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Introducción:
en
cualquier
niño con dificultad de
alimentación , vómitos,
ictericia, falla de
crecimiento, apnea ó
taquipnea, hipotonía o
hipertonía, convulsiones,
letargia ó coma debe
considerarse alguna de las
siguientes
enfermedadess:
-
infección ,
-
disfunción
cardiopulmonar u otras
causas de
hipoxemia
-
toxinas
-
trauma
-
anomalías
cerebrales congénitas
estructurales ó
-
error congénito del
metabolismo.
Incidencia:
-
La
incidencia sumada de
errores congénitos
del metabolismo es de
hasta 1 niño cada
1.000
nacimientos.
-
En
muchos casos solo el rápido
diagnóstico y manejo
pueden prevenir la
muerte ó importante
morbilidad.
-
Deben
realizarse
inmediatamente exámenes
de laboratorio como
gases sanguíneos,
glicemia,
electrolitos, lactato,
amonio, cuerpos cetónicos
en orina.
Herencia:
+
La
mayoría se heredan como
rasgos autosómicos
recesivos
+ Algunos
son ligados al cromosoma X
(Ej; deficiencia de
transcarbamilasa de
ornitina)
Diagnóstico
-
Historia familiar
detallada puede revelar un
familiar afectado con enfermedad
similar .
-
El
familiar afectado es pariente del mismo sexo
(autosómica recesiva)
ó una
madre u otra mujer
levemente afectadas en
enfermedad ligada al sexo.
-
Algunas
patologías son causadas
por mutaciones del DNA
mitocondrial y se observa
la transmisión materna a
todos sus niños .
-
Debe
prestarse especial atención
a
mortinatos , muertes inexplicadas, y enfermedades neurológicas ó desarrollo retrasado
de algún grado o
severidad.
-
La enfermedad materna en el embarazo tambien se ha asociado con
enfermedades metabólicas
específicas . Por ejemplo hígado
graso agudo del embarazo e
hipertensión, enzimas hepáticas
elevadas , trombocitopenia
(HELLP) pueden ocurrir en una madre heterocigota portadora de un feto con
deficiencia de cadena
larga 3-hidroxiacyl-CoA
deshidrogenasa (LCHAD)
.
Signos
y síntomas:
-
Los
síntomas generalmente
ocurren postnatalmente
después de un intervalo
de aparente buena salud
después de un embarazo
normal.
-
El intervalo puede
ser tan corto como pocas
horas ó puede ser de
varios días o más largo.
-
El niño puede estar bien
hasta que sufre un insulto
catabólico (infección,
ayuno, deshidratación)
o una carga proteica
o de carbohidratos
excesiva.
-
La
irritabilidad y dificultad
de alimentación pueden
asociarse con succión
descoordinada y sudoración
ó tono muscular anormal.
-
Pueden
ocurrir vómitos severos y
persistentes y
convulsiones.
-
Estas pueden incluir staring spells, eye rolling or myoclonus y
diversas combinaciones de
anomalías del tono ,
temblores, letargia y
llanto débil.
-
Los niños más
severamente afectados
progresan de letargia a
coma a episodios de apnea
y muerte .
-
A
menos que se sospeche
de un error congénito
del metabolismo el
niño puede ser mal
diagnosticado como
encefalopatía
hipóxico isquémica,
hemorragia
intraventricular,
sepsis,
insuficiencia
cardíaca ó
enfermedad gastrointestinal
como estenosis
pilórica u
obstrucción intestinal
.
-
Sepsis
por Escherichia coli es frecuente en niños con galactosemia
y la anorexia e
ictericia de esta
patología pueden
atribuirse
incorrectamente solo a
sepsis .
-
Hemorragia
pulmonary ó alcalosis
respiratoria primaria
pueden verse en defectos
del ciclo de la urea
-
Electroencefalografía
puede sugerir encefalopatía
difusa no específica.
Hallazgos
físicos:
-
Es
esencial un examen
ocular detallado
(Table 1).
-
Puede
haber hepatomegalia en
alteraciones del
metabolismo de
carbohidratos (galactosemia,
glicogenosis,
intolerancia
hereditaria fructosa),
peroxisomal disorders,
tirosinemia,
enfermedad Niemann-Pick
, enfermedad Gaucher ,
inborn errors of
bile acid metabolism,
neonatal hemochromatosis,
some forms of
congenital lactic acidosis
(mitochondrial respiratory
chain defects), and
other organic acidemias
and fatty acid oxidation
defects that may
have a Reye syndrome-like
presentation.
