LA INVESTIGACION QUE CONDUJO A LA IDENTIFICACION DE LA MINOCICLINA

La investigación que condujo a la identificación de la minociclina
From the November 2011 FAST Newsletter Desde noviembre de 2011 Boletín de FAST
Title: Approaching clinical trials...."What a long, strange trip it's been" Título: Acercarse a los ensayos clínicos .... "¡Qué largo y extraño viaje que ha sido"
Author: Edwin J. Weeber, Ph.D. Autor: Edwin J. Weeber, Ph.D.

Para aquellos de ustedes que son nuevos para ayudar y no han leído los artículos anteriores, y / o escuchar mis anécdotas sobre mi participación en el síndrome de Angelman (AS) la investigación, me gustaría caminar por la "vía corta" de donde eran hace unos años, y cómo un enfoque de ciencia básica se ha forjado un camino inesperado en el primer ensayo clínico para probar una próxima terapéutico para la EA. . Mi sincera esperanza es que se pueden ver, como lo hice yo, la progresión lógica de la investigación ha tenido, cómo se cruza y mucho caminar mano a mano con la misión de FAST. Nuestro progreso nos ha permitido formar una perspectiva única para el futuro de la investigación Síndrome de Angelman y esperanza para los ángeles en todas partes.

Un punto de inflexión importante para la investigación del síndrome de Angelman, en general, fue el trabajo del Dr. Elgersma y creado en 2007, titulada "El rescate de los déficits neurológicos en un modelo de ratón para el síndrome de Angelman, por la reducción de la alfa-CaMKII fosforilación inhibitoria".. Este documento contiene datos interesantes que se generan en dos laboratorios diferentes, separados por el Atlántico. However,. Sin embargo, más allá del valor de los datos que presentamos, fue el hecho de que no es una enzima directamente asociado con el gen AS (UBE3A) fue capaz de eliminar todos los síntomas principales en el modelo de ratón de síndrome de Angelman.. Después de la definición estricta de una cura (una forma de corregir o aliviar todo lo que es molesto o perjudicial), se trataba de una auténtica cura genética del modelo animal. . Este método particular de un cura no podría ser utilizado para los seres humanos con síndrome de Asperger, simplemente porque los cambios genéticos que dieron lugar a la cura de la modelo de ratón, literalmente, se produjo antes de la concepción.
. En pocas palabras, el. Rescatado como ratones desarrollaron y nacieron tanto con la mutación en UBE3A y una mutación en un gen diferente, CaMKII, que permitió que los ratones que nacen y maduran sin que los síntomas de la EA Lo que no nos dijo, es si o no la modificación de CaMKII en un individuo que ya tenía como sería de beneficio tanto tiempo después de que el cerebro se había formado y desarrollado. . Sin embargo, se cree que esta enzima (CaMKII) no es significativamente expresada en el cerebro humano hasta después del nacimiento, por lo que el rescate se vio en el modelo de ratón podría representar una "cura" después del desarrollo del cerebro.
. Es probable que los procesos de desarrollo que forman el cerebro en personas con síndrome de Asperger no se ven afectados y sólo después de su nacimiento se la disfunción comienzan a manifestarse. Il. Es importante tener en cuenta que el término "trastornos del desarrollo" se utiliza para la mayoría de los trastornos de la infancia cognitivas, es decir, X frágil, síndrome de Rett y el autismo, y propone que el trastorno está relacionado con el útero en el desarrollo del individuo. Piense en esto: el cerebro se compone de 100 mil millones de neuronas que hacen de 3-5 billones de conexiones sinápticas con el fin de funcionar. . Un insulto genéticos o ambientales a la increíble complejidad de las conexiones durante la formación del cerebro es devastador e irreversible. En otras palabras, simplemente no hay manera de volver a colocar un cerebro que ha sido mal conectado durante el desarrollo. . Sin embargo, si el Síndrome de Angelman no era un trastorno del desarrollo, y el cerebro se forma correctamente, y luego una terapia efectiva puede ser posible.

