AUTHOR INFORMATION

Section 1 of 12

Authored by Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston

Coauthored by Paul J Benke, MD, PhD, Director of Clinical Genetics, Associate Professor, Department of Pediatrics, University of Miami

Richard E Frye, MD, PhD, is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and International Neuropsychological Society

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Richard E Frye, MD, PhD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, June 23 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 12

Background: Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome is a very rare inborn error of metabolism that varies widely in age of presentation and long-term prognosis. Growth and developmental delays, learning disabilities (especially speech delay), and periodic confusion and ataxia are typical presenting symptoms. A defect in the transport of ornithine into the mitochondrial matrix significantly inhibits the urea cycle, thereby impeding nitrogen disposal. Early detection and treatment may lead to favorable outcome.

Pathophysiology: The urea cycle maintains the concentration of the toxic ammonium ion in a narrow, tolerable range despite variations of more than 10-fold in dietary intake of its precursor, nitrogen. A total of 5 enzymes in 2 subcellular compartments (mitochondrial matrix and cytosol) convert ammonia into urea; urea is excreted by the kidney (see Image 1). Periportal hepatocytes express these enzymes; epithelial cells of the small intestine and kidney also express these enzymes to a lesser extent, but their contribution to urea production is not significant. Urea-cycle enzyme activity is regulated by dietary protein. Glucagon and cyclic adenosine 3',5'-monophosphate (cAMP), in part, regulate urea-cycle enzyme transcription.

The first 2 steps of the urea cycle occur in the mitochondrial matrix. Carbamoyl phosphate is produced from ammonia and bicarbonate by carbamoylphosphate synthetase I. This reaction is stimulated by ornithine. An inner mitochondrial membrane transporter directs ornithine to the transcarbamoylase enzyme to keep intramatrix ornithine levels low. The specifics of the liver transporter have been identified recently.

Cationic L-ornithine is electroneutrally transported into the matrix in exchange for a proton and citrulline. The inner membrane pH gradient and the availability of proton-yielding anions may affect the transport rate. The ornithine carrier is typical of other mitochondrial carrier family proteins, being composed of 300 amino acids that constitute 3 repeated motifs of approximately 100 amino acids each. These motifs contain 2 hydrophobic alpha-helical segments connected by an extensive hydrophilic sequence, resulting in 6 transmembrane portions of the protein. The transporter was identified by probing a mammalian expressed sequence tag database with 2 fungal mitochondrial ornithine carrier protein sequences. Ornithine incorporation was restored in fibroblasts derived from patients with HHH syndrome by transforming the fibroblasts with transporter complementary deoxyribonucleic acid (cDNA). Incorporation was traced by using ornithine labeled with radioactive carbon (¹⁴C).

Following incorporation of ornithine into the mitochondrial matrix, carbamoyl phosphate and ornithine are condensed to form citrulline by ornithine transcarbamoylase. Citrulline is believed to diffuse passively across the inner mitochondrial matrix to the cytosol. The contribution of the ornithine/citrulline antiporter to citrulline transport from the mitochondria to the cytosol is not known.

The next 3 steps of the urea cycle occur in the cytosol. Argininosuccinic acid is produced from the condensation of citrulline and aspartate by a synthetase enzyme. It then is cleaved to produce fumarate and arginine by a lyase enzyme. Urea and ornithine are produced by arginase. Under normal circumstances, the ornithine produced outside the mitochondrial matrix is transported into the mitochondrial matrix, where it is reused in the urea cycle.

This transport of ornithine across the inner mitochondrial membrane is essential to the urea cycle. Ornithine also can be produced in the matrix by aminotransferase, but this enzyme is active in pericentral venous, rather than periportal, hepatocytes.

In HHH syndrome, the mitochondrial ornithine transporter ORNT1 is defective. The carrier protein and gene sequence have been identified only recently; before its identification, the carrier's dysfunction was deduced biochemically by the fact that a patient with HHH syndrome has abnormally high ornithine levels despite normal ornithine transcarbamoylase function. Since the urea cycle cannot continue without ornithine inside the mitochondria, ammonia disposal slows and blood ammonia levels rise. A second mitochondrial ornithine transporter, ORNT2, has been suggested and may account for a mild variation of HHH syndrome in French Canadian probands.

Ornithine transcarbamoylase within the mitochondrial matrix may convert lysine to homocitrulline in the absence of ornithine, causing high blood levels of homocitrulline and homocitrullinuria. However, this theory is controversial, since some studies have shown no correlation between lysine supplementation and homocitrulline levels; moreover, the role of the lysine transcarbamoylase that lies outside the inner mitochondrial membrane is not known.

