Molecular Genetics and Metabolism 122 (2017) 1–7

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Molecular Genetics and Metabolism

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Developmental and behavioral aspects of mucopolysaccharidoses with brain T

manifestations — Neurological signs and symptoms
⁎
Elsa G. Shapiroa,b, , Simon A. Jonesc, Maria L. Escolard
a
Shapiro Neuropsychology Consultants, LLC, Portland, OR, USA
b
Departments of Pediatrics and Neurology, University of Minnesota, Minneapolis, MN, USA
c
Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre, University of Manchester, CMFT, Manchester,
United Kingdom
d
Program for the Study of Neurodevelopment in Rare Disorders, Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of
UPMC, Pittsburgh, PA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders, caused by muta-
Mucopolysaccharidoses tions in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). The resulting accumu-
Lysosomal storage diseases lation of GAGs in the body leads to widespread tissue and organ dysfunction. The spectrum, severity, and
Neurobehavioral manifestations progression rate of clinical manifestations varies widely between and within the different MPS types. In addition
Cognition disorders
to somatic signs and symptoms, which vary between the different MPS disorders, patients with MPS I, II, III, and
VII present with significant neurological signs and symptoms, including impaired cognitive abilities, difficulties
in language and speech, and/or behavioral and sleep problems. To effectively manage and develop therapies that
target these neurological manifestations, it is of utmost importance to have a profound knowledge of their
natural history and pathophysiology. This review describes the appearance and progression of neurological signs
and symptoms in patients with MPS I, II, and III, based on presentations and discussions among an international
group of experts during a meeting on the brain in MPS on April 28–30, 2016, and additional literature searches
on this subject.

1. Introduction cognitive development is rarely detected in the first year of life, as a

course of normal development usually precedes symptoms [1]. There-
The mucopolysaccharidoses (MPS) are comprised of seven rare ly- fore, diagnosis of MPS I, II, and VII is mostly triggered by the appear-
sosomal storage disorders caused by deficiencies in lysosomal enzymes ance of somatic symptoms. Diagnosis of MPS III is usually delayed until
involved in the degradation of glycosaminoglycans (GAGs). The re- 2 to 4 years of age, or even later, due to the lack of somatic symptoms
sulting accumulation of GAGs causes widespread tissue and organ da- and/or a misdiagnosis of autism, as patients can show autistic-like be-
mage. All MPS disorders are inherited in an autosomal recessive havior [6–10]. The profound and life-limiting nature of neurocognitive
manner, except MPS II which is X-linked and therefore predominantly problems in MPS patients warrant early diagnosis and treatment, to
affects males. There is a wide spectrum of clinical manifestations and limit irreversible neurological damage. An accurate description of the
progression rates between and within MPS disorders [1,2]. Depending natural history of neurological manifestations in these patients can help
on the type, somatic manifestations of MPS may include skeletal and in the early identification of patients, the design of clinical studies, and
joint abnormalities, coarse facial features, hepatosplenomegaly, ob- the development of effective therapies.
structive and restrictive respiratory disease, cardiac (valve) disease, The present review focuses on the appearance and progression of
impaired vision and/or hearing, and dental abnormalities [2]. Neuro- neurological signs and symptoms in patients with MPS I, II, and III. Its
logical and/or behavioral abnormalities are observed in MPS disorders content is based on presentations and discussions during a closed expert
associated with accumulation of heparan sulfate (HS), i.e. MPS I, II, III, meeting about the brain in MPS on April 28–30, 2016, in Stockholm,
and VII, and can include aggressive and hyper/overactive behavior, Sweden, and additional literature searches. During the meeting, 39
sleep problems, and global development delay and decline in mile- international experts in MPS and neurology reviewed and discussed
stones (including language and cognitive ability) [1,3–5]. Abnormal existing relevant literature and clinical data on neurological signs and

⁎
Corresponding author at: 820 NW 12th Ave, Portland, OR 97209, USA.
E-mail address: [email protected] (E.G. Shapiro).

https://doi.org/10.1016/j.ymgme.2017.08.009
Received 31 May 2017; Received in revised form 23 August 2017; Accepted 23 August 2017
Available online 26 August 2017
1096-7192/ © 2017 Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
E.G. Shapiro et al. Molecular Genetics and Metabolism 122 (2017) 1–7

Fig. 1. Physical features of patients with MPS I and III.