. Esta revelación no es exclusiva de los investigadores. 1-estaban llegando a las mismas conclusiones con sus propios modelos de ratón único, trastornos humanos asociados con un trastorno cognitivo no eran necesariamente debido a la interrupción del desarrollo en la formación del cerebro. Nuestros pensamientos en el contexto de esta revelación, luego se volvió a una pregunta muy básica: ¿Podría rescatar a los defectos cognitivos en el adulto como el ratón, uno que ha mostrado los síntomas de la AS durante toda la vida, con sólo dar vuelta la capacidad de hacer UBE3A?. Para ello se utilizó un virus mediada por la estrategia de terapia génica. We made an Adeno-Associated viral (AAV) particle containing the Ube3a gene. Hicimos un virus adeno-asociados (AAV) de partículas que contiene el gen UBE3A.Al permitir que las partículas virales para infectar a las regiones en el hipocampo y el cerebro circundante, hemos sido capaces de entregar el gen UBE3A a cientos de miles de neuronas en ratones con síndrome de Asperger.. Después de unas semanas probamos el AS ratones y encontraron que su capacidad para aprender y recordar las pruebas específicas de comportamiento aumentado de manera espectacular. De hecho, hemos encontrado que la función de las sinapsis en el hipocampo eran casi igual a la de los ratones normales. . La capacidad de utilizar partículas AAV en los seres humanos no está actualmente disponible y ciertamente implicaría un procedimiento muy invasivo. H. Sin embargo, como una prueba de concepto, esta investigación mostró que el tratamiento de manera convincente en el modelo de ratón adulto podría mejorar los síntomas de la AS. Por lo tanto, debería ser posible hacer lo mismo con humanos los pacientes con EA, y lo más importante de esta mejora debería poder obtenerse independientemente de la edad.

Esto nos lleva al Compuesto Tres (C-3). La idea para la prueba de los medicamentos aprobados por la FDA en el AS del ratón nació en FAST como una manera de traer un potencial terapéutico para utilizar con la mayor rapidez y eficiencia. . En vista del éxito con el virus mediada por la terapia de gen UBE3A se ha descrito anteriormente, se trataba de una propuesta interesante, pero era un riesgo - mayor enfoque experimental recompensa. . Esto es porque el enfoque científico típica sería la de determinar primero el objetivo de un medicamento, a continuación, elegir el fármaco potencial que trabajar en ese objetivo específico si existiera. Nosotros todavía no está seguro de los mecanismos moleculares exactos que subyacen a la deficiencia de UBE3A y cómo se produce la interrupción sináptica. ¿Cómo fue trabajar para nosotros es un conocimiento íntimo de la modelo de ratón, y una reunión colectiva de algunas de las mejores mentes científicas relacionadas con FAST para identificar compuestos que puedan ser de utilidad debido a sus mecanismos de acción conocidos. También tuvimos que determinar los parámetros de la duración del tratamiento, las concentraciones de los fármacos, el método de administración de los medicamentos, etc Lo más importante era que estábamos seguros de un cambio puede ser detectado después de rigurosas pruebas de comportamiento y de la función sináptica en un tratamiento eficaz como el ratón .Varios medicamentos aprobados por la FDA, incluyendo C-3, se inyectaron en los ratones todos los días durante tres semanas. A continuación, prueba una serie de parámetros de comportamiento afectados en el AS del ratón: la actividad de la audiencia, la coordinación motora y el aprendizaje motor, el aprendizaje asociativo y la memoria, la percepción sensorial, y la ansiedad. También hemos probado la capacidad para crear duradera plasticidad sináptica (nuestro modelo celular para el aprendizaje y la memoria).
Se encontró que en los ratones tratados con C-3 de la coordinación motora era casi idéntica a los ratones típicos y su capacidad para aprender y recordar se incrementó también. . Además, hemos encontrado que la función sináptica en el hipocampo de nuestros ratones tratados fue significativamente mayor que los ratones inyectados salinos e igual a la de los ratones normales. ! En muchos aspectos, estos resultados fueron más dramáticos que los observados con el enfoque de la terapia génica se ha descrito anteriormente! La lógica nuevamente suscrito que estas indicaciones son suficientes para mover el C-3 a un pequeño ensayo clínico.
