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\begin{document}

\title{Successful Umbilical Cord Blood Stem Cell Transplantation for
Pelizaeus-Merzbacher Disease}



\author[1]{Neha Rastogi}%
\author[1]{Yeeshu  Sudan}%
\author[1]{Satya Yadav}%
\affil[1]{Medanta The Medicity}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\begin{abstract}
Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive
leukodystrophy caused by mutations in the proteolipid protein-1 gene on
the Xq22.2 chromosome and is characterized clinically by nystagmus,
spastic quadriplegia, ataxia and developmental delay. There is no
definitive curative treatment. We report here a successful matched
unrelated umbilical cord blood stem cell transplantation for PMD in a
2-year-old boy. He was conditioned with Busulfan, Cyclophosphamide and
Rabbit anti-thymoglobulin. MMF and Cyclosporine were used as
graft-vs-host disease prophylaxis. His neutrophil engrafted on day+29
and platelets on day+33. It lead to disease stabilisation and
improvement in development of the child with PMD.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive
leukodystrophy caused by mutations in the proteolipid protein-1 (PLP1)
gene on the Xq22.2 chromosome (1,2). The primary biological deficiency
in affected patients with PMD is the failure of oligodendrocytes to
properly myelinate axons, resulting in axonal degeneration and
neurological dysfunction (1). More than 50\% of cases are caused by
duplication of a genomic region, including the entire PLP1 gene (2,3).
PMD is characterized clinically by nystagmus, spastic quadriplegia,
ataxia, and developmental delay (1). There is no definitive curative
treatment. We report here a successful matched unrelated umbilical cord
blood stem cell transplantation (UCBT) for PMD in a 2-year-old boy.

\textbf{Methods}

A 2-year-old Russian boy, first child of non-consanguineous parentage,
presented to us with global developmental delay. Child had a history of
prolonged seizures at 1\selectlanguage{ngerman}½ years of age and was symptomatically managed in
his native country. Subsequently child had total 5 episodes of right
sided focal seizures. On examination, he had hypotonia, unable to stand
or walk, no speech and had developmental delay (developmental age was 10
months at 2-years of age) with no evidence of dysmorphism or
neurocutaneous markers. Magnetic resonance imaging (MRI) of brain
revealed symmetrical and widespread abnormality of the white matter of
the cerebrum, brainstem, and cerebellum.~ Computerised tomography scan
of head showed agenesis of corpus callosum \& cerebellar vermis along
with moderate ventriculomegaly. Genetic testing showed PLP-1 gene
duplication confirming diagnosis of PMD. He then underwent an UCBT from
a 10/10 matched unrelated cord at our centre. Parents gave written
informed consent before transplant. Myeloablative conditioning was used
with Busulfan day-9 to -6 (3.2mg/kg/day), Cyclophosphamide day-5 to -2
(50mg/kg/day), Rabbit anti-thymoglublin day-3 to -1 (2.5mg/kg/day) and
Rituximab on day-8 (100mg/m2). Cord blood stem cell (CD34+) dose was 0.2
million/kg. Mycophenolate mofetil (MMF) and Cyclosporine were used as
graft-vs-host disease (GVHD) prophylaxis.

\textbf{Results}

His neutrophil engrafted on day+29 and platelets on day+33.
Post-transplant on day+30 he had reactivation of Cytomegalovirus and BK
virus along with haemorrhagic cystitis which was managed successfully.
On day+53, he had an episode of hematemesis and melena with sudden drop
in hemoglobin. Upper and lower gastrointestinal endoscopies were
performed. Biopsies were suggestive of MMF induced enterocolitis which
resolved after discontinuation of MMF. Chimerism on day+32, day+56 and
day+100, 1-year and 2-years was fully donor. There was no evidence of
acute or chronic GVHD. His further post-transplant period was
uneventful. Neurodevelopmental assessment was done at 12 months and 24
months post-transplant which showed overall improvement in all domain of
development. His motor skills improved, he can walk independently, run
with infrequent falls and climb stairs. Child could speak in sentences
play with blocks and follow instructions and had better social
communications skills. No further seizures were recorded
post-transplant. At present child is more than two years post-transplant
and has developmental age of 3 years at 4 years of age. MRI of brain
24-months post UCBT has shown no change in myelination.