symptoms in MPS I, II, and III. MPS VII was not discussed because of its mostly in MPS IH [26], and generally associated with impaired cogni-
extreme rarity [11], and is therefore not included in this review. Ad- tion [15]. Communicating hydrocephalus (with associated increased
ditional relevant literature was obtained from PubMed searches with head circumference) can be observed early in MPS I, and may trigger
search terms “Mucopolysaccharidoses” [Mesh] AND “cognition” (44 diagnosis. It is likely due to ineffective cerebrospinal fluid (CSF) re-
items) and “Mucopolysaccharidoses” [Mesh]) AND “behavior” AND absorption (related to problems in the venous part of the vascular
Species = Humans (66 items). Publications on animal studies or not system or the meninges) [27–29]. Hydrocephalus is often associated
available in English were excluded. Searches were performed without with increased intracranial pressure that may require shunting
date restriction. Additional publications were identified from reference [24,29,30]. In addition, patients may show atrophy, ventriculomegaly,
lists within the most relevant MPS-related papers focusing on neuro- and enlargement of perivascular spaces (PVS) in the subcortical and
logical signs and symptoms. The literature search was completed in periventricular white matter, basal ganglia, corpus callosum, thalami,
August 2016. and brainstem [26,29]. Treatment with HSCT can prevent CNS damage
[20,21] and hydrocephalus [15,22–24] and reduce spinal cord com-
pression [15,24].
2. MPS I

In MPS I, deficiency of α-L-iduronidase (EC 3.2.1.76) leads to ac-

2.2. Neurocognitive development
cumulation of dermatan sulfate (DS) and HS [1,12]. Frequently ob-
served somatic symptoms include coarse facial features (Fig. 1), hepa-
MPS IH patients typically show cognitive decline and/or a delay in
tomegaly, corneal clouding, and cardiac valve abnormalities, although
speech and language milestones. In many MPS IH patients, cognitive
the occurrence and severity of these symptoms differ from patient to
ability (measured with the mental development index or intelligence
patient [13]. There are 3 subtypes: Hurler (MPS IH), Hurler-Scheie
quotient [IQ] score) is more than two standard deviations below the
(MPS IH/S), and Scheie (MPS IS), which can be distinguished based on
mean (indicative of impairment) by the age of 2 years. Cognition
clinical phenotype [1,2]. MPS IH, the severe form of MPS I, is asso-
reaches a plateau by 2 to 4 years of age, followed by rapid deterioration
ciated with cognitive impairment, rapid disease progression, and early
with aging (Fig. 2) [5,15,31]. This progressive decline can be halted by
mortality (often during childhood) [13,14]. Somatic symptoms such as
HSCT, which leads to stabilization of IQ [15]. Even after HSCT, a re-
gibbus, recurrent ear infections, and umbilical or inguinal hernias can
lationship between greater white and gray matter volumes and a higher
be observed in the first year of life, prompting early diagnosis [13,14].
IQ, as observed in normal control subjects, was not found in MPS IH
Patients with MPS IS and MPS IH/S (the intermediate phenotype)
patients. This suggests that the cognitive decline in MPS I is associated
generally show milder or no cognitive involvement, milder somatic
with abnormal cortical white and gray matter development [15].
symptoms, and slower disease progression [1,13,15].
MPS IH patients only attain limited language skills in the first two
The majority of MPS IH patients are treated with hematopoietic
years of life, probably due to a combination of developmental delay and
stem cell transplantation (HSCT) [16] as it halts cognitive decline
hearing problems/loss, possibly also affected by enlargement of the
[17–19] and central nervous system (CNS) damage [20–24]. However,
tongue [1,13,32]. For example, Neufeld et al. [1] described a case of a
this therapy does not completely correct neurological symptoms as
4-year-old MPS IH patient whose language consisted of 4–5 words. The
some studies report that cognitive development fell behind immediately
language skills the patients acquire are delayed and below normal
post-transplantation and stabilized after approximately 1 year [20,25].
[32,33]. MPS I patients also typically show an early delay in attainment
In this section we will focus on the natural progression of neurological
of motor skills, considered to be more related to the patients' limited
signs and symptoms in MPS IH patients that did not receive HSCT,
range of joint motion, progressive orthopedic manifestations, and per-
unless stated otherwise.
ipheral neuropathy, rather than to brain abnormalities [23,33–35]. A
peripheral neuropathy that is frequently present in MPS I patients is
2.1. Brain abnormalities carpal tunnel syndrome, which is caused by compression of the median
nerve in the carpal canal at the wrist [36,37]. This can contribute to
Brain abnormalities are frequently observed in patients with MPS I, poor fine motor function and somewhat limits the performance of daily

