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\begin{document}

\title{Dementia as a core clinical feature of a patient with aceruloplasminemia}



\author[1]{Farzad Ashrafi}%
\author[2]{Mehri  Salari}%
\author[2]{Fatemeh Nouri}%
\author[2]{fatemeh shiravi}%
\affil[1]{Shohada-e Tajrish Hospital}%
\affil[2]{Shahid Beheshti University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 29, 2024}


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\selectlanguage{english}
\begin{abstract}
Aceruloplasminemia is an autosomal recessive disease, caused by systemic
iron accumulation due to mutations in the Ceruloplasmin gene. We report
two Iranian siblings who have diagnosed with aceruloplasminemia. Based
on our researches, dementia hasn't been published as the first
neurological feature while one of them was presented with pure dementia%
\end{abstract}%



\sloppy


\textbf{Introduction}

Aceruloplasminemia was firstly defined in 1987 as a rare adult-onset, an
autosomal recessive disorder which is caused by mutations in the
ceruloplasmin gene. {[}1--3{]}

As a consequence of this mutation iron accumulates all over the body,
mostly in brain, retina, pancreas, and liver, which causes~neurologic
disturbance (68\%),~retinal degeneration~(76\%),~and diabetes~(70\%),~as
main features.~ {[}4, 5{]}

The iron deposition involves the dentate nuclei of the cerebellum,
striatum, and thalamus, and is demonstrated in magnetic resonance
imaging (MRI).{[}6{]}

The disease can start at different ages and by various features.{[}4{]}
The patients may experience diabetes in the third to the fifth decade,
the retinal disorder in the second decade, and neurological problems in
the forth to the sixth decade of life. Neurological manifestation can be
ataxia (71\%), Parkinsonism (20\%) cognitive dysfunction (60\%) and
involuntary movements (64\%) like tremors, chorea and blepharospasm. The
retinal disorder is early beginning macular degeneration rather than
diabetic retinopathy. {[}5{]}

Aceruloplasminemia~is~detected~with specific MRI findings, quite one
amongst the above clinical manifestations~and typical results on
laboratory tests, such as microcytic anemia, lack of serum
ceruloplasmin, low~serum~copper and transferrin saturation, and
increased ferritin. {[}4, 7, 8{]}

In this~paper,~we~describe~a family with two affected siblings
with~aceruloplasminemia, which dementia was the sole clinical
manifestation in one of them.

\textbf{Case report}

\emph{Case 1:}

A 64-year-old woman was referred to our movement disorder clinic with
four years history of bradykinesia and rigidity. She was born as a first
child of consanguineous parents and has history of diabetes mellitus,
myelodysplastic syndrome, and gout for 15 years.

On examination, she had generalized bradykinesia and rigidity without
tremor, slow saccadic eye movements, limbs dysmetria and ataxic gait.
Other neurological examination including, cognitive, sensory, and motor
function were unremarkable.

On follow-up, after 2 years, she became wheelchair-bound due to severe
gait freezing, cognitively declined (MOCA: 19), and tremor was added to
her clinical manifestations. In addition, at that time she had severe
aggression, agitation, and visual hallucination.

The evaluation showed microcytic anemia, low serum ceruloplasmin, copper
and transferrin saturation, and increased ferritin. (Table 1) Brain MRI
detected abnormal signal intensity of the cerebellum, basal ganglia, and
midbrain. (Figure A, B) According to imaging findings and other
laboratory assessments, the diagnosis of aceruloplasminemia was
suspected. Genetic analysis was requested. The direct DNA Sequencing
revealed homozygote pathogenic variant defined as
(c.2425+1G\textgreater{}C) in splice region of exon 13 of CP gene. DNA
was extracted from the patient sample using salting-out technique. PCR
was used to intensify the indicated exons plus extra flanking intronic
or other non-coding sequences. Subsequently cleaning of the PCR
supplies, cycle sequencing was carried out using the ABI Big Dye
Terminator v.3.0 kit. Products were resolved by electrophoresis on an
ABI 3130 capillary sequencer. Sequencing was accomplished separately in
both the forward and reverse directions.

\emph{Case 2:}

The 56-year-old sibling had had cognitive decline for 8 years, and
Alzheimer's disease had been diagnosed. . He has a history of diabetes
mellitus (DM) since the age of 28. On examination, he had mostly
attention, concentration, memory, executive dysfunction, and his MOCA
was 5. Other examinations including, cerebellar, pyramidal,
extrapyramidal, eye movements, and sensory function were unremarkable.

