A: daniela marianicerati <marianicerati@yahoo.it>; Autismo
Biologia <autismo-biologia@autismo33.it>
Inviato: Venerdì 19 Ottobre
2012 8:25
Oggetto: R: Re:
[autismo-biologia] Fwd: [2661] Disabilità intellettiva, una app scopre se si
tratta di una malattia rara
Guarda science di
oggi
Ciao
Alberto
Gli
articoli comparsi oggi su Science si inseriscono proprio nella discussione in
atto su questo forum.
Un
lavoro originale parla di una nuova mutazione che porta ad una forma di
autismo potenzialmente trattabile con aminoacidi a catena ramificata e un
articolo di commento prende in considerazione altre forme di autismo da causa
nota tra cui la deficienza di biosintesi di carnitina prevenibile o trattabile
con supplementi di carnitina.
Una
cosa che viene sottolineata è il fatto che in questi errori del metabolismo
non ci sono tratti somatici caratteristici, come per molti altri errori del
metabolismo
For
both disorders, physical examinations are generally normal with
no
dysmorphic features described (as is
true
for most inborn errors of metabolism).
Riporto
l’abstract e alcuni stralci degli articoli
19
OCTOBER 2012 VOL 338 SCIENCE
www.sciencemag.org
Mutations
in BCKD-kinase
Lead
to a
Potentially
Treatable Form of Autism
with
Epilepsy
Gaia
Novarino,1*†
Paul
El-Fishawy,2*
Hulya
Kayserili,3
Nagwa
A. Meguid,4
Eric
M. Scott,1
Jana
Schroth,1
Jennifer
L. Silhavy,1
Majdi
Kara,5
Rehab
O. Khalil,4
Tawfeg
Ben-Omran,6
A.
Gulhan Ercan-Sencicek,7
Adel
F. Hashish,4
Stephan
J. Sanders,7
Abha
R. Gupta,8
Hebatalla
S. Hashem,4
Dietrich
Matern,9
Stacey
Gabriel,10
Larry
Sweetman,11
Yasmeen
Rahimi,12
Robert
A. Harris,12
Matthew
W. State,7
Joseph
G. Gleeson1†
Autism
spectrum disorders are a genetically heterogeneous constellation of syndromes
characterized by
impairments
in reciprocal social interaction. Available somatic treatments have limited
efficacy. We
have
identified inactivating mutations in the gene BCKDK
(Branched
Chain Ketoacid Dehydrogenase
Kinase)
in consanguineous families with autism, epilepsy, and intellectual disability.
The encoded
protein
is responsible for phosphorylation-mediated inactivation of the E1a
subunit
of branched-chain
ketoacid
dehydrogenase (BCKDH). Patients with homozygous BCKDK
mutations
display reductions in
BCKDK
messenger
RNA and protein, E1a
phosphorylation,
and plasma branched-chain amino acids.
Bckdk
knockout
mice show abnormal brain amino acid profiles and neurobehavioral deficits
that
respond
to dietary supplementation. Thus, autism presenting with intellectual
disability and epilepsy
caused
by BCKDK
mutations
represents a potentially treatable syndrome.
Preventable
Forms of Autism?
NEUROSCIENCE
Arthur
L. Beaudet
Inborn
errors of metabolism underlying some
cases
of autism present possibilities for
prevention
and treatment.
The
use of DNA
microarrays
and exome sequencing to detect
pathological
copy number variants (CNVs)
and
point mutations, respectively, is making
progress
in identifying genetic causes of
autism
On
page 394 of this issue, Novarino et
al.
(
5)
use exome sequencing in consanguineous
families
to discover an inborn metabolic
error
associated with autism, epilepsy, and
intellectual
disability, in which the clinical
manifestations
are likely to be treatable or,
even
better, preventable.
Empirical
results reveal that the more
severe
and complex the autistic phenotype,
the
greater the likelihood that a causative
mutation
can be found.
It
has emerged from recent genetic
studies
that the number of different CNV loci
and
individual genes that—when mutated—
can
cause autism ranges into the hundreds,
reflecting
extreme genetic heterogeneity
Novarino
et
al.
identifi ed a point mutation
in
a gene encoding the branched-chain
keto
acid dehydrogenase kinase (BCKDK).
BCKDK
inactivates an enzyme complex
that
converts branched-chain amino acids to
the
corresponding keto acids. Thus, defective
BCKDK
results in unchecked degradation
and
depletion of branched-chain amino
acids.
This is effectively the reverse of the
metabolic
problem present in maple syrup
urine
disease, where deficiency of the same
enzyme
complex leads to toxic accumulation
of
branched-chain amino acids and their
metabolites.
In
a mouse model of BCKDK
deficiency,
similar metabolic and neurobehavioral
abnormalities
are found, and the
animals
improve upon dietary supplementation
with
branched-chain amino acids.
Assuming
that it would be desirable to
prevent
rather than reverse symptoms of
BCKDK
deficiency, newborn screening
could
be explored.
Over
50 inborn errors
of
metabolism are detectable by newborn
screening,
and its use in treatable disorders is
particularly
beneficial
BCKDK
defi ciency is not the first inborn
error
of metabolism to be linked with autism.
Deficiency
of carnitine biosynthesis was
also
reported recently as a likely risk factor
for
autism
carnitine
supplementation might be useful
for
treatment or prevention
The
authors suggest
that
abnormalities of carnitine metabolism
including
intake, loss, transport, or synthesis
may
be important in a larger fraction
of
nondysmorphic autism cases.
For
both disorders, physical
examinations
are generally normal with
no
dysmorphic features described (as is
true
for most inborn errors of metabolism).
Both
could involve neuronal deficiency of
essential
nutrients. Malnutrition is widely
accepted
to contribute to intellectual disability,
and
perhaps specific nutritional deficiencies
(e.g.,
of branched-chain amino acids or
carnitine)
in the brain can lead to abnormal
synaptic
development