At present five urea cycle diseases have been described, each representing a defect in the biosynthesis of one of the enzymes of that metabolic pathway. Four of these diseases-deficiencies of carbamyl phosphate synthetase, ornithine transcar-bamylase, argininosuccinic acid synthetase, and argininosuccinase-have similar clinical presentations (the most severe expression is symptomatic neonatal hyperammonemia, but they may also manifest as episodic changes in mental state, which may appear from infancy to adulthood), which result from the accumulation of urea precursors, principally ammonium and glutamine (1). Arginase deficiency, the least common of the urea cycle disorders (2), is distinct both in laboratory abnormalities, clinical manifestations, and treatment. The first probable case was reported in 1965 by Peralta-Serrano (3), and the first completely documented case was described by Terheggen et al. in 1969 (4).
Hyperargininemia is an autosomal recessive inherited disease, characterized by the accumulation of arginine, the substrate proximal to the metabolic block (1,2). Hyperammonemia occurs neither as commonly nor as severely as the other disorders of this group (1,5). Symptoms are usually noticed in childhood: progressive spastic tetraplegia with predominant involvement of the lower limbs, seizures, ataxia, athetosis, psychomotor regression, hyperactivity, vomiting, hepatomegaly, and growth failure (1,2,5).
The authors describe a case of arginase deficiency that manifested as persistent neonatal jaundice with a biopsy showing hepatic cirrhosis, without neurologic symptoms, which is, to our knowledge, the first reported case with such a clinical presentation.
Our patient was a 2-month-old white girl, the first child of healthy, nonrelated parents, with no history of familial disease. She was born by normal delivery after an uneventful pregnancy, with an Apgar score of 9/10 at the first and fifth minutes, respectively. Physical examination at birth was normal, with weight and length at the 50th percentile and head circumference at the 25th percentile. She was exclusively breast-fed.
Jaundice appeared at the third day and frequent vomiting and regurgitation was present by the end of the first month, although she showed good vitality, maintenance of normal appetite, and good physical growth. Feces and urine were normal colored, and she had no neurologic symptoms.
The infant was sent to us at 2 months of age, for persistent neonatal jaundice and hepatomegaly. On physical examination she presented no dysmorphic features, weight and length at the 50th percentile, head circumference at the 25th percentile, and normal neurological examination. Skin and sclerae were jaundiced. The abdomen was distended, without visible venous circulation or signs of ascites; the liver was palpable 5 cm and the spleen 3 cm below the costal edge. Remaining physical examination was within normal limits.
Laboratory investigation revealed normal blood count, ESR, creatinine, glucose, electrolytes, pH and gases, and urine culture. Other values are shown on Table 1. Abdominal ultrasound confirmed the hepatosplenomegaly; the liver had homogeneous hyperechogenecity and intra- and extrahepatic bile ducts were normal. Amino acid chromatography (ion-exchange chromatography, LKB Biochrom 20) showed an elevated plasmatic arginine level with increased urinary excretion of taurine, glutamine, citruline, cystine, ornithine, lysine, and arginine. Plasma and urinary levels of guanidino compounds (B. Marescau, Antwerp) were high, although samples were taken under an arginine-free diet. Cerebral CT scan was normal and EEG showed occasional diffuse slow-wave bursts.
Liver biopsy, performed at 4 months of age, showed a picture of hepatic cirrhosis with formation of regenerative nodules and marked cholestasis (Fig. 1). Electron microscopy confirmed the severe fibrosis and showed large swollen hepatocytes with dilated endoplasmic reticulum and normal mitochondria.
At 3 months of age she began a normoproteic (2 g/kg/day), hypercaloric (160 kcal/kg/day), arginine-free diet, supplemented with calcium, zinc, and vitamins A, C, D, E, and K, with lowering of arginine and ammonia serum levels. At 6 months she began alimentary diversification with a natural protein intake of 0.5 g/kg/day; the arginine-free amino acid mixture was reduced to 1.5 g/kg/day until 12 months and to 1.0 g/kg/day thereafter. The child is now 26 months old and she has been admitted three times for infectious events (urinary infection, acute gastroenteritis, and bronchiolitis), with transient worsening of hepatic function. She has good vitality, normal neurologic examination (normal mental status and no behavior problems; cranial nerve examination is normal; tonus and deep tendon reflexes are normal at the four extremities), and psychomotor development (she is able to run and climb stairs without aid, to hold a pencil and draw a circle, and to make phrases of four words), although with growth delay (weight 9450 g, length 80 cm, and head circumference 46 cm are now below but progressing parallel to the third percentile). She still has hepatosplenomegaly (liver is palpable 5 cm and spleen 4 cm below the costal edge), without analytical evidence of further deterioration of hepatic function: total bilirubin 50 μmol/L, AST 297 U/L, ALT 320 U/L, alkaline phosphatase 992 U/L, γ-GT 185 U/L; cholesterol, prothrombin time, total protein, and electrophoresis are normal. Serum arginine has lowered to 197 μmol/L and ammonia to 90 μmol/L. Urinary orotic acid, which was normal at the time of diagnosis, is now 26 μmol/mmol creatinine (normal 0-20), and it transiently rises (to 140 μmol/mol creatinine) whenever catabolism or protein intake increase. EEG has the same pattern of occasional diffuse slow-wave bursts.
Hyperargininemia is generally described as being characterized by a clinical picture of progressive neurological impairment (1,5). Some patients with documented hepatic dysfunction and fibrosis and/or steatosis have been reported, but the neurological features are always predominant (6,7). In most reported cases, clinical manifestations are noticed in preschool or early school years, although retrospective analysis suggests the symptoms may occur in the first year of life, including irritability, unconsolable crying, anorexia, vomiting, self-restricted protein intake, and development delay (1,8,9). The clinical picture of this patient differs from the majority of the earlier cases by the neonatal onset and by the preponderance of hepatic symptoms and signs. Jordá et al. described a case of hyperargininemia presenting with jaundice and hepatomegaly in the neonatal period with documented hepatic steatosis and fibrosis, but there too neurological symptoms were preeminent and the clinical picture dramatic, leading to death on the 49th day of life (7).
