3.1.- Una patologia on est implicada.

Modificaci estructural i funcional (100

paraules) (Jose)
Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle error causing
hyperammonemia and orotic aciduria. Clinical diagnosis is generally confirmed by mutation
detection. However, in approximately 20% of the patients, no mutation is found by conventional
mutation-searching strategies, which fail to detect deletions spanning at least a whole exon,
large rearrangements, or mutations at non-coding regions. To detect large deletions or
duplications, we have applied the multiplex ligation-dependent probe amplification (MLPA)
methodology to three OTCD patients (two females and one male). MLPA revealed copy number
alterations of OTC exons in all of them. The two females were found to be heterozygous for
deletions of either exon 2 or exons 6-9, and the male was confirmed to lack all OTC exons.
Females' characterization of the deletion breakpoints by long polymerase chain reaction and
sequencing revealed the mutations c.78-3544_217-129del5921 and c.541-600_1005 +
1880del10862 corresponding to exon 2 and exon 6-9 deletions, respectively. Examination of the
deletion-flanking regions suggests that exon 2 deletion probably resulted from replication
slippage facilitated by a secondary structure formed by two inverted Alu repeats, whereas an
Alu-Alu homologous recombination was probably responsible for the exon 6-9 deletion. This
work contributes to the identification of novel disease-causing mutations in OTCD and increases
the knowledge on possible mutational mechanisms generating deletions in OTC.
Aim: Ornithine carbamoyltransferase (OCT) is reported to be a liver-specific marker for the
evaluation of hapatocellular damage. In this study, we investigated its clinical significance in
non-alcoholic steatohepatitis (NASH). Methods: Serum OCT levels were measured by the
ELISA (enzyme-linked immunosorbent assay) method. One hundred and twenty patients with
NASH (18 liver cirrhosis induced by NASH and 9 NASH combined with hepatocellular
carcinoma) were measured. Results: The serum levels of OCT and the ratios of OCT : alanine
amino transferase (ALT) and OCT : aspartate amino transferase (AST) were increased in
parallel with the progression of NASH. Especially, OCT and both ratios were markedly
increased in hepatocellular carcinoma. As for the relationship between fibrosis grade and OCT,
the serum OCT levels and the ratio of OCT : ALT levels were increased in parallel with liver
fibrosis. In NASH patients with ALT within normal range, about 30% showed elevation of OCT.
Conclusion: Serum OCT levels and the ratios of OCT : ALT and OCT : AST increase in parallel
with the progression of NASH. It was suggested that OCT is a useful marker in the progression
of NASH.

Wikipedia
Ornithine transcarbamylase deficiency (OTCD), a urea cycle disorder, is a rare metabolic
disorder, occurring in one out of every 80,000 births. OTCD is a genetic disorder resulting in
a mutated and ineffective form of the enzyme ornithine transcarbamylase.

Symptoms
Like other urea cycle disorders, OTC affects the body's ability to get rid of ammonia, a
toxic breakdown product of the body's use of protein. As a result, ammonia accumulates in
the blood causing hyperammonemia. This ammonia travels to the various organs of the body.
Another symptom of OTC is a buildup of orotic acid in the blood. This is due to
an anapleurosis that occurs with carbamoyl phosphate entering the pyrimidine
synthesis pathway.

