Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: SLC25A13
• Condition: Citrin Deficiency
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• SLC25A13 ⇔ 0016602 (citrin deficiency): Moderate Actionability

Actionability Rationale

The experts agreed with the suggested assertion of moderate, given the evidence for effectiveness of this outcome-intervention pair within individuals of specific ancestries. However, the experts were all concerned that the penetrance data for this condition is limited to only symptomatic populations. While it is unclear how penetrant this condition is within a larger unselected population, it is presumed that there is some penetrance among unselected populations.

Final Consensus Scores

Gene Condition Pairs: SLC25A13 ⇔ 0016602 (OMIM:605814)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity due to citrin deficiency / Surveillance by specialists to guide management, including diet, supplements, nitrogen scavengers, emergency planning, and possible transplant	2	2D	2C 1	2	8DC

1. Extrapolated from urea cycle disorders in general.

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Citrin deficiency encompasses two distinct well-recognized phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and type II citrullinemia (CTLN2), and a third intermediate phenotype: failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). Based on newborn screening using mass spectrometry, the observed prevalence of NICCD in Japan is 1:34,000. The observed prevalence of CTLN2 in Japan is 1:100,000-230,000. Incidence of NICCD and CTLN2 elsewhere is unknown. Incidence of FTTDCD was not identified.
Until recently, citrin deficiency was thought to be restricted to Japan; however, it is now recognized to be pan ethic with individuals in Israel, Pakistan, the United States, the United Kingdom, China, and the Czech Republic. [1, 2, 3]

Clinical Features

Citrin deficiency can manifest in newborns and infants as NICCD, in older children as FTTDCD, and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in CTLN2.
NICCD is characterized by cholestasis and variable hepatic dysfunction. Children younger than age one year have a history of low birth weight with growth restriction, intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, hepatic fibrosis, variable (mainly mild) liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia. Clinical presentations include jaundice, full cheeks, and hepato(spleno)megaly.
FTTDCD is characterized by post-NICCD growth restriction before onset of CTLN2. Beyond age one year, many children with citrin deficiency develop special food preferences. Clinical presentations may include appetite loss, growth restriction, hypoglycemia, gastroenteropathy, pancreatitis, and severe fatigue.
CTLN2 is characterized by the individual's preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Manifestations of CTLN2 are sudden and may resemble those of encephalopathy or urea cycle disorders (UCDs) and are often provoked by alcohol and sugar intake, medication and/or surgery. Symptoms may include nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma due to hyperammonemia. Death can result from brain edema. Complications occurring in more than 10% of individuals include: pancreatitis, hyperlipidemia, fatty liver, and hepatoma. Intrahepatic cholestasis may occur in rare cases; however these individuals may have had signs of NICCD or FTTDCD in childhood. Most individuals are thin with a BMI lower than 20 in 90% and below 17 in 40% of individuals. Asymptomatic or presymptomatic individuals with citrin deficiency do not always show biochemical abnormalities. [1, 2, 3, 4, 5]

