RESEARCH PAPER Neurologia i Neurochirurgia Polska

Polish Journal of Neurology and Neurosurgery

2019, Volume 53, no. 6, pages: 476–483
DOI: 10.5603/PJNNS.a2019.0062
Copyright © 2019 Polish Neurological Society
ISSN 0028–3843

Clinical and genetic spectrum of an orphan disease MPAN:

a series with new variants and a novel phenotype
Nihan Hande Akçakaya1,2, Garen Haryanyan2, Sevcan Mercan2, Nejla Sözer3, Asuman Ali4,
Temel Tombul5, Uğur Özbek6, Sibel Aylin Uğur İşeri2, Zuhal Yapıcı7
1
Council of Forensic Medicine, Kımız sokak no:1 Bahçelievler, Istanbul, Turkey
2
Department of Genetics, Institute of Aziz Sancar Experimental Medicine (ASDETAE), Istanbul, University, Istanbul, Turkey
3
Department of Neurology, Dr. Sadi Konuk Training and Research Hospital, Health Sciences University, Istanbul, Turkey
4
Department of Neurology, Yuksek Ihtisas Training and Research Hospital, Health Sciences University, Bursa, Turkey
5
Department of Neurology, Yuzuncu Yil Faculty of Medicine, Yuzuncu Yil University, Van, Turkey
6
Department of Medical Genetics, Acibadem Faculty of Medicine, Acibadem University, Istanbul, Turkey
7
Department of Child Neurology, Istanbul University, Istanbul, Turkey

Abstract:
Introduction. Pathogenic variations in C19orf12 are responsible for two allelic diseases: mitochondrial membrane protein-as-
sociated neurodegeneration (MPAN); and spastic paraplegia type 43 (SPG43). MPAN is an orphan disease, which presents with
spasticity, dystonia, peripheral nerve involvement, and dementia. The pattern of iron accumulation on brain MRI may be a clue
for the diagnosis of MPAN. SPG43, on the other hand, is characterised by progressive lower limb spasticity without brain iron
accumulation. We here present clinical and genetic findings of MPAN patients with potentially pathogenic C19orf12 variants.
Materials and methods. Patients from 13 different families having progressive motor symptoms with irritative pyramidal signs
and brain iron accumulation were screened for C19orf12 gene variants.
Results. C19orf12 screening identified seven variants associated with MPAN in eight patients from seven families. We associated
two pathogenic variants (c.24G > C; p.(Lys8Asn) and c.194G > A; p.(Gly65Glu)) with the MPAN phenotype for the first time. We
also provided a genetic diagnosis for a patient with an atypical MPAN presentation. The variant c.32C > T; p.(Thr11Met), common
to Turkish adult-onset MPAN patients, was also detected in two unrelated late-onset MPAN patients.
Conclusions. Genetic analysis along with thorough clinical analysis supported by radiological findings will aid the differential
diagnosis of MPAN within the neurodegeneration with brain iron accumulation spectrum as well as other disorders including
hereditary spastic paraplegia. Dystonia and parkinsonism may not be the leading clinical findings in MPAN patients, as these
are absent in the atypical case. Finally, we emphasise that the existence of frameshifting variants may bias the age of onset
toward childhood.
Key words: MPAN, C19orf12, SPG43, iron accumulation, spastic paraplegia, HSP
(Neurol Neurochir Pol 2019; 53 (6): 476–483)

Introduction combination of extrapyramidal motor system involvement and

iron accumulation at the basal ganglia on brain magnetic res-
Neurodegeneration with brain iron accumulation (NBIA) onance imaging (MRI) leads simply to a suspicion of an NBIA
comprises a group of rare inherited movement disorders ac- disorder. However, identifying the distinct NBIA subtype can
companied by varying degrees of cognitive dysfunction. The be challenging due to clinical and genetic heterogeneity [1, 2].