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E.G. Shapiro et al. Molecular Genetics and Metabolism 122 (2017) 1–7

Fig. 3. Cognitive development in MPS II patients with and without CNS disease, assessed
with the Mullen Scales of Early Learning, Differential Ability Scale or Leiter International
Performance Scale Revised (based on estimated developmental function). Cognitive tra-
jectories were created by plotting developmental age against chronologic age for each
group over time. The gray-shaded area represents the variability ( ± 2 standard devia-
Fig. 2. Cognitive development in untreated MPS IH patients. Without treatment, the tions) in the normal developmental trajectory (reproduced from Holt et al. 2011 [49]
30 months age equivalent (on the Bayley Scales of Infant Development or the Mullen with permission from Elsevier). (For interpretation of the references to color in this figure
Scales of Early Learning) may be a ceiling in the development of MPS IH patients. The legend, the reader is referred to the web version of this article.)
plateauing line was created by polynomial curve fitting.

3.1. Brain abnormalities

living skills. In turn, decreased motivation to perform and psychological
problems due to impaired development of motor skills may impact Brain abnormalities described in MPS II patients include enlarged
cognitive development, particularly in more attenuated phenotypes PVS in the subcortical and periventricular white matter, thalami, basal
[15]. ganglia, corpus callosum, and brain stem; ventriculomegaly; corpus
Although neurocognitive problems have been frequently reported in callosum thinning; and cortical atrophy [26,29,42]. In neuronopathic
rapidly progressing phenotypes of MPS I, psychiatric problems have not MPS II patients, neurological decline can lead to severe cognitive im-
been described. In contrast, serious psychiatric symptoms (e.g. de- pairment and is associated with behavioral problems [1,49].
pression, withdrawal), cognitive deficits (lower IQ, attention, and
verbal memory scores), and general decline have been described for a
3.2. Neurocognitive development
subgroup of slowly progressing MPS I patients that have a combination
of the missense mutation L238Q with a null mutation and are treated
Retrospective evaluation of neurodevelopmental performance and
with enzyme replacement therapy [38,39]. As neurological disease
progress can clearly distinguish attenuated from neuronopathic MPS II
generally starts to develop at a later age in these patients than in MPS
patients [42,46,50,51]. Attenuated MPS II is associated with normal or
IH patients, they appear to have an intermediate phenotype between
mildly impaired cognitive development [42] and normal adaptive be-
MPS IH and MPS IH/S.
havior with increasing age. In neuronopathic patients, cognitive de-
velopment and adaptive ability plateau around a mean age of 4 to
4.5 years, although there is significant variability, followed by pro-
2.3. Behavioral problems
gressive deterioration [42,49,50] (Fig. 3). These patients also develop
severe speech and language delay [50,51], which mirrors the cognitive
Young MPS IH patients are perceived as social, compliant, and
decline. Hearing loss is almost universal among MPS II patients and is
somewhat fearful [3,40]. When they become older, treated MPS IH
generally diagnosed at around 2 years of age (mean age
patients can present with attention problems [39,41]. A study of brain
23 ± 17.3 months), during active speech and language development,
function and structure showed an association between worse perfor-
affecting the acquisition of these skills [42,52].
mance on attention tests and lower fractional anisotropy (indicative of
The degree of motor impairment in MPS II patients is related to
poorer white matter integrity) in the corpus callosum [41] of MPS IH
skeletal problems and carpal tunnel syndrome, and is more severe in
patients, even after HSCT. During adolescence, MPS I patients often
neuronopathic patients [42,49]. Gross motor skills plateau around the
show low self-esteem, depression, and social withdrawal [25,28].
age of 3 to 4 years and deteriorate thereafter, although there is some
variability. Fine motor skills are severely impaired and start to decline
by 4 to 5 years of age. Both gross and fine motor skills are severely
3. MPS II
reduced in most patients after the age of 6 years, leaving the patients
ambulatory but with poor coordination [42,51].
MPS II, or Hunter syndrome, is caused by iduronate-2-sulfatase (EC
3.1.6.13) deficiency, resulting in accumulation of DS and HS [2]. Di-
agnosis is generally based on somatic signs that develop around the age 3.3. Behavioral problems
of 2 to 4 years, including otitis media, facial dysmorphism, enlarged
tongue and tonsils, enlarged liver or spleen, and joint stiffness) [42–44]. Abnormal behavior in MPS II patients starts at a mean age of 4 years
Patients are classified as neuronopathic or attenuated based on the (ages ranged from around 1.5 to 7.5 years in a study including 49 pa-
presence or absence of progressive neurological involvement and be- tients [49]), when cognitive function starts to slow down, and is among
havioral problems [42,45–49]. the first symptoms indicating neurological involvement [42,49–51].
The most frequently observed behavioral problems in neuronopathic