Natural History

NICCD is generally not severe, although liver transplantation has been required in rare instances. Most children show spontaneous improvement by one year of age with treatment with fat-soluble vitamin supplementation and use of modified formulas. Some children have a progressive course of failure to thrive (FTT) and dyslipidemia, and some develop chronic liver disease such as liver cirrhosis which may become severe or fatal. In some rare cases infants succumb to infection. The male-to-female ratio in NICCD is roughly equal.
Onset of FTTDCD is typically around 1-2 years of age, when many children with citrin deficiency develop a protein-rich and/or lipid-rich food preference and aversion to carbohydrate-rich foods. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2; however individuals with CTLN2 may or may not have a prior history of NICCD or FTTDCD. The proportion of persons with NICCD or FTTDCD that evolves into CTLN2 is unknown. Historically, the time between NICCD and CTLN2 has been considered a silent, apparently healthy phase. However, laboratory and clinical abnormalities have been identified during this time and characterized as FTTDCD.
CTLN2 presents with hyperammonemia in adolescence or adulthood. Presentation is sudden and usually between ages 20 and 50 years. One case series reported the mean age of onset as 34.4 ±12.8 years with a range of 11-79 years. Individuals develop severe CTLN2 with neuropsychiatric symptoms. Pancreatitis may be recurrent. Some individuals present with nonalcoholic hepatic steatosis or develop hepatic fibrosis or hepatocellular carcinoma. In some cases, rapid progression can lead to brain edema and death within a few years of onset if liver transplantation is not possible. Affected individuals may or may not have a prior history of NICCD or FTTDCD. For unknown reasons, the male-to-female ratio of CTLN2 is 2.4 to 1. [1, 2, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs of an individual diagnosed with a phenotype of citrin deficiency, the following are recommended:
NICCD
•Assess the size of the liver and spleen.
•Seek evidence of fatty liver by abdominal imaging.
•Investigate feeding pattern.
FTTDCD
•Perform detailed anthropometric examination and evaluation using age- and sex-matched growth standards.
•Investigate feeding pattern.
CTLN2. Investigate carbohydrate, protein, and lipid composition of the diet. (Tier 4) [1]

In general for UCDs, long-term management aims to maintain stable metabolic control, reduce chronic complications, and achieve as close to normal development and growth as possible. For all UCDs, supplementation of essential amino acids can be considered. A specialist metabolic dietitian should be involved. (Tier 2) [6]

Treatment of manifestations for each phenotype are as follows:
NICCD
Treatment of intrahepatic cholestasis by way of achieving the appropriate protein-fat-carbohydrate (PFC) ratio is crucial for infants with NICCD. Medium chain triglyceride (MCT) fortified milk is necessary for nutritional management. The use of lactose-free milk should be considered in infants with hypergalactosemia. (Tier 4) [7]

The use of lactose-free and MCT-enriched therapeutic formulas, and supplementation with fat-soluble vitamins resolves symptoms in most infants with NICCD by 12 months of age. Some children with NICCD improve without treatment. A study of 4 infants with NICCD treated with lactose-restricted and MCT-supplemented formula found that the formula rapidly improved the clinical condition (cholestasis, jaundice, FTT, steatorrhea, low body weight) and laboratory findings for all individuals. A retrospective investigation of 21 Chinese infants with NICCD found that those treated with therapeutic formulas had catch-upgrowth and biochemical improvement. Early treatment was more effective and did not require long-term administration (between 21 days to 13 months). (Tier 3) [1, 5, 7]

MCT milk can be reduced and lactose restriction can be terminated following the improvement of liver function and cholestasis. The bile acid, ursodeoxycholic acid (UDCA), may be used for infants with persistent and prolonged cholestasis. (Tier 4) [7]

By age one year, protein- and lipid-enriched textured or solid supplements can be introduced. Whether continued treatment beyond a year can reduce the likelihood of the FTTDCD and CTLN2 phenotype is currently unknown. (Tier 4) [1]

Since severe infection has been reported to be a lethal complication in some individuals, active infection control is recommended in infants with NICCD. (Tier 4) [1]

Liver transplantation should be considered for infants with NICCD with severe/progressive and unmanageable liver failure. (Tier 4) [4, 7]

FTTDCD
Few treatment measures have been described for this citrin-deficient phenotype. In addition to dietary treatment, anecdotal evidence suggests that administration of sodium pyruvate may be effective in correcting growth restriction. (Tier 4) [1]

CTLN2
To prevent hyperammonemia a diet rich in protein and lipids and low in carbohydrates is recommended. Unlike other UCDs, low-protein/high-caloric (high carbohydrate) diet is harmful for individuals with CTLN2. A high carbohydrate diet may result in hyperammonemia, fatty liver, and hypertriglyceridemia. (Tier 3) [1]

Arginine and sodium pyruvate administration may be effective in preventing hyperammonemic crises (by reducing blood ammonia concentrations) and fatty liver, thereby delaying the need for liver transplantation. (Tier 4) [1, 3]

Administration of sodium pyruvate has been reported as effective in decreasing frequency of hyperammonemic episodes and improving growth in several case reports. (Tier 3) [1]

