Proyecto FOLTRA

Histórica recuperación de un niño con el síndrome Aicardi-Goutieres


Histórica recuperación de un niño con el síndrome Aicardi-Goutieres

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Correo electrónico
Viernes 01 de Septiembre de 2017 10:37
 
De nuevo, en Foltra se ha dado un caso único en la historia de la medicina al llevar a cabo con éxito la recuperación de un niño con el síndrome Aicardi-Goutieres, un logro que se suma a otros anteriores, también primeros casos.
 
Para los que no entiendan el texto en inglés, recomendamos que se fijen en las figuras que se presentan en la publicación
 
 
A Rare Case of Aicardi-Goutières Syndrome Who Showed a Positive
Evolution after Being Treated with Growth Hormone, High Doses of
Melatonin and Neurorehabilitation
 
 
Jesús Devesa 1,*, Alba Alonso 2, Patricia Porto 3, Ana Quintana 4, María Carrillo 5, Pablo Devesa6
and Carlos I. Puell 7.
1 Scientific Direction. Medical Center Foltra. 15886-Teo. Spain. Email: Esta dirección electrónica esta protegida contra spambots. Es necesario activar Javascript para visualizarla .
Phone: +34-981802928. Fax: +34-981807650.
2 Children Physiotherapy. Medical Center Foltra. 15886-Teo. Spain. Email:
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3 Occupational Therapy. Medical Center Foltra. 15886-Teo. Spain. Email:
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4 Neuropsychology. Medical Center Foltra. 15886-Teo. Spain. Email:
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5 Speech Therapy. Medical Center Foltra. 15886-Teo. Spain. Email:
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6 Research and Development. Medical Center Foltra. 15886-Teo. Spain. Email:
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7 Physical Medicine and Rehabilitation. Medical Center Foltra. 15886-Teo. Spain. Email:
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* Correspondence: Esta dirección electrónica esta protegida contra spambots. Es necesario activar Javascript para visualizarla or Esta dirección electrónica esta protegida contra spambots. Es necesario activar Javascript para visualizarla ; Tel.: +34-981-802-928
 
 
Abstract (Resumen)
1) Background: The Aicardi-Goutières syndrome (AGS) is a rare congenital disease which
courses with severe psychomotor delay in neurodevelopment. We studied a 3-years and 4-
months old child with very important growth and weight affectation, microcephaly and loss of
his developmental skills from 16-months of age, in which previous metabolic and genetic studies
discarded any abnormality. Therefore diagnosis was cerebral palsy of unknown etiology. He
presented spastic paraparesia, poor fine motricity, cognitive impairment and absence of oral
communication. One year after discharge, a de novo mutation was detected in a single nucleotide
in the gene IFIH1: c.2317G>C, being then diagnosed of AGS. 2) Methods: Blood analysis showed
very low IGF-1 and slightly elevated liver transaminases. Treatment consisted in GH (0.04
mg/kg/day), melatonin (20 mg/day, and after 3-months 50 mg/day), and daily intense
neurorehabilitation (5 days/week). Tests for evaluating childhood developmental milestones
(GMFM-88, BDIST and the WeeFim test) were carried out every 3-months. 3) Results: The
equivalent age at admission (10-months) increased to 24-months at discharge. There were clear
improvements in spasticity, fine motor function, swallowing, cognition and autonomy as well as
in communication, growth and weight. 4) Conclusion: Most likely melatonin blocked or
decreased the interferon signature, allowing GH and neurorehabiltation to act on
neurodevelopment.
Keywords: Aicardi-Goutiéres syndrome; interferon 1; melatonin; growth hormone;
neurorehabilitation
 