Address for correspondence: Nihan Hande Akçakaya, Council of Forensic Medicine, Kımız sokak no:1 Bahçelievler, 34034 Istanbul, Turkey;
e-mail: nhakcakaya@gmail.com

476 www.journals.viamedica.pl/neurologia_neurochirurgia_polska
 Nihan Hande Akçakaya et al., Clinical and genetic spectrum of an orphan disease MPAN

Mitochondrial membrane protein-associated neurodegener- Patients and methods

ation (MPAN) is the third most frequent subtype of NBIA
(MIM:614298). MPAN, also known as NBIA4 and first defined Fourteen patients from 13 different families having pro-
in a Polish NBIA cohort, comprises 38% of total cases [1]. The gressive motor symptoms with irritative pyramidal signs and
C19orf12 protein shows mitochondrial localisation. Lewy iron accumulation in basal ganglias were recruited in this study
bodies, tangles, spheroids, and tau pathology were present for a possible genetic diagnosis of MPAN (Supplementary
in histopathological examination of the brain in an autopsy Tab.1). All patients had previously tested negative for patho-
case [1]. The major clinical features of MPAN are spasticity, genic variations in PANK2 associated with PKAN. Informed
dystonia, peripheral nerve involvement, and dementia [1]. consent was obtained from the patients and family members
The prominent clinical features of MPAN may show a great in accordance with the ethics approval obtained for the study
variability among patients, such as manifesting severe periph- from the Ethics Committee of Istanbul University, Istanbul
eral motor axonal neuropathy or amyotrophic lateral sclerosis Faculty of Medicine.
mimicking clinical progress [1–3].
The age of MPAN onset can vary from childhood to Genetic analysis
adulthood. The earliest onset of MPAN has been reported
at the age of 3, and the oldest at the age of 36 [3, 4]. Initial G e nom i c DNA w as is ol ate d f rom p e r iphe r a l
symptoms involve movement abnormalities, behavioural blood using standard protocols. All exons and exon-in-
disturbances, cognitive impairment, optic atrophy, motor tron boundaries of the C19orf12 transcript variant
axonal neuropathy, and bladder incontinence [5]. Gait NM_001031726.3 (ENST00000392278.2) coding the largest
problems and spasticity, predominantly in the lower limbs, protein isoform were investigated for sequence variations
are also early symptoms of MPAN [1]. In early onset MPAN using PCR and Sanger sequencing protocols. This reference
cases, dystonia and spasticity comprise the most common transcript was also used to perform all variant annotations.
motor symptoms. Parkinsonism is mostly observed in cases Segregation analysis was performed in available family mem-
with a later onset. Emotional lability, anxiety, compulsions, bers upon identification of a potentially causative variation.
depression, impulsiveness and psychosis are the non-motor Primer sequences are given in the supplementary data. PCR
symptoms [5]. The rate of progression of MPAN is not clearly conditions are available upon request. Sequence data was an-
defined, but adulthood onset cases can show an aggressive alysed using a CLC Main Workbench v6.5. (CLC Bio, Aarhus,
progression leading to death [4–6]. Denmark). The frequency of identified variations was evalu-
The radiological spectrum of MPAN is also heteroge- ated through the Genome Aggregation Database (GnomAD).
neous, without a distinct MRI sign. Nevertheless, the main All variants were annotated with an ENSEMBL-Variant Effect
MRI finding is iron accumulation at globus pallidus (GP) Predictor to identify all possible consequences on RNA and
equally with substantia nigra (SN) [1, 5]. However, iron protein structure and also to evaluate with in silico tools,
accumulation may be undetectable in the early stages of namely SIFT and Polyphen.
MPAN [7]. Medial medullary lamina linear streaking on
T2 sequences is an important sign supporting a differential Results
diagnosis of MPAN [5]. Cerebral and cerebellar atrophy
may be observed in the late stages [5]. Rare cases have been We detected seven different potentially pathogenic
reported with a so-called ‘eye-of-the-tiger’ pattern in MRI, C19orf12 variants in eight patients from seven families. A re-
defined as hyperintensity in the anteromedial area of GP view of the clinical and genetic findings of these patients is
surrounded by low-signal intensity rings on a T2-weighted set out in Table 1. Two of these variants were associated with
MRI [7, 8]. This MRI pattern is typical for pantothenate MPAN for the first time in this study, including c.194G > A in
kinase-associated neurodegeneration (PKAN), which is the rs752450983 locus and one novel variant c.24G > C. These two
most common subtype of NBIA [1, 9]. variants were submitted to the freely accessible NCBI ClinVar
The pathogenic variations in C19orf12 lead to MPAN Database, with SUB4966204 and SUB4967569 submission
through a possible defect affecting fatty acid biosynthesis and numbers respectively. All variants were in the homozygous
branched-chain amino acid metabolism [1, 10]. C19orf12 is state except for the variants of two siblings in Family 3, which
also responsible for another allelic disease, namely hereditary were confirmed to be in a compound heterozygous state by
spastic parapalegia (HSP) type 43 (MIM: 615043). HSP is ba- segregation analysis. c.32C > T; p.(Thr11Met) (rs397514477),
sically an umbrella term for different rare neurodegenerative which has previously been reported to be common among
diseases that feature progressive spasticity of the lower limbs. adult Turkish patients with MPAN, was found to be homo-
Brain iron accumulation is not obvious in HSPs. Below, we zygous in two unrelated patients [4]. Figure 1 shows three
present genetic findings of eight patients from seven Turkish selected variants for which segregation analysis was possible.
families, along with their clinical and neuroimaging findings. Interestingly, another patient (M8) was found to be
We discuss the implications on the MPAN phenotype. heterozygous for a single variant in C19orf12 gene, which