-
Abnormal,
brittle hair
may be seen in some urea
cycle defects
(argininosuccinic aciduria,
citrullinemia),
holocarboxylase synthetase
deficiency, and
Menkes syndrome (pili
torti).
-
Un
olor inusual de la
orina puede ser
asociado con estas
enfermedades
(Table 2).
-
Ketosis
acompaña muchas de
estas condiciones con
el olor dulce de los
cuerpos cetónicos en
orina.
-
Un
color urinario inusual
tambien puede señalar
alguno de estos
errores (Table 3).
Encefalopatía
sin acidosis metabólica:
-
Algunos
errores congénitos
del metabolismo se
asocian con
encefalopatía ó convulsiones aisladas en período neonatal (Table 4
).
-
If
the degree of
encephalopathy appears
greater than would be
expected from
careful review of the
perinatal history, an
inborn error
should be considered
strongly.
Maple Syrup Urine
Disease (MSUD):
Infants
who have MSUD typically
develop symptoms in the
first few days
to weeks of life after
appearing normal at birth.
Poor feeding and
vomiting may be the
initial symptoms, but
lethargy and progressive
neurologic
deterioration supervene.
The child may be hypotonic
or appear markedly
hypertonic with
opisthotonus. Not all
infants develop
a "maple syrup"
smell. Although ketosis is
prominent, metabolic acidosis
is not often present until
later in the course of
disease.
Mevalonic
Aciduria: Mevalonic
aciduria is a disorder of
cholesterol biosynthesis
that usually is not
associated with metabolic
acidosis. Severe neurologic
involvement may occur in
neonates, but patients
often have
other findings, such as
dysmorphic features,
hepatosplenomegaly, recurrent
fevers, and anemia.
Urea
Cycle Defects
The early clinical course
of patients who have urea
cycle defects is
similar to that in MSUD,
except that hypotonia
typically is
more severe, and a
respiratory alkalosis is
common. Severe hyperammonemia
is the hallmark of these
conditions. However, sepsis
often is suspected
initially, and unless an
ammonia level is
evaluated, these infants
may die of unknown cause
early in the
newborn period. Aside from
the X-linked ornithine
transcarbamylase
deficiency, these
are autosomal recessive
disorders. Transient
hyperammonemia of the
newborn (THAN) is an
important consideration
in the differential
diagnosis of these
conditions. THAN
tends to occur in the
first day of life; urea
cycle disorders typically
present after 1 or 2 days.
Other inborn errors,
including pyruvate
carboxylase deficiency,
organic acidemias, fatty
acid oxidation
defects, lysinuric protein
intolerance, and the
hyperammonemia-hyperornithinemia-homocitrullinuria
syndrome, can
cause marked
hyperammonemia by
secondary inhibition of
urea cycle
function. Standard
metabolic investigations
are usually sufficient
to diagnose these
conditions.
Peroxisomal
Disorders
Infants who have
peroxisomal disorders
(Zellweger syndrome, neonatal
adrenoleukodystrophy)
often exhibit severe
neonatal features,
including craniofacial
dysmorphism, neuronal
migration defects,
pigmentary retinopathy,
profound hypotonia,
seizures, hepatomegaly,
jaundice, and renal cysts.
Short limbs, joint contractures,
and epiphyseal stippling
are characteristic of
rhizomelic
chondrodysplasia punctata.
Evidence of hepatocellular
dysfunction is
common.
Isolated
Seizures
A growing list of
metabolic disorders are
associated with isolated
seizures or
progressive encephalopathy
without obvious
biochemical abnormalities
on routine metabolic
screening (Table 4
).
It is important
to save a sample of
cerebrospinal fluid (CSF)
for specialized
testing in case a common
cause for neonatal
seizures is not
identified. Approximately
two thirds of patients who
have nonketotic
hyperglycinemia exhibit
symptoms within 48 hours
of delivery. Infants
typically present
with lethargy, apnea,
profound hypotonia,
feeding difficulty,
hiccups, and
intractable seizures. The
only consistent
abnormalities are
elevated urine, plasma,
and CSF glycine levels. A
CSF-to-plasma glycine
ratio of greater than 0.08
confirms the diagnosis.
