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