www.journals.viamedica.pl/neurologia_neurochirurgia_polska 477
 Table 1. Clinical and genetic findings for patients with C19orf12 variants

478
Patients M1 M2 M3 M4 M5 M6 M7 M8
Family 1 2 3 3 4 6 7 5

Sex female male male female male female female male

Paternal present present absent absent present present present present

consanguinity
Age of onset (years) 9 9 12 12 9 22 28 27
Age at last 22 18 34 (deceased) 36 22 27 32 29 (deceased)
examination
Symptoms at onset Spasticity and Drowsiness, Spasticity and Spasticity and Spasticity in the Psychosis, rigidity, Cognitive problems, Spasticity and
dystonia in the lower cognitive decline dystonia in the dystonia in the lower limbs tremor and dysartria psychosis, dystonia in the
limbs lower limbs, gait lower limbs, gait parkinsonism, gait lower limbs, gait
disturbances disturbances disturbances disturbances and
seizures
Pyramidal signs +++ ++ +++ +++ +++ ++ ++ +++
Dystonia ++ ++ +++ ++ absent + + +++
Neurologia i Neurochirurgia Polska 2019, vol. 53, no. 6

Parkinsonism + + + + absent +++ +++ ++

Optic atrophy present present present present present present present present
Neuropathy absent absent present present absent absent absent absent
Psychiatric signs absent absent absent absent absent Hallucination, Hallucination absent
insomnia and
billingsgate
Cognitive + +++ +++ +++ + +++ +++ absent
impairment
Developmental absent absent absent absent present absent absent absent
delay
Age at loss of 16 15 16 16 19 26 30 28
ambulation

www.journals.viamedica.pl/neurologia_neurochirurgia_polska
GP & SN iron present present present with medial present with large present with medial present with medial present with large present
accumulation at MRI streaking medial streaking streaking streaking medial streaking
cerebral and absent present present present absent absent present absent
cerebellar atrophy
at MRI
 Nihan Hande Akçakaya et al., Clinical and genetic spectrum of an orphan disease MPAN

has conflicting predictions of pathogenicity in ClinVar

missense & uncertain

(rs146170087). Although the alternative allele frequency
19-29702747-T-C

p.(Lys142Glu)

rs146170087

significance
(AAF = 0.002) is relatively high compared to other variants
c.424A > G;

(C: 0.002)
M8

Het
identified in this study, it still fits the carrier frequency esti-
mation of MPAN (carrier frequency range of 0.002–0.005 for
MPAN with a prevalence of 1–9:1,000,000 from Orphanet;
ORPHA:289560). However, the variant was in a heterozygous
state and another accompanying allele was not detected in any
19-29708415-G-A

(A: 8.13392e-06)
C19orf12 regions analysed.
p.(Thr11Met)

rs397514477

pathogenic
missense &
c.32C > T;

Hom

The age of onset for patients with MPAN variants ranged

M7

from 9 to 27 years (Tab. 1). The most frequent clinical pre-

sentation was lower extremity-onset spasticity with dystonia
(5/8). All patients had dystonia except for M5. The phenotype
of patient M5 was submitted to the NCBI ClinVar Database
19-29708415-G-A

(A: 8.13392e-06)
p.(Thr11Met)

rs397514477

with the SUB4967579 submission number. Among adult-onset

pathogenic
missense &
c.32C > T;

Hom

MPAN patients, the initial symptoms can be listed as psychosis,

M6

dystonia-parkinsonism, and spasticity.