CSF and blood
samples for glycine
analysis must be obtained
as near to
simultaneously as possible
for accurate calculation
of the glycine
ratio. Sulfite
oxidase deficiency may
occur in isolation or
combined with
xanthine oxidase
deficiency. The combined
defects are secondary
to molybdenum
cofactor deficiency.
Patients have seizures
that are
recalcitrant to therapy
starting in the first few
days of life. A
low uric acid level may be
noted in molybdenum
cofactor deficiency,
but other laboratory
findings are normal. A
specific assay
for elevation of plasma or
urine S-sulfocysteine
is required to
make the diagnosis. Infants
who have
pyridoxine-dependent
seizures may present as
early as the first
day of life with
flaccidity, abnormal eye
movements, and
irritability. The
diagnosis is clinical and
is based on
documented response of
seizures to intravenous
pyridoxine (vitamin
B6). The
enzyme 4-aminobutyrate
aminotransferase (GABA
transaminase) catalyzes
the initial step in the
conversion of GABA, a
central nervous
system inhibitory
neurotransmitter, to
succinic acid. Elevated
GABA concentrations in the
central nervous system
result in
neonatal seizures,
lethargy, hypotonia,
hyperreflexia, and a high-pitched
cry. Folinic
acid-responsive seizures
is a newly described
disease of
unknown etiology. Seizures
occur as early as 2 hours
after birth.
High-performance
liquid chromatography
documents a characteristic
peak. Infants
respond to folinic acid
supplementation. Patients
who have guanidinoacetate
methyltransferase
deficiency, a
recently identified
disorder of creatine
metabolism, usually present
in infancy with seizures,
developmental delay, and
extrapyramidal signs,
but symptoms have been
described in neonates. Low
plasma creatinine levels
and elevated
guanidinoacetate are
characteristic. A
reduced CSF glucose
concentration
(hypoglycorrhachia) is
present in the
GLUT-1 deficiency syndrome
(glucose transporter
defect). This
autosomal dominant
disorder causes severe
clinical symptoms, including
seizures, acquired
microcephaly, and
developmental delay.
Patients have become
symptomatic as early as
the third week
of life, but it is unclear
whether symptoms may occur
earlier because of
the paucity of reported
cases.
Encephalopathy
With Metabolic Acidosis
Inborn
errors of metabolism that
are characterized by a
nonspecific encephalopathy
with associated metabolic
acidosis include organic
acidemias, fatty
acid oxidation defects,
and primary congential
lactic acidoses
(Table 5). Distinctive
clinical features are
often absent.
Tabla
5.- Errores congénitos
del metabolismo asociados
con Encefalopatía con
Acidosis metabólica.
Organic
acidemias that present in
the newborn period with
encephalopathy and
severe metabolic acidosis
are virtually
indistinguishable clinically.
Hyperammonemia may be
severe, with ammonia
levels similar
to those encountered in
urea cycle disorders. In
addition, neutropenia
and thrombocytopenia
are common, and sepsis or
a bleeding diathesis may
supervene. Distinctive
odors may be present in
some of these conditions
(Table 2), but often only
the nonspecific sweet
smell of ketone
bodies is noticeable.
Fatty
acid oxidation disorders
may have a Reye
syndrome-like presentation.
Approximately 5% to 10% of
unexplained sudden infant
deaths may be attributed
to these conditions.
Although encephalopathy
may dominate the clinical
picture, multiorgan system
involvement is common,
with infants showing
various degrees of
cardiac, skeletal muscle,
ophthalmologic, and
hepatic involvement.
Hyperammonemia and
lactic acidosis may occur.
Cardiomyopathy is
particularly common
in long-chain defects (Table 6
).
Hepatomegaly and
hepatocellular dysfunction
are typical of these
conditions when they occur
in neonates. A
pigmentary retinopathy is
often present in
long-chain
3-hydroxyacyl-CoA dehydrogenase
deficiency, but it tends
to develop later in
childhood.
