Clinical manifestations

Presentation and course

The onset of symptoms in HHH syndrome ranges from the neonatal period (28 days or younger) to late adolescence/adulthood (older than 12 years). A review showed that early onset of symptoms (before 28 days of age; 22%) is less frequent than late onset (more than 28 days of age; 78%). Comparing the age at onset of symptoms with the age of diagnosis, there is a diagnostic delay of 6.3 + 10.1 years (38). Apart from the severe neonatal onset form, there is no direct correlation between onset type and disease severity (38; 24). The clinical phenotype is heterogeneous with variable disease progression, even in individuals harboring the same pathogenic variant (16).

Typically, the affected neonate is born after an uncomplicated full-term pregnancy, labor, and delivery with normal Apgar scores. Symptoms can mirror other urea cycle disorders and bring to mind a neonatal sepsis-like picture with hyperventilation, respiratory distress, and temperature instability. Poor sucking, vomiting, muscular hypotonia, and abnormal motor functions may be observed (33; 34). Lethargy and coma at disease onset are common in the early-onset group (38). Symptoms can rapidly progress from somnolence and lethargy to hyperammonemic coma (24), which may be caused by high-protein intake (eg, barbecue meat, parenteral nutrition), or triggers for catabolic stress. Such triggers might be fever, infections, gastrointestinal bleeding, vomiting, decreased energy, or increased protein intake as well as seizures, trauma, burns, and surgery. Furthermore, severe exercise, drugs (steroids, valproate, haloperidol, chemotherapy with L-asparaginase or pegaspargase, or catabolism and the involution of the uterus in the postpartum period) are all important triggers for late-onset hyperammonemia (35). Interestingly, HHH syndrome may also present with a hepatitis-like disease or even fulminant liver failure with severe coagulation abnormalities (eg, subdural hematoma, gingival bleeding, melena); elevations of transaminases with or without signs of acute liver failure (ie, coagulopathy) may occur in the absence of hyperammonemia (38). Liver pathologic changes include vacuolated hepatocytes with intracytoplasmic glycogen deposition, small nuclei, dense chromatin, and fat droplets without fibrosis. Furthermore, mitochondria appear abnormally shaped and sized with lamellar cristal-like inclusions (38). Reduced levels of serum IgG and functional alterations in B and T cell responses have been reported, which might be related to the high frequency of intercurrent infections observed in individuals with HHH syndrome as well as other urea cycle disorders (53).

Common are insidious clinical presentations, such as recurrent vomiting, aversion to protein-rich food, neurocognitive deficits (ie, developmental delay, progressive encephalopathy with mental regression), progressive neurologic impairment (ie, ataxia, progressive spastic paraplegia, abnormal motor function, dysdiadochokinesia, dysarthria, nystagmus, intentional tremor, seizures), or chronic liver dysfunction (unexplained elevation of liver transaminases with or without coagulopathy and hyperammonemia) (10; 32; 21; 38). Independent from the onset type, only 34% of patients with HHH syndrome have normal cognitive development (38), and significant behavioral problems have been reported.

Published data from the UCDC consortium report neuroimaging and neurocognitive findings of more than 600 urea cycle disorder patients, including patients suffering from HHH syndrome (59). Neuroimaging reveals subcortical and cortical atrophy, cerebellar atrophy, multiple stroke-like lesions, increased signal and foci of gliosis in white matter, or basal ganglia calcifications (02; 21). Individuals with HHH syndrome might present with recurrent episodes of metabolic (leuko)encephalopathy due to increased intracerebral glutamine concentrations as determined by magnetic resonance spectroscopy, which is reversible when ammonia levels in plasma are sufficiently lowered (27; 51). Acute hyperammonemic episodes demonstrate a diffuse or focal pattern of cerebral MRI changes and potentially brain edema (14; 04; 23).