1. Introduction
The Aicardi-Goutières syndrome (AGS: MIM 225750) was first described in 1984 by
Aicardi and Goutières, paediatric neurologists who gave their name to this neuropathology [1].
According to their description of the findings observed in eight patients, the syndrome is
characterized by an early and progressive affectation of the developing brain leading to bilateral
spasticity, microcephaly and a rapid evolution to brain atrophy and demyelination. They also
observed calcifications in the basal ganglia and lymphocytosis in the cerebrospinal fluid (CSF).
These authors postulated that the syndrome was familial and that, most likely, had a genetic
origin [1]. Two years later a new case of this encephalopathy was described [2]. In this case, in
addition to the findings first described by Aicardi-Goutières [1], abnormal movements of the eyes
were also observed, and the child quickly evolved to a vegetative state. The authors concluded
that this syndrome may be the consequence of a genetic degenerative encephalopathy, autosomal
recessively transmitted [2].
     A new study in a higher population of children suffering AGS, revealed that in 19 of the
27 cases studied, the clinical manifestations of the encephalopathy appeared in the first 4-months
of life [3]; head circumference was normal at birth in most of these cases, but 21 of the 27 patients
developed microcephaly during the first year of life. CSF lymphocytosis existed and high levels
of interferon-alpha (IFN-α) (or type I interferon: IFN-1) were detected both in serum and CSF in
14 of these AGS children. Moreover, IFN-α levels were higher in CSF than in serum, which
suggested an intrathecal synthesis of this antiviral cytokine, but also that it could play a role in
the pathogenesis of this encephalopathy [3, 4]. These authors concluded that their study revealed
that the syndrome was inherited in an autosomal recessive manner, a conclusion also suggested
by previous and further reports [2-14]. Interestingly, studies in sibs demonstrated that AGS may
course with a highly variable phenotype [9, 11, 12], which suggests that different genes or the
existence of different mutations in a single gene may be responsible for the appearance or the
evolution of the AGS.
     Since these pioneering studies were performed, a large number of publications reflect the
heterogeneity in the type of genes involved in the onset of the syndrome and its clinical
manifestations [13-17].
     Here we describe the case of a child affected with an unusual presentation of AGS, who
showed clear improvements after being treated with GH, high doses of Melatonin (MT) and
neurorehabilitation during 16-months, in which the genetic study carried out at six years of age,
1-year after discharge, demonstrated the existence of a de novo pathogenic mutation in the IFIH1
gene (c.2317G>C).
 
2. Results
2.1. Physiotherapy
Initially, there was a remarkable dorsal flexion with the pelvis fixed in retroversion due
to the high muscular tone in the lower limbs. The spontaneous mobility on a mat was based on
turns made with great difficulty due to the global flexor pattern. He was able to maintain the
prone position with the support of his hands, being able to achieve the crawling although there
was an insufficient dissociation of scapular and pelvic waists. Therefore, main objectives in this
therapy were: a) to potentiate the active movement in lower limbs towards a normalization of the
muscular tone that allowed him to make movements with greater fluidity, without conditioning
so much the upper part of the trunk; b) to achieve a dissociation and stability at the level of waists
in order to reach a functional sedestation and better management of his upper limbs; c)
straightening and extension at the trunk level that would allow him greater motor independence.
     At discharge, the patient was able to maintain sedestation without plantar support and
perform lateral support reactions with open hands. There were clear improvements in
bipedestation, maintaining this position quite more time than at admission, improving the
extension of the lower limbs. Similarly, there were improvements in bipedestation with anterior
support (his hands). With regard to gait, a step with an adequate triple flexion was achieved,
although the patient needed the support of the therapist for walking. Therefore, the Gross Motor
Function Test [GMFM-88] increased from 17.2% at admission to 43% at discharge. These changes
mean an increase from level I to level III according to the study by Hanna et al. in children with
cerebral palsy [18]. Figure 1 shows the evolution in the GMFM-88 scores from admission to
discharge, and Figure 2 shows the physical changes in the patient during the same period of time.
Spasticity (Modified Assworth Scale [MAS]) decreased from grade 3 at admission to grade 1+ at
discharge. An X-ray exam showed that there was not subluxation of hips (data not shown).
 
 
Figure 1.- Graphic representation of the scores reached in GMFM-88 from admission (Pre-) to
discharge (6º). Controls were performed every 3-months after admission.
 
 
Figure 2.- Upper graph (1 to 3) shows the physical situation of the patient at admission. 1: Turns
in mat; 2: Unstable standing, although the back is leaning against the window and the therapist
is holding ankles, due to the dorsal flexion and that the pelvis is fixed in retroversion; 3: Observe
dorsal flexion and impossible bipedestation. Lower graph (4 to 6) shows the situation of the
patient at discharge. 4: Note the stable sedestation and the loss of dorsal flexion; 5: Note the stable
bipedestation with open hands, although the back is leaning against the glass wall; 6: Gait with
support, but note the normal movement of the lower limbs.
 