A continuación, puede utilizar este mismo método científico y las rigurosas pruebas y evaluaciones para determinar la eficacia de la C-3.


Nuestro laboratorio está investigando el mecanismo por el cual el C-3 puede afectar de manera tan dramática el AS modelo de ratón en un período relativamente corto de tiempo.
. Esta investigación actual podría identificar nuevos objetivos para medicamentos aprobados por la FDA, o revelar similitudes moleculares de la EA a otros trastornos para los cuales un tratamiento ya está disponible. The future will tell us how effective C-3 is, but the identification of this drug has not made us complacent. El futuro nos dirá cuán efectivo es el C-3, pero la identificación de este medicamento no ha hecho darnos por satisfechos. With the help of FAST, we are continuing to look for other readily available drugs and compounds that can be "FAST-tracked" for use as a therapeutic. Con la ayuda de FAST, seguimos en busca de otras drogas fácilmente disponibles y los compuestos que pueden ser "vía rápida" para su uso como agente terapéutico. And the long, strange trip continues... Y el largo y extraño viaje continúa ...

C-3 - Minocyclyne

Hola Paco , la semana pasada estuvo por canarias el neurologo de Texas y vio interesante el estudio de la minociclina y me pidio si podia conseguir el ensayo clinico original en ratones como tú estas buscando siempre informacion sobre estudios ,mira entre todo lo que has consultado si me puedes decir donde puedo conseguir el original en inglés ,gracias.

Juanjo en esta direccion esta toda la informacion del estudio
[clinicaltrials.gov]
y aqui la web de FAST, Foundation Angelman Syndrome Therapeutics [www.cureangelman.org].
De donde he traducido este articulo,
Juanjo espero te sea util un abrazo.

Muchas gracias Paco se lo enviaré por email al neurologo para ver si es lo que necesitaba,saludos

Os mando un artículo que acaba de aparecer. Me lo manda el neurólogo que atiende a Lidia.
Lo único, es que está en inglés, pero bueno.
Saludos

LidEpilepsia, **(*):1–5, 2012
doi: 10.1111/j.1528-1167.2012.03537.x
FULL LENGTH ORIGINAL RESEARCH
1
be severe, with up to 77% of individuals developing seizures
that are medically refractory (Thibert et al., 2009).
The ketogenic diet (KD) has been utilized in the treatment
of epilepsy for nearly a century. In the classic KD, the
majority of an individual’s calories (90%) come from fats,
and carbohydrate intake is extremely limited. These parameters
mimic the metabolic and physiologic effects of fasting
and have been associated with a significant antiepileptic
response (Bailey et al., 2005; Kossoff et al., 2009). The literature
on dietary intervention for the treatment of seizures
in Angelman syndrome is limited to two case reports, both
describing the KD as highly effective for Angelman syndrome–
related epilepsy (Evangeliou et al., 2010; Stein
et al., 2010).
In 2005, the low glycemic index treatment (LGIT) was
developed as a liberalized alternative to the KD. The structure
of this treatment aims to maintain a stable serum
glucose level by limiting carbohydrates to 10% of an individual’s
daily caloric intake and by limiting the types of carbohydrates
to those with a glycemic index of <50 (Pfeifer &
Thiele, 2005). This prospective trial was designed to evaluate
the efficacy and tolerability of the LGIT in the treatment
of Angelman syndrome–related epilepsy, as well as to
assess the effects of the LGIT on electroencephalography
(EEG) findings and neurocognitive functioning.
Methods
Subjects were recruited through the Angelman Syndrome
Foundation (ASF) via email and website advertisements.
Enrollment criteria included the following: age 1–18 years,
confirmed genetic or clinical diagnosis of Angelman syndrome,
current seizure frequency ‡2 events/month, and a
history of ‡2 antiepileptic drugs (AEDs) tried. Exclusion
criteria included a history of dietary therapy for epilepsy.
