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This retrospective, single-center review of 40 patients undergoing allogeneic HSCT
for MLD is the largest to date. In this study, we aimed to characterize survival and
long-term functional outcomes associated with transplantation. The estimated survival
at 5 years post-HSCT was 59 %. Survival did not depend on the MLD subtype classification
of the patient, nor did it depend upon the presence of symptoms at the time of transplant.
In general, previous studies and case reports have documented improved survival outcomes
for transplants performed pre-symptomatically or in those with older age at disease
onset 7]–9], 11], 12]. However, our data suggest that allograft source may play a more significant role. Not surprisingly, a trend towards improved survival was seen for those who received
HLA-matched sibling marrow grafts. For patients receiving unrelated donor grafts,
survival following UCB transplantation appeared favorable as has been previously reported
7]. Most deaths in our cohort occurred from treatment-related complications within the
first year of transplant and comparatively few patients died due to progressive MLD.
It is difficult to know whether the relatively high incidence of TRM at 6 months (23 %)
is dependent to any degree upon the diagnosis of MLD itself. Importantly, a significant
fraction of the cohort was treated in an era when HSCT was riskier, regardless of
the underlying disease necessitating transplant. With advances in donor-recipient
HLA typing and matching, pathogen detection, antimicrobial therapies, busulfan targeting
and allograft availability, it is likely that a similar cohort transplanted in the
current era would demonstrate less TRM.

Five patients underwent RIC transplantation according to existing institutional protocols
available at the time of treatment. While no TRM was observed for these 5 patients,
2 (40 %) experienced autologous hematopoietic recovery. Even for those who demonstrated
donor engraftment, an essential question that cannot be answered in this analysis
due to insufficient numbers of evaluable long-term survivors is whether the agents
and doses employed in transplant conditioning might impact long-term neurologic outcomes.
While a rational argument can be made for the use of CNS-sparing regimens for transplantation
of neuropathic metabolic disorders, recent pre-clinical data suggest that HSCT conditioning
using CNS penetrating agents, in particular high-dose busulfan, improves donor-derived
microglial engraftment which may then be essential for metabolic cross-correction
within the CNS 31], 32]. It is perhaps noteworthy that all fatal veno-occlusive disease of the liver (n?=?3)
in our cohort occurred following busulfan-based conditioning, as MLD can be associated
with abnormalities of the biliary system 3]. However, this complication may be expected to be less frequent in the era of therapeutic
busulfan monitoring, as data from a more modern MLD transplant cohort is notable for
an absence of morbidity from veno-occlusive disease 7].

It is difficult to assess whether transplantation provided a survival advantage compared
to natural history for patients within our cohort who did not die from transplant-related
causes. Perhaps the largest analysis for untreated MLD survival is provided by a recent
literature meta-analysis of 98 LI-MLD, 78 J-MLD, and 127 A-MLD patients 33]. In that report which recognized variability in the “definition” of disease subtypes,
the estimated J-MLD survival probability was 50 % at approximately 10 years following
MLD symptom onset. Among 16 J-MLD patients in our cohort who did not die from transplant-related
causes, 2 have died from progressive MLD at 8 years and 5 years following initial
disease onset. Fourteen J-MLD patients survive at a median most recent follow-up of
14.5 years following first symptoms (or from when symptoms would be anticipated based
on proband sibling history). Comparison of LI-MLD and A-MLD is difficult owing to
relatively small numbers within our cohort.

Long-term neurologic function remains a highly relevant outcome following any therapeutic
intervention for MLD. Despite this, relatively few robust, prospective, longitudinal
natural history descriptions exist for MLD. Biffi et al provided perhaps the most thorough such analysis with their assessment of 26 primarily
LI-MLD and J-MLD patients in which they catalogued performance on detailed motor and
neuropsychological scales over time 34]. The retrospective nature of our analysis did not allow for such high-resolution
longitudinal assessments of our cohort. However, investigators with the German LEUKONET
group have recently developed and applied simpler scales to describe the decline of
gross motor and expressive language function in large, untreated LI-MLD and J-MLD
cohorts 20]–22]. Importantly, their GMFC-MLD and ELFC-MLD tools were designed for either prospective
or retrospective assessment of an individual patient over time.

