Clinical Description
Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia.
Neonatal ("classic") form. The infant appears normal at birth. After an interval of one to a few days, the infant becomes progressively more lethargic, feeds poorly, may vomit, and may develop signs of increased intracranial pressure [Brusilow & Horwich 2001]. Fifty-six percent of infants with classic citrullinemia type I are symptomatic by age four days and 67% by age one week [Bachmann 2003a].
Children diagnosed and referred for appropriate treatment (see Management) survive for an indeterminate period of time, usually with significant neurologic deficits. All children with a peak plasma ammonia concentration greater than 480 µmol/L or an initial plasma ammonia concentration greater than 300 µmol/L have cognitive impairment [Bachmann 2003b]. The longest survival of an untreated infant with classic citrullinemia type I is 17 days.
Non-classic form. The clinical course may be similar to or milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. However, specific ASS1 pathogenic variants may be associated with the non-classic form (see Genotype-Phenotype Correlations and Molecular Genetics). When episodes of hyperammonemia occur, they are similar to those seen in the acute neonatal form, but the neurologic findings may be more subtle because of the older age of the affected individuals. These can include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy, and somnolence. Individuals with hyperammonemia also display respiratory alkalosis and tachypnea [Brusilow & Horwich 2001]. Without prompt intervention, increased intracranial pressure occurs, with increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death.
Liver failure is now recognized as a primary presentation of CTLN1, contradicting established dogma of CNS symptoms as the primary finding [Salek et al 2010, Faghfoury et al 2011, Lee et al 2013, Rüegger et al 2014]. Hepatic dysfunction, when present, is frequently noted at the time of the initial hyperammonemic episode but has also developed in an affected individual who was not experiencing significant hyperammonemia (>250 µmol/L) at the time [Lee et al 2013].
Possible long-term complications. An individual with classic citrullinemia treated with chronic protein restriction and scavenger therapy (see Treatment of Manifestations) developed progressive hypertrophic cardiomyopathy (diagnosed at age 23 years) and bilateral cataracts (diagnosed at age 27 years) [Brunetti-Pierri et al 2012]. No additional individuals with classic CTLN1 have been identified with similar findings. As such, the necessity for cardiac and ophthalmologic surveillance remains controversial until more affected individuals have been studied.
Pregnancy. A healthy woman with untreated CTLN1 underwent two successful pregnancies [Potter et al 2004]; however, women with onset of severe symptoms during pregnancy or in the postpartum period have been reported [Gao et al 2003, Ruitenbeek et al 2003].
Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [
Häberle et al 2009].
Individuals remaining asymptomatic up to at least age ten years have been reported; it appears that they could remain asymptomatic lifelong [Häberle et al 2002, Häberle et al 2003].
Neuroimaging. CT scan of infants with citrullinemia type I demonstrates cerebral atrophy, particularly in the cingulate gyrus, the insula, and the temporal lobes, as well as general cortical hypo-attenuation (i.e., the cortex appears darker than in unaffected individuals) [Albayram et al 2002].
Brain MRI findings in classic citrullinemia include restricted diffusion and T2 signal hyperintensities in the basal ganglia, thalami, and subcortical white matter of the bilateral temporal, parietal, and occipital cortex [Majoie et al 2004, Bireley et al 2012]. Multicystic encephalomalacia and cerebral atrophy have been seen as early as age three to four months in an individual with classic CTLN1 [Lee et al 2013].