Given the positive initial results after the first five children
completed the study, an amendment to the institutional
review board protocol was approved allowing for the enrollment
of children who had previously tried only one AED.
One final subject was then enrolled under these modified
parameters.
Before any dietary changes, LGIT trial subjects first completed
a baseline EEG and parents completed a seizure log
(date, time, semiology) for a minimum of 1 month, to establish
the child’s baseline seizure frequency. EEG recordings
were read by an epileptologist for the following three markers
of cortical irritability and/or neuronal pathology: generalized
slowing of the background rhythm, epileptiform
discharges, and notched delta activity. The LGIT dietary
therapy was initiated according to the standard protocol
(Pfeifer et al., 2008; Muzykewicz et al., 2009). Study
requirements included clinical evaluation and education
with a neurologist and dietitian at the time of enrollment, as
well as following both the first and fourth months of LGIT
therapy. Parents and caregivers of subjects continued to
record seizure activity over the complete therapeutic interval.
At baseline, 1 month, and 4 months, blood for laboratory
chemistries was drawn and anthropometric measures
were obtained. For families who needed to travel long distances
(>100 miles) to the trial site, the 1-month visit was
done by telephone, with the laboratory studies completed at
a local hospital. At the 4-month visit, EEG recordings were
completed and subsequently interpreted by the same
clinician as the baseline studies.
Caloric goals were calculated from a baseline 3-day food
record. All subjects followed the LGIT guidelines, which
allow for approximately 40–60 g of low glycemic carbohydrates
(glycemic index < 50 relative to glucose) per day.
The macronutrient distribution follows 10% carbohydrates,
20–30% protein, and 60–70% fat. Calories were monitored
and adjusted to maintain consistent growth and body mass
index. While patients were on the LGIT, medication
changes were not made unless deemed medically necessary
by the attending neurologist. At the end of the trial, parents
and caregivers were given the option of continuing the
LGIT as part of the patient’s ongoing clinical care.
To assess each child’s adaptive or everyday living skills,
developmental quotients were obtained from two questionnaires,
the Scales of Independent Behavior-Revised (SIB-R)
and the Vineland Adaptive Behavior Scales-2nd Edition
(VABS-2). Each is a standardized measure of adaptive
skills, although the items used to assess behaviors (e.g.,
communication, motor, personal living skills) often differ,
resulting in different scores for each domain; both were used
to more carefully assess each child’s functioning. A developmental
quotient is often used when data about intellectual
functioning falls below the basal level of a test or scale,
which is often the case for children with Angelman syndrome.
The quotient is a means of describing a child’s developmental
level relative to the performance of other infants
of the same age and is obtained by dividing the child’s developmental
age (obtained from questionnaire data) by the
chronologic age and multiplying by 100. Therefore, if a
child’s skills are at an age appropriate level, the developmental
quotient would be 100; if the skills are 50% lower
than the child’s chronological age, the quotient would be 50.
Results
Six individuals with genetically confirmed Angelman
syndrome, all with a maternal deletion of chromosome 15q,
were enrolled in this prospective study and completed a
4-month treatment protocol of the LGIT (Table 1). The
average age for this cohort was 3.3 years (range 1.1–4.8).
Seizure severity was indexed by age at seizure onset (mean
1.6 years, range 0.3–2.7 years), and total number of lifetime
AEDs (mean 3, range 1–6). The average baseline seizure
frequency was 10.1 events/week (range 0.4–30.9) and the
average number of AEDs being administered to enrollees at
the start of dietary therapy was 1.5 (range 1–2). On baseline
2
R. L.Thibert et al.
Epilepsia, **(*):1–5, 2012
doi: 10.1111/j.1528-1167.2012.03537.x
EEG, six (100%) of six cases had generalized slowing of the
background rhythm, four (67%) of six had epileptiform discharges,
and six (100%) of six had occipital notched delta
activity. In addition, for case 5, the notched delta pattern
had a classic ‘‘spike and wave’’ morphology on the baseline
study.
