). Montrouge,
France: John Libbey Eurotext, 2009.
3. Larner AJ. Presenilin 1 mutation Alzheimer’s
disease: A genetic epilepsy syndrome? Epilepsy
Behav 2011;21:20–2.
4. Horvath R, Hudson G, Ferrari G, et al.
Phenotypic
spectrum
associated
with
mutations of the mitochondrial polymerase
gamma gene. Brain 2006;129:1674–84.
5. Tzoulis C, Engelsen BA, Telstad W, et al.
The spectrum of clinical disease caused by the
A467T and W748S POLG mutations: a study of
26 cases. Brain 2006;129:1685–92.
6. Engelsen BA, Tzoulis C, Karlsen B, et al.
POLG1 mutations cause a syndromic epilepsy
with occipital lobe predilection. Brain
2008;131:818–28.
7. Janssen W, Quaegebeur A, Van Goethem G,
et al. The spectrum of epilepsy caused by POLG
mutations. Acta Neurol Belg 2016;116:17–25.
8. Neeve VC, Samuels DC, Bindoff LA, et al.
What is influencing the phenotype of the
common homozygous polymerase-γ mutation
p.Ala467Thr? Brain 2012;135:3614–26.
9. Rajakulendran S, Pitceathly RD, Taanman
JW, et al. A clinical, neuropathological and
genetic study of homozygous A467T POLGrelated mitochondrial disease. PLoS One
2016;11:e0145500.
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