Ornithine transcarbamylase deficiency often becomes evident in the first few days of life,
however it can present at middle age.[1] Because newborns are usually discharged from the
hospital within 1-2 days after birth, the symptoms of a urea cycle disorder are often not seen
until the child is at home and may not be recognized in a timely manner by the family and
primary care physician. The typical initial symptoms of a child with hyperammonemia are nonspecific: failure to feed, loss of thermoregulation with a low core temperature, and somnolence.
Symptoms progress from somnolence to lethargy and coma. Abnormal posturing and
encephalopathy are often related to the degree of central nervous system swelling and pressure
upon the brain stem. About 50% of neonates with severe hyperammonemia have seizures.
Hyperventilation, secondary to cerebral edema, is a common early finding in a
hyperammonemic attack, which causes a respiratory alkalosis. Hypoventilation and respiratory
arrest follow as pressure increases on the brain stem. An infant with ornithine transcarbamylase
deficiency may be lacking in energy (lethargic) or unwilling to eat, and have poorly-controlled
breathing rate or body temperature. Some babies with this disorder may experience seizures or
unusual body movements, or go into a coma. In cases where OTC enzyme production is low or
non-existent, death can occur within the first days of life. Complications from ornithine
transcarbamylase deficiency may include developmental delay and mental retardation.
Progressive liver damage, skin lesions, and brittle hair may also be seen. Other symptoms
include irrational behavior (caused by encephalitis), mood swings, and poor performance in
school. In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be
triggered. by illness or stress at almost any time of life, resulting in multiple mild elevations of
plasma ammonia concentration [Bourrier et al 1988]. The hyperammonemia is less severe and
the symptoms more subtle. In patients with partial enzyme deficiencies, the first recognized
clinical episode may be delayed for months or years. There is an incidence of 1 in 70000 in
adults of ornithine transcarbamylase deficiency. In some affected individuals, signs and
symptoms of ornithine transcarbamylase may be less severe, and may not appear until later in
life. Some female carriers become symptomatic later in life in times of metabolic stress. This
can happen as a result of anorexia, starvation, malnutrition, pregnancy or even (in at least one
case) as a result of gastric bypass surgery. It is also possible for symptoms to be exacerbated
by extreme trauma of many sorts, including, (at least in one case) adolescent pregnancy
coupled with severe stomach flu. Despite late presentations in
adulthood, hyperammonemia, encephalopathy, cerebral edema and death can occur.

Genetics
Ornithine transcarbamylase deficiency is an X-linked recessive disorder caused by a number of
different mutations in the OTC gene. Since the gene is on the X chromosome, females are
primarily carriers while males with nonconservative mutations rarely survive past 72 hours
of birth. Half of those survivors die in the first month, and half of the remaining by age 5.
Prognosis is less clear in cases of adult onset OTCD, as detection of the disease is almost
universally post symptomatic.[2]

Treatment
Since the disease results in an inability to handle large amounts of nitrogen load, the treatment
includes strategies to decrease the intake of nitrogen (low-protein diet), prevention of excessive
body protein breakdown during acute illnesses (hydration and nutrition) and administration of
medications scavenging nitrogen (sodium benzoate and sodium phenylbutyrate). These form
benzoyl-CoA and phenylacetyl-CoA which respectively help clear glycine (to hippurate) and
glutamine (to phenylacetylglutamine).[3] These conjugates are excreteable and functionally help

replace urea as an excretion method. Some patients may need to have supplemental amino
acids (arginine, citrulline, valine, leucine, isoleucine). Arginine in particular may be useful due to
its role in the urea cycle, but it is also pro-viral and excess nitric oxide (which is synthesized
from arginine) can be problematic[citation needed]. Biotin may also be useful due to its stimulatory
effect on the ornithine transcarbamylase enzyme [4] and its reported ability to reduce ammonia
levels in experimental animal studies.[5]
In cases where the OTC enzyme production is very low or non-existent and treatment consisting
of low-protein diet and dietary supplementation are inadequate, liver transplant may become a
treatment option.
New efforts to combat the illness starts with prenatal treatment to protect the fetus which has
been identified with OTC deficiency through amniocentesis. There is a case report of success
using this approach.[6]