The brain MRIs of all patients were suggestive for iron
accumulation equally at GP and SN. Five of them had hyper-
intense streaking of the medial medullary lamina, between
19-29702966-C-T

rs515726205 (T:
2.45982e-05)
p.(Gly69Arg)

the external and the internal part of the GP on T2 and FLAIR

pathogenic
c.205G > A;

missense &
Hom

sequences. This radiological feature is not specific for a par-

M5

ticular clinic. In patient M4, the medial streaking of GP was

reminiscent of the ‘eye of the tiger’ sign common to PKAN
(Fig. 2). Global brain atrophy was present in four patients,
who also showed cognitive decline.
AACAGCCCCCCG-A

(del: 6.96836e-05)
19-29708423-C-G
p.(Gly69Argfs*10)

Missense and/
19-29702956-

c.204_214del;

rs515726204

or splicing &
frameshift &

Optic atrophy, seizures and peripheral sensory-motor

pathogenic

pathogenic
p.(Lys8Asn)
Comp. het.
c.24G > C;

Novel
M4

axonal neuropathy were the other clinical findings. Although

optic atrophy was detected on examination in all patients, no
patients had visual complaints. Patient M8 had a history of gen-
eralised seizures. Patient M6 had frontal intermittent rhythmic
delta activity (FIRDA) in her EEG. Polyneuropathy was de-
AACAGCCCCCCG-A

(del: 6.96836e-05)
p.(Gly69Argfs*10)
19-29708423-C-G

Missense and/
19-29702956-

c.204_214del;

rs515726204

or splicing &
frameshift &
pathogenic

pathogenic

tected in two siblings from Family 3 with C19orf12 compound

p.(Lys8Asn)
Comp. het.
c.24G > C;

Novel
M3

heterozygous variations. Generalised dystonia was the most

prevalent symptom for patients M3 and M8. These patients
died aged 29 and 34, respectively, due to status dystonicus.
Table 1 cont. Clinical and genetic findings for patients with C19orf12 variants

Discussion
19-29702971-GC -G

p.(Ala67Leufs*6)

COSM1180868

frameshift &
pathogenic
CD132613;
c.199delG;

Hom
M2

Herein, we present genetic analyses and associated clinical

findings for seven C19orf12 variants identified in a cohort of
14 patients from 13 families with NBIA. Differential genetic
diagnosis of MPAN was reached in seven patients from six
+ mildly present, ++ moderately present, +++ severely present

families upon identification of biallelic C19orf12 variants.

19-29702977-C-T

(T: 8.20075e-06)

Missense and/
rs752450983

or splicing &
p.(Gly65Glu)

pathogenic
c.194G > A;

One patient had a monoallelic C19orf12 associated variant

Hom
M1

with inconsistent evaluations of pathogenicity (rs146170087).

NBIA patients from the remaining six families with het-
erogeneous clinical findings were negative for potentially
pathogenic C19orf12 variants, and were therefore noted as
and NP_001026896)

good candidates for exome sequencing for the identification

ACMG classification
reference to hg38,
NM_001031726.3
(annotation with

(AAF-gnomADe)

Consequence &

of new genes for NBIA.