To date the most successful therapy for symptomatic individuals has been liver transplantation which prevents episodic hyperammonemic crises, corrects the metabolic disturbances, and eliminates preferences for protein rich foods. Nearly all individuals with CTLN2 required liver transplantation in the past; however the introduction of arginine and sodium pyruvate has altered the situation. (Tier 3) [1, 3]

A review of 77 CTLN2 case reports (age of onset: mean 34.1 years, range 12-60 years) reported that 21 individuals were treated with liver transplantation, and all showed good prognosis with a survival rate of 100%. Of the 56 individuals that received conservative treatment (without liver transplantation), 29 died within a few years of onset (48% survival rate). Survival of individuals treated with conservative medical treatment improved to 76.5% when limited to individuals treated after 2003 compared to 39.5% survival prior to 2002. This improvement was attributed to the identification of the SLC25A13 gene as the cause of CTLN2 and development of more effective conservative therapy (arginine with carbohydrate-restricted diet). In addition, recent case reports have found that arginine and sodium pyruvate administration combined with a carbohydrate-restricted diet may be effective therapy for CTLN2. (Tier 5) [8]

For acute management of individuals with citrin deficiency, prompt assessment and meticulous treatment of acute hyperammonemia is important as there is a high risk of serious complications. The management of acute illness in citrin deficiency is different from other metabolic disorders as these individuals have a special oral emergency regimen consisting of a high protein, high fat, low carbohydrate diet. Glucose should only be given if individual has proven and symptomatic hypoglycemia. Contact local metabolic unit for further advice about management. (Tier 2) [9]

In general, for UCDs, emergency regimen for treatment of intercurrent illness is recommended. Management of individuals during biological stressors such as surgery and pregnancy is recommended. (Tier 2) [6]

Surveillance

In general in UCDs, individuals require lifelong monitoring by a multidisciplinary team. Clinical and biochemical monitoring depends on age and metabolic status. Young and severely affected individuals should be seen at least every 3 months, while older or less severely affected individuals may only need annual appointments. Regular review and monitoring of diet, growth, and clinical status are essential. (Tier 2) [6]

Surveillance for each phenotype are as follows:
NICCD
During infancy, total bile acids, α-fetoprotein (AFP), blood sugar, coagulation parameters, blood amino acids, ammonia, blood count, and general biochemistry in addition to growth parameters (body height and weight) should be checked every 1 or 2 months, depending on the condition of the individual. Abdominal echo should be used to detect possible fatty liver. (Tier 4) [7]

In order to detect deficiencies in lipid-soluble vitamins, tests should include measurement of serum calcium concentrations, bone X-ray to assess any rickets, ophthalmological examination, and the tendon reflex test. (Tier 4) [7]

For those with NICCD who have no special medical concerns other than dietary management, close medical observation is recommended since they still have biochemical alterations even at the silent stage. (Tier 3) [1]

FTTDCD
To monitor for emergence of the FTTDCD phenotype during early childhood (>1 year of age), close surveillance of anthropometric indices (e.g., height, weight, and head circumference); and serum lipid levels including triglycerides, total cholesterol, HDL-cholesterol, and LDL-cholesterol) is appropriate. The following should be measured every few months:
•Blood count, general biochemistry, blood amino acids, and blood sugar
•Plasma ammonia (especially in the evening or 2 hours after feeding)
•Plasma citrulline
•Serum pancreatic secretory trypsin inhibitor (PSTI). (Tier 4) [1, 7]

Diet should be evaluated on a regular basis. Individuals should consume the proper amount of energy with the appropriate PFC ratio. Infants and children may need supplementary food in the morning, afternoon, and/or before sleep, in addition to the main three meals. It is also necessary to explain to school that the children should not be forced to take carbohydrate-rich food at lunch and to stress the importance of supplementary food. Inappropriate diet at school may lead to hunger, fatigue, and hypoglycemia. The similar attention is required for hospital meals. (Tier 4) [7]

