Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum and gastroparesis

Article (PDF Available)inAutonomic neuroscience: basic & clinical 170(1-2):70-2 · July 2012with59 Reads
DOI: 10.1016/j.autneu.2012.06.002 · Source: PubMed
Abstract
Clinical expression of POLG mutations is largely variable. We present a patient with a new mutation in spacer region of mitochondrial polymerase gamma protein (P765T). The clinical picture is characterized by the presence of sensory-ataxic neuropathy, ophthalmoplegia, dysarthria and gastroparesis, which had not been previously observed in ataxia neuropathy spectrum.

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Short communication
Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum
and gastroparesis
Alionka Bostan
a,
, Gerald Glibert
a
, Bernard Dachy
a
, Bernard Dan
b
a
Department of Neurology, CHU Brugmann, Universite Libre de Bruxelles, Place A. Van Gehuchten 4, Brussels B 1020, Belgium
b
Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Universite Libre de Bruxelles (ULB), Brussels, Belgium
abstractarticle info
Article history:
Received 17 November 2011
Received in revised form 15 June 2012
Accepted 17 June 2012
Available online xxxx
Keywords:
Polymerase gamma
Mitochondrial DNA
Polyneuropathy
Gastroparesis
Clinical expression of POLG mutations is largely variable. We present a patient with a new mutation in spacer
region of mitochondrial polymerase gamma protein (P765T). The clinical picture is characterized by the pres-
ence of sensoryataxic neuropathy, ophthalmoplegia, dysarthria and gastroparesis, which had not been pre-
viously observed in ataxia neuropathy spectrum.
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
DNA polymerase gamma (POLG), the only DNA polymerase found in
mitochondria, is entirely responsible for all DNA synthetic reactions in-
cluding mtDNA replication and repair (Hance et al., 2005). POLG is a
heterodimeric enzyme containing a Pol I-like catalytic core (PolgA) and
an accessory subunit (PolgB), encoded by POLG at locus 15q25 and
POLG2 at locus 17q24.1, respectively (Chan and Copeland, 2009). PolgA
possesses both polymerase and proofreading exonuclease activities;
PolgB increases enzyme's processivity (Lee et al., 2009). Mutations in
the catalytic subunit of POLG can cause mtDNA instability, inducing its de-
letion and/or depletion. Mutation database (http://tools.niehs.nih.gov/
polg/) currently lists more than 150 POLG mutations, which are evenly
distributed over the protein sequence. In addition to the clinical heteroge-
neity, POLG mutations can be either dominant or recessive, posing a great
diagnostic challenge for the clinician.
The phenotypic spectrum is wide, including encephalopathy, epilep-
sy, ataxia, ophthalmoplegia, neuropathy, myopathy and hepatopathy.
Among neurological features of POLG related disorders, the ataxia neu-
ropathy spectrum (ANS) has been dened, comprising mitochondrial
recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dys-
arthria and ophthalmoplegia (SANDO).
We report a P765T POLG missensemutationinapatientwithsensory
ataxic neuropathy, ophthalmoplegia, dysarthria and gastroparesis. To our
knowledge, this mutation of POLG coding region has not been reported
previously (Cohen and Naviaux, 2010).
2. Case report
A 52year-old Moroccan woman, presented with a 10-year history
of drooping eyelids (without daytime uctuation) and slurred speech,
she developed over the past six months progressive gait instability,
leg numbness and inability to feel the ground under her feet. Several
weeks prior to admission, she suffered from anorexia and had a dra-
matic weight loss; she lost 15kg over past two months. She was
complaining of early satiety, bloating, upper-abdominal discomfort
and tendency to constipation. The patient's deceased mother had a
similar bilateral ptosis, without any other ocular signs, her parents
were not consanguineous. The patient has one healthy daughter.
On neurological examination, she had unaltered mental status, bi-
lateral ptosis, complete ophthalmoplegia, optic discs atrophy. Pupils
were equally reactive. A accid type dysarthria was noted. She had
mild upper and lower limb muscle weakness with distal predomi-
nance. Deep tendon jerks were absent, plantar responses were exor.
Muscular tone was normal, no dysmetria was observed. Sensation to
touch and pin prick was normal. She had impaired vibratory and po-
sition sensation in both feet. Gait was staggering and wide-based,
which made the Romberg test impracticable. General examination
was otherwise unremarkable.
The patient had normal liver, renal and thyroid functions, normal
electrolytes, sedimentation rate, creatine kinase, serum protein elec-
trophoresis, serum lactate and urine organic acid prole.
A 1.5 Tesla brain MR I showed mild cor ticalsubcortical atrop hy
without any ot her parenchymal abnormalities. Sensory nerve con-
duc tion studies showed low amplitude radial sensory nerve action
pot ential (SNAP) ( 4.8 μV; normal >20μV) and absent sural SNAP.
Mot or conduction velocities were decreased in the median nerve
Autonomic Neuroscience: Basic and Clinical xxx (2012) xxxxxx
Corresponding author at: Neurology Department, CHU Brugmann, Université Libre
de Bruxelles, Place A. Van Gehuchten 4, 1020 Brussels, Belgium. Tel.: +32 2 477 24 49.
E-mail address: abostan@ulb.ac.be (A. Bostan).