Baseline daily seizure logs, recorded before dietary
changes, were kept for ‡4 weeks in five and six cases (34, 33,
23, 31, 45, and 48 days). When comparing the baseline and
4-month follow-up data, all cases had a reduction in seizure
frequency on the LGIT, with five of six exhibiting >80% seizure
frequency reduction (Table 2). Five of the six patients
stayed on the LGIT after the trial, all of whom had >90% seizure
reduction at 1-year follow-up per parental report.
When baseline and 4-month EEG studies were compared,
two (33%) of six cases had an improved background
frequency, three (75%) of four who had epileptiform
discharges on initial EEG had no discharges present on
follow-up EEG, and two (33%) of six had less frequent
occipital notched delta activity (Table 3.). In addition, the
baseline EEG with a ‘‘spike and wave’’ quality to the
notched delta pattern (case 5) showed a more typical morphology
of this focal variant on 4-month follow-up.
Exit scores for the SIB-R and the VABS-2 were compared
with baseline scores (n = 4). The mean developmental
quotient was obtained both at baseline and at 4-month
follow-up, with results indicating no notable difference in
the mean scores. For the SIB-R, the baseline mean score
was 25 (range 14–35) and the follow-up was 31 (range
21–47). For the VABS-2, the baseline mean score was 30.44
(range 21–40), and the follow-up was 29.50 (range 19–38).
Therapeutic changes to AED doses over the 4 months
were limited to two subjects. Case 1 starting AEDs: valproate
250 mg, twice daily, and clobazam 7.5 mg daily. Valproate
was tapered off completely in the fourth month due to side
effects (significant tremor, which improved off valproate),
and clobazam was increased to 15 mg daily. These changes
were not made until the fourth month after three seizure-free
months and were made because the family perceived the tremor
as intolerable. The tremor had been present since beginning
valproate and did not change significantly on dietary
therapy. For case 2, levetiracetam dose was reduced slightly
from 150 to 125 mg twice daily at the start of the trial due to
conversion from suspension to tablets, as the suspension is
higher in carbohydrates. The following medication doses
changed in terms of mg/kg/day due to weight gain or loss on
the diet. For case 3 there was a 3% decrease in valproate; case
4 a 4% increase in levetiracetam; case 5 a 4% decrease in
levetiracetam; and case 6 a 16%decrease in levetiracetam.
There were no significant side effects observed in this
therapeutic trial of the LGIT. Average change in nonfasting
laboratory chemistries observed between baseline and
4-month follow-up levels were as follows (n = 6): glucose
decreased by 15.4%, triglycerides increased by 12.5%, carbon
dioxide decreased by 0.5% (three cases had an incremental
increase and the other three had a decrease).
Baseline and 4-month b-hydroxybutyrate levels and weightfor-
height z-scores are presented in Table 1.
Four additional children enrolled in this study but did not
initiate the LGIT. Before initiation, the first two had gastrostomy
tubes (g-tubes) placed with indications of failure to
thrive and gastroesophageal reflux, respectively. The first
child became seizure-free within a month of starting noncarbohydrate
restricted enteral formula. The second child was
having up to 80 seizures/day and it was therefore clinically
recommended for her to start KD therapy rather than LGIT.
By parental report, this child was seizure-free within
2 weeks of starting dietary therapy. The third patient moved
overseas shortly after LGIT education and therefore did not
initiate the diet. In the fourth case, the family received
education on the dietary parameters, but decided not to initiate
the treatment due to social and financial limitations.