Since infants are prone to hypoglycemia, parents are advised to measure the blood sugar level of the infant before feeding as often as necessary. After school age, individuals are advised to go for a medical check-up every 4-6 months. An abdominal echo should be done according to the liver condition as necessary. Diet should be evaluated every 1-2 years even for individuals with adequate total energy intake and PFC ratio. (Tier 4) [7]

Circumstances to Avoid

While glycerol-containing osmotic agents are conventionally used for treatment for hyperammonemia and brain edema, these should be avoided in individuals with citrin deficiency. Glycerol-containing infusions for encephalopathy-related brain edema have resulted in continued and exacerbated deterioration and are contraindicated in those with CTLN2. Degradation of large amounts of glycerol and fructose may disturb liver function. Infusion of high concentration glucose may also exacerbate hyperammonemia and may precipitate liver failure. Mannitol infusion appears to be safer. A retrospective study of 3 adults with CTLN2 treated for brain edema at one institute and an additional 11 adults previously reported found that all 12 adults treated with 10% glycerol (with or without 20% mannitol) died due to rapidly deteriorating encephalopathy and brain edema while the 2 adults who received only 20% D-mannitol recovered with the disappearance of brain edema. (Tier 3) [1, 3, 5]

Although a low-protein/high-caloric diet helps prevent hyperammonemia in other UCDs, it is harmful for individuals with all forms of citrin deficiency. A high-carbohydrate diet may have several downstream biochemical effects, resulting in hyperammonemia, fatty liver, and hypertriglyceridemia and should therefore be avoided. (Tier 3) [1, 7]

Careful attention should be paid to excessive intake/administration of carbohydrate during treatment in acute and/or chronic settings. (Tier 4) [7]

Four infants at and below one year of age with citrin deficiency have received liver transplantation in Japan. In all 4 cases hyperalimentation with high-glucose concentration was the factor that eventually led to the need for liver transplantation. (Tier 3) [7]

Acetaminophen and rabeprazole may trigger CTLN2. (Tier 3) [1, 7]

Alcohol needs be avoided since it can trigger encephalopathy. (Tier 3) [7]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [1, 2, 3]

Prevalence of Genetic Variants

In Japan, the frequency of homozygotes or compound heterozygotes for SLC25A13 pathogenic variants (PVs) is calculated to be 1:17,000-21,000. Carrier or heterozygote rates have been estimated as 1:65-1:67. The estimated frequency in Korea is 1:50,000 and 1:17,000 in China with an estimated carrier frequency of 1:65 in China and 1:112 in Korea, higher than expected given incidence data. (Tier 3) [1, 2, 3, 5]

In a study that performed whole genome sequencing on 3552 individuals from the general population in Japan, the carrier frequency for SLC25A13 PVs was estimated to be between 0.01951 and 0.03022. This was much higher than the estimated carrier frequency based on the observed incidence rate (0.00685, based on a Japanese newborn screening report on 1,949,987 newborns). (Tier 5) [10]

In Japanese persons with citrin deficiency, 2 PVs account for the majority (~70%) of pathogenic alleles. (Tier 4) [1]

In a cohort of 274 persons with citrin deficiency from 264 Chinese families, 4 PVs account for approximately 85% of pathogenic alleles. (Tier 3) [1]

Only one PV has been found in both Japanese and northern European populations. Some of the 20 PVs identified in Japanese individuals have been found in Chinese, Vietnamese, and Korean individuals with citrin deficiency (NICCD or CTLN2), and different PVs have been found in Israel, the United States, the United Kingdom, and China. (Tier 3) [1]

Between 85%-90% of probands have PVs in the SLC25A13 gene, while the remaining 10-15% are positive for large deletions or duplications in SLC25A13. (Tier 3) [1]

Penetrance

One study of 19 Japanese individuals (median age of 40 years) who presented at the hospital with neuropsychological symptoms, confirmed to have elevated plasma ammonia and citrulline levels, and subsequently genetically confirmed to have CTLN2, reported the following:
•Hepatic steatosis: 17 of 19 individuals (89%)
•Nonalcoholic fatty liver disease prior to neuropsychiatric symptoms: 4 (21%)
•Pancreatitis preceding diagnosis with CTLN2: 5 (26%)
•Previous prolonged neonatal jaundice suggestive of prior NICCD: 1 individual
•Hypertriglyceridemia: 6 (32%)
•Hepatic fibrosis: 12 of the 14 (79%) individuals from whom liver samples were obtained. (Tier 3) [1, 3]