According to his positive family history, more workup showed microcytic
anemia, elevated ferritin, and low serum ceruloplasmin. (Table 1)

The brain MRI revealed low signal intensity on the T2/fluid attenuated
inversion recovery weighted image. (Figure C, D)

After careful history taking, it was showed that the apart that case 1,
other siblings have diabetes, plus the younger brother has a high
ferritin level and mild cognitive dysfunction without other neurological
findings.

The family history, laboratory and imaging results were leading to the
diagnosis of aceruloplasminemia, therefore, the genetic study was asked
and showed homozygote pathogenic variant defined as
(c.2425+1G\textgreater{}C) in splice region of exon 13 of CP gene.

\textbf{Discussion}

Ceruloplasmin which is mostly~synthetized~in liver cells~has~a crucial
role within the iron metabolism by~oxidation~of~Fe2+~to~Fe3+. {[}8{]}
This~protein's~gene~is~positioned~in~chromosome~3q25,~and~according~to
human~gene~mutation databank more than 40~CP~gene~variant has been
described; previous studies~failed to show any correlations between the
genotypes and, phenotypes.{[}9, 10{]} In our~patients~by direct DNA
Sequencing we~revealed~a unique variant which
is~(\emph{c.2425+1G\textgreater{}C} )~in splice region of exon 13
of~CP~gene.

CP~mutation causes iron to accumulate all over the body~that
provides~free~radicals and lipoperoxidation supplies that cause
oxidative stress and eventually organ damage. {[}9{]}

According~to prior researches, the initial neurological presentation
varies in different races as an example in Japanese patients, the
primary neurological manifestations mostly are movement disorders, and
cognitive dysfunction will be added in several years. Although, in other
races such as Caucasians around 50\% of patients at first presented with
cognitive disorders or psychiatric complaints such as depression,
anxiety and apathy or a mixture of non-motor and motor
manifestations.{[}11{]}.~ Based~on these researches,~dementia~has~not
been published~as the sole~neurological~feature while
we~reported~a~case~which was~presented~with pure~dementia~without any
other neurological findings which hitherto~no
other~neurological~symptoms have been~added. Forasmuch as there~are~the
first Iranian cases of~Aceruloplasminemia~no previous research has been
done.

\textbf{Acknowledgment:}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{Authors list:}

\textbf{Farzad Ashrafi, MD}Functional Neurosurgery Research Center,
Shohada-e-Tajrish Neurosurgical Center of Excellence, Shahid Beheshti
University of Medical Sciences, Tehran, Iran. Email:
farzad.ashrafi@gmail.com

\textbf{Mehri Salari, MD}

Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical
Center of Excellence, Shahid Beheshti University of Medical Sciences,
Tehran, Iran. Email: mehri.salari@gmail.com

\textbf{Fatemeh Nouri *}Student Research Committee, School of Medicine,
Shahid Beheshti university of Medical Science, Tehran, Iran. Email:
mel29.nor@gmail.com

\textbf{Fatemeh Shiravi*}Student Research Committee, School of Medicine,
Shahid Beheshti university of Medical Science, Tehran, Iran. Email:
fatemeh.sh1996@gmail.com

*These authors contributed equally to the study and share corresponding
authorship.

\textbf{Corresponding author:}

Fatemeh Nouri * Student Research Committee, School of Medicine, Shahid
Beheshti university of Medical Science, Tehran, Iran. E-Mail:
mel29.nor@gmail.com

Tel: +98-21-22724214

ORCID: 0000-0001-6671-3845

Fatemeh shiravi* Student Research Committee, School of Medicine, Shahid
Beheshti university of Medical Science, Tehran, Iran.

E-Mail: fatemeh.sh1996@gmail.com Tel: +98-21-22724214 ORCID:
0000-0003-0751-7478

\textbf{Author Contributions:}

All authors have made substantial contributions to the conception and
design and acquisition of data and interpretation of data, and all of
them have been involved in drafting the manuscript or revising it
critically for important intellectual content. All the listed authors
have given final approval of the version to be published. They all
agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.

\textbf{Farzad Ashrafi, MD:} Conception, Organization

\textbf{Mehri Salari, MD:} Conception, Organization, Execution, Review
and Critique.

\textbf{Fatemeh Nouri *:} Writing of the first draft, Corresponding
author

\textbf{Fatemeh Shiravi*:} Writing of the first draft, Corresponding
author

*These authors contributed equally to the study and share corresponding
authorship.