Table 1. Prospective trial of the low glycemic index treatment in Angelman syndrome: demographics, daily
carbohydrate intake, b-hydroxybutyric acid levels, and weight for height z-scores
Case Sex
Age
(years) AEDs
Carbohydrate intake
Glucosea
(mg/dL)
b-Hydroxybutyrate
(mM)
Weight-for-height
z-score
g/day
% of total
calories
Baseline LGITb Baseline LGIT Baseline LGIT Baseline LGIT Baseline LGIT
1 F 3.5 VPA, CLBc 248 58 52 14 99 70 0.10 1.46 )0.14 0.01
2 M 4.4 VPA, LEV 121 41 37 12 79 82 0.10 0.30 0.73 1.4
3 F 4.8 VPA 168 105 54 11 98 74 – – 0.67 1.01
4 M 1.1 LEV 118 30 61 10 78 63 0.10 2.80 )0.98 )0.09
5 M 4.1 LEV 189 137 57 29 90 – 0.10 0.10 )0.05 0.86
6 M 1.8 LEV 264 32 69 11 83 70 0.10 2.30 )1.03 0.11
AEDs, antiepileptic drugs; VPA, valproic acid; CLB, clobazam; LEV, levetiracetam.
aNonfasting.
bBased on the food record, laboratory values, and anthropometric measurements from the 4-month LGIT follow-up appointment.
cDuring the fourth month of dietary therapy, VPA was discontinued and CLB was increased.
3
Low Glycemic Index Treatment and Angelman Syndrome
Epilepsia, **(*):1–5, 2012
doi: 10.1111/j.1528-1167.2012.03537.x
Discussion
This prospective study indicates that the LGIT is highly
effective in treating Angelman syndrome–related epilepsy.
After 4 months of dietary therapy, five of six children experienced
>80% seizure frequency reduction. Beyond the prospective
trial window, it was also clinically observed that all
five patients who remained on the diet experienced >90%
seizure frequency reduction at 1 year of LGIT therapy.
Despite the small sample size, these data suggest a potentially
higher degree of LGIT efficacy in the Angelman syndrome
population compared to that seen in the general
epilepsy population (44% of cases with >90% reduction at
1 year) (Muzykewicz et al., 2009).
Although it has not yet been systematically evaluated in
the clinical setting, the LGIT is consistently described by
parents and caregivers as more palatable and easier to incorporate
into everyday life than the KD. This observation is
consistent with the results of a large Angelman retrospective
cohort study, which showed a higher percentage of individuals
sustaining ongoing LGIT treatment as compared to the
KD (57% vs. 19%) (Thibert et al., 2009). Furthermore, the
Angelman syndrome population may demonstrate greater
adherence to dietary restrictions due to the primary and consistent
role that parents and caregivers play in food choice.
It is possible that this tighter adherence may contribute to
the increased efficacy of the LGIT observed in Angelman
syndrome.
When baseline and 4-month follow-up EEG studies were
compared, all cases showed improvement in one or more of
the following quantitative and qualitative indices: generalized
slowing of the background rhythm, epileptiform
discharges, and notched delta activity. These changes, representing
a reduction in cortical irritability, are consistent
with the reduction in observed clinical events reported in
this trial.
One subject, case 4, did experience a moderate increase
in seizure frequency during the initial weeks of the trial,
prior to the reduction that was later observed. We hypothesize
that the significant metabolic change, from a high
Table 2. Average weekly seizure frequency on the low glycemic index treatment (LGIT) for Angelman syndrome
cohort
Case Baseline 1 m 2 m 3 m 4 m LGITa
1 0.4 0.0 0.0 0.0 0.0 Seizure Free
2 15.1 0.0 0.0 0.0 0.0 Seizure Free
3 4.6 0.0 0.0 0.0 0.0 Seizure Free
4 4.3 9.6 5.5 5.3 3.9 <50%
5 5.3 2.3 0.3 1.0 0.4 >90%
6 30.9 8.3 6.2 0.5 3.9 80–90%
aBased on a comparison of seizure frequency for the fourth month of LGIT therapy with the baseline frequency.