Another study reported on long-term outcomes in 222 Japanese individuals with citrin deficiency, with a total of 74% having confirmed biallelic PVs in SLC25A13. Individuals had been diagnosed with one of the following 3 phenotypes: NICCD (n=192, 91 males/101 females), FTTDCD (n=13, 6 males/7 females) and CTLN2 (n=17, 11 males/6 females). One female with CTLN2 died from pancreatitis (age 54 years). Three adults with CTLN2 developed liver tumor such as hepatoma or hepatocellular carcinoma, 4 individuals (1 NICCD, 3 CTLN2) required a liver transplant (at 9 months, 12 years, 37 years, and 43 years). (Tier 5) [11]

The same study reported the clinical manifestations of Japanese individuals with NICCD. At the time the survey was conducted, the clinical manifestations reported (past and present combined) in individuals who had been symptomatic and diagnosed as infants with NICCD (n=192, median age of onset 1 month) were:
Liver manifestations:
•Cholestasis: 151 (79%)
•Hepatomegaly: 42 (22%)
•Splenomegaly: 5 (26%)
•Fatty liver: 63 (33%)
•Elevated transaminases: 136 (71%)
•Hyperammonemia: 21 (11%)
•Hyperammonemic coma: 1 (0.5%)
•Seizure: 10 (5%)
Non-hepatic manifestations:
•Short stature (< -2.0 SD): 29 (15%)
•Poor weight gain: 62 (32%)
•Anorexia: 22 (11%)
•Nausea/vomiting: 18 (9%)
•Fatigue: 40 (21%)
•Intellectual disability: 7 (4%)
•Hypoglycemia: 57 (30%)
•Hyperlipidemia: 46 (24%)
•Hypoproteinemia: 75 (39%)
•Anemia: 33 (17%)
•Prolonged prothrombin time: 65 (34%) (Tier 5) [11]

A study of the clinical features of 51 citrin-deficient children in China after the NICCD state reported that 3 individuals (6%) died of disease-related complications (hepatic encephalopathy, intracranial infection, disseminated intravascular coagulation), but 46 individuals (94%) diagnosed with NICCD recovered or improved clinically. Of the 46 individuals assessed after the NICCD state:
•15 (33%) showed feeding problems including poor appetite and picky eating habits
•13 (28%) demonstrated FTT
•25 individuals (54%) had dyslipidemia, 9 of whom presented with concurrent FTT and dyslipidemia. (Tier 5) [12]

Relative Risk

No information on relative risk was identified.

Expressivity

No significant correlation between SLC25A13 PV types and decreased level of hepatic enzyme ASS activity/protein or age of onset in individuals with CTLN2 is observed. (Tier 3) [1]

Occasionally a parent may have two SLC25A13 PVs without severe symptoms of CTLN2, a finding in 2 of 48 fathers and one of 54 mothers tested in 163 Japanese families with NICCD. One asymptomatic father has been found to have the same SLC25A13 genotype as his son who had NICCD. (Tier 3) [1]

Reduced penetrance and intrafamilial clinical variability have been observed among families with biallelic SLC25A13 PVs. (Tier 3) [1]

While the male-to-female ratio of NICCD is roughly equal (73:80), the unequal male-to-female ratio of CTLN2 (2.4:1) suggests that among individuals with biallelic SLC25A13 PVs, females are more resistant to the CTLN2 phenotype than males. (Tier 3) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Identified interventions include liver transplantation and/or dietary therapy, ongoing blood monitoring, and avoidance of possible triggers (e.g., medications and alcohol).
Individuals with UCDs require lifelong monitoring by a multidisciplinary team. Long-term treatment of UCDs is challenging for individuals and families because of the poor palatability (particularly of essential amino acids), the volume and frequency of diet and drug administrations. Nasogastric tube or gastrostomy feeding may be necessary to ensure sufficient energy and/or protein intake. Sodium pyruvate is administered orally as a powder, granules, capsules, tablets, or liquid. [6]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

