Akademik Veri Yönetim Sistemi
INTERNATIONAL INBORN ERRORS OF METABOLISM AND NUTRITION CONGRESS, İstanbul, Türkiye, 10 - 14 Nisan 2019, ss.303-306
Urea cycle disorders (UCD) are inborn errors of metabolism of the nitrogen detoxification
pathway. Six major enzymes and two transporters are involved in the cycle. Mutations
leading to impaired activity of one of these eight enzymes or transporters are responsible for
the diseases known as UCDs.
Citrin deficiency is a recessively inherited metabolic disorder characterized by agedependent
clinical manifestations: neonatal intrahepatic cholestasis (NICCD: OMIM
605814), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia
(CTLN2: OMIM 603471) (1,2). Most of the patients with citrin deficiency show a resolution
of symptoms but some patients may have persistent severe symptoms and require liver
transplantation. Citrin deficiency was first reported in Japan, but later was recognized as a
worldwide disease with high prevalence in East-Asian countries.
Patients with NICCD complicated with galactosemia or cholestasis have been treated with
lactose (galactose)-free formula which contains medium-chain triglyceride (MCT)
supplemented with fat-soluble vitamins (3,4). For CTLN2, clinical benefit has been
demonstrated with liver transplantation (5). Recently, a favorable result was reported in one
patient with therapy using sodium pyruvate and arginine under the low carbohydrate formula
(6).
Herein, we report four patients with citrin deficiency to draw attention to early clinical
response with dietary treatment
Patient 1-2
Two of the patients who are twin boys born at 38 weeks gestational age referred to
hospital when National Newborn Screening tests had revealed hyperphenylalaninemia
(patient 1 5.5 mg/dl, patient 2 2.6 mg/dl-N <2 mg/dl) on postnatal 10th day. The plasma
quantitative amino acid analysis showed elevated citrulline 376 μmol/L (N 10-50 μmol/L),
glutamine 323 μmol/L (N 21-150 μmol/L) and threonine 685 μmol/L (N 55-220 μmol/L)
but phenylalanine, arginine and ornithine levels were normal in patient 1; citrulline 243.1
μmol/L (N 10-50 μmol/L) and threonine levels 563.4 μmol/L (N 55-220 μmol/L) were
elevated but phenylalanine, glutamine, arginine and ornithine levels were normal in patient
2. They also had cholestasis and coagulopathy. Twin boys referred to outpatient clinic with
facial and extremity edema on their postnatal 48th day. Their physical examination revealed
jaundice, bilateral periorbital and pretibial pitting edema, hepatosplenomegaly. Laboratory
results showed elevated alkaline phosphatase (ALP), gamma-glutamyl transferase levels
(GGT), hypoalbuminemia and prolonged prothrombin time and INR. In the hospital their diet
was changed from breast milk and infant formula to a special formula containing, 41% of fat
with 19.3% medium chained triglycerides (MCT), 10% protein and 49% carbohydrates with
restricted galactose for energy supply. Bilateral cataracts were detected in both patients. With
dietary treatment edema resolved after 4th day of hospitalization, cholestasis and coagulation
parameters returned to normal after first week and they were discharged after two weeks of
hospitalization. Their parents had consanguineous marriage (1.5 degree cousins) and
molecular gene analysis confirmed homozygous c.995C>T (p.Arg319X, p.R319X) mutation
on exon 10 of SLC25A13 gene. This mutation was associated with neonatal cholestasis due
to citrin deficiency.
Patient 3
The third patient is a female sibling of the twins, born at 33+5 gestational week with
low birth weight and followed in newborn intensive care unit for 37 days due to respiratory
distress. She was exclusively breast fed during that period. Tandem MS revealed elevated
citrulline 283 μmol/L (N<55) and low ornitine/citrulline levels. She referred to hospital on
postnatal 41st day. Even though there was no sign of jaundice and organomegaly, laboratory
results showed liver insufficiency characterized by coagulopathy, cholestasis and
hypoalbuminemia. Bilateral cataracts were detected with ocular examination. Her diet was
arranged as 47% of fat, 10% of protein and 43% carbohydrates with galactose restriction.
