Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in

argininosuccinate synthetase Argininosuccinate synthase or synthetase (ASS; ) is an enzyme that catalyzes the synthesis of argininosuccinic acid, argininosuccinate from citrulline and aspartic acid, aspartate. In humans, argininosuccinate synthase is encoded by the ''ASS ...

, an enzyme involved in excreting excess

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...

from the body. There are mild and severe forms of the disease, which is one of the

urea cycle disorders The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts highl ...

Signs and symptoms

Signs and symptoms of CTLN1 in infants are caused by increasing levels of

ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...

in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

and

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

and include excessive

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

, refusal to eat, irritability, increased

intracranial pressure Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury (mmHg) and at rest, is normally 7–15 Millimeter of mercury, mmHg ...

, and worsening

lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

respiratory distress Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...

hepatomegaly Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...

, and

cerebral edema Cerebral edema is excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compressio ...

. These symptoms appear within days of birth in the more severe forms of the disease with complete deficiency of the enzyme. As ammonia accumulates further, the affected infant may enter a hyperammonemic

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...

, which indicates neurological damage and can cause

developmental delays Specific developmental disorders (SDD) was a classification of disorders characterized by delayed development in one specific area or areas.Ahuja Vyas: ''Textbook of Postgraduate Psychiatry'' (2 Vols.), 2nd ed. 1999 Specific developmental disorders ...

cognitive disabilities There are a variety of disabilities affecting cognitive ability. This is a broad concept encompassing various intellectual or cognitive deficits, including intellectual disability (formerly called ''mental retardation''), deficits too mild to pr ...

cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sensa ...

hypertonia Hypertonia is a term sometimes used synonymously with spasticity and rigidity in the literature surrounding damage to the central nervous system, namely upper motor neuron lesions. Impaired ability of damaged motor neurons to regulate descending ...

spasticity Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles. ...

, ankle

clonus Clonus is a set of involuntary and rhythmic muscular contractions and relaxations. Clonus is a sign of certain neurological conditions, particularly associated with upper motor neuron lesions involving descending motor pathways, and in many cas ...

, seizures, and liver failure. Milder forms of the disease are caused by partial arginosuccinate synthetase deficiency and may manifest in childhood or in adulthood. Symptoms of mild CTLN1 include

failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

, avoidance of high-protein foods,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

, worsening lethargy, and vomiting. Hyperammonemic coma can still develop in these people. CTLN1 can also develop in the perinatal period.

Genetics

ASS1 Argininosuccinate synthetase is an enzyme that in humans is encoded by the ''ASS1'' gene. The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene ...

'' is the gene mutated in citrullinemia type I. Mutations in this gene have an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

mode of inheritance.

Pathogenesis

Arginosuccinate synthetase is an enzyme in the

urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts highl ...

, which removes excess ammonia from the body. When it is deficient, either fully or partially, ammonia can build up and cause the signs and symptoms of CTLN1.

Diagnosis

As one of the urea cycle disorders, citrullinemia type I needs to be distinguished from the others:

carbamoyl phosphate synthetase deficiency Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in ...

, argininosuccinic acid lyase deficiency,

ornithine transcarbamylase deficiency Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder is the final enzyme in the proximal portion of the urea cycle, re ...

arginase deficiency Argininemia is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a buildup of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels b ...

, and

N-Acetylglutamate synthase deficiency ''N''-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder. Signs and symptoms The symptoms are visible within the first week of life and if not detected and diagnosed correctly immediately consequences are fatal. ...

. Other diseases that may appear similar to CTLN1 include the organic acidemias and citrullinemia type II. To diagnose CTLN1, a blood test for citrulline and ammonia levels can indicate the correct diagnosis; high levels of both are indicative of this disorder. Newborns are routinely screened for CTLN1 at birth. A genetic test is the only definitive way to diagnose it.

Treatment

The main treatments for CTLN1 include a low-protein, high-calorie diet with amino acid supplements, particularly

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

. The Ucyclyd protocol, using buphenyl and ammonul, is used for treatment as well.

Hyperammonemia Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammonia is a substance that contains nitrogen. It i ...

is treated with

hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...

; intravenous arginine,

sodium benzoate Sodium benzoate is the sodium salt of benzoic acid, widely used as a food preservative (with an E number of E211) and a pickling agent. It appears as a white crystalline chemical with the formula C6H5COONa. Production Sodium benzoate is commo ...

, and sodium phenylacetate. In some cases,

liver transplantation Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...

may be a viable treatment.

L-carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, an ...

is used in some treatment protocols.

Epidemiology

1 in 57,000 babies in the US are affected.

References

External links

{{Medical resources , ICD10 = E72.2 , ICD9 = , ICDO = , OMIM = 215700 , DiseasesDB = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = , GeneReviewsNBK = , GeneReviewsName = , Orphanet = 247525 Urea cycle Inborn errors of metabolism Rare diseases