     Interestingly, one year after discharge the parents notified us that cognitive and physical
evolution continued (Figure 3), and that the patient was able to move in a wheelchair
autonomously. Independent gait was still imposible, mainly because of the shortening of
abductors, who need a corrective surgery.
 
 
Figure 3.- One year after discharge. The patient is swinging autonomously on a swing.
 
2.2. Speech Therapy
2.2.1. Speech
Before commencing the treatment the patient only was able to emit babbles, presenting
disruptive behaviors with great frequency to avoid working. Progressively, improvements in the
functionality and voluntary control of the orofacial musculature were observed; likewise, the
patient improved the protrusion and lingual retraction movements and began to perform
lateralization movements of the tongue, previously non-existent. Therefore, the patient began to
be able to emit an increasing number of vocables improving intelligibility, until he began to say
some words. Disruptive behaviors disappeared and at discharge there were important advances
in the understanding of complex orders. Full language was not achieved, but according to reports
from his parents improvements in this area continue one year after discharge.
 
2.2.2. Swallowing
Initially the patient showed a great aversion to food with marked peri and intraoral
hypersensitivity, and an excessively advanced nausea reflex. Therefore, their diet was based on
semi-solid food to avoid rejection and vomiting. The passage from the oral to pharyngeal phase
was performed by means of suction reflex. Due to his lingual hypotonia and lingual mobility
deficit there was poor management of the bolus during the oral phase of swallowing. He did not
chew and did not drink by glass, he only drank by feeding bottle. Moreover, the meal times were
very high. Consequently, the patient showed a clear undernourishment.
     At discharge, these affectations had disappeared, and the patient was able to swallow
hard solids, although not yet had gotten a complete rotational movement during mastication. His
body weight increased being already in the percentile 3 (p3) for his age.
Figure 4 shows the changes observed in this area of treatment.
 
 
Figure 4.- Orofacial changes. Upper graph (1 to 3) shows the situation at admission. 1: The patient
only drank by feeding bottle; 2: Lingual hipotony and lack of lateral movements of the tongue; 3:
Advanced nausea and vomiting reflex. Lower graph (4 and 5) shows changes at discharge. 4: The
patient was able to move the tongue laterally. 5: Rejection to semi-solid food disappeared and the
patient was able to swallow hard solids.
 
2.3. Neuropsychology
At admission the patient showed a very poor social ability for interacting with other
children, and he was absolutely dependent for any activity of daily life. He was not able to get
his hands on the middle line. His attention span was very low, both at a sustained and selective
level. Therefore, scores in the Battelle Developmental Inventory Screening Test (BDIST), which
permits to evaluate the evolution of a child in five different areas (Social/personnel, Adaptive,
Communication, and Cognition) were very low (Table 1, Pre-); therefore while his chronological
age was 51-months, the equivalent age according to this test was 10-months. Sixteen months later,
the evolution of the patient was quite positive, mainly at the cognitive level, as Table 1 (Post-)
shows. He began to interact both with adults and other children, his attention improved, he began
to try to find alternatives to solve single problems, he began to use the spoon or the fork to eat,
and he asked for food or water. In the motor area, he was already able to make the clamp, take
and deliver objects, turn pages of a book and hold the paper while drawing. His chronological
age was 67-months and the equivalent age was 24-months. These data indicated that the
neurodevelopment of the patient not only stopped when he was 16-months old, but also suffered
a regression that began to be recovered when the patient initiated the treatment in our Medical
Center, increasing his neurodevelopment in 14-months during the 16-months treatment period.
 
Table 1. Scores in the Battelle Developmental Inventory Screening Test at admission (Pre-) and
at discharge (Post-). Note the significant improvements in all areas, excepting Gross motor
functions and Expressive communication. In all, the patient increased his neurodevelopment in
14-months during the 16-months of treatment, as the difference between Total scores Post- and
Pre-treatment reflects.
 