Cardiomyopathy
may be present in other
inborn errors of
metabolism, including
organic acidemias,
tyrosinemia, congenital
disorders of
glycosylation, and other
lysosomal storage
disorders, but tends to
occur after the newborn
period. Disorders of
pyruvate metabolism and
mitochondrial disorders
may cause congenital
lactic acidosis. Many
infants who have pyruvate
dehydrogenase deficiency
exhibit dysmorphic
features. Brain
abnormalities, including
cerebral and cerebellar
atrophy, agenesis
of the corpus callosum,
and Leigh syndrome, may be
present. Patients
who have the neonatal form
of pyruvate carboxylase
deficiency have
hepatomegaly,
hyperammonemia,
citrullinemia, and
ketosis. Infants who have
mitochondrial disease
often have lactic acidosis
with an elevated
lactate-to-pyruvate ratio.
Virtually any
organ system may be
affected, either in
isolation or in any
combination, in patients
who have mitochondrial
disease. However,
involvement of the
neuromuscular systems is
especially common.
Cardiomyopathy
: Long-chain
fatty acid oxidation
defects are a significant
cause of
neonatal cardiomyopathy.
Although cardiomyopathy
may occur in
mitochondrial disorders,
onset is often in early
infancy. The
infantile form of Pompe
disease presents between
birth and 6
months of age with muscle
weakness and a rapidly
progressive cardiomyopathy.
Electrocardiography may
show very large QRS complexes
and a short PR interval
due to the electrical
conductive properties
of glycogen.
Phosphorylase b kinase
deficiency is another
glycogen storage
disorder that rarely
causes cardiomyopathy.
Several of the
lysosomal storage
disorders may be
associated with
cardiomyopathy, but
this tends to develop
after the newborn period
(Table 6
).
Liver
Disease: Neonates
who have classic
galactosemia often have a
history of
persistent
hyperbilirubinemia,
hepatomegaly, and
hepatocellular dysfunction.
The hyperbilirubinemia
tends to be unconjugated
initially, but it
becomes mostly conjugated
in later untreated disease.
Patients who have
alpha-1-antitrypsin
deficiency also may
exhibit persistent
neonatal jaundice that may
progress to cirrhosis
over several months. Severe
hepatocellular dysfunction
is common in fatty acid
oxidation defects
and is characteristic of
hereditary tyrosinemia
type I and
neonatal hemochromatosis.
Hereditary fructose
intolerance may
present in the newborn
period with acute liver
dysfunction if
an affected infant is
exposed to fructose.
Hepatomegaly associated
with hypoglycemia
(without encephalopathy)
is characteristic of
glycogen storage disease
type I and some disorders
of gluconeogenesis. Causes
of neonatal liver disease
are shown in Table 7
Dysmorphic
Features: An
increasing number of
inborn errors are being
recognized that may
be associated with
dysmorphic features (Table
8
).
Infants who
have peroxisomal disorders
may have striking facial
dysmorphism and
structural anomalies.
Pyruvate dehydrogenase
deficiency, cholesterol
biosynthetic disorders
(mevalonic aciduria,
Smith-Lemli-Opitz syndrome),
3-hydroxyisobutyric
aciduria, multiple
acyl-CoA dehydrogenase
deficiency (glutaric
aciduria type II),
D-2-hydroxyglutaric aciduria,
and mitochondrial
disorders also may be
associated with
dysmorphic features.
Children who have
congenital disorders of
glycosylation (formerly
carbohydrate deficient
glycoprotein syndrome)
typically exhibit inverted
nipples and an unusual
distribution of fat,
often with suprailiac fat
pads and buttock lipodystrophy.
The coarse features
characteristic of
lysosomal storage
disorders usually evolve
in infancy and early
childhood, but some
of these conditions may
present in the neonatal
period with
hydrops. Therefore, the
presence of dysmorphic
features does
not exclude an inborn
error of metabolism from
diagnostic consideration.
Nonimmune
Fetal Hydrops:Inborn errors of metabolism may be associated with nonimmune fetal
hydrops (Table 9
).
Although the association
of metabolic disorders
that cause anemia with
fetal hydrops is clear,
the cause of
the massive generalized
edema that may accompany
many of these
conditions remains
obscure.
RESUMEN:
In aggregate, inborn
errors of metabolism are a
significant cause
of neonatal distress. A
presumptive diagnosis, or
at least a
narrow differential
diagnosis, may be apparent
after taking into
account family history,
clinical features, and
results of
basic laboratory studies.
The consideration of these
conditions in
any infant who has
nonspecific signs of
distress may lead to
rapid diagnosis and
provide the best chance of
decreasing the morbidity
and mortality associated
with metabolic diseases.
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