Neuromotor development, height and weight percentiles were age appropriate for all three
siblings and their cataracts resolved during dietary treatment.
Clinical and laboratory findings of twins were stable and dietary treatment was
stopped after 3 years of age. Only the patient who is 2 years and 3 months of age is still under
dietary treatment. There was no sign of recurrence of liver insufficiency in any of them.
Patient 4
Jaundice was detected on postnatal 2nd day and had resolved without further
intervention. At the age of 3.5 months old hepatomegaly was detected. Laboratory findings
showed conjugated hyperbilirubinemia and elevated transaminase levels. His feces and urine
colors were normal. The differential diagnosis of neonatal cholestasis showed reducing
substances in urine without any specific findings in thin layer chromatography of
monosaccharides. Succinylacetone was negative in urine organic acids analysis and plasma
quantitative amino acid analysis showed elevated citrulline 61 μmol/L (N: 10-50 μmol/L),
methionine 84 μmol/L (N 9-44 μmol/L), threonine 183 μmol/L (N: 33-160 μmol/L) and
ornithine 133 μmol/L (N: 9-123μmol/L) but glutamine 229 μmol/L (N: 373-709 μmol/L)
and arginine 88.65 μmol/L (N: 18-102 μmol/L) levels were normal. The diagnosis of citrin
deficiency was considered.
There was no consanguineous marriage between his parents. The patient had
cholestasis from newborn period and molecular analysis showed heterozygous
c.74C>A(p.Ala25Glu) at 3rd exon and c.1359G>T (p.Lys453Asn) at 14th exon of
SLC25A13 gene. There was no sign of cataract on ocular examination. The diet was diverted
from breast milk and infant formula to 29% fat from MCT, 13% protein and 58%
carbohydrates with restricted galactose. The dietary treatment was stopped after 3 years of
age due to stability of clinical and laboratory findings.
Three of our patients referred with cholestatic jaundice, coagulation defects and
cataracts. Scaglia et al reported all NICCD patients presented with cholestatic jaundice and
twelve of sixteen subjects in their cohort had prolonged prothrombin time (7). Typical
profiles of multiple aminoacidemia, such as high citrulline, threonine, methionine and
tyrosine, in such patients seem to be relatively characteristic (8). Amino acid analysis our
patients showed elevated levels of citrulline, threonine and methionine. These profiles of
NICCD were significantly different from patients with INH and biliary atresia (8). Both
cholestatic hepatitis and neonatal liver failure often show nonspecific multiple
aminoacidemia.
Majority of the studies on SLC25A13 mutations are from China. 851_854del4,
IVS16ins3kb, 1638-1660dup mutations are the most common with a frequency of 42.41%,
16.46% and 6.33 (9). The genetic heterogeneity of Korean patients was characterized by the
highest frequency of mutation: IVS16ins3kb, and three novel mutations of SLC25A13 were
identified (8). Molecular gene analysis of our patients confirmed homozygous c.995C>T (p.
Arg319X, p. R319X) mutation in twin boys and compound heterozygous c.74C>A(p.
Ala25Glu) c.1359G>T (p. Lys453Asn) mutations of SLC25A13 gene for the 4th patient.
These were different from the mutations detected in patients from Eastern Asia.
We present four cases including three siblings with NICCD treated with a lactose
(galactose)- restricted and MCT-supplemented formula. The diet management with the high
protein, lactose-free diet with low carbohydrates and the
introduction of medium chain fatty acids (MCT) is helpful for our cases. This is compatible
with reported cases.The biochemical abnormalities began to improve within a month and
returned to a normal range within six months after switching the formula to a soy based or
lactose free formula milk in 15 out of 16 patients (7). Therapy were required until age of 1
year old by which time all laboratory findings were nearly normalized for 4 patients
(Hayasaka et al. 2010). An MCT-containing formula induced rapid improvement in our
patients. All these data suggests that early treatment is highly effective and longterm
administration is not required.
To conclude, early dietary intervention with galactose-restricted and medium-chain
triglyceride supplemented formula is very effective in improving clinical symptoms in
neonatal intrahepatic cholestasis caused by citrin deficiency and attaining metabolic
normalcy.