Frequency:

• Internationally: Only about 50 cases have been reported.

Mortality/Morbidity: Neonatal death has been reported but is rare. Some patients are observed to have progressive neurologic and cognitive deterioration, but other patients demonstrate good function if metabolic anomalies are well controlled. Clearly, this is a very serious and potentially life-threatening and often life-shortening disorder.

Race: Most reported cases have been in the French-Canadian population in the Quebec Province of Canada.

Sex: Male-to-female ratio is unknown.

Age: The severity ranges from minimal neurologic dysfunction in adulthood to neonatal death. Age at diagnosis is also highly variable, probably due, in part, to variation in the degree of residual enzyme activity and to the nonspecific symptoms of this disorder.

CLINICAL

Section 3 of 12

History:

• Neonatal onset type
  • Formula intolerance is evidenced by vomiting and lethargy following feeding of high-protein formula.

  • Neonatal period may be uneventful if the neonate is breastfed.

  • Symptoms may be mild and may include only bottle refusal.

  • Severe hyperammonemia with rapidly progressive deterioration after formula feeding is rare but has occurred.



• Infant onset type
  • Symptoms may coincide with the introduction of high-protein solid food around the time of weaning.

  • Choreoathetosis episodes may occur, with normal neurological function between episodes.

  • Hypotonia progressing to spasticity may be seen.

  • Seizures may resemble infantile spasms.

  • Developmental milestones are delayed typically.

  • Growth may be retarded.



• Childhood onset type
  • Ataxia or choreoathetosis episodes may occur, with normal neurological function between episodes.

  • The child may refuse to eat meat and fish or to drink milk.


• • Other signs may include the following:
    • Seizures

    • Developmental delays

    • Learning disabilities

    • Intelligence quotient (IQ) below average

    • Attention deficit hyperactivity disorder (ADHD)

    • Conduct disorder

    • Failure to thrive
  
  
  
• Adult onset type
  • Patients may experience learning disabilities.

  • Patients may avoid high-protein foods and possibly have a vegetarian diet.

  • Periodic blurred vision, confusion, and ataxia are common symptoms.



• Other historical information
  • Deficiencies in clotting factors VII and X may be present.

  • A sibling with the disorder or consanguinity is not uncommon.

  • Ask about a history of previous neonatal deaths or miscarriages.



• Common presenting signs include the following:
  • Developmental delays

  • School difficulties

  • Recurrent liver dysfunction

  • Increased transaminases with mild coagulopathy detected on laboratory tests



• Episodic lethargy and vomiting may be presenting signs.

Physical:

• Eyes: Retinal depigmentation and chorioretinal thinning are uncommon findings. In contrast, chorioretinal atrophy with punched-out lesions is a standard finding in gyrate atrophy.



• Abdomen: Liver and spleen may be enlarged.



• Neurologic
  • Pyramidal syndrome characterized by increased deep tendon reflexes, spasticity, positive Babinski reflex, and nonpersistent clonus

  • Decreased vibration sensation

  • Buccofaciolingual dyspraxia

  • Poor visuomotor function

  • Poor hand coordination

  • Poor fine-motor coordination

  • Dysdiadochokinesia



• Development
  • Global motor delay

  • Speech delay

Causes: HHH is a genetic/metabolic disorder caused by a defect in the mitochondrial ornithine transporter, ORNT1.

• The ORNT1 gene has been mapped to band 13q14. This gene is also identified as SLC25A15 for its membership in the solute mitochondrial carrier protein family. Its expression is similar to that of other urea-cycle enzyme genes; it is expressed at high levels in hepatocytes, and its expression can be promoted by an increase in dietary protein.



• Three ORNT1 mutant alleles were identified in a survey of 11 HHH probands; these mutant alleles accounted for 21 of 22 possible mutant ORNT1 genes in the population.


• • A 3-base-pair (bp) in-frame deletion of codon 188 for phenylalanine, which causes an unstable carrier protein, is common in French-Canadians with the HHH syndrome. Of 10 patients tested for this mutation, 9 were homozygous and 1 was heterozygous. The mutation accounting for dysfunction of the heterozygote's remaining allele was not identified.
  
  
  
  • A missense mutation at codon 189, resulting from a G-to-A transition at bp 538, impaired carrier activity without affecting targeting or stability in a non–French-Canadian patient. The patient was heterozygous for this mutation and had a microdeletion on chromosome 13 that, presumably, accounted for dysfunction in the corresponding allele.
  
  
  
• Inheritance is autosomal recessive.