For this analysis, we used detailed longitudinal clinical neurology notes or, when
possible, recent parental telephone interviews to assess individual performance on
the GMFC-MLD and ELFC-MLD scales for long-term survivors. Only two surviving patients
in our transplanted MLD cohort fit late-infantile classification as employed by the
LEUKONET natural history study, One of these LI-MLD patients (ID3), pre-symptomatic
at transplant, showed rapid decline similar to natural history expectations as described
by the LEUKONET group. The other (ID2), also pre-symptomatic at transplant, demonstrated
more protracted motor decline post-HSCT compared to that reported in the large LEUKONET
LI-MLD cohort (Fig. 3) 20]. Similarly, Brazilian investigators documented a relatively large LI-MLD natural
history cohort, but included all children who became symptomatic before the age of
48 months. When extrapolated to the GMFC-MLD scale, reported mean ages at entry to
motor levels 3, 5 and 6 were 26, 27 and 25.6 months, respectively, for their untreated
“late-infantile” patients 17]. In contrast, when considering all four long-term survivors in our transplanted cohort
who met this definition for “late-infantile” MLD applied to the Brazilian cohort (ID2,
3, 4 and 9) the ages to entry into the same motor levels were 70, 86, and 137 months,
respectively. These findings suggest that HSCT may attenuate the steep motor decline
for some LI-MLD patients, even though all such transplanted patients in our cohort
ultimately experienced severe motor dysfunction.

Only one long-term surviving LI-MLD patient in our cohort (ID3) was evaluable for
expressive language function compared to existing natural history description by LEUKONET.
She showed a similar trend compared to untreated patients with perhaps modest prolongation
of expressive language function 22]. When extrapolated to the ELFC-MLD tool, the large Brazilian “late-infantile” cohort
appeared to enter level 4 at a mean age of 25.4 months 17]. For three evaluable long-term survivors in our transplanted cohort meeting the same
definition of “late-infantile” applied in the Brazilian analysis, the mean age at
entry into level 4 was 74.5 months (with one patient, ID4, still expressing single
word ideas at 34 years of age). Again, these findings suggest that HSCT might modestly
blunt the rapid expressive language deterioration in untreated very early-onset MLD,
even as all such transplanted patients in our cohort ultimately experienced severe
expressive language dysfunction.

As expected given their propensity to have a slower natural history decline, our J-MLD
patients showed better preservation of motor and expressive language function following
HSCT when compared to LI-MLD counterparts . A relatively large number of long-term
J-MLD survivors (n?=?13) were evaluable for gross motor and expressive language functioning
at a median age of 23 years at the most recent assessment. Of this J-MLD group, 7
patients, all symptomatic at the time of transplant, demonstrated motor decline following
HSCT similar to that described by J-MLD natural history cohorts 5], 17]. Interestingly, relative preservation of expressive language was seen for these same
patients at the same time. In contrast, other J-MLD patients, particularly those who
were pre-symptomatic or only had mild deficits at transplantation, demonstrated gradual
or no loss on the GMFC-MLD and ELFC-MLD scales.

The relative preservation of skills and increased variability of response to HSCT
in J-MLD may be due to the greater phenotypic variation within this subtype. Therefore,
when comparing performance on the LEUKONET scales between the transplanted and reported
non-transplanted J-MLD groups, it may be most useful to assess the age of entry into
early levels of motor and expressive language dysfunction which would represent more
subtle disability. While 2 J-MLD patients in the cohort continue to show no evidence
of motor dysfunction at last follow-up, 11 have entered into motor levels 1 and 2
(Fig. 1) at mean ages of 139 and 167 months, respectively. In contrast, the LEUKONET group
reported median entry for untreated J-MLD into the same levels at 64.5 and 91 months,
respectively 20]. Comparison with the small number of J-MLD patients reported in the Brazilian natural
history study also suggests superior motor performance for transplanted J-MLD patients
in our cohort 17].

Expressive language function of the transplanted J-MLD group also appeared better
than reports for untreated counterparts. While the LEUKONET group reported 50 % of
their untreated J-MLD cohort having first evidence of language decline (E1-50 %) at
approximately 90 months of age, our surviving transplanted cohort of 13 reached E1-50 %
at age 105 months 22]. Furthermore, LEUKONET data revealed 50 % of the J-MLD natural history cohort experienced
a total loss of expressive language (E4-50 %) at age 150 months 22]. In contrast, in our transplanted cohort only 4 of 13 evaluable J-MLD patients (31 %)
have fully lost expressive language at an average age of 147 months. Importantly,
the mean age at most recent follow-up for the remaining 9 transplanted J-MLD patients
with functioning level E3 or better is 287 months. Overall, the aggregate motor and
expressive language function over time of evaluable J-MLD patients in our transplanted
cohort appears to be favorable when compared to previous natural history reports.