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E.G. Shapiro et al. Molecular Genetics and Metabolism 122 (2017) 1–7

patients are hyperactivity, challenging behaviors, frustration, and im-

pulsivity. In addition, approximately half of these patients develop
perseverative chewing behavior (uncontrollable repetition of chewing),
which is different from the abnormal open-mouth posture, swallowing
difficulties, enlarged tongue, and gingival hypertrophy that also fre-
quently occur in these patients [49]. Seizures also frequently occur in
patients with neuronopathic MPS II [49–51], with reports of seizure-
like behavior, staring, myoclonus episodes, and tonic-clonic seizures
[49]. The type of seizures evolves with disease progression, with per-
iods of absence mostly occurring first, followed by tonic-clonic seizures
later in the disease course.
Many MPS II patients have sleeping problems, such as reduced rapid
eye movement sleep, night-time wakening, difficulty settling, or in-
somnia [42,49], which may be attributed to sleep apnea or seizure
(-like) activity [3,53]. Sleeping problems may also result from primary
CNS involvement, since they occur more frequently in neuronopathic
patients [42,49]. However, more research is needed to identify the
mechanism(s) that cause(s) these sleeping problems.
Although patients with attenuated MPS II have normal or mildly Fig. 4. Cognitive growth by age for rapidly and slowly progressing MPS IIIA patients,
assessed with the Bayley Scales of Infant and Toddler Development III or the Kaufman
impaired intellectual ability and memory measures, attention problems
Assessment Battery for Children II (based on anticipated age and ability range). The gray-
have also been documented in these patients. These seem to correlate
shaded area represents published normative data. The red line represents the mean tra-
with the level of somatic disease burden and brain structure volumes. jectory of the rapidly progressing group (reproduced from Shapiro et al. 2016 [57] with
Larger corpus callosum and cortical white matter volumes have been permission from Elsevier). (For interpretation of the references to color in this figure
linked to a better reaction time and less variability in the Test of legend, the reader is referred to the web version of this article.)
Variables of Attention; less somatic disease burden correlates with less
variability in the attention test [45]. In patients with attenuated dis- and epilepsy in the later stages of the disease [7,8,54,55].
ease, attention problems and hyperactivity tend to improve with age,
while sense of inadequacy and anxiety worsen and self-esteem de-
creases, leading to greater risks of depression and withdrawal [46]. 4.2. Neurocognitive development
Recently, Holt et al. [49] identified seven early clinical markers of
neurological involvement in MPS II patients before cognitive decline MPS III patients generally keep acquiring neurocognitive skills until
starts: increased activity, behavioral difficulties, inability to achieve the age of 3 years, although at a slower rate than normal. In rapidly
bowel and bladder training, perseverative chewing, seizure-like beha- progressing phenotypes, development plateaus around 3 years of age
vior, and sleep disturbances. They developed an index severity score and declines rapidly thereafter, resulting in cognitive skills at less than
(ranging from 0 to 7), in which a total score of ≥3 indicates a high a two-year-old level after the age of 6 years (Fig. 4). Patients with
likelihood of developing CNS disease. slowly progressing disease show gradual but inconsistent decline over
time and tend to be diagnosed after the age of 6 years
4. MPS III [6–8,54,55,57,59].
Speech and language delay are the most frequent initial symptoms
MPS III, or Sanfilippo syndrome, is associated with severe neuro- of MPS IIIA and IIIB. Language delay may be apparent by the age of
logical manifestations and, unlike the other MPS disorders, only mild 2 years, before cognitive decline starts [6,57]. Only 50% of these pa-
somatic involvement (Fig. 1). Somatic features and symptoms, which tients acquire the capacity to associate two words before the age of
occur in over half of patients (versus almost all MPS I and II patients), 3 years [7,54,55]. Hearing loss, which generally develops in some
may include coarse facial features, hepatomegaly, hearing loss, and an children with MPS III around 2–3 years of age [6,7], when children
enlarged tongue [6]. The disease is characterized by accumulation of acquire most language, may also contribute to the speech and language
HS and has four biochemical subtypes, MPS IIIA, B, C, and D, caused by delay.
deficiencies in the enzymes heparan sulfamidase (EC 3.10.1.1), N- Patients with rapidly progressing MPS IIIA can usually acquire
acetylglucosaminidase (EC 3.2.1.50), heparan-α-glucosaminide N- adaptive skills up to approximately 4 years of age, after which these are
acetyltransferase (EC 2.3.1.78), and N-acetylglucosamine 6-sulfatase lost [57]. Fine motor skills reach a plateau at around 2 to 3 years of age,
(EC 3.1.3.14), respectively. The two most prevalent subtypes are MPS mirroring cognitive decline [6]. As MPS III patients have minimal
IIIA and IIIB, with reported incidences ranging between 0.2 and 1.89 musculoskeletal problems, development of gross motor skills tend to be
per 100,000 live births [1,2,7]. Both subtypes have slowly and rapidly preserved until 5 to 6 years of age. Due to cognitive impairment and
progressing forms [54,55]. MPS IIIC (0.07–0.21 per 100,000 live births) hearing loss, difficulties in following instructions together with poor
has a slowly progressive disease course [56]. MPS IIID is extremely rare imitative skills impair the ability to perform motor tasks after this age.
(0.1 per 100,000 live births), making it difficult to draw conclusions Hence, initial MPS III symptoms include cognitive impairment with age
regarding the severity and progression rate of this subtype [1,2,7]. appropriate motor activity [6,57]. Motor skills are lost later in the
disease course, with MPS IIIA and B patients usually at an earlier age
4.1. Brain abnormalities than with MPS IIIC and D [7,54,55].