Area                                    Pre                            Post

Social/Personnel                   14                               23
Adaptive                              10                               25
Gross motor                          2                                  8
Fine motor                            4                                 29
Total motor                           3                                 13
Receptive communication      19                                38
Expressive communication     14                                19
Total communication             15                                 26
Cognition                             11                                 44

TOTAL                                 10                                 24

2.4. Occupational Therapy
As in other therapies, at admission the patient showed a clear rejection to any tactile
stimulation (he avoided plantar and palmar support) and showed a clear displeasure against
different textures and products (creams, foams, plasticine, soft/rough or hard/soft objects),
causing alterations in other areas, such as feeding). There was no sphincter control. Therefore his
scores in the scale WeeFim were very low (Table 2, Pre-).
     Once analyzed the patient the objectives in this therapy were: a) to favor postural control
(trunk extension) and to reach active sedestation and standing, to better integrate his right upper
limb and to improve manipulative dexterity and oculo-motor control; b) to favor sensory
integration, both at the vestibular and proprioceptive levels, and reduce tactile rejection; c) to
normalize eating behavior; d) to achieve sphincter control.
     At discharge, the patient was more independent for daily life activities. He needed lesser
help for dress and undress, putting on or taking off his socks and footwear. Sphincter control had
begun. Cognition improved and the patient showed a good level of understanding, memory, and
problem resolution. With regard to mobility, the instrument WeeFim only detects general aspects
related to it; terefore, the scores reached in this component of the scale did not change from its
initial value (Table 2, Post-). However, the therapist reported clear improvements at motor level,
such as better gross and fine motor, better ability for performing bimanual activities, better
control and extension of the upper trumk, and better dissociation of scapular and pelvic waists,
but these aspects are not examined in the WeeFim test. These motor changes are shown in Figure 5.
 
Table 2.- Scores in the different areas evaluated by the WeeFim test at admission (Pre-) and at
discharge (Post-). As it can be observed main changes appeared in the personal care and
cognition. No changes were observed in the area examining the mobility for the reasons
explained in the text.
 

Area                  Pre             Post

Personal care     11/56        25/56
Mobility               5/35          5/35
Cognition           13/35        24/35

TOTAL             29/126       54/126

 
 
Figure 5.- Motor improvements. 1 and 2 show the patient working in the multi-sensory
stimulation room Snoezelen. In both cases it can be seen how the fine motricity of the patient
improved at discharge; 1: the patient press a button to get the color required by the therapist; 2:
the patient touches the screen to change the color of it. 3: Note how sensory integration was
improved, the patient balances without fear, pushed by the therapist.
 
2.5. Blood Analysis
The pre-treatment blood analysis was normal, except for a very low IGF-I value (< 25
μg/L), clearly under the limits of normal values for the age of the patient (50-300 μg/L), while the
insulin like growth factor binding protein 3 (IGFBP3) was in normal values (2.9 μg/L, normal
range: 0.7-3.9 μg/L). Plasma liver transaminases GOT and GPT were increased to values slightly
higher than normal upper range (GOT: 46 U/L, range: 10-40; GPT: 42 U/L, range: 10-40). Despite
the malnutrition of the patient, plasma proteins were also in normal values.
     3-months after commencing the treatment with GH and MT, plasma IGF-I values
increased to 122.3 μg/L (normal). Plasma liver transaminases were still slightly increased, but this
was no longer observed in the subsequent analysis performed during the 16-months of treatment.
Plasma IGF-I remained in normal values during the total period of treatment ranging between
125 and 141 μg/L, while plasma IGFBP3 values oscillated between 3.1 and 4.2 μg/L.
Blood analysis performed throughout the treatment did not show any alteration in all the
parameters analyzed.
      Treatment with GH and MT did not cause any adverse side effects, and the child grew 9
cm, although his height was still slightly below p3.
 
2.6. Genetic studies
A first cytogenetic study carried out at age 1-year and 11-months (CHG-Array 60K,
KaryoNIM) showed a deletion of 168 Kilobases in the cytoband 14q11.2, genomic coordinates
20.253.739-20.421.677. However this deletion was considered benign, since it had been described
in the general population [19] and it had been not associated with any phenotypic effect on the
carrier.
     A further study, carried out at the age of 4-years and 2-months, just before admission in
our Center, specifically designed for the patient (CHG-array containing 60,000 probes, from
which 37,600 were composed by exonic sequences belonging to 453 genes involved in
neurodevelopment; 16,900 probes uniformly distributed throughout the genome and 5,500
control probes) did not reveal any change in the gene dose that could relate to the pathology of
the patient.
     In spite of all this, and given the changes experienced by the patient after being treated,
a new genetic study was carried out in his Hospital of reference, at the age of 6 years and 6-
months, that is almost 1-year after he was discharged from our Medical Center. In this case, the
exoma was sequenced by using the Ion AmpliSeq™ Exome Kit for detecting variants in the
sequence of a group of genes related to neurodevelopment. The results obtained detected the
existence of a single nucleotide mutation in the gene IFIH1. Genomic coordinate was
Chr2:162,273,932, nucleotide change: c.2317G>C; this led to a change in glutamic acid 773 to
glutamine whose result is the transcription of a pathologic protein (transcript NM_022168). The
change, confirmed by conventional Sanger sequencing, was not observed in the parents of the
patient, indicating that it was a de novo heterocygous mutation.
 