The biochemical mechanisms underlying the neurological damage are not yet completely understood. In this patient, despite all the laboratory abnormalities that have been implicated in neurologic damage (ammonia, arginine, and guanidino compounds) (10-13), there is apparent neurologic normality. As neurologic impairment usually appears later in life, we can speculate this child has no neurological symptoms because she is still too young, or she may never have neurological damage as she was precociously put on an arginine-free diet (14).
As hyperargininemia is a heterogeneous disorder at the genotypic level (15), it is possible that a different mutation may give rise to a different clinical presentation. A particular mutation occurring in the Iberian peninsula would also explain the clinical differences that have been reported in Iberian patients (7,16).
In hyperargininemia orotic acid is commonly elevated. In this child, it was normal at the time of diagnosis; probably, there was a low protein intake, and so ammonia was not high enough to stimulate the pyrimidine pathway. However, when catabolism or protein intake increase, orotic acid rises.
Light microscopy study of the liver revealed a picture of hepatic cirrhosis and cholestasis. Electron microscopy documented hydropic cellular change, with dilated endoplasmatic reticulum, and normal-appearing mithocondria. Variable degrees of hepatic fibrosis have been described both in hyperargininemia and other urea cycle disorders (6,7,17), raising questions about its pathogenesis. We could not find in this child any other cause that might explain such an early development of hepatic cirrhosis. Liver and neurological dysfunction may be two constant features of the disease, with different phenotypic expression from case to case. Megamithocondria, described in other cases of hyperargininemia (7), as in other physiologic and pathologic conditions, is not a constant feature in these patients (6). Its cause and significance remain obscure.
Hyperargininemia is considered to be a metabolic disease amenable to nutritional therapy; Snyderman et al. obtained good long-term results by instituting a diet shortly after birth (14). Nutritional management is based on an hypoproteic diet or a mixture of essential amino acids free from arginine. The last seems to be the preferable approach, as it allows the control of both hyperammonemia and the plasma arginine level (14). We used an hypercaloric, normoproteic diet, in which nitrogen was exclusively furnished by an arginine-free mixture of essential amino acids. After alimentary diversification, natural protein intake has never exceeded 0.5 g/kg/day. With this regimen ammonia and arginine levels clearly diminished, and the child is clinically controlled, without physical or laboratory signs of further hepatic function deterioration. Growth is progressing below but parallel to the third percentile.
This case illustrates the need for a thorough metabolic investigation of all infants presenting with conjugated hyperbilirubinaemia; one day we may arrive at the conclusion that metabolic diseases are not as rare as we previously thought.
1. Brusilow SW, Horwich AL. Urea Cycle Enzymes. In: Saiver CR, Beaudet A, Sly W, Valle D, eds. The metabolic basis of inherited disease
. New York: McGraw-Hill, 1989:629-63.
2. Walser M. Urea cycle disorders and other hereditary hyperammonemic syndromes. In: Standbury JB, Wyngaarden JB, Frederickson DS, eds. The metabolic basis of inherited disease
. New York: McGraw-Hill, 1983:402-38.
3. Peralta-Serrano A. Argininuria, convulsiones y oligofrenia: un nuevo error innato del metabolismo? Rev Clin Esp
4. Terheggen HG, Schwenk A, Lowenthal A, Van Sande M, Colombo JP. Argininaemia with arginase deficiency. Lancet
5. Bachmann C. Urea cycle disorders. In: Fernandes J, Saudubray JM, Tade K. Inborn metabolic diseases diagnosis and treatment
. New York: Springer-Verlag, 1990:211-28.
6. Cederbaum SD, Shaw KNF, Spector EB, Verity MA, Snodgrass PJ, Sugarman GI. Hyperargininemia with arginase deficiency. Pediatr Res
7. Jordá A, Rubio V, Portolés M, Vilas J, García-Piño J. A new case of arginase deficiency in a Spanish male. J Inher Metab Dis
8. Cederbaum SD, Shaw KNF, Valente M. Hyperargininemia. J Pediatr
9. Scheuerle AE, McVie R, Beaudet AL, Shapira SK. Arginase deficiency presenting as cerebral palsy. Pediatrics
10. Ampola MG. Nutrition in inborn errors of amino acid metabolism. In: Grand RJ, Sutphen JL, Dietz WH. Pediatric nutrition theory and practice
. Boston: Butterworth, 1987.
11. Mizutani N, Hayakawa C, Ohya Y, Watanabe K, Watanabe Y, Mori A. Guanidino compounds in hyperargininemia. Tohoku J Exp Med
12. Snyderman SE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV. Argininemia. J Pediatr
13. Lambert MA, Marescau B, Desjardins M, et al. Hyperargininemia: Intellectual and motor improvement related to changes in biochemical data. J Pediatr
14. Snyderman SE, Sansaricq C, Norton PM, Goldstein F. Argininemia treated from birth. J Pediatr
15. Grody W, Klein D, Dodson AE, et al. Molecular genetic study of human arginase deficiency. Am J Hum Genet
16. Vilarinho L, Senra V, Vilarinho A, et al. A new case of argininaemia without spastic diplegia in a Portuguese male. J Inher Metab Dis
17. Labrecque DR, Latham PS, Biely CA, Hsia YE, Klatskin G. Heritable urea cycle enzyme deficiency-liver disease in 16 patients. J Pediatr