Prognosis and complications

Although mortality has decreased, morbidity in urea cycle disorders remains high in survivors of neonatal hyperammonemic coma. Frequent comorbidities in urea cycle disorders are associated with the most vulnerable organ, ie, the brain, leading to mental retardation, cerebral palsy, seizures, movement and speech disorders (34). Data demonstrate that the (neurocognitive) outcome does depend on the initial and peak-blood ammonia level (PBAL) (49). Early disease onset and initial PBAL of more than 500 µmol/L is a marker for poor neurologic outcome (49). Interestingly, in HHH syndrome the degree of hyperammonemia is usually significantly less than in other urea cycle disorders (10) and not proportionally related to the degree of intellectual disability (38). A detailed overview of organ-specific disease manifestations and complications in patients suffering from urea cycle disorders including HHH syndrome was evaluated by Kölker and colleagues (34). Prognosis of HHH syndrome is, unfortunately, still uncertain, especially for individual patients. Progression of neurologic dysfunction may occur despite good control of hyperammonemia (32). A low-protein diet initiated early in life may prevent postprandial hyperammonemia and hyperammonemic crises and permit a substantial improvement of the quality of life. Therefore, early diagnosis appears important for the best possible outcome (21).

Clinical vignette

Patient 1: HHH syndrome with fulminant hepatitis-like presentation. Here we summarize the case of a 3-year-old Italian boy that has been previously published (19). The child was born at term to unrelated healthy parents by Caesarean section because of fetal distress with normal birth weight. In the first years of life, the child showed normal neurologic development, with the exception of speech delay and a moderate aversion to protein-rich food.

At the age of 3 years and 6 months, he presented with lethargy during an intercurrent gastrointestinal infection. Biochemical investigation revealed hyperammonemia (171 μmol/L; reference value: < 50 μmol/L) and moderately elevated transaminases (aspartate aminotransferase 79 UI/L, normal range: 15 to 55; alanine aminotransferase 224 UI/L, normal range: 5 to 45) without signs of jaundice or splenomegaly. This was followed by rapidly progressive hepatocellular necrosis (AST and ALT peaking at 20,000 UI/L and 18,400 UI/L respectively) and moderate to severe coagulopathy (PT ranged from 48% on day 2 to less than 5% on day 5, normal range 70 to 120; aPTT from 54 seconds on day 2 decreased to below detection limits on day 5, normal range 26 to 44; INR from 1.88 on day 3 to below detection limits on day 5, normal range 0.8 to 1.3). Blood cell count and investigations for EBV, CMV, adenovirus, HSV 1 and 2, hepatitis A, B, and C, and anti-nuclear (ANA), anti-mitochondrial (AMA), anti-smooth muscle (SMA) autoantibodies were all negative or normal.

Parenteral vitamin K substitution was only partially helpful in correcting plasma coagulopathy. Liver transplantation was considered as an emergency therapeutic option. Metabolic tests were suggestive of HHH syndrome.

An emergency protocol for the treatment of acute hyperammonemia with intravenous arginine supplementation and a protein-restricted diet were started immediately, and blood ammonia normalized in 24 hours and transaminases more slowly. The need for liver transplantation was postponed and long-term therapy with oral arginine supplementation started, allowing an increased protein intake, without further metabolic dysfunction.

Molecular analysis of the SLC25A15 gene revealed a compound heterozygous status for two novel mutations: c.496G>T in exon 3, resulting in the change of a glycine residue at codon 113 into a cysteine (G113C), and c.977T>A in exon 6, resulting in the change of a methionine at codon 273 into a lysine (M273K) (19).

Patient 2: HHH syndrome in adulthood. Here we summarize the case of a 36-year-old Caucasian man that has been previously published (21). The man had a history of mild developmental delay, learning difficulties, panic disorder, occasional mild incoordination, lethargy, and abdominal pain while in primary school. Protein-rich foods were avoided.

At 36 years of age, he showed a severe episode of vomiting and unsteadiness while standing and walking. Neurologic examination showed a pyramidal-cerebellar syndrome characterized by ataxic gait, nystagmus, poor fine-motor coordination, dysdiadochokinesia, proximal lower limb weakness with stiff legs, increased deep tendon reflexes, and persistent ankle clonus.

Serum ammonia was twice the normal value; determination of plasma and urine amino acids showed increased plasma ornithine (309 µmol/L, normal values: 27 to 98) and urine homocitrulline. MRI of the brain showed multiple foci of gliosis in the subcortical white matter and moderate atrophy of frontoparietal opercula and cerebellar hemispheres. Investigation of the SLC25A15 gene revealed compound heterozygous pathogenic variants, c.562_564delTTC/p.F188del and c.568T>C/p.L193P (novel).

After diagnosis of HHH syndrome, the patient was started on a low-protein diet. Soon after start of treatment, serum ammonia decreased to and remained within the normal range. Neurologic symptoms remained unchanged. Thus, it is important to always include urea cycle disorders, particularly HHH syndrome and hyperargininemia, in the clinical assessment of the pyramidal-cerebellar syndromes in young adults. Red flags are fluctuations of gait and motor disturbances as well as avoidance or discomfort with protein-rich meals (21).