3. Discussion
This study describes the neurodevelopmental changes observed in a child initially
diagnosed as diplegic spastic cerebral palsy, after being treated during 16-months with GH, MT
and neurorehabilitation. The interest of this report is that the first genetic study carried out in the
patient indicated the existence of a microdeletion 14q11.2, encompassing 4 genes, considered to
be benign [19] and not responsible for the pathology observed in the patient. However, more
recently, Zahir et al. described submicroscopic chromosome 14q11.2 deletions, ranging in size
from 101 kb to 1.6 Mb, in three children that showed developmental delay and cognitive
affectations, together with dysmorphic features [20]. They concluded that this chromosomic
region has few stability, therefore de novo mutations or deletions may be relatively frequents in
this region. We can not know whether the microdeletion first detected in our patient was
responsible of his neurodevelopmental abnormalities, but some of the clinical characteristics
described for the chromosome 14q11-q22 deletion syndrome (OMIM # 613457) coincided with
those found in our case [21]. For instance: failure to thrive and poor growth, microcephaly, poor
head control, low-set ears, poor eye contact, neonatal hypotonia, delayed psychomotor
development, inability to walk, lack of speech, hypertonia, spasticity, hyperreflexia, abnormal
myelination. Contradictorily, a posterior genetic study, performed two years later, did not find
any significant change in the gene dose that could justify the pathology of the patient. We don’t
know the reason for these contradictions between both studies, performed in different
laboratories. Moreover, brain imaging studies also showed conflicting results because while the
CT-SCAN performed at 2-years of age showed frontal bilateral calcifications, these were not
observed in posterior magnetical resonance (MRI) imaging studies, which, in turn reported the
existence of diffuse hypomyelination.
     For these reasons, the patient had a diagnosis of cerebral palsy of unknown etiology
when he came to our Medical Center for being treated. We treated him according to our protocols
for children with cerebral palsy, both in terms of medication received (GH and MT) and
neurorehabilitation [22, 23]. GH was prescribed not only because of the low height of the patient
and low plasma IGF-I values, a very common finding in children with cerebral palsy [24], but
also for the known effects of the hormone on brain repair after a damage [25-28], particularly on
cognition, executive functions and working memory [27, 29-32]. These GH effects were also
observed in the patient, as the great improvement in the BDIST showed (14 months in 16 months
of treatment), mainly in areas related to cognitive functions. This was specially important since,
as described, the patient had suffered a very important regression in his neurodevelopmental
milestones when he was 16-months old. In fact, some of his clinical manifestations had led to
think of the existence of an autistic spectrum disorder. In turn, MT was given, preventively,
because of its potent scavenging effects on the toxic reactive oxygen species (ROS) [33, 34], to
which the brain is particularly sensitive, most likely elevated because of the clinical situation of
the patient and the work carried out in his neurorehabilitation. Moreover, the clinical history
indicated that neopterin, a marker of inflammatory-immune processes [35], had been detected to
be elevated in a CSF sample of the patient; therefore, given the anti-inflammatory effects of MT
[36, 37], we thought that the administration of this indolamine could add more beneficial effects
to the patient.
     The evolution of the patient has to be considered very good, mainly if we look at the
starting point (chronological age: 4-years and 3-months; equivalent age: 10-months) after the
regression he had suffered at an age in which brain development still continues, and since
improvements continued after he was discharged, despite his motor limitations due to shortenig
of tendons in lower limbs (abductors and Achilles).
     Surprisingly, a new cytogenetic study carried out almost 1-year after discharge detected
the existence of a mutation in the exon 12 of the gene IFIH1 (Interferon-induced helicase C
domain-containing protein 1). This gene encodes the expression of a receptor (Melanoma
Differentiation-Associated protein 5 [MDA5]), which acts as a cytoplasmic sensor of viral nucleic
acids responding to them by activating a cascade of antiviral pathways; for instance inducing the
expression of type I interferons (alpha and beta) and proinflammatory cytokines [38], therefore
this gene plays a key role in the innate immune response. This physiological response becomes
pathological when there is a mutation in the gene IFIH1 that leads to an overexpression of
interferon 1, which is known as “interferon signature” [39]. Type 1 interferons regulate the
transcription of a number of genes belonging to the immune system, by multiple and different
signaling pathways (JAK/STATS, MAPK p38, Pi3K/Akt) [40]. Therefore it is logic that the
existence of interferon signature has been linked to the development of a number of autoinmune
diseases, such as systemic lupus erythematosus, Sjögren’s syndrome, myositis, psoriasis,
systemic sclerosis, rheumatoid arthritis and even it has been considered as a risk factor for
developing type I diabetes in children with a genetic predisposition for this disease [41-43].