• Although the genes for clotting factors VII and X also are located on chromosome arm 13q, these genes are believed to be too distant from the ornithine transporter gene to be part of a contiguous gene syndrome.

DIFFERENTIALS

Section 4 of 12

Arginase Deficiency
Argininosuccinate Lyase Deficiency
Autoimmune Chronic Active Hepatitis
Citrullinemia
Constitutional Growth Delay
Failure to Thrive
Fetal Alcohol Syndrome
Fulminant Hepatic Failure
Growth Failure
Hepatitis A
Hepatitis B
Hepatitis C
Hepatorenal Syndrome
Hyperammonemia
Malabsorption Syndromes
Malnutrition
N-Acetylglutamate Synthetase Deficiency
Ornithine Transcarbamylase Deficiency
Phenylketonuria
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)
Pyruvate Carboxylase Deficiency
Pyruvate Dehydrogenase Complex Deficiency

Other Problems to be Considered:

Gyrate atrophy

WORKUP

Section 5 of 12

Lab Studies:

• Amino acids


• • Plasma ornithine is increased at presentation, thus differentiating HHH syndrome from other urea-cycle disorders. Ornithine levels are slightly lower than those seen in gyrate atrophy and may range from 200-1000 mmol/L. Plasma ornithine level may be lowered by protein restriction or even normalized by extreme protein restriction. Neonatal ornithine levels may be normal.
  
  
  
  • Postprandial homocitrullinuria biochemically differentiates this disorder from gyrate atrophy.
  
  
  
  • Homocitrulline and free ornithine levels in the urine are elevated, although the latter can be highly variable. Levels of metabolites of ornithine and other gamma-glutamyl amino acids may be elevated in urine.
  
  
  
  • Glutamine and alanine levels often are elevated at presentation, and glutamine levels may paradoxically increase with protein restriction.
  
  
  
• Orotic acid: Orotic acid level in the urine is elevated despite normal serum ammonia values.

Imaging Studies:

• MRI may demonstrate increased signal in cortical white matter.



• Liver-spleen scan may show increased uptake with mild diffuse liver involvement.

Other Tests:

• Electrophysiologic studies may identify abnormalities in older patients


• • Electroencephalogram showing diffuse slowing of background activity
  
  
  
  • Nerve-conduction velocity and short-latency somatosensory evoked potential results compatible with mild sensorimotor peripheral neuropathy
  
  
  
  • Visual evoked potential results showing prolonged cortical conduction time and shape and amplitude anomalies
  
  
  

TREATMENT

Section 6 of 12

Medical Care:

• Ornithine supplementation reduces ammonia levels in some patients. A suggested dose of 22-44 mg/kg per dose given 3 times per day with protein ingestion may improve protein tolerance and growth. Other studies show that 6 g/d reduces ammonia levels. This treatment increases ornithine levels further, and the long-term effects of hyperornithinemia are not known. Citrulline supplementation has also been used.



• Arginine supplementation (7.5 g/d) reduces ammonia levels in some patients; however, this treatment has caused deleterious effects in others and generally is not recommended.



• Sodium benzoate and sodium phenylacetate may reduce ammonia levels by providing an alternative pathway. The combination of benzoate and phenylacetate is an investigational new drug for use in urea cycle disorders and as such has not been approved for use in HHH syndrome. Oral sodium phenylbutyrate, which is approved by the Food and Drug Administration (FDA) for urea cycle defects, could be helpful in HHH syndrome, but additional studies are needed. Oral sodium benzoate could be effective as well.



• Hyperammonemic crisis might be managed with short-term protein restriction and IV fluids containing large amounts of glucose followed by slow reintroduction of small amounts of protein. Theoretically, IV arginine and IV sodium benzoate and sodium phenylacetate might be effective, but these medications have not been approved in the United States for use in this disorder, and IV arginine could be dangerous and ineffective. Supportive measures are indicated.

Consultations: A comprehensive team approach is justified and should include a physician with expertise in treating metabolic diseases, a clinical biochemical geneticist, a developmental pediatrician, a neurologist, and other development specialists. This team should assess all aspects of cognitive function and monitor the patient periodically for development surveillance. A nutritionist with expertise in treating metabolic diseases also should be consulted.

Diet: A low-protein diet (1.2 g/kg/d, depending on age) may prevent postprandial hyperammonemia and has permitted normal development in several patients when initiated early in life.

MEDICATION

Section 7 of 12

Drug Category: Metabolic agents -- These assist in excreting nitrogen and serve as an alternative to urea to reduce waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.