Biological basis

Etiology and pathogenesis

HHH syndrome (OMIM #238970) is an autosomal recessive disease caused by mutations in the SLC25A15 (solute carrier family 25, member 15) gene on chromosome 13q14.11, spanning about 23 kb and coding for the ornithine carrier (ORNT1). The carrier is located in the inner mitochondrial membrane of the liver, pancreas, lungs, testis, and brain (12; 11; 38), transports ornithine, lysine, and arginine into the mitochondrial matrix, and catalyzes an ornithine/citrulline exchange reaction. An overview of various diseases caused by mutations in mitochondrial carrier genes is presented separately (45). Importantly, ornithine from the cytosol must be shuttled into hepatic mitochondria for the ornithine transcarbamylase reaction.

Thus, the ornithine transporter is essential for function of the urea cycle. Two human isoforms of the mitochondrial carrier have been identified with the second showing broader substrate specificity, less affinity, and less expression in liver (20). ORNT1 deficiency leads to accumulation of ornithine in the cytosol causing hyperornithinemia leading to increased levels of polyamines (38). Intramitochondrial ornithine is decreased; thus, ammonia and carbamoyl phosphate levels increase, explaining hyperammonemia. Carbamoyl phosphate binds lysine, forming homocitrulline, and enters the pyrimidine pathway, leading to increased formation and excretion of orotic acid (38). The increased cytosolic ornithine concentrations inhibit the enzyme arginine: glycine amidinotransferase and, thus, the formation of creatine leading to secondary creatine deficiency (38). Secondary creatine deficiency may be aggravated by low intracellular arginine concentrations due to the block in the urea cycle (38). Furthermore, Braissant and colleagues suggest that reduced endogenous creatine production results in a higher vulnerability of the brain to ammonia exposure (05). Finally, ornithine and homocitrulline can cause protein and lipid oxidation and negatively interfere with Krebs cycle function of rat brain, with secondary oxidative stress (38). Toxicity of ornithine and homocitrulline was also suggested by Zanatta and coworkers in neonatal rat cortical astrocytes that were stressed by menadione. Ornithine and homocitrulline decreased cell viability, impaired antioxidant defenses, and increased mitochondrial dysfunction, implying that the pathogenesis of HHH syndrome is not only restricted to effects of hyperammonemia (61).

A comprehensive overview of hitherto reported disease-causing mutations, published between 1999 and 2014, was summarized by Martinelli and colleagues, demonstrating that the majority of mutations are found in residues that have side chains protruding into the internal pore of ORNT1 where the substrate is translocated (38). Two common mutations, p.F188del and p.R179*, accounting for 30% and 15% of patients with HHH syndrome, respectively, were emphasized. Although the disease has a pan-ethnic distribution, it is much more frequent in Canada as result of a founder mutation in Quebec. Other “hotspots” include Italy and Japan (38).

The mechanisms of ammonia-induced brain damage are only partly understood. Ammonia is detoxified in astrocytes by mitochondrial glutamate dehydrogenase and cytosolic glutamine synthase. The accumulation of ammonia and subsequently increased astrocytic glutamine production in concert with disturbed autoregulation of cerebral blood perfusion results in a number of deleterious effects on the brain. These include depletion of intermediates of cell energy metabolism and of organic osmolytes, altered amino acid and neurotransmitter concentrations, increased extracellular potassium concentrations, potentially altered water transport through aquaporin 4 channels, and oxidative and nitrosative stress due to increased free radical production and increased nitric oxide synthesis (09; 43; 37). A zebrafish model was used to analyze the effects of hyperammonemia, demonstrating strongly enhanced transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Withdrawal of 2-oxoglutarate from the tricarboxylic acid (TCA) cycle with consecutive TCA cycle dysfunction ultimately caused impaired oxidative phosphorylation with ATP shortage, decreased ATP/ADP-ratio, and elevated lactate concentrations. Interestingly, inhibition of ornithine aminotransferase is a promising and effective therapeutic approach for preventing neurotoxicity and mortality by hyperammonemia in zebrafish (62; 63).