Existing Variant

In our cohort with C19orf12 variants, the age of onset

Patients

Zygosity
Variants

was dramatically clustered into two groups: MPAN started at

ages 9 to 12, or 22 to 27. We wondered whether the variant

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Neurologia i Neurochirurgia Polska 2019, vol. 53, no. 6

Figure 2. Brain MRI findings for Patient M4. Axial T2-weighted ima-
ge of M4 shows hypointensities at bilateral globus pallidi indicative
of iron accumulation. Red arrows mark abnormal hyperintense
signals in the middle of the globus pallidus, which is known as
medial streaking. Medial streaking is so marked in this patient that
it could be confused with the ‘eye of the tiger’ sign

type had any impact on this strict assemblage. At first glance,

C both missense and frameshifting variants are found in the
early-onset group. However, re-annotation of the variants
with VEP revealed a potential splicing effect for variants
c.24G > C and c.194G > A, which alter the first nucleotide
of exons 2 and 3, respectively. Interestingly, the missense
variant c.205G > A (rs515726205) residing 12 bp into exon
3 has the potential to alter splicing, as suggested by the
Human Splice Finder algorithm. A potential frameshifting
effect by a splicing impact may be associated with earlier
disease onset. RNA-based analyses are required in large co-
horts with early-onset MPAN to test this effect on different
C19orf12 transcripts. C19orf12 is a small gene with exons
ranging from 2 to 4 in different. Therefore, it is not possible
to predict if the frameshifting effect results in null alleles
through the nonsense mediated decay (NMD) mechanism
or truncated proteins.
The patients who carried variant c24G > C, i.e. M3 and
Figure 1. Segregation analysis in three families. (A) Patients M3 M4, showed a catastrophic disease progression characterised
and M4 from Family 3 are found to be compound heterozygotes for
by cognitive decline, spasticity, and dystonia. Patient M3 died
c.24G > C (novel) and c.204_214del variants. (B) Patient M2 from
aged 36 due to a respiratory infection. His sister, M4, has
Family 2 is homozygous for c.199delG variant, while his healthy
sisters do not carry this variant. (C) Patient M5 from Family 4 is
been bedridden since her late twenties. In a patient with c
homozygous for c.205G > A. Parents and one of his sisters are 194G > A, M1, spasticity and dystonia were the prominent
carriers for the variant symptoms. Despite pharmacological treatment with baclofen,

480 www.journals.viamedica.pl/neurologia_neurochirurgia_polska
 Nihan Hande Akçakaya et al., Clinical and genetic spectrum of an orphan disease MPAN