Patients with MPS IIIA show increased ventricular volume and re- 4.3. Behavioral problems
ductions in cortical gray matter and amygdala volumes, which occur in
parallel with cognitive decline, and are much more severe in rapidly Severe behavioral symptoms of rapidly progressing MPS III begin at
progressing than in slowly progressing phenotypes [57]. Atrophy is 2 to 4 years of age and include hyperactivity, expression of frustration,
present in all MPS III subtypes, while enlargement of the PVS occurs decreased attention, and severe sleep disturbances. These symptoms
less regularly and is less noticeable than in MPS IH and II accompany, and are probably associated with, the significant in-
[26,28,57,58]. Approximately 30% of MPS III patients develop seizures tellectual decline and developmental regression [3,7,8,60,61].

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E.G. Shapiro et al. Molecular Genetics and Metabolism 122 (2017) 1–7

Overview of the neurological signs and symptoms in MPS disorders with central nervous system involvement. Given ages represent approximations of mean ages in classical/rapidly progressing phenotypes, unless indicated otherwise. FA: fractional
Behavioral problems eventually diminish due to progressing cognitive

Plateaus at 2 to 3 years of age, then progressive decline (skills of a 6-month-old at 6 years)

decline [54,62,63].
Most children with MPS IIIA and B appear to develop autistic-like
behaviors, primarily social and emotional abnormalities, around the
age of 4 years [9,10], which are associated with a reduction in hippo-
campal volume [64]. However, unlike patients with autism, they do not
show deficits in communicative behavior before the age of 3 years and,

Decline at ± 2 years of age (before start of cognitive impairment)

apart from hyperorality, show no restricted and repetitive behaviors
[9,10]. By the mid-stage of the disease, lack of fear becomes evident.
Although MPS IIIB patients are similar in their behavioral phenotype,
they tend to be slightly more inattentive and more fearful than MPS IIIA
patients [10,40]. In the latter, lack of fear has been associated with

Variable age of detection (median age 5 years):

atrophy of the amygdala [40,64].

Aggressive behavior at 3 to 4 years of age

Many MPS III patients show sleep disturbances, including daytime
sleepiness, difficulties settling, night-time and early morning wakening,

Lack of fear, acquired autistic deficits

MPS IIIA and B [6,7,9,10,26,57,76]
and insomnia, due to disturbances in their circadian rhythm. In addi-

Loss of skills after 4 years of age

tion, most children show sleep disruptive behaviors, like laughing and

Mirrors decline in cognition

singing, during the night [57,65]. Studies revealed alterations in the

Affected by hearing loss

circadian rhythm of melatonin levels in the saliva [65] and urine [66]

• Ventriculomegaly
• Seizures/epilepsy
Decreased attention
of MPS III patients, with higher levels in the early morning and lower

Sleeping problems
levels in the evening/night, which might explain the phase delayed
circadian rhythm cycle [65–67]. Treatment with melatonin has been

• Atrophy
b
• ↑PVS
shown to improve sleep problems in over half of the patients assessed
[61,68].