Phenotypic similarity of HHH syndrome with other urea cycle disorders, eg, arginase 1 deficiency, as well as delta-1-pyrroline-5-carboxylate synthase (P5CS) deficiency, suggest possible common mechanisms contributing to corticospinal dysfunction in these disorders independent from ammonia-induced brain damage (44). This common phenotypic presentation might be induced by the formation of toxic compounds, resulting from the accumulation of substrates, or alteration in mitochondria, where ornithine is low or absent. Those observations point toward an impairment of the ornithine/arginine metabolism as a common mechanism for the development of the neurodegenerative phenotype observed in all three metabolic disorders. Moreover, it could also be possible that alteration of arginine levels might deregulate autophagy (46).

Epidemiology

Up to now, more than 100 patients suffering from HHH syndrome have been reported (38). The estimated cumulative prevalence of urea cycle disorders is 1 in 35,000 to 52,000 newborns (42). HHH syndrome, along with N-acetylglutamate synthase (NAGS) deficiency and citrullinemia type 2 (CTLN2) are the rarest urea cycle disorders with a calculated incidence of about 1 in 2,000,000 people or less (56).

Prevention

No method is known for preventing HHH syndrome. Successful prenatal diagnosis of HHH syndrome by mutation analysis using chorionic villus samples or amniotic fluid cells is available. Before mutation analysis was available, enzyme assays studying ornithine incorporation in amniotic fluid cells was performed (38; 24).

Differential diagnosis

Confusing conditions

Hyperammonemia. Urea cycle disorders must be excluded in individuals presenting with hyperammonemia, with special emphasis on females at risk for hyperammonemia during pregnancy. Urea cycle disorders usually present with elevation of ammonia and glutamine as well as metabolic alkalosis. Organic acidurias, presenting with metabolic acidosis, and fatty-acid oxidation defects, presenting with hyperammonemic hypoglycemia, expand the differential diagnostic panel. Furthermore, lysinuric protein intolerance with low plasma ornithine concentration, pyruvate carboxylase deficiency, presenting with lactic acidosis and hyperinsulinism (hypoglycemia)-hyperammonemia syndrome (HIHA syndrome), as well as mitochondrial carbonic anhydrase VA are also to be considered in the differential diagnosis (10; 57; 38; 24).

Hyperornithinemia. Another condition causing hyperornithinemia is ornithine amino transferase deficiency. The clinical picture is different from HHH syndrome, with progressive ophthalmological changes known as hyperornithinemia with gyrate atrophy of the choroid and retina with loss of peripheral vision, night blindness, and often posterior subcapsular cataracts. Similar to HHH syndrome, patients with ornithine amino transferase deficiency were found at birth to have normal plasma ornithine concentrations that increased in the following weeks (10; 38).

Homocitrullinuria. Other conditions in which homocitrulline can be observed in urine are lysinuric protein intolerance, ornithine transcarbamylase deficiency, and arginase deficiency. Furthermore, canned formulas (canned milk production) may present a source of detectable homocitrulline in urine (10; 38).

Associated or underlying disorders

Associated disorders comprise the group of hereditary spastic paraplegia (HSP), a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive weakness and rigidity of the lower limbs. Three inborn errors of metabolism, ie, HHH syndrome, arginase 1 deficiency, and P5CS deficiency, appear to share alterations of an interconnected pathway of glutamate and the urea cycle, an underlying pathogenetic mechanism leading to the HSP phenotype (46).

Diagnostic workup

In HHH syndrome, the principal metabolic triad consists of hyperornithinemia, hyperammonemia, and urinary excretion of homocitrulline; however, some patients may present with an incomplete biochemical phenotype (38). Plasma ammonia levels can be elevated; however, HHH syndrome mostly leads to a lower degree of hyperammonemia than other urea cycle disorders. Ammonia levels quickly normalize on metabolic pharmacotherapy. In contrast, plasma ornithine levels are always elevated at diagnosis and usually remain elevated despite dietary treatment and metabolic pharmacotherapy. Homocitrullinuria is the biochemical hallmark of the disease but may sometimes be normal (32; 38). Similar to other urea cycle disorders, plasma glutamine levels and urinary orotic acid may be elevated, and plasma lysine, citrulline, and arginine levels might be in the normal to low-normal range (10; 38; 24). Furthermore, increased urinary excretion of Krebs cycle intermediates (succinate, citrate, etc.) as well as lactate has been observed (19; 10).

