Hyperammonemia disorders

Last update: December 4, 2018

Panel testing recommended at Breda Genetics for this condition:

Urea cycle and hyperammonemia disorders (ACADM, ACADS, ACADVL, ARG1, ASL, ASS1, BCKDHA, BCKDHB, CPS1, CPT1A, CPT2, DBT, DLD, ETFA, ETFB, ETFDH, GLUD1, HADHA, HADHB, HCFC1, HLCS, HMGCL, HMGCS2, IVD, MCCC1, MCCC2, MMAA, MMAB, MMACHC, MMADHC (C2ORF25) , MUT, NAGS, OTC, PC, PCCA, PCCB, SLC22A5, SLC25A13, SLC25A15, SLC25A20, SLC7A7, SUCLA2, SUCLG1, TMEM70)

Medicines

Summary

Hyperammonemia is a metabolic condition characterized by elevated levels of ammonia in the blood. Increased entry of ammonia to the brain is a primary cause of neurologic disorders, such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathies, Reye syndrome, several other metabolic disorders, and some toxic encephalopathies.

Onset of these disorders is mostly variable. Besides the severe manifestations of the newborn, signs and symptoms of late-onset hyperammonemia (later in life) may include intermittent ataxia, intellectual impairment, failure to thrive, gait abnormality, behavior disturbances, epilepsy, recurrent Reye syndrome, protein avoidance, episodic headaches and cyclic vomiting.

The therapeutic aims in patients with hyperammonemia are to correct the biochemical abnormalities and ensure adequate nutritional intake. Treatment involves compounds that increase the removal of nitrogen waste.

Causes of hyperammonia disorders can be caused by different class of disorders: enzyme defects in urea cycle, organic acidemias, congenital lactic acidosis, fatty acid oxidation defects, dibasic amino acid transport defects, transient hyperammonemia of the newborn, asphyxia, Reye syndrome, drugs, liver or renal disease, neonatal herpes simplex pneumonitis, parenteral alimentation, Hashimoto encephalopathy and as a rare complication of multiple myeloma.

Detailed clinical description and molecular genetics

With particular regard to the genetic causes we must mention the following:

Enzyme defects in urea cycle

  • N-acetylglutamate synthetase deficiency: autosomal recessive, caused by homozygous or compound heterozygous mutation in the NAGS gene. The clinical and biochemical features of the disorder are indistinguishable from carbamoyl phosphate synthase I deficiency (CPS1 mutation). Onset occurs at any age, but neonatal presentation appears to be the most frequent. The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress. The treatment for patients with NAGS activity is daily administration of N-carbamyl-L-glutamate (NCLG), a structural analogue of NAG that activates CPSI, which in most cases, if given before the onset of permanent neurological sequelae, allows normal psychomotor development and an excellent quality of life. Carbaglu (Recordati) is used in NAGS deficiency.
  • Ornithine transcarbamoylase (OTC) deficiency: X-linked, caused by mutation in the OTC gene. Onset is variable (there are also late-onset – partial – forms of the diseases and some female carriers may show some symptoms). Males with the severe, neonatal-onset type are normal at birth but develop poor sucking, hypotonia and lethargy after a few days, rapidly progressing into somnolence and coma. Many female carriers are asymptomatic; however they can be affected to the same extent as males if the degree of X-inactivation of the disease allele is unfavorable. Diagnosis is based on clinical manifestations and plasma ammonia levels are typically high (>200 µmol/L) when encephalopathy is present. The disorder is treatable with supplemental dietary arginine and low protein diet.
  • Argininosuccinic lyase deficiency (also known as argininosuccinic aciduria): autosomal recessive, caused by mutation in the ASL gene. Two forms of argininosuccinic aciduria have been recognized: an early-onset, or malignant, type and a late-onset type (in childhood).
  • Citrullinemia: autosomal recessive, caused by ASS1 mutations (citrullinemia type I) or SLC25A13 mutations (citrullinemia type II). Onset is usually between hours 24 and 72 of life, but late-onset forms have been described in the literature. The disease presents with a large range of manifestations including neonatal hyperammonemic encephalopathy with lethargy, seizures and coma; hepatic dysfunction in all age groups; episodes of hyperammonemia and neuropsychiatric symptoms can be seen in children or adults. Some individuals detected by newborn screening may even be asymptomatic.
  • Argininemia (also known as arginase deficiency): autosomal recessive, caused by homozygous or compound heterozygous mutation in the ARG1 gene.