AUTNEU-01426; No of Pages 3
1566-0702/$ see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.autneu.2012.06.002
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Please cite this article as: Bostan, A., et al., Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum and
gastroparesis, Auton. Neurosci. (2012), doi:10.1016/j.autneu.2012.06.002
(44 m/s; normal>48m/s ) and the tibial nerve (35 m/s; normal>
40 m/s). F-wa ve latencies were mildly prolonged in the tibial nerve
(minimal latency 58.8ms; normalb 58 ms). This is suggestive of an
axonal sensori-motor neuropa thy with sensory predominance. Nee-
dle electromyogra phic studies (EMG) showed some polyphasic
motor unit action potentials in upper and lower extremities. These
were also found in the orbic ularis oris, orbicularis oculi and
sternocleidomastoid muscles, whi ch also showed a myogenic EMG
patternwithshort,low-amplitudemotorunitactionpotentials.
Brainstem auditory evoked potentials and blink reex were normal.
Neuro-ophthalmologic examination (including electro-retinography)
suggested chronic progressive external ophthalmoplegia without
retinopathy. X-ray studies demonstrat ed gastric and bowel disten-
tion. Isotope gastric emptying show ed markedly delayed empty-
ing, consistent with gastroparesis (Fig. 1).
Deltoid muscle immunohistochemistry showed changes character-
istic of a muscular dystrophy with COX-negative bers, suggesting mi-
tochondrial disorder. Electron microscopy showed paracrystalline
mitochondrial inclusions (Fig. 2). All oxidative phosphorylation enzyme
complexes were diminished on mitochondrial enzymatic activity as-
says. Analysis of TYMP gene demonstrated normal coding sequences.
Direct sequencing of POLG gene exons showed a homo- or hemizygous
point mutation in 765 codon (P765T) located in exon 14, which is an
evolutionary conserved amino acid. The MLPA analysis performed indi-
cates the mutation at homozygous state in our patient. The patient's
daughter carries the same mutation at heterozygous state.
3. Discussion
We report a patient with dramatic weight loss, gastroparesis, ptosis,
ophthalmoplegia and peripheral neuropathy. The latter caused signi-
cant sensory ataxia. The absence of dysmetria and the accid character
of the dysarthria were inconsistent with additional cerebellar involve-
ment. Muscular involvement was proven by the biopsy suggestive of
mitochondrial disorder. Most of our patient's features, and particularly
sensoryataxic neuropathy, dysarthria and ophthalmoplegia, t best
with SANDO of the ANS, typically associated with POLG mutations
(Van Goethem et al., 2001; Santoro et al., 2006). Our patient's clinical
picture may be also evocative of mitochondrial neurogastrointestinal
encephalopathy (MNGIE) (Nishino et al., 2000) but was excluded by
the absence of white matter abnormalities on MRI and normal TYMP
sequencing.
The POLG protein maintains mitochondrial DNA integrity and replication
(Kasiviswanathan et al., 2010). Its catalytic subunit contains exonuclease and
Fig. 1. A Isotopic gastric emptying study showing markedly delayed gastric emptying with clearance time (T ½orT
50%)
of 100 minutes. Normal range is 50±15minutes. B X-ray
study showing important gastric and bowel distention.
Fig. 2. A COX-SDH staining showing cox negative muscle bers (arrow) in deltoid muscle biopsy; B electron microscopy showing paracrystalline inclusions (arrow).
2 A. Bostan et al. / Autonomic Neuroscience: Basic and Clinical xxx (2012) xxxxxx
Please cite this article as: Bostan, A., et al., Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum and
gastroparesis, Auton. Neurosci. (2012), doi:10.1016/j.autneu.2012.06.002
polymerase domains separated by spacer (Lee et al., 2009). This has two
subdomains involved in intrinsic processivity and DNAprotein interac-
tion, respectively (Lee et al., 2009). Our patient's P765T mutation is
situated in the intrinsic processivity subdomain, thought to impart
additional enzyme processivity through additional primer-template
interactions. Mutations in the spacer region induce varied biochemical
abnormalities and associated clinical manifestations (Wong et al.,
2008). Our patient shows features described in other mutations in
POLG spacer unit. G763R POLG mutation was associated with progres-
sive external ophthalmoplegia and sensorimotor neuropathy (Santoro
et al., 2006), and A767D mutation with epilepsy without any peripheral
nervous system involvement (Horvath et al., 2006). In our patient, a
novel POLG mutation is associated with ANS plus gastroparesis, which
has not been observed previously. The digestive dysregulation could be
the result of energy deprivation following mitochondrial loss of function
due to accumulation of mtDNA mutations/deletions and decline of respi-
ratorychainfunctionwithsevereconsequencesforallenergy-dependent
cellular fun ctions, including gastric nerve cells. Our report illustrates
clinical variability of POLG mutations and underlines the importance
of further biochemical and translational research to better address the
pathogenicity of POLG dysfunction. In addition, gastric dysmotility should
be more readily searched for in this clinical conjuncture.
Acknowledgements
We thank Prof. H. Kadhim for performing the pathological studies
and Prof. G. Van Goethem for genetic studies.
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3A. Bostan et al. / Autonomic Neuroscience: Basic and Clinical xxx (2012) xxxxxx
Please cite this article as: Bostan, A., et al., Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum and
gastroparesis, Auton. Neurosci. (2012), doi:10.1016/j.autneu.2012.06.002
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