\textbf{Discussion}

In this report, we have described the clinical outcome of PMD after UCBT
in a young boy. There was initial stabilization followed by improvement
in neurological symptoms. There are mainly two clinical phenotypes of
PMD - conatal and classic. Conatal~PMD refers to the most severe form of
the disease, with symptoms appearing at birth or within few weeks of
life. These patients have severe stridor, seizures, hypotonia which
later on develops to spasticity, dystonia and inability to walk or talk.
The other form, classic PMD, is milder and presents with nystagmus at 2
to 6 months of age (1). Our patient although presented at 18-months of
age but had severe symptoms -hypotonia, seizures and had developmental
delay at presentation. MRI brain of PMD patients showed diffuse pattern
of hypomyelination. Affected white matter regions include the cerebral
hemispheres, cerebellum, and brainstem. Thinning of the corpus callosum
and atrophy of the cerebral hemispheres is sometimes seen. Since this is
a rare disease, formal natural history studies are lacking.

There are no curative treatments available. Various researchers have
used different strategies. Although UCBT has been used to treat many
inherited metabolic disorders but only recently, it has been
investigated in PMD patients. Wishnew et al. demonstrated neurological
improvement in two patients aged 9 months and 29 months respectively who
underwent UCBT for PMD in their centre. With 7-year and 1-year
follow-up, they showed stabilization of disease with significant gains
in cognitive skills and modest gains in motor development along with
stable engraftment. MRI results also suggested interval myelination in
these patients (4). Our patient is now more than 24-months post UCBT and
has shown overall good improvement in all domain of development. Child
can walk, speak, play and follow instructions. No further seizures were
recorded post-transplant. Post-transplant MRI in our case has not shown
much change in myelination.

Gupta et al. reported a 1-year open-label phase 1 study undertaken to
evaluate safety and to detect evidence of myelin formation after human
central nervous system stem cells (HuCNS-SC) transplantation. Allogeneic
HuCNS-SCs were surgically implanted into the frontal lobe white matter
in four male subjects with an early-onset severe form of PMD. Modest
gains in neurological function were observed in three of the four
subjects (5). Further follow up of these 4 children for another 4-years
has been reported recently. At year 2, all subjects exhibited diffusion
MRI changes at the implantation sites as well as in more distant brain
regions. There were persistent, increased signal changes in the three
patients who were studied up to year 5. Two of four subjects developed
donor-specific HLA alloantibodies, demonstrating that neural stem cells
can elicit an immune response when injected into the CNS (6). Osorio et
al. reviewed the use of various stem cells in the treatment of PMD
without any breakthrough success (7). Our case has achieved better
developmental milestones as compared to all the reported cases in
literature; 2 post UCBT and 4 post HuCNS-SC who had minimal to modest
improvement. In conclusion, UCBT lead to disease stabilisation and
improvement in development of the child with PMD. Long-term follow up of
our case is needed.

\textbf{Disclosure} -- All authors have nothing to declare

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Hobson GM, Garbern JY. Pelizaeus-Merzbacher disease,
  Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating
  disorders. Semin Neurol. 2012 Feb;32(1):62-7.
\item
  Yamamoto T, Shimojima K. Pelizaeus-Merzbacher disease as a chromosomal
  disorder. Congenit Anom (Kyoto). 2013 Mar;53(1):3-8.
\item
  Hoffman-Zacharska D, Mierzewska H, Szczepanik E, Pozna\selectlanguage{polish}ń\selectlanguage{english}ski J,
  Mazurczak T, Jakubiuk-Tomaszuk A, M\selectlanguage{polish}ą\selectlanguage{english}dry J, Kierdaszuk A, Bal J. The
  spectrum of PLP1 gene mutations in patients with the classical form of
  the Pelizaeus-Merzbacher disease. Med Wieku Rozwoj. 2013
  Oct-Dec;17(4):293-300.
\item
  Wishnew J, Page K, Wood S, Galvin L, Provenzale J, Escolar M,
  Gustafson K, Kurtzberg J. Umbilical cord blood transplantation to
  treat Pelizaeus-Merzbacher Disease in 2 young boys. Pediatrics. 2014
  Nov;134(5):e1451-7.
\item
  Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E,
  Gaetano L, Mandelli ML, Ryan T, Perry R, Farrell J, Jeremy RJ, Ulman
  M, Huhn SL, Barkovich AJ, Rowitch DH. Neural stem cell engraftment and
  myelination in the human brain. Sci Transl Med. 2012 Oct
  10;4(155):155ra137.
\item
  Gupta N, Henry RG, Kang SM, et al. Long-Term Safety, Immunologic
  Response, and Imaging Outcomes following Neural Stem Cell
  Transplantation for Pelizaeus-Merzbacher Disease.~\emph{Stem Cell
  Reports} . 2019;13(2):254-261. doi:10.1016/j.stemcr.2019.07.002
\item
  Osorio MJ, Rowitch DH, Tesar P, Wernig M, Windrem MS, Goldman SA.
  Concise Review: Stem Cell-Based Treatment of Pelizaeus-Merzbacher
  Disease. Stem Cells. 2017 Feb;35(2):311-315.
\end{enumerate}

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