\textbf{References}

1. Piperno A, Alessio M. 2018. Aceruloplasminemia: Waiting for an
Efficient Therapy. Front Neurosci.12:1--8.

2. Marchi G, Busti F, Zidanes AL, et al . 2019. Aceruloplasminemia: A
severe neurodegenerative disorder deserving an early diagnosis. Front.
Neurosci..13:1--8.

3. Doyle A, Rusli F, Bhathal P . 2015. Aceruloplasminaemia:A rare but
important cause of iron overload. BMJ Case Rep:1--4.

4. Yamamura A, Kikukawa Y, Tokunaga K, et al . 1905--1910. Pancytopenia
and myelodysplastic changes in aceruloplasminemia: A case with a novel
pathogenic variant in the ceruloplasmin gene. Intern Med 2018. 57:.

5. Miyajima H, Hosoi Y . Aceruloplasminemia Summary Genetic counseling.
University of Washington, Seattle.2019.

6. Hayashida M, Hashioka S, Miki H, et al . 2016. Aceruloplasminemia
with psychomotor excitement and neurological sign was improved by
minocycline (Case Report). Med (United States). 95:1--7.

7. Miyajima H . 2015. Aceruloplasminemia. Neuropathology. 35:83--90.

8. Roberti M do RF, Filho HMB, Gon\selectlanguage{ngerman}çalves CH, Lima FL . 2011.
Aceruloplasminemia: A rare disease - diagnosis and treatment of two
cases. Rev Bras Hematol Hemoter. 33:389--392.

9. Watanabe M, Ohyama K, Suzuki M, et al . 2018. Aceruloplasminemia with
abnormal compound heterozygous mutations developed neurological
dysfunction during phlebotomy therapy. Intern Med. 57:2713--2718.

10. Tai M, Matsuhashi N, Ichii O, et al . 2014. Case of presymptomatic
aceruloplasminemia treated with deferasirox. Hepatol Res. 44:1253--1258.

11. Vroegindeweij LHP, Langendonk JG, Langeveld M, et al . 2017. New
insights in the neurological phenotype of aceruloplasminemia in
Caucasian patients. Park Relat Disord. 36:33--40.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Case 1 & Case 2 & Normal Range\tabularnewline
\midrule
\endhead
white blood cell (/uL) & 5900 & 7900 & 4000-10800\tabularnewline
red blood cell (\selectlanguage{ngerman}×106/uL) & 4.64 & 5.11 & 3.8-5.2\tabularnewline
Hemoglobin (g/dL) & 10.6 & 11.90 & 11.5-16\tabularnewline
Hematocrit (\%) & 34.5 & 38.80 & 32-46\tabularnewline
mean corpuscular volume (fL) & 74.4 & 75.90 & 80-96\tabularnewline
mean corpuscular hemoglobin (pg) & 22.8 & 23.30 & 24-35\tabularnewline
Mean corpuscular hemoglobin concentration (\%) & 30.7 & 30.70 &
28-38\tabularnewline
Red blood cell distribution width (\%) & 19 & 17.50 &
\textless{}15\tabularnewline
erythrocyte sedimentation rate (mm/hr) & 10 & 10 & 0-30\tabularnewline
Fasting Blood Sugar (mg/dL) & 90 & 307 & 70-115\tabularnewline
Urea (mg/dL) & 21 & 29 & 15-45\tabularnewline
blood urea nitrogen (mg/dL) & 9.8 & 9.9 & 4-23\tabularnewline
Creatinine (mg/dL) & 0.8 & 0.8 & 0.5-1.3\tabularnewline
Serum copper (\selectlanguage{greek}μ\selectlanguage{english}g/dL) & 9 & 25 & 80-155\tabularnewline
Ceruloplasmin (mg/dL) & 6.4 & 6 & 15-60\tabularnewline
Ferritin (\selectlanguage{greek}μ\selectlanguage{english}g/L) & 1008.8 & 1460 & 5-73.3\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table:}

Laboratory Examinations

\textbf{Figure:}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure legend:}

\textbf{Figure. A, B} Magnetic resonance imaging (FLAIR) of \emph{case
1} : There were low-signal intensities in the bilateral lentiform
nuclei, caudate nuclei, and thalamus.

\textbf{Figure. C, D} Magnetic resonance imaging (T2/FLAIR) of\emph{case
2} : There were low-signal intensities in the bilateral lentiform
nuclei, caudate nuclei, thalamus, and cerebellar dentate nuclei.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/MRI/MRI}

\end{center}
\end{figure}

\selectlanguage{english}
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