\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Cerebrotendinous xanthomatosis and infertility: a case report}



\author[1]{Narges Karimi}%
\author[2]{Zahra Amiri}%
\author[2]{Sima Naeini}%
\author[2]{Ali Asghar Okhovat}%
\affil[1]{Mazandaran University of Medical Sciences}%
\affil[2]{Tehran University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Cerebrotendinous xanthomatosis is a lipid storage disorder that causes
neurological, ophthalmic, vascular, and musculoskeletal disorders due to
the deposition of cholesterol in the tissues. Hence, we report clinical
and imaging of a 31-year-old mentally retarded man with cerebellar
ataxia, bilateral swelling of the posterior aspect of Achill, and
infertility.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disorder of
lipid storage characterized by abnormal deposition of cholestanol and
cholesterol in multiple tissues, particularly in the brain and
tendons\textsuperscript{1}. Mutations in \emph{CYP27A1} lead to a
deficiency in sterol 27-hydroxylase \textsuperscript{2}. The deficiency
of this enzyme prevents cholesterol being converted into bile acid
chenodeoxycholic acid. The block in the synthesis of this bile acid
creates the accumulation of bile acid pathway intermediates and
cholestanol in the blood and tissues of the affected individuals. The
balance between synthesis and catabolism of cholesterol should be
tightly regulated to ensure normal cellular processes
\textsuperscript{3}. Up to now, more than 400 cases have been reported
worldwide \textsuperscript{4}. The clinical manifestations usually start
at infancy and develop during the first and second decades of life
\textsuperscript{4}. Patients with CTX demonstrate diverse
manifestations with multi-organ involvement and an extensive range of
neurological and non-neurological symptoms. The neurological features of
CTX reported in the literature include pyramidal and cerebellar signs,
sensory-motor peripheral neuropathy, intellectual disability, and
dementia. Common non-neurological disorder include early-onset bilateral
cataract in childhood, formation of tendon xanthomas (most often in the
Achilles' tendons), and diarrhea\textsuperscript{5,6}. In addition,
patients with CTX suffer from severe premature atherosclerosis,
pulmonary involvement, and osteoporosis with repeated bone fractures
\textsuperscript{7}. A diagnosis of CTX is made based on clinical
findings, biochemical testing, neuroimaging, and molecular genetic
analysis \textsuperscript{8,9}. This is the first report of a CTX
patient with infertility due to azoospermia.

\textbf{2. Case presentation}

A 31-year-old mentally retarded man was referred to our neurologic
clinic with a progressive gait disorder, impaired balance, and repeated
falling episodes. The patient was the third child of kinship marriage.
He was delivered following a normal term pregnancy with normal birth
weight and height. No history of atheromatous disease or intractable
infantile-onset diarrhea was distinguished. At the age of five, he
developed a blurred vision, which was diagnosed as a bilateral cataract.
The patient was a school dropout due to intellectual and
neuropsychiatric disability. He had developmental delays in the mental
functioning and speech with a normal physical growth. At the age of 20,
he developed bilateral tendinous swelling of the posterior part of the
ankles that became worse over time. He complained of severe gait
disturbance and ataxia since 3-4 years ago. He had frequent falling
episodes resulting in multiple bone fractures. Gait disorder progressed
gradually and he became non-ambulatory and wheelchair-bound. Physical
examination demonstrated bilateral and symmetrical painless hypertrophy
of the Achilles tendons (Fig.1). Neurological examination showed muscle
weakness predominant in the distal muscles of upper and lower limbs (MRC
score of 3 in the foot dorsiflexion and MRC score 2 in the finger
adduction and abduction), hypertonia, brisk deep tendon reflexes,
bilateral positive Babinski reflexes, and ankle clonus. The finger to
nose was normal but the heel to shin was abnormal bilaterally. The
laboratory results were normal for the thyroid, liver, and kidney
function, serum electrolytes, and triglyceride and cholesterol level. A
brain magnetic resonance imaging (MRI) discovered cerebral and
cerebellar atrophy, high-intensity areas in the dentate nuclei, and
symmetric hyperintensities in the cerebellar deep white matter and
paraventricular white matter on T2-weighted (T2W) and fluid-attenuated
inversion recovery (FLAIR) images with corresponding hypointensities on
T1-weighted (T1W) images (Fig. 2). Ultrasonography demonstrated focal
areas of hypoechogenicity on the bilateral Achilles tendons measuring 3,
7, 9, 12, and 16 mm on the right and 8, 15, 11, and 14 mm on the left
side. Whole exome sequencing identified a homozygous splicing mutation,
NM\_000784: exon3: c.465C\textgreater{}A; p. Tyr155* in
\emph{CYP27A1}gene compatible with a diagnosis of CTX. The patient was
married but he was infertile. Sex hormones tests were normal. Testicular
ultrasound showed that the size of the testes was in the lower limit of
normal range with a normal epididymis and vein plexus. Semen analysis
showed azoospermia. Analysis of the most common Y chromosome
microdeletions using multiplex polymerase chain reaction and gel
electrophoresis showed no microdeletions in AZFa, AZFb, and AZFc
sub-regions of the long arm of chromosome Y.