Molecular genetic testing is the gold standard to confirm the diagnosis and is nowadays more often used to confirm diagnosis than measurement of enzymatic activity (48). Diagnosis of HHH syndrome can also be confirmed by studying the cellular transport of radiolabelled ¹⁴C-ornithine in cultured skin fibroblasts demonstrating up to 80% reduction in ornithine transport from patients with null mutation, suggesting a role of alternative transporters (12; 13). A correlation between ornithine transport capacity, genotype, and phenotype could not be established (12; 11; 10; 38).

Management

For a detailed discussion of HHH syndrome management see the article “Suggested guidelines for the diagnosis and management of urea cycle disorders” by Haberle and colleagues (24).

Management of acute hyperammonemia of HHH syndrome. In the newborn period, management of acute hyperammonemia may be anticipatory or reactive. In families who have had an index patient, the birth of an at-risk or prenatally diagnosed infant provides the opportunity for prospective management. Within hours after birth, the child can be placed on oral therapy with appropriate ammonia scavengers and amino acids as subsequently described.

In newborns or infants who have been diagnosed during hyperammonemia or coma, therapy must not be delayed because coma duration of less than 1.5 days and timely start of treatment are the most important determinants of good outcome (47). Specialized pediatric hospitals should have first-line medications and consensus-based treatment-protocols and must act according to the following principles:

Table 1. Protein, Liquid, and Glucose Management of Acute Hyperammonemia of HHH Syndrome

Table 2. First-Line Medication for HHH Syndrome Management****

Suggestions for a consensus-based treatment protocol, following above outlined principles, are depicted in Tables 1 and 2. Each specialized pediatric hospital should be able to adapt these recommendations to facility-specific conditions to provide best care medicine for their patients and prevent delay of treatment. In case of significant hyperammonemia, at least an arginine and glucose infusion should be started and the patient then transported to the tertiary care center. Ammonia scavengers (sodium benzoate, sodium phenylacetate/-butyrate) provide alternate pathways to eliminate waste nitrogen (06). A few studies demonstrate that treatment with sodium benzoate and sodium phenylbutyrate is safe and effective for the treatment or prevention of hyperammonemia in urea cycle disorders (28; 03). Sodium benzoate is conjugated with glycine to form hippurate, and sodium phenylbutyrate is conjugated with glutamine to form phenylacetylglutamine, both of which are cleared by the kidneys. Glutamine contains two nitrogen atoms; thus, two moles of waste nitrogen are removed for each mole of phenylacetate/-butyrate administered. Theoretically, on a mole-per-mole basis, nitrogen-disposing efficacy of sodium phenylbutyrate should be twice that of sodium benzoate, and although biochemical superiority of sodium phenylbutyrate has been demonstrated, no systematic studies regarding the effects of long-term pharmacotherapy on neurologic or cognitive outcome, as defined by clinical endpoints, exists thus far (41).

Energy is supplemented via oral, nasogastric, or intravenous routes by 20% to 100% above the recommended daily requirements using carbohydrate (such as glucose orally or dextrose 20% orally or glucose intravenously) and fat (intralipid 20%) starting at 1 and up to 3 g/kg per day. Soluble insulin is provided to support intracellular glucose uptake and to avoid hyperglycemia. The intake of natural protein is stopped for 24 hours to (maximally) 48 hours and is then reintroduced gradually as tolerated (49; 26). In the event that ammonia concentrations do not respond to this management and biochemical or clinical symptoms worsen, continuous veno-venous hemodiafiltration (CVVHDF) must be started immediately (planned and organized earlier) at levels greater than 500 µmol/L (see Table 1) or at lower levels in adults or if response to medical treatment is inadequate, especially if no drop of ammonia is evident. Note, even though CVVHDF is the optimal modality for extracorporal ammonia detoxification (47), prognosis is not related to dialysis modality but mainly to the duration of coma before start of treatment and to the initial PBAL (49), confirming the necessity for rapid and aggressive management. In fact, a retrospective data analysis of 202 published cases revealed that current practice in dialysis does not impact on outcome, and only 20% of all investigated individuals had a normal clinical outcome. In conclusion, dialysis along with conservative pharmacotherapeutic treatment is recommended to be initiated as early as possible and at lower ammonium concentrations; however, long-term data analyzing these recommendations are not available (25).