Drug Name	Sodium phenylacetate and sodium benzoate (Ammonul, Ucephan) -- Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol of nitrogen). Ammonul must be administered with arginine for carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.
Adult Dose	Loading: 55 mL (5.5 g)/m2 IV over 90-120 min via central line Maintenance: 55 mL (5.5 g)/m2/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration
Pediatric Dose	Ucephan: 250 mg/kg/d PO in 3-6 equally divided doses, not to exceed 10 g/d each of sodium benzoate and sodium phenylacetate Ammonul: <20 kg: Loading: 2.5 mL (250 mg)/kg IV over 90-120 min via central line Maintenance: 2.5 mL (250 mg)/kg/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration >20 kg: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Penicillin may decrease effects of sodium benzoate and sodium phenylacetate; probenecid may inhibit renal excretion of products of sodium benzoate and sodium phenylacetate; valproate may antagonize efficacy of sodium benzoate and sodium phenylacetate; corticosteroids may increase body protein metabolism, thereby increasing plasma ammonia levels; do not use concomitantly with oral sodium phenylbutyrate (Buphenyl) because of additive effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin binding sites on albumin); because of its sodium content, exercise caution when giving the drug to patients with congestive heart failure, severe renal dysfunction, and sodium retention with edema; common side effects include nausea, vomiting, tinnitus, and visual disturbance; IV must be diluted with dextrose 10% and administered via central line; phenylacetate may cause neurotoxicity; typically administered with antiemetic to prevent common occurrence of nausea and vomiting; caution in severe congestive heart failure or severe renal insufficiency because the drug contains large amount of sodium (30.5 mg/mL in undiluted IV product)

FOLLOW-UP

Section 8 of 12

Further Outpatient Care:

• Annual ophthalmologic examinations and electroretinograms are often recommended.



• Growth and developmental milestones need to be monitored closely.



• Follow-up should be with the comprehensive development team.



• A dietary log helps determine total daily protein ingestion.



• Ammonia, liver transaminases, and ornithine levels should be monitored periodically, especially after changing or starting diet or supplement therapy.

Deterrence/Prevention:

• First-trimester diagnosis of HHH syndrome may be achieved by study of the incorporation of [¹⁴C]ornithine into proteins of chorionic villi cells. Although this is theoretically possible, it never has been reported in the literature.



• Amniocytes demonstrate decreased incorporation of [¹⁴C]ornithine, but amniotic fluid amino acids are normal.



• Because neonatal ornithine levels may be normal, especially if the patient has not developed any symptoms, these levels cannot be used to screen neonates for this disorder.

Prognosis:

• Growth improves with treatment.



• Pregnancy is possible. A woman with HHH syndrome gave birth to a healthy baby on a diet comprising 1 g/kg of protein per day.



• Some patients do not respond to diet therapy.



• One case has been reported of rapidly progressive deterioration after formula feeding, leading to neonatal death.



• Older patients may develop progressive disease, but patients have been reported who have had good neurologic and cognitive function into adulthood. Abnormalities of the central and peripheral nervous systems in older patients can be detected on electrophysiologic tests, as discussed above, but the following manifestations also can occur:


• • Conduct disorder, as manifested by irritability, opposition, and aggressiveness
  
  
  
  • Lower IQ st delete the expansion to IQ since it’s introduced above and is not a key idea/term in this article](ie, in the mildly mentally retarded range)
  
  
  

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to measure ammonia levels: Ammonia levels should be measured in any individual with mental status changes or coma with no obvious etiology.



• Diagnosis failure: Early intervention can prevent damage to the central nervous system (CNS). Failure to consider this diagnosis in a child with one or more developmental delays may allow significant progression of CNS damage. CNS symptoms, especially seizure or choreoathetosis, along with unusual feeding patterns should suggest HHH syndrome. This disorder can be diagnosed by a standard workup for developmental delay that includes urine organic acids and serum amino acids.



• Failure to monitor progression: Progression of developmental delays, neurologic symptoms, or abnormal liver function should suggest either noncompliance with treatment or an alternate diagnosis. Formal periodic neurologic, cognitive, and ophthalmologic examinations should be performed.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Incorporation of ornithine labeled with carbon 14 into protein is decreased in a patient's fibroblasts. Which other enzyme(s) must be tested to make the diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome?

A: Carbamoylphosphate synthetase I
B: Ornithine transcarbamoylase
C: Ornithine aminotransferase
D: Arginase
E: More than one of the above

The correct answer is C: Normal ornithine aminotransferase must be demonstrated to rule out gyrate atrophy. Both disorders result in hyperornithinemia. Although ammonia levels are normal in gyrate atrophy, ammonia level varies with protein intake, and patients with HHH syndrome who restrict protein intake may not have hyperammonemia.