PUBMED
DISEASE CHARACTERISTICS:
Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in
males (but rarely in females) and as a late-onset (partial) disease in males and females. Males
with severe neonatal-onset OTC deficiency are typically normal at birth but become
symptomatic from hyperammonemia on day two to three of life and are usually catastrophically
ill by the time they come to medical attention. After successful treatment of neonatal
hyperammonemic coma these infants can easily become hyperammonemic again despite
appropriate treatment; they typically require liver transplant by age six months to improve quality
of life. Males and heterozygous females with late-onset (partial) OTC deficiency can present
from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a
hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at
any age and in any situation in life. For all individuals with OTC deficiency, typical
neuropsychological complications include developmental delay, learning disabilities, intellectual
disability, attention deficit hyperactivity disorder (ADHD), and executive function deficits.
DIAGNOSIS/TESTING:
Formal diagnostic criteria for OTC deficiency have been established. Confirmation of the
diagnosis in a proband requires ONEof the following findings: 1. A pathogenic OTC mutation; 2.
Decreased OTC enzyme activity in liver; 3. Family history of OTC deficiency AND elevated
urinary orotate after an allopurinol challenge test; OR if 1 and 2 are normal, inconclusive, or not
performed: 4. Elevated urinary orotate after an allopurinol challenge test, which indicates
reduced urea cycle function.
MANAGEMENT:
Treatment of manifestations: Treatment is best provided by a clinical geneticist and a nutritionist
experienced in the treatment of metabolic disease; treatment of hyperammonemic coma should
be provided by a team coordinated by a metabolic specialist in a tertiary care center
experienced in the management of OTC deficiency. The mainstays of treatment of the acute
phase are rapid lowering of the plasma ammonia level to 200 mol/L if necessary with renal
replacement therapy; use of ammonia scavenger treatment to allow excretion of excess
nitrogen via alternative pathways; reversal of catabolism; and reducing the risk of neurologic
damage. The goals of long-term treatment are to promote growth and development, and to

prevent hyperammonemic episodes. In severe, neonatal-onset urea cycle disorders, liver

transplantation is typically performed by age six months to prevent further hyperammonemic
crises and neurodevelopmental deterioration. In females and males with partial
OTC deficiencyliver transplant is typically considered in those who have frequent
hyperammonemic episodes. Complications of OTC deficiency, including ADHD and learning
disability/intellectual disability are treated according to the standard of care for these conditions
while monitoring for signs of liver disease.Prevention of primary manifestations: If neonatalonset OTC deficiency is diagnosed prenatally, intravenous (IV) treatment with ammonia
scavengers within a few hours of birth (before the ammonia level rises) can prevent a
hyperammonemic crisis and coma. For preventive measures after the neonatal period see
Treatment of manifestations. Prevention of secondary complications: Avoid over-restriction of
protein/amino acids; use gastrostomy tube feedings as needed to help avoid malnutrition;
practice careful hand hygiene among all that have contact with the patient to minimize risk of
infection; give immunizations on the usual schedule, including annual flu vaccine; provide
multivitamin and vitamin D supplementation; and use antipyretics appropriately (e.g., ibuprofen
is preferred over acetaminophen because of the potential for liver toxicity). Surveillance: At the
start of therapy, routine measurement of plasma ammonia and plasma amino acids. Assess liver
function (depending on symptoms) every three to six months or more often when previously
abnormal. Perform neuropsychological testing at the time of expected significant developmental
milestones.Agents/circumstances to avoid: Valproate, haloperidol, systemic corticosteroids,
fasting, and physical and psychological stress. Evaluation of relatives at risk: If the diseasecausing mutation in the family is known and if prenatal testing has not been performed, it is
appropriate to perform molecular genetic testing on at-risk newborns (males and females) as
soon after birth as possible so that the appropriate treatment or surveillance (for those with the
family-specific mutation) can be promptly established. Pregnancy management: Heterozygous
females are at risk of becoming catabolic during pregnancy and especially in the postpartum
period. Those who are symptomatic need to be treated throughout pregnancy as necessary;
those who are asymptomatic need to avoid catabolism in the peripartum and postpartum
periods and should be treated as needed.
GENETIC COUNSELING:
OTC deficiency is inherited in an X-linked manner. If an affected male reproduces, none of his
sons will be affected and all of his daughters will inherit the mutation and may or may not
develop clinical symptoms related to the disorder. Heterozygous females have a 50% chance of
transmitting the disease-causing mutation with each pregnancy: males who inherit the mutation
will be affected; females who inherit the mutation may or may not develop clinical findings
related to the disorder. Carrier testing for females at risk of being heterozygous and prenatal
testing for pregnancies at increased risk are possible if the OTC mutation has been identified in
an affected family member.

Bibliografia
Autors

ttol

any

revista

vol.

Pps.