Dietary therapy aims to minimize external protein (and, thus, nitrogen) intake and at the same time to prevent endogenous protein catabolism by meeting high-energy demands of the patient. The initial dietary emergency regimen should be protein-free, but protein or essential amino acids must be reintroduced after 24 to 48 hours or once blood ammonia level has fallen to less than 100µmol/L (24). In addition to close control of laboratory parameters like ammonia, electrolytes, glucose, etc., plasma amino acids must be determined at least daily. The reduction of protein intake must be carefully monitored to prevent over-restriction, which can impair protein synthesis and aggravate metabolic decompensation (26).

According to the physician’s advice, an oral dietary emergency regimen might be applicable to treat a hyperammonemic episode as long as the patient is not at risk of developing catabolism due to insufficient energy supply as a consequence of vomiting, loss of appetite, or diarrhea. Protein, liquid, and glucose management is identical to the protocol in Table 1.

Patients and families might start with an oral emergency dietary regimen at home. Antipyretic measurements must be consequently carried out if temperature exceeds 38°C; however, patients and parents must be aware that these measures must not postpone or replace adequate emergency treatment in hospital (26; 65).

Patients should be supplied with an emergency card, letter, or bracelet containing instructions for emergency measures and phone numbers. Logistics of rational therapeutic measures should be repeatedly evaluated by the specialist team with the family and the primary care physicians.

Long-term management of HHH syndrome. Long-term management of HHH syndrome relies on the goals of preventing recurrent hyperammonemia and neurologic sequelae and improving quality of life by the following principles (26; 24):

Table 3. Long-Term Medication for HHH Syndrome****

Catabolism must be avoided as much as possible. In addition to intercurrent illnesses, especially if associated with high fever and decreased intake of food and fluids, dangerous triggers are severe exercise, seizures, trauma or burns, steroid administration, chemotherapy, and gastrointestinal hemorrhage. Dietary treatment is an essential anchor point of long-term management and requires the knowledge of a specialist metabolic dietitian. A diet with inadequate intake can impair protein synthesis and lead to metabolic decompensation or failure to thrive (26). For infants and children, nutritional management may involve the use of a high-caloric, low-protein diet supplemented with an essential amino acids formula and, if necessary, vitamins and minerals. This is most readily accomplished by using small amounts of natural protein, an essential amino acids formula, and supplemental calories provided by a formula that does not contain protein. The goal of long-term management is based on minimizing the nitrogen load on the urea cycle. The FAO/WHO/UNO 2007 Report can be used as age- and gender-dependent recommendations for energy intakes (24). Especially in young infants and children, long fasts should be avoided and snacks given to reduce the possibility of (overnight) catabolism.

Long-term medication comprises the use of sodium benzoate and sodium phenylbutyrate as well as the essential amino acids L-arginine or L-citrulline. Supplementations of L-arginine or L-citrulline aim at maximizing ammonia excretion through the urea cycle. In patients with creatine deficiency, additional creatine supplementation is recommended (24). A detailed overview is provided in Table 3. Drugs may not be well tolerated by the child or family. Sodium phenylbutyrate tastes and smells unpleasant and may be irritating to the stomach. Glycerol phenylbutyrate (RAVICTI®) has the same mechanism of action as sodium phenylbutyrate but is a sodium- and sugar-free prepro-drug of phenylacetic acid that has little odor or taste. Phenylbutyrate may deplete branched chain amino acid levels and cause menstrual dysfunction or amenorrhea in up to 25% of postpubertal females (08; 24). Acute toxicity of benzoate and phenylbutyrate has been rare, but severe overdoses (2 to 10 times recommended doses) have led to symptoms that may be clinically mistaken for hyperammonemic episodes, including lethargy, hyperventilation, metabolic acidosis, cardiopulmonary collapse, and death (50). To avoid complications, eg, mucositis or gastritis, sodium benzoate and sodium phenylbutyrate should be administered several times daily during meals with abundant fluids (24).

Periodic measurement of plasma amino acids (including glutamine) and ammonia may permit adjustment of therapy before clinical symptoms appear. The benefit of vaccinations outweighs the risk of metabolic decompensations. Vaccinations are recommended at the same schedule as for healthy children (40; 24).