Table 3. Electroencephalography data and change in seizure frequency for children with Angelman syndrome on
the low glycemic index treatment (LGIT)
Background (Hz) Epileptiform activity Occipital Notched delta activity
Case Baseline LGITa Baseline LGIT Baseline LGIT
1 4.5–5.5 4.5–5.5 Frequent generalized
2.0–2.5 Hz spike and
wave activity in sleep
No discharges Notched delta Slightly less frequent
activity
2 4.0–5.0 5.0–6.0 No epileptiform
discharges
No epileptiform
discharges
Notched delta Slightly less frequent
activity
3 4.5–6.5 5.0–7.0 Occasional runs of
2.0–2.5 Hz generalized
spike and wave activity
Occasional runs of
2.0–2.5 Hz generalized
spike and wave activity
Notched delta Notched delta
4 5.0–6.0 5.0–6.0 Frequent multifocal and
generalized discharges
No discharges Notched delta Notched delta
5 4.5–5.5 4.5–5.5 No epileptiform
discharges
No epileptiform
discharges
Notched delta, at times
with a classic ‘‘spike and
wave’’ appearance
Typical morphology
6 4.0–5.0 4.0–5.0 Rare bursts of
2.0–2.5 Hz generalized
spike and wave activity
No discharges Notched delta Notched delta
aBased on the electroencephalography data from the 4-month LGIT follow-up appointment.
4
R. L.Thibert et al.
Epilepsia, **(*):1–5, 2012
doi: 10.1111/j.1528-1167.2012.03537.x
carbohydrate intake to an extremely low intake, may induce
a transient systemic stress, which in some individuals could
result in a brief period of increased cortical irritability and
reduced seizure threshold. This subject had the highest
serum b-hydroxybutyrate and the lowest serum glucose,
which correlates with his having the lowest percentage of
calories from carbohydrates while on the diet. This rapid
change perhaps explains why he, more so than the other subjects,
may have had a transient increase in seizure activity
before experiencing a seizure reduction, due to more significant
changes in metabolism. The exact mechanism of action
for dietary therapy is still unknown, although low, stable
glucose and insulin levels likely play a role. Past studies
have shown that ketosis does not improve seizure outcome
with the LGIT (Pfeifer & Thiele, 2005).
To date, there is insufficient quantitative data to determine
the effects of the LGIT on the adaptive living skills of
a child with Angelman syndrome. Parental observation suggests
general improvement in skills; however, additional
studies are needed to investigate this trend and to delineate
the specific developmental domains affected by the LGIT.
The clinical courses of the four subjects who received diet
education but did not start the LGIT each highlight an
important clinical concept of dietary interventions for epilepsy
care. The first case, with a seemingly direct link
between improved nutrient intake and reduced seizure frequency,
powerfully demonstrates the influence of adequate
nutrition on systemic stress and, in turn, seizure activity.
The second case illustrates that when clinicians are selecting
a treatment protocol, specifically deciding between LGIT
and KD, patients with a g-tube are always placed on KD due
to ease of administration. Furthermore, although the efficacy
of LGIT in previous studies seems to approach that of
the KD, additional experience is needed to determine if the
LGIT is as effective as the KD.
The third case, where the family moved overseas, demonstrates
the need for routine clinical follow-up with both a
neurologist and dietitian. Side effects including constipation
and metabolic acidosis are not uncommonly seen with LGIT
therapy, and continuing dietary treatment without addressing
these side effects could result in an adverse outcome.
Therefore, especially when working with a nonverbal
patient population, close clinical follow-up is imperative.
In the fourth case, the family did not initiate the LGIT due
to financial limitations. Although the diet is not extremely
expensive, with the reduction of carbohydrates (cereal,
pasta, rice), daily food costs for the child often increase. The
KD can be more cost effective, when provided enterally, as
ketogenic formulas are covered by some insurance plans.
Additional research into the treatment of Angelman syndrome–
related epilepsy is needed; however, of the treatments
available, the LGIT may be one of the safest, most
effective, and best tolerated options. Although this study is
too small to make definitive recommendations, based on
these data, LGIT dietary therapy should be considered as
one of the primary seizure treatments for children with Angelman
syndrome.
Acknowledgments
This study was supported by the ASF.
Disclosure
None of the authors has any conflict of interest to disclose. We confirm
that we have read the Journal’s position on issues involved in ethical publication
and affirm that this report is consistent with those guidelines.
References
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doi: 10.1111/j.1528-1167.2012.03537.xia (10 años del +)