     As described in the Introduction, interferon 1 (IFN-α) overproduction was early related
to the development of AGS [3, 4, 11, 12]. Since then, mutations in several genes leading to the
apparition of interferon signature have been implicated in this syndrome [13-17, 44]; however it
was not until 2014 that mutations in the IFIH1 gene were involved in the etiopathogeny of AGS
[45, 46], demonstrating that IFIH1 mutations led to an increase in the production of type 1
interferon and to an increased transription of genes stimulated by this cytokine. Interestingly, in
the last of these studies it was shown that all the patients with IFIH1 mutations presented
autoantibodies, which suggested that these mutations contributed to the presentation of
autoinmune phenotypes [46]. This was also observed in another study in patients presenting AGS
[47]. INF-1 can be produced in the CNS, but also it can easily reach the CNS from plasma,
modulating the function of microglia, astrocytes, neurons and oligodendrocytes; therefore, its
overproduction leads to severe inflammatory encephalopathies, including AGS [48].
     To our knowledge the mutation detected in the IFIH1 gene in our patient has never been
previously described or has been associated with the development of AGS, but the geneticists
who did the study identified it as pathological and associated with the occurrence of this
syndrome. Moreover, since the diagnosis of AGS was made almost 1-year after discharge from
our Medical Center, we did not measure CSF levels of IFN-1. Therefore, we don’t know whether
this cytokine is increased or its level of penetrance. However, the clinic of the patient was similar
to that of two AGS cases previously described by the group of Rice [45], in which the onset of
neurological regression with loss of motor and cognitive skills and onset of spasticity and
dystonia appeared at 15-months of age. In our patient, the absence of some major clinical features
usually found in AGS produced by IFIH1 gene mutations, such as clear intracranial calcifications,
or deep white mater affectations, recurrent non-infectious fevers, chilblains, neonatal
thrombocytopenia, among others, corresponds to the wide spectrum of the presentation of AGS
[49, 50]. Although the existence of AGS seemed to be clear in the case here described, we can not
discard that some of the clinical features that the patient presented from birth were due to the
microdeletion in cytoband 14q11.2 detected in the first genetic study carried out, as shown in
OMIM database [21]. Then, the possibility exists that two genetic abnormalities contributed to the
clinical features observed.
     AGS is the consequence of inadequate immune activation, showing features of
autoinflammatory and autoimmune disorders. These are the reasons by which different
treatments combining corticoids with immunosuppressants or immunoglobulins have been used
without known effectivity [51]. On the other hand, and given that the type 1 interferon-signature
is a constant in AGS, independently of the causal genotype, other therapeutic approaches
consider to block IFN-1 or its receptor by using monoclonal antibodies. More recently, the use of
reverse transcriptase inhibitors, such as those used to treat HIV-1 infections, in children and
adults has been suggested for treating AGS [for a detailed review, see ref. 51].
     Therefore, how to explain the significant improvements achieved in our patient when the
treatment with GH and MT began together with neurorehabilitation, after almost 3-years
receiving intense rehabilitation without significant results?
     Apart of the high number of beneficial effects that MT plays in the human organism, this
hormone has anti-inflammatory properties and it is a mitochondrial protector [36, 37, 52]; in
addition, it has been shown that, in rats, melatonin protects the liver against ischemia/reperfusion
injury by inducing heme-oxygenase-1 overexpression, which, in turn, suprresses the type 1 IFN
signaling pathway dowstream of Toll-like receptor 4 [53], a transmembrane receptor whose
activation leads to the induction of a type 1 IFN response in Trex1 null mice [54], one of the genes
whose mutations lead to AGS [44].
     Since CSF or plasma levels of IFN-1 were not measured in our patient either before or
during treatment with MT we can not affirm that the improvement obtained has been due to the
blockade of IFN-1, but a recent study utilizing a novel MT derivative which possessess stronger
anti-inflammatory properties than the physiological hormone, demonstrated that its potent
effects are exerted via the regulation of IFN-dependent signaling patway from Toll-like receptors
[55]. Moreover, we treated a women with rheumatoid arthritis, an autoimmune disease with
interferon-signature, with 100 mg/day of MT and one month after beginning the treatment her
joint pains had disappeared and plasma markers of inflammation were fully normalised,
something that had never happened during the long time that she had been treated with
immunosuppressants or corticoids (unpublished data).
     In summary, we believe that the positive results obained in our AGS patient have been
produced by the effects of MT on IFN-1 and inflammation, then allowing GH and
neurorehabilitation to act on his psychomotor disabilities and growth.
     Currently the dose of MT has been increased to 100 mg/ay and his cognitive and motor
skills continue to being improved.
 