CME Question 2: Which of the following is not part of the general treatment of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome because of deleterious effects?

A: Ornithine
B: Arginine
C: Sodium benzoate
D: Low-protein diet
E: All of the above are part of treatment

The correct answer is B: Arginine supplementation may reduce ammonia levels but has been associated with seizures and, therefore, is not used by many clinicians. Ornithine supplementation reduces ammonia levels but also increases ornithine levels. The long-term effects of hyperornithinemia are not known, causing some clinicians to avoid ornithine supplementation; however, high ornithine levels have not been linked to any particular abnormality. A low-protein diet and sodium benzoate are the standard treatments to reduce ammonia levels.

Pearl Question 1 (T/F): Early (ie, first-trimester) prenatal diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome can be performed by amniocentesis.

The correct answer is False: HHH syndrome can be diagnosed in the second trimester by testing incorporation of ornithine labeled with carbon 14 into protein in cultured amniocytes obtained by amniocentesis. However, this allows only for a second-trimester termination of pregnancy. However, chorionic villi sampling can obtain cells for testing in the first trimester.

Pearl Question 2 (T/F): Mild coagulopathy with deficiencies in factors VII and X is a common component of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome and constitutes a contiguous gene syndrome.

The correct answer is False: Although a mild coagulopathy with deficiencies in factors VII and X is seen in some patients with HHH syndrome, the distance between the genes for these coagulation factors and the ornithine transporter is too great to be part of a contiguous gene syndrome.

Pearl Question 3 (T/F): Episodic lethargy and vomiting with hyperammonemia is a common presentation of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.

The correct answer is False: Common presentations include learning disabilities, developmental delays, and liver dysfunction of unknown etiology, although periodic lethargy and vomiting may occur.

Pearl Question 4 (T/F): Most physical abnormalities in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome are found by a thorough neurologic examination.

The correct answer is True: A pyramidal syndrome characterized by increased deep tendon reflexes, spasticity, positive Babinski reflex, and nonpersistent clonus is found in most patients with this disorder. Other common findings include decreased vibration sensation, buccofaciolingual dyspraxia, poor visuomotor function, poor hand coordination, poor fine-motor coordination, and dysdiadochokinesia.

PICTURES

Section 11 of 12

Caption: Picture 1. Important products and enzymes of ornithine metabolism (see text for pathway detail). Enzymes and transporters are highlighted in italics.
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BIBLIOGRAPHY

Section 12 of 12

• Camacho JA, Obie C, Biery B: Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 1999 Jun; 22(2): 151-8[Medline].
• Camacho JA, Rioseco-Camacho N, Andrade D, et al: Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder. Mol Genet Metab 2003 Aug; 79(4): 257-71[Medline].
• Korman SH, Kanazawa N, Abu-Libdeh B, et al: Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family. J Neurol Sci 2004 Mar 15; 218(1-2): 53-8[Medline].
• Lemay JF, Lambert MA, Mitchell GA: Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients. J Pediatr 1992 Nov; 121(5 Pt 1): 725-30[Medline].
• Nakajima M, Ishii S, Mito T: Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Brain Dev 1988; 10(3): 181-5[Medline].
• Shih VE, Laframboise R, Mandell R: Neonatal form of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and prenatal diagnosis. Prenat Diagn 1992 Sep; 12(9): 717-23[Medline].
• Shimizu H, Maekawa K, Eto Y: Abnormal urinary excretion of polyamines in HHH syndrome (hyperornithinemia associated with hyperammonemia and homocitrullinuria). Brain Dev 1990; 12(5): 533-5[Medline].
• Smith L, Lambert MA, Brochu P: Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy. J Pediatr Gastroenterol Nutr 1992 Nov; 15(4): 431-6[Medline].
• Tuchman M, Knopman DS, Shih VE: Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Arch Neurol 1990 Oct; 47(10): 1134-7[Medline].
• Valle D, Simell O: The Hyperornithinemias. The metabolic basis of inherited disease Eds: CR Scriver, et al., New York: McGraw-Hill; 1995: 1147-1185.
• Wong P, Lessick M, Kang S: Maternal hyperornithemia-hyperammonemia-homocritrullinuria (HHH) syndrome. Am J Hum Genet 1989; 45 (suppl): A14.
• Zammarchi E, Ciani F, Pasquini E: Neonatal onset of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with favorable outcome. J Pediatr 1997 Sep; 131(3): 440-3[Medline].

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