Neuroradiographic and neurophysiologic outcomes following HSCT for our cohort generally
mirror those reported by others 35], 36]. Lack of access to consistent, primary source data and images precluded our ability
to provide longitudinal quantitative description. By qualitative assessment, most
patients demonstrated relatively stable brain MRI white matter disease over time.
Some patients, particularly in the LI-MLD group, showed improvement following HSCT,
though this may have reflected developmental myelination rather than transplant effect.
J-MLD patients were most likely to show myelin loss following transplant, but the
reason for this is unclear. What is more evident is that the stabilization of MRI
findings did not equate to stabilization of peripheral nerve disease. With very few
exceptions, NCV scores followed serially throughout the pre- and post-transplant course
were conspicuous for a frequent decline over time, even if MRIs performed at the same
point in time were similar or better than previous exams (Fig. 5). These collective findings appear to support previous reports and speculations that
ARSA secretion by hematopoietically-derived cells of donor origin may more favorably
impact central nervous demyelination compared to peripheral nervous system disease
15], 37], 38].

Long-term adaptive behavior functioning and cognitive outcome data after HSCT for
MLD are sparse in the medical literature. In our cohort, most long-term survivors
had adaptive behavior functioning data captured by the composite VABS score across
multiple pre- and post-transplant time points. An inherent advantage of this tool
is its reliability in assessing function remotely. Indeed, by parental telephone survey
we were able to evaluate 12 long-term survivors in our cohort for current adaptive
behavior functioning at a median post-HSCT follow-up of more than 13 years. Although
some LI-MLD and J-MLD patients initially displayed adaptive behavior functioning trajectories
within a normal range, almost all patients eventually plateaued and then regressed.
All evaluable A-MLD patients in the cohort were symptomatic at the time of HSCT and
showed relatively stable, although abnormally low, adaptive behavior functioning over
time. In contrast to adaptive behavior functioning, longitudinal VIQ appeared to demonstrate
less dramatic decline over time for evaluable patients. This finding perhaps also
supports relative sparing of central nervous system function, as compared to peripheral
nervous system function, following transplant for MLD.

As parents and clinicians consider the utility of HSCT for MLD, they may wish to weigh
quality-of-life and daily functioning aspects of patients’ post-transplant courses.
Tables 3 and 4 show intriguing data characterizing these outcomes. In this study we used the Cornell-Brown
Scale, as it has been designed for proxy (parent/caregiver) assessment of quality-of-life
in patients with dementing disorders. Of 12 evaluable long-term survivors, 11 had
positive (greater than zero) total scores suggesting a favorable quality-of-life.
Furthermore, many J-MLD and A-MLD patients retained the ability to independently perform
a wide array of ADLs many years after transplant. Although no robust published data
addressing these aspects of untreated MLD patients exist for comparison, these findings
may provide more concrete evidence which parents might utilize in making the difficult
decision to have their child with MLD undergo transplant. We ultimately asked parents
if they were satisfied with their decision to have their child undergo HSCT for MLD.
All 11 respondents (100 %) answered affirmatively at a median follow-up of over 12 years
following transplant. Interestingly, over half of these responding parents had another
child with MLD, many of whom were either not transplanted (due to advanced disease
at diagnosis) or underwent transplantation but died due to treatment-related complications.