4. Materials and Methods
The patient was a 4-years and 3-months old male born by scheduled caesarean carried
out at week 40, due to loss of fetal growth and failure of labor induction. He was the unique child
from a nonconsanguineal marriage. His mother had suffered two previous abortions in the first
trimester of pregnancy. The mother did not have any kind of toxic habits; she did not take any
kind of pharmaceutical drugs during their pregnancies, nor she had been exposed to toxic agents
or had suffered from an illness.
As the only significant family history, the child had a cousin with Asperger’s syndrome.
Apgar score at birth was 9/10 (1 min/5 min); his weight at birth was 2.740 kg (<p3) and his size
was 46 cm (<p3). The child presented microcephaly (head circumference: 34 cm).
Gastroesophageal reflux existed until 14-months of age. The evolution of weight and growth were
very low (<< p3) from birth until 16-months of age where there was a stagnation; however, at 9-
months old he was able to initiate sedestation, and at 16-months of age began ambulation, but
both were totally lost in the next six months. At this time axial hypotony and spasticity in lower
limbs appeared, while in upper limbs distony existed, more marked in the right side. At 3-years
old he was only able to say two words. Therefore he began to communicate through his shown
to be elevated own sign language.
     Blood analysis were normal (hematimetry, biochemistry and hormones), with the
exception of increased plasma IgE values (622 UI/mL, normal: <40 UI/mL), which was attributed
to intolerance to cow’s milk, and persistently low values of plasma IGF-I (< 25 μg/L). All types of
metabolic (including organic acids and very long chain fatty acids) and serological studies
(Borrelia burgdoferi, Cytomegalovirus and Herpes simple) were normal. Interestingly, an
increased value of neopterin in CSF was observed (198 nmol/L; normal: 12-55 nmol/L), but it was
thought to be the expression of an inflammatory process or an autoinmune disease.
     A first genetic study (CHG-Array 60K, KaryoNIM) showed a deletion of 168 Kilobases in
the cytoband 14q11.2. However this deletion was considered benign [19]. A new genetic study,
performed 3-years later showed no loss in the genetic endowment, therefore contradicting the
previous genetic findings.
     A CT-SCAN performed at 2-years old indicated the existence of bilateral frontal
subcortical hyperdensic foci, secondary to calcifications. However, these were not observed in
further cerebral MRIs, which, in turn, showed moderated diffuse hypomyelination for the age of
the patient. A MRI study of the spinal cord indicated that there were no anomalies in this
territory.
     Electroencephalograms were normal. Electromyograms showed that motor and sensitive
conductions were normal in the lower limbs. Auditory and visual evoked potentials were normal.
     Based on these data the patient was diagnosed of cerebral palsy of unknown etiology,
mainly manifested by spastic paraplegia and anarthria.
     Since the clinical symptoms began to be manifested the child received an intense
rehabilitation (Doman’s method) without significant improvements.
     At admission to our Medical Center (age 4 years and 3 months), the patient had a height
(85 cm) strongly below p3 for his age, Similarly, his body weight (9,200 kg) was clearly below p3.
The patient presented microcephaly, low-set ears, enognatism, anarthria and lingual hypotonia,
axial hypotony with poor cephalic control and unstable sedestation. There was spasticity in the
lower limbs (MAS grade 3), presenting an extension pattern. Spasticity had led to a marked
shortening of the abductors and Achilles tendon; therefore, there was equine feet and scissoring
gait when the patient tried to walk with the support of his parents. The angle of abduction had a
severe limitation, Babinski sign was + and marked hyperreflexia of the lower limbs existed.
Interestingly, the patient showed a strong hypersensitivity to any stimuli in hands and feet, as
well as refusal to be fed and only was able to eat crushed food. Vomiting reflex was advanced.
No nistagmus existed and there was poor eye contact. However, according to the information
given by his parents, the child liked to watch cartoons in TV. The patient never suffered seizures,
and there were some small stereotypies.
     Once the medical examination was performed, standard tests for evaluating childhood
developmental milestones (GMFM-88, BDIST and the WeeFim test) were carried out. These tests
were repeated at 3-months intervals.
Routine blood analysis (hematimetry and biochemistry) and plasma TSH, fT4, cortisol
and IGF-I were performed before commencing medical and neurorehabilitation treatments. All
plasma values were normal, with the exception of IGF-I which was below the lower limit of
normality for his age (< 25 μg/L). These blood analysis were repeated every 3-months until
discharge.
     Medical treatments consisted in Growth Hormone (GH) and Melatonin (MT). GH
(Nutropin, Ipsen) was given at a dose of 0.04 mg/kg/day (5 days/week) for 3-months, followed
by 15 days resting. After this, the same schedule was performed during the 16-months that the
patient was treated in our Center, adjusting the GH dose to the body weight every 3-months. MT
was given orally before bedtime at an initial dose of 20 mg/day. 3-months later the dose was
increased to 50 mg/day. These doses of MT were prepared as a syrup, because of the aversive
behavior of the patient to be fed, by magistral formula.
      Neurorehabilitation (45 minutes/session, 5 days/week) consisted in: physiotherapy,
speech therapy, neuropsychology and occupational therapy.
     Treatments were conducted according to the protocols of the Medical Center Foltra and
in compliance with the Spanish legislation for using GH and MT “off label” and the Code of
Ethics of the World Medical Association (Declaration of Helsinki). Signed informed consent for
the use of GH and MT was obtained from the parents of the patient.
      Videos were taped in the Medical Center Foltra. Images in this manuscript have been
obtained from these videos, excepting the image in Figure 3 which was sent by the parents of the
patient. The parents of the patient gave signed informed consent for the publication of the results
and images, but due to ethical reasons we decided to blur his face for avoiding any recognition
of him.
 
