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.
Disclosure – All authors have nothing to declare