5. Conclusion and future directions

Gross motor skills affected ± 1 year of age before fine motor

Plateaus at 4 to 4.5 years of age, then progressive decline
Neurological signs and symptoms occur in four of the seven MPS
disorders (MPS I, II, III, and VII). They can be very debilitating and pose
a substantial burden on the patient's family and environment [69–71].

Variable age of detection (median age 6 years):

Despite considerable differences in somatic symptoms between these

Hyperactive & aggressive at ± 4 years of age

MPS disorders, the present review revealed some similarities in the
MPS II, rapidly progressing [26,42,50,75]

natural history of neurological disease in patients with rapidly pro-

gressing phenotypes (Table 1), which might be of importance when
Mirrors cognitive delay and decline

deciding on outcomes for clinical trials and treatment. In these patients,

neurocognitive function seems to follow a similar pattern of develop-
ment, plateauing and then progressive decline. The age of plateau and
Affected by hearing loss

• Ventriculomegaly
• Seizures/epilepsy

Variable time, magnitude, and frequency of occurrence between and within different MPS disorders.
decline appears to be slightly later and more variable in the neurono-

• Hydrocephalus
Plateaus at 4 years

Sleeping problems

pathic form of MPS II than in MPS IH (2 to 3 years of age). In MPS IIIA,

the decline occurs around 3 to 4 years of age in the rapidly progressive
type. Speech and language skills are similarly affected in all three types,
with developmental slowing around the age of 2 years and affected by • ↑Atrophy
PVS
skills

hearing loss. Finally, MPS II and III are associated with behavioral •
problems and sleep disorders. Attenuated and treated forms of MPS I
Limited skills develop until 2 years of age, then decline

and II show low self-esteem and mild depression in adolescence, with

Plateaus at ± 3 years of age, then progressive decline

one phenotype of MPS I showing more severe psychiatric problems.

Gross motor skills affected before fine motor skills

A good knowledge of the natural history of neurological disease in

Adolescents: depression and social withdrawal

MPS disorders is important, as it can help in the optimization and de-

velopment of treatments, and contribute to a better understanding of
anisotropy; ICP: intracranial pressure; PVS: perivascular space.

Most are evident at < 2 years of age:

treatment effects on neurological symptoms. In addition, it might im-

Older children: attention problems
Probably affected by hearing loss

prove the identification and prediction of neurological decline in an

MPS IH [15,23,24,26,33,40,41]

Decline from ± 2 years of age

Less common/severe than in MPS IH and MPS II.

early stage, thus allowing timely intervention/treatment, before irre-

Young: somewhat fearful

versible damage occurs. In MPS IH patients, earlier HSCT has been

• ↓ FA corpus callosum
• ↑Ventriculomegaly

shown to result in better somatic and cognitive outcomes [24,72].

• Hydrocephalus

While newborn screening can help in the earlier diagnosis of MPS pa-
tients, early markers of neurological involvement can help predict
• Atrophy

neurological decline at an early stage. Such early markers have already

• ↑ PVS
ICP

been described for MPS II [49], but need cross-validation. In MPS I,

•

genotype can help to predict the severe form of MPS IH [73], but
variability and many private mutations make this impossible for MPS II
Brain abnormalitiesa

[2]. In addition, in MPS IIIA, some mutations can predict whether it will
Speech & language

present as a slow or rapid progressing type; however, no such markers

Neurocognition

Motor skills

are available for MPS IIIB [54].

Behavior

Although current literature provides some insights into the natural

Table 1

history of neurocognitive disease in MPS, more research is warranted to

b
a

better determine progression rates for each MPS disorder and the

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R.E. Harris, M.K. Rozans, J. Kurtzberg, G.H. Grayson, T.E. Williams, C. Lenarsky,
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LLC. syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploiden-
Dr. Jones is principal investigator and consultant for BioMarin, tical related donor bone marrow transplantation in fifty-four children. The Storage
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Therapeutics, RegenXbio, and Shire Human Genetics, and received an
A. Durin, K. Kebaili, C. Galambrun, Y. Bertrand, R. Froissart, C. Dorche,
honorarium from Abeona to attend scientific advisory board meetings. L. Gebuhrer, C. Garin, J. Berard, P. Guibaud, Outcome of 27 patients with Hurler's
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