5. Conclusions
According to our results, a combination of a medical treatment with MT plus GH,
together with neurorehabilitation, may be very useful for the treatment of children with AGS.
The treatment is safe and its utility has to be greater the earlier one begins once the disease is
detected.
Acknowledgements
We acknowledge the parents of the patient for giving us written informed consent to publish this
case report and any accompanying images.
     Funds for covering the costs to publish in open access proceeded from Foundation Foltra (Teo,
Spain).
Author Contributions
Jesús Devesa and Carlos I. Puell conceived and designed the work to be carried out and the
medical treatment given; Alba Alonso, Patricia Porto, Ana Quintana and María Carrillo
performed the work carried out in neurorehabilitation and successive control tests; Jesús Devesa
and Carlos I. Puell analysed the data; Pablo Devesa looked for genetic references and clinical
symptoms in databases; Jesús Devesa wrote the manuscript. All the authors have read and
approved the final version of the manuscript.
Radiological, MRI and genetic studies were performed in the Hospital Universitario La Fe
(Valencia, Spain), with the exception of the first genetic study (Clínica VistaHermosa, Alicante,
Spain). X-ray studies of the hips were performed inn the Hospital La Rosaleda (Santiago de
Compostela, Spain).
 
Conflicts of Interest
The authors declare no conflict of interest.
 
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