\textbf{3. Discussion}

Cerebrotendinous xanthomatosis is a rare autosomal recessive genetic
disorder in which cholesterol cannot be converted into bile acids due to
mutations in the CY27A1 gene that encodes the mitochondrial enzyme
sterol 27-hydroxylase \textsuperscript{3}. Half of the mutations in
CYP27A1 have been detected in exons 6--8, 16\% in exon 2, and 14\% in
exon 4 \textsuperscript{10,11}. The mean age at onset of clinical
manifestations has been reported 19 years, but most patients are
diagnosed late (about 35 years) \textsuperscript{12}. In our case, the
patient had developmental delays in mental functioning and speech with
neuropsychiatric disorders in childhood. In terms of clinical symptoms,
patients with CTX often manifest non-neurological and neurological
symptoms such as chronic diarrhea, cataracts, tendon xanthomas, ataxia,
corticospinal tract involvement, and mental disorder. The initial
presentation of non-neurological symptoms in our patient was a cataract
that was revealed at the age of 5 years. In this patient, a CYP27A1
mutation was identified in exon 3. The characteristic brain MRI findings
are T2/FLAIR hyperintensities in the bilateral dentate nuclei, adjacent
cerebellar white matter, basal ganglia, spinal cord, and periventricular
white matter as well as cerebellar atrophy. Our patient had T2/FLAIR
hyperintensities in the bilateral dentate nuclei, white matter
alternations, and cerebellar atrophy \textsuperscript{13--15}. One of
the symptoms in our case was infertility, which was not reported in
previous studies. The cause of infertility in this patient was
non-obstructive azoospermia due to a lack of spermatogenesis in the
testicles. The sex hormones, prolactin, and testosterone levels were
normal. Co-occurrence of azoospermia in CTX patients may be due to the
accumulation of cholesterol in the scrotum sac affecting spermatogenesis
and the function of the male reproductive system. Cholesterol has been
revealed to cause a reduction in sperm kinetics and has negative effects
on Leydig and Sertoli cells secretory capacity in rabbits. Previous
studies found that changed lipid metabolism in seminal plasma plays a
role in male infertility \textsuperscript{16--18}. Accumulation of
cholesterol in tissues is one of the obvious symptoms of CTX, but the
resultant functional abnormalities are unknown. The relationship between
infertility and cholesterol should be further investigated since it has
not been addressed so far.

\textbf{Conclusion}

CTX was diagnosed based on clinical manifestations, biochemical
analysis, neuroimaging, and molecular genetic investigation. One of the
detected disorders in our patient was infertility. To date, no study has
investigated the relationship between infertility and azoospermia with
CTX. The association between CTX and infertility is unclear. Further
research is warranted to investigate the association between azoospermia
and CTX.

\textbf{References}

1. Berginer VM, Salen G, Shefer S. Cerebrotendinous
xanthomatosis.\emph{Neurol Clin} . 1989;7(1):55-74.

2. Bj\selectlanguage{ngerman}örkhem I. Cerebrotendinous xanthomatosis. \emph{Curr Opin Lipidol}
. 2013;24(4):283-287. doi:10.1097/MOL.0b013e328362df13

3. Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid
biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous
xanthomatosis. \emph{J Biol Chem} . 1991;266(12):7779-7783.