In the US, citrin deficiency is only screened for in 36 states. However, the sensitivity and specificity of screening varies by state, and current newborn metabolic screening cannot reliably identify all cases. (Tier 4) [2]

Studies of Japanese individuals with citrin deficiency have found that between 26-50% of NICCD is detected by newborn screening. (Tier 5) [11]

Clinical diagnosis of FTTDCD is difficult if there is an absence of a history of unique food preferences. (Tier 4) [1]

More than 30% of individuals with CTLN2 have been misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia); others may be diagnosed as having diseases such as hepatoma, pancreatitis, and hyperlipidemia. (Tier 4) [1]

Since CTLN2 exhibits various neuropsychiatric symptoms, it is not uncommon for the initial diagnosis to be epilepsy, depression, or schizophrenia. (Tier 4) [7]

Date of Search: 08.12.2024

Reference List

1. Saheki T, Song YZ. Citrin Deficiency. GeneReviews. (2017) Website: https://www.ncbi.nlm.nih.gov/books/NBK1181/

2. N. Ah Mew, B. C. Lanpher, A. Gropman, K. A. Chapman, K. L. Simpson, C. Urea Cycle Disorders, et al. Urea Cycle Disorders Overview. GeneReviews(. (2019) Website: https://www.ncbi.nlm.nih.gov/books/NBK1217/

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. CITRULLINEMIA, TYPE II, ADULT-ONSET; CTLN2. MIM: 603471: 2016 Nov 10. World Wide Web URL: http://omim.org.

4. Amendola M, Squires JE. Pediatric Genetic Cholestatic Liver Disease Overview. GeneReviews. (1993) Website: https://www.ncbi.nlm.nih.gov/books/NBK584020/

5. Vernon, H. MIM # 605814; CITRULLINEMIA, TYPE II, NEONATAL-ONSET. OMIM® - Online Mendelian Inheritance in Man®. (2020) Website: https://omim.org/entry/605814

6. Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. (2019) 42(1573-2665):1192-1230.

7. Okano Y, Ohura T, Sakamoto O, Inui A. Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: Strategy to prevent CTLN2. Mol Genet Metab. (2019) 127(1096-7206):175-183.

8. Kimura N, Kubo N, Narumi S, Toyoki Y, Ishido K, Kudo D, Umehara M, Yakoshi Y, Hakamada K. Liver transplantation versus conservative treatment for adult-onset type II citrullinemia: our experience and a review of the literature. Transplant Proc. (2013) 45(9):3432-7.

9. British Inherited Metabolic Disease Group (BIMDG). Citrin Deficiency. (2017) Website: https://www.bimdg.org.uk/store/guidelines/ER-HHH-LPI-v5_221725_15042017.pdf.

10. Yamaguchi-Kabata Y, Yasuda J, Uruno A, Shimokawa K, Koshiba S, Suzuki Y, Fuse N, Kawame H, Tadaka S, Nagasaki M, Kojima K, Katsuoka F, Kumada K, Tanabe O, Tamiya G, Yaegashi N, Kinoshita K, Yamamoto M, Kure S, Tohoku Medical Megabank Project Study Group. Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. Hum Genet. (2019) 138(1432-1203):389-409.

11. Kido J, Häberle J, Sugawara K, Tanaka T, Nagao M, Sawada T, Wada Y, Numakura C, Murayama K, Watanabe Y, Kojima-Ishii K, Sasai H, Kosugiyama K, Nakamura K. Clinical manifestation and long-term outcome of citrin deficiency: Report from a nationwide study in Japan. J Inherit Metab Dis. (2022) 45(1573-2665):431-444.

12. Song YZ, Deng M, Chen FP, Wen F, Guo L, Cao SL, Gong J, Xu H, Jiang GY, Zhong L, Kobayashi K, Saheki T, Wang ZN. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. Int J Mol Med. (2011) 28(1791-244X):33-40.