A number of patients with various urea cycle disorders have received partial or total orthotopic liver transplants to provide enzyme replacement therapy (60), including few patients with HHH syndrome (58; 15). In essentially all successful cases, this procedure has cured the hyperammonemia and permitted a normal protein intake. However, its effectiveness is hampered by expense, limited availability of donor organs, and significant morbidity and mortality from complication of the transplantation or immunosuppression. A retrospective survey study investigated if patients would profit from liver transplantation by preventing further recurrent decompensations. Individuals with urea cycle disorders had improved neurocognitive outcome if they received a liver graft. This suggests that affected individuals should undergo liver transplantation after comparatively low maximum blood ammonia concentrations in order to protect the patient’s neurocognitive abilities (31; 30). However, further data suggest rather limited impact of liver transplantation on the neurodevelopmental outcome of individuals with a severe disease burden (29).

Some medications are contraindicated in urea cycle disorders because of secondary inhibition of the urea cycle--most importantly valproic acid, which inhibits NAGS (01). Even in well controlled and managed patients very acute deadly coma can occur. Systemic steroid treatment can have the same result. Less often but also to be considered is the potential development of hyperammonemic crises by the treatment with carbamazepine, the use of asparaginase or 5-fluorouracil in cancer therapy, or bladder or joint irrigation with glycine solution during surgery.

New trends and emerging therapies include the use of hypothermia in neonatal hyperammonemia. Mild systemic hypothermia was used in the treatment of neonatal hyperammonemic coma, with the rationale of lowering the enzymatic rate of ammonia production (36). At present, there appears to be no place yet for gene or enzyme replacement therapy in the routine treatment of urea cycle disorders (24). Hepatocyte transplantation is an interesting therapeutic option in urea cycle disorder patients waiting for liver transplantation (39). A further approach for treatment of acute hyperammonemia is inhibition of ornithine aminotransferase leading to transamination-dependent decrease of glutamate and glutamine. If this approach might indeed be a potential new therapeutic-principle for individuals with urea cycle disorders, mammalian transfer will provide more insight (62). It has been suggested that autophagy cooperates with the urea cycle in ammonia homeostasis. Selective activation of hepatic autophagy might, therefore, be used to treat hyperammonemia due to acquired or inherited diseases. However, it remains to be elucidated if autophagy also plays an important role during hyperammonemic conditions in the brain. Better understanding of this phenomenon will be necessary to determine if autophagy is a suitable target for treatment of hyperammonemic conditions (54).

Outcomes

Although some publications suggest improved outcome (eg, neurologic manifestation, mortality) of individuals with urea cycle disorders, a review and metaanalysis showed less convincing results, suggesting that no improvement of survival for urea cycle disorders was observed over more than three decades between 1978 and 2014 (07). Some studies showed that noninterventional variables reflecting disease severity are associated with the highest risk of mortality and poor neurologic outcome (17; 49). Long-term morbidity is still substantial in urea cycle disorder patients. More information and long-term data are needed in order to evaluate major predictors of good and poor neurocognitive outcome and to evaluate the impact of diagnostic and therapeutic strategies on neurologic outcome for individuals with urea cycle disorders.

Special considerations

Pregnancy

Limited information exists about pregnancies in women suffering from HHH syndrome. A woman going through three pregnancies experienced nausea, dizziness, and unsteadiness with mild hyperammonemia. She was in good health during the first trimester. In the course of her pregnancy she developed petit mal seizures, and at term she delivered a baby who had intrauterine growth retardation. The two other babies’ growth was not hindered at birth. Within 24 hours after delivery, the woman developed elevated ammonia levels; however, she did not develop hyperammonemic coma and responded well to treatment (32).

Langendonk studied a series of pregnancies in women with inherited metabolic disease and strongly suggested that special care must be taken not to confuse behavioral changes of hyperammonemia for symptoms of postpartum psychosis or depression (35). Routine monitoring of plasma ammonia levels in those women is mandatory (18). Pregnancy in women with urea cycle disorders should, therefore, be monitored in close contact with or in a metabolic center (35).

Anesthesia

It is prudent to use anesthetics with low toxicity to the liver. Surgery requires stopping oral medication and may be associated with a catabolic condition, both of which may induce hyperammonemia. It is important to resume oral medication as soon as possible and, if necessary, continue alternate pathway therapy intravenously until the patient is able to tolerate his oral medication. The patient should also receive adequate glucose infusion to prevent catabolism. Surgery should only be carried out in centers prepared for dealing with acute hyperammonemic episodes. After surgery, close monitoring of the clinical status and ammonia and glutamine levels as well as shifting to oral medications are required (24).

A case was reported emphasizing that appropriate guidelines for the pre- and postoperative care of patients with inherited metabolic diseases of the urea cycle are indispensable (22).