4. Stelten BML, Dotti MT, Verrips A, et al. Expert opinion on
diagnosing, treating and managing patients with cerebrotendinous
xanthomatosis (CTX): a modified Delphi study. \emph{Orphanet J Rare Dis}
. 2021;16(1):353. doi:10.1186/s13023-021-01980-5

5. Atallah I, Millán DS, Benoît W, Campos-Xavier B, Superti-Furga A,
Tran C. Spinal cerebrotendinous xanthomatosis: A case report and
literature review. \emph{Mol Genet Metab Rep} . 2021;26:100719.
doi:10.1016/j.ymgmr.2021.100719

6. van Heijst AF, Wevers RA, Tangerman A, Cruysberg JR, Renier WO,
Tolboom JJ. Chronic diarrhoea as a dominating symptom in two children
with cerebrotendinous xanthomatosis. \emph{Acta Paediatr} .
1996;85(8):932-936. doi:10.1111/j.1651-2227.1996.tb14189.x

7. Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a
comprehensive review of pathogenesis, clinical manifestations,
diagnosis, and management. \emph{Orphanet J Rare Dis} . 2014;9:179.
doi:10.1186/s13023-014-0179-4

8. Patni N, Wilson DP. Cerebrotendinous Xanthomatosis. In: Feingold KR,
Anawalt B, Boyce A, et al., eds. \emph{Endotext} . MDText.com, Inc.;
2000. Accessed November 21, 2021.
http://www.ncbi.nlm.nih.gov/books/NBK395578/

9. Mignarri A, Gallus GN, Dotti MT, Federico A. A suspicion index for
early diagnosis and treatment of cerebrotendinous xanthomatosis. \emph{J
Inherit Metab Dis} . 2014;37(3):421-429. doi:10.1007/s10545-013-9674-3

10. Schneider H, Lingesleben A, Vogel HP, Garuti R, Calandra S. A novel
mutation in the sterol 27-hydroxylase gene of a woman with autosomal
recessive cerebrotendinous xanthomatosis. \emph{Orphanet J Rare Dis} .
2010;5:27. doi:10.1186/1750-1172-5-27

11. Lorbek G, Lewinska M, Rozman D. Cytochrome P450s in the synthesis of
cholesterol and bile acids--from mouse models to human
diseases.\emph{FEBS J} . 2012;279(9):1516-1533.
doi:10.1111/j.1742-4658.2011.08432.x

12. Pilo-de-la-Fuente B, Jimenez-Escrig A, Lorenzo JR, et al.
Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and
genetic survey. \emph{Eur J Neurol} . 2011;18(10):1203-1211.
doi:10.1111/j.1468-1331.2011.03439.x

13. Mehta BP, Shmerling RH. Teaching neuroimage: cerebrotendinous
xanthomatosis. \emph{Neurology} . 2008;71(2):e4.
doi:10.1212/01.wnl.0000316806.01406.74

14. Vanrietvelde F, Lemmerling M, Mespreuve M, Crevits L, De Reuck J,
Kunnen M. MRI of the brain in cerebrotendinous xanthomatosis (van
Bogaert-Scherer-Epstein disease). \emph{Eur Radiol} .
2000;10(4):576-578. doi:10.1007/s003300050964

15. Mignarri A, Dotti MT, Del Puppo M, et al. Cerebrotendinous
xanthomatosis with progressive cerebellar vacuolation\selectlanguage{english} : six-year MRI
follow-up. \emph{Neuroradiology} . 2012;54(6):649-651.
doi:10.1007/s00234-012-1026-8

16. Diaz-Fontdevila M, Bustos-Obregon E, Fornes M. Distribution of
filipin-sterol complexes in sperm membranes from hypercholesterolaemic
rabbits. \emph{Andrologia} . 1992;24(5):279-283.
doi:10.1111/j.1439-0272.1992.tb02653.x

17. Yamamoto Y, Shimamoto K, Sofikitis N, Miyagawa I. Effects of
hypercholesterolaemia on Leydig and Sertoli cell secretory function and
the overall sperm fertilizing capacity in the rabbit. \emph{Hum Reprod}
. 1999;14(6):1516-1521. doi:10.1093/humrep/14.6.1516

18. Sebastian SM, Selvaraj S, Aruldhas MM, Govindarajulu P. Pattern of
neutral and phospholipids in the semen of normospermic, oligospermic and
azoospermic men. \emph{J Reprod Fertil} . 1987;79(2):373-378.
doi:10.1530/jrf.0.0790373

Figure 1. Swelling on the posterior aspect of left Achill tendon

Figure 2. Axial image of brain MRI showing bilateral FLAIR hypersignal
of the dentate nuclei and periventricular\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fig-1/fig-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fig/fig}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