trihexyphenidyl and intra-muscular botulinum toxin injec- hereditary spastic paraplegias (HSPs) are a heterogenous
tions, she underwent deep brain stimulation surgery at the group of rare neurological disorders characterised by pro-
age of 18. There is no MPAN-specific treatment option. The gressive lower extremity spasticity without apparent brain
therapeutic effect of iron chelation with deferiprone in NBIA iron accumulation. The condition is designated as compli-
has not been proven. Treatment of spasticity, dystonia, and cated HSP if spasticity is accompanied by additional features
parkinsonism, as well as significant neuropsychiatric symp- including cognitive impairment, cerebellar syndrome,
toms, are indicated in MPAN [1, 4, 9]. thin corpus callosum, or neuropathy. In this sense, patient
In patients with NBIA, dystonia with spasticity, espe- M5 with early-onset MPAN had a distinct and overlapping
cially in the lower extremities, are frequent symptoms for clinical course with complicated HSP. Our patient had slowly
childhood- and adolescence-onset MPAN. Dystonia and progressive spastic paraparesis without extrapyramidal
pyramidal symptoms are also prevalent motor symptoms signs. Distal muscle atrophy with weakness was present.
common to both age groups. A late onset, but a rapidly He had knee flexion and Achilles tendon contractures.
progressive course with psychiatric symptoms and par- Nerve conduction study was normal at the age of 15, but he
kinsonism are features confined to adult-onset MPAN [4, had first motor neuron signs at needle electromyography.
6, 10]. The rapid progressive course includes both motor He had mild mental retardation and optic atrophy. There
deterioration and cognitive decline, which eventually leads was no evidence for dystonia, parkinsonism or any other
patients to be bed-bound. The c.32C > T; p.(Thr11Met) extrapyramidal findings. Therefore, his clinical picture
variant has previously been reported as the most frequent was compatible with complicated HSP, except for the iron
variant in Turkish adult-onset MPAN cases [4]. In our co- accumulation in his brain MRI (Fig. 3). Therefore, patient
hort, we found this variant in two of our three adult-onset M5, who is currently 22, has restricted the differential di-
MPAN cases. At this point, we would like to emphasise the agnosis of early-onset MPAN, as he has not yet developed
possibility of the misinterpretation of clinical findings of either dystonia or parkinsonism.
late-onset MPAN patients. For example, patient M6 with Although MPAN demonstrates a wide phenotypical
homozygous c.32C > T; p.(Thr11Met) variant was first sent spectrum, the most common finding is iron accumulation
to a psychiatry clinic due to catatonic psychosis. Further equally in GP and SN and medial medullary lamina linear
neurological evaluations revealed Parkinson-like findings hyperintense streaking on T2 sequences. In some cases,
with predominant dystonia. Only then was she assigned such as patient M4 when the linear streaking is prominent,
for MRI analysis which led to the identification of iron it resembles the ‘eye of the tiger’ sign (Fig. 2). This can lead
accumulation in the brain. She then received dopaminergic to a misdiagnosis. In PKAN cases, the hyperintensity of GP
therapy with a good response. Adult-onset MPAN should is located in the anteromedial area of GP on a T2-weight-
also be distinguished from atypical neuroaxonal dystrophy ed MRI. Global brain atrophy and spasticity may help to
(NAD) due to PLA2G6 mutations [5]. Both MPAN and atyp- distinguish MPAN from PKAN. As shown in our cohort,
ical NAD show dystonia-parkinsonism and iron deposition most MPAN cases had brain atrophy and all had spasticity.
at GP and SN. Atypical NAD differs from MPAN in terms Brain atrophy and spasticity are not features of the PKAN
of cerebellar findings including cerebellar atrophy and eye phenotype [9].
movement anomalies [1, 11]. A correct genetic diagnosis The C19orf12 variants caused a wide spectrum of
will in turn assist in such differential diagnoses. overlapping phenotypes and histopathological findings.
The third adult-onset MPAN case had an interesting MPAN can present as juvenile ALS [3], HSP [12], Behr
genetic finding: we could only detect heterozygosity for syndrome [13] and dystonia-parkinsonism [1]. Lewy
a relatively common variant c.424A > G; p.(Lys142Glu) in bodies, tangles, spheroids, and tau pathology are known
C19orf12. This variant was originally reported to be patho- in MPAN histopathology. Cognitive decline, global brain
genic and found to be in a compound heterozygous state with atrophy, parkinsonism, and histopathological findings show
c.205G > A; p.(Gly69Arg) [1]. However, since this original another overlap between MPAN and other Lewy body and
report, this variant has had conflicting interpretations of taupathy-associated neurodegenerative diseases [1]. The
pathogenicity ranging from benign to pathogenic in ClinVar. clinical involvement in MPAN is not uniform. Variable
Because this patient had characteristic adult-onset MPAN degrees of cognitive decline, pyramidal and extrapyrami-
findings with fast progression and death only two years after dal findings are seen in MPAN patients. The C19orf12 has
the emergence of initial symptoms, we cannot exclude the been reported to code for a mitochondrial and endoplasmic
possibility that an as yet unidentified variant, maybe a CNV reticulum membrane protein responsible for the transfer of
event along with c.424A > G; p.(Lys142Glu), was responsible essential lipids, and it has a role in calcium and magnesium
for his condition. metabolism and in autophagosome formation [12, 14]. New
Pathogenic variations in C19orf12 are responsible for functional studies of C19orf12 will eventually shed light on
two allelic diseases with autosomal recessive inheritance: the overlapping phenotypes such as HSP and Parkinson’s
MPAN and spastic paraplegia (SPG) type 43 [12]. SPGs or and Alzheimer’s diseases.

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Neurologia i Neurochirurgia Polska 2019, vol. 53, no. 6

A B

Figure 3. Brain MRI findings for Patient M5. (A) The T2 and (B) T2_tse_dark fluid weighted axial section images showing hypointensity at
globus pallidi. White arrows indicate confluent medial streaking in the globus pallidus (B)

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manifests with severe peripheral motor axonal neuropathy. Clin Genet.
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