Marked variation in MLD phenotypes, even within a subtype classification, have greatly
hampered the ability to generalize outcomes following treatment. Although intra-familial
disease behavior can also vary, it may be less likely to do so. As such, sibling cohort
comparisons might allow for optimal assessment of intervention efficacy 8], 12], 39], 40]. Therefore, we described outcome data for all available sibling pairs in which at
least one sibling underwent transplant in our cohort (Table 5). Of 5 total dyads, 3 consisted of one treated and one untreated sibling; in all
cases, the treated patient has survived their deceased sibling by a significant margin.
Expressive language and ADL function were notably superior for all transplanted patients
as well. For one LI-MLD pair (A), our transplant cohort member experienced more rapid
motor decline compared to her non-transplanted sibling. The reason for this is unclear
but may stem from transplant-related toxicity as the decline was immediately following
HSCT. It should be noted, however, that this patient demonstrated prolonged preservation
of expressive language function compared to her untreated sibling and is still alive
nearly 15 years longer than she might presumably be without transplant. For the sibling
pairs in which both were transplanted, the pre-symptomatic siblings continue to demonstrate
significantly greater retention of function compared to their symptomatic counterparts,
again reflecting the importance of transplant in delaying disease progression. In
one such sibling dyad, J-MLD pair E, both sisters were transplanted in our cohort.
While both patients survive to date, patient ID22 (pre-symptomatic at HSCT) has shown
a dramatically superior clinical course characterized by normal-for-age motor, expressive
language, ADL, and adaptive functioning. Although she experiences seizures, at age
21 years she is pursuing a university degree. In contrast, her sister, symptomatic
at transplant, showed relatively significant decline over the same period. In the
other such dyad, J-MLD pair D, the symptomatic familial proband (ID17) underwent transplant
in our cohort, while her brother was transplanted while pre-symptomatic at another
center. He continues to demonstrate superior function in motor, expressive language
and ADL performance when compared to his sister. In summary, these sibling pair data
suggest utility in HSCT for MLD and highlight the dramatic benefit that HSCT may provide
when performed pre-symptomatically in J-MLD.

While our study provides a relatively robust characterization of various outcomes
following HSCT for MLD, there are several recognized limitations. First, owing to
the relatively high prevalence of the ARSA pseudodeficiency allele, it is important to acknowledge that low ARSA activity alone
is not sufficient to diagnose MLD. Exclusion of other rare demyelinating disorders
(with coincidental ARSA pseudodeficiency carriage) is typically achieved by the demonstration
of hyper-excretion of accumulating substrate (urine sulfatide assessment), pathognomonic
histopathology on nervous tissue biopsy, or/and presence of causative ARSA mutations on molecular analysis 30]. Very few patients in our cohort had evaluable histopathologic or ARSA mutation data for confirmation of MLD diagnosis. All 40 patients included in our
analysis had either primary or secondary source documentation of elevated urine sulfatide
excretion to implicate MLD as causative of their low ARSA activity and personal or
family history of leukodystrophy. As well, patients for whom only secondary source
data exists for confirmation of MLD diagnosis are cautiously included in this analysis.

The span of time encompassed in this cohort, nearly three decades, carries with it
certain inherent analytic risks and biases. Some data, especially before electronic
medical records were widely available, were not as readily collected or evident in
paper charts. Yet all attempts were made to track down any data through all resources
available. While quantifiable assessment of longitudinal changes in the neuroradiographic
and neurophysiologic burdens of MLD are ideal, the lack of retrospective access to
consistently obtained, primary source data relegated our analysis to a qualitative
one. We were also limited in terms of longitudinal data by difficulties in contacting
family members of survivors. However, over half of the families were reached and were
willing to participate, some of them decades out from their transplant. Since MLD
is a very rare disease and it is even rarer to present in time to be a candidate for
transplant, this participation was encouraging and important for analysis of long-term
outcomes. The potential exists for recall bias in regards to the retrospective assessment
of GMFC-MLD, ELFC-MLD and ADL skills. Yet we recognize that the exact timing of when
these abilities were lost is less important than the general trends of skill retention.
It must also be noted that all of these skills gradually diminish over time rather
than abruptly change which can limit precision. Still, existing natural history data
has similarly relied on retrospective parental assessments 20], 22].

Though our data add to existing evidence suggesting utility in HSCT for MLD, it is
also clear from both this and previous analyses that transplantation is generally
not expected to fully abrogate disease manifestations. And though it would be intriguing
to formally assess the effects of graft source, conditioning regimen, age, symptom
status and degree of donor hematopoietic engraftment on functional outcomes following
transplant for MLD, the small number of evaluable patients in our cohort along with
relative homogeneity of outcomes precluded such formal analysis. Still, the limits
of HSCT are particularly evident in LI-MLD, even when the child is treated prior to
clinically evident disease. Clearly, novel treatment strategies are needed that could
be used independently of transplantation or in association with it. A recent report
documented the utility of genetically corrected autologous hematopoietic stem cell
therapy in a small MLD case series; larger systematic gene therapy studies are ongoing
41]. And although broad-population newborn screening is attractive for the purpose of
very early intervention, several unique aspects of MLD present significant challenges
to identifying those newborns with true “disease” 42].