Organic acidemias

Usually these disorders are associated with ketosis and acidosis in addition to hyperammonemia. However, sometimes hyperammonemia dominates the picture, misleading the diagnosis (the patient can be initially diagnosed as affected by an urea cycle disorder):

  • Isovaleric acidemia: autosomal recessively inherited, caused by mutation in the IVD gene. The disease can present from infancy to childhood. Chronic intermittent presentations and asymptomatic patients have also been reported.
  • Propionic acidemia: autosomal recessive, PCCA or PCCB mutations. Onset is variable with severe neonatal forms to intermittent late onset form.
  • Isolated methylmalonic acidemia/aciduria: autosomal recessive, caused by mutation in any of the following genes: MUT, MMAA, MMAB, MCEE, or MMADHC. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress.
  • Multiple acyl-CoA dehydrogenation deficiency (MADD): also known as glutaric acidemia type IIA, IIB or IIC, autosomal recessive, caused by ETFA, ETFB or ETFDH gene mutations respectively. It is a clinically heterogeneous disorder ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.
  • Multiple carboxylase deficiency: also known as holocarboxylase synthetase deficiency, is an autosomal recessive disorder caused by HLCS gene mutations. It can present in the newborn or later in infancy. Biotinidase deficiency is another form of multiple carboxylase deficiency with a later onset which is characterized primarily by cutaneous and neurologic abnormalities (BTD gene mutations).
  • Alpha-methylacetoacetic aciduria: also knon as beta-ketothiolase deficiency, autosomal recessive inheritance, caused by mutations in the ACAT1 gene. It is characterized by intermittent ketoacidotic episodes associated with vomiting, dyspnea, tachypnoea, hypotonia, lethargy and coma, with an onset during infancy or toddlerhood and usually ceasing by adolescence.

Congenital lactic acidosis

Hyperammonemia and citrullinemia have been observed in some cases of congenital lactic acidosis, which is mainly characterized by increased lactate (10-20 mmol/L), increased lactate/pyruvate ratio, metabolic acidosis, and ketosis. Congenital lactic acidosis can be seen in:

  • Pyruvate dehydrogenase deficiency: signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. Impaired psychomotor development, hypotonia and neurological dysfunction are typical. The disorder can be caused by mutation th PDHA1, PDHB, PDHX, PDP1 or DLAT gene.
  • Pyruvate carboxylase deficiency: three clinical presentations of PC deficiency, probably constituting a continuum, have been described: infantile PC deficiency (type A); severe neonatal PC deficiency (type B); and intermittent/benign PC deficiency (type C). Diagnosis is based on detection of characteristic laboratory test abnormalities in amino acid, organic acid, glucose, and ammonia serum concentrations. PC deficiency is caused by mutations in the PC gene.
  • Mitochondrial disorders

Fatty acid oxidation defects

  • Medium- or very long-chain Acyl CoA dehydrogenase deficiency (ACADM or VLCAD gene mutations repsectively): patients can present with severe hypoglycemia, but some patients have modest hyperammonemia secondary to hepatic dysfunction.
  • Systemic carnitine deficiency: it encompasses a broad clinical spectrum including from infantile, to adult to asymptomcatic forms. Mutations can be found in the SLC22A5 gene (autosomal recessive inheritance). Systemic primary carnitine deficiency (CDSP) should be considered in the following clinical situations: infant with positive newborn screening, infants with hypoketotic hypoglycemic episodes that may be associated with hepatomegaly, elevated transaminases, and hyperammonemia, children with skeletal myopathy and/or elevated serum concentration of creatine kinase (CK), children with cardiomyopathy, adults with unexplained fatigability, sudden death.

Dibasic amino acid transport defects

  • Lysinuric protein intolerance: autosomal recessive, caused by mutation in the SLC7A7 gene. Affected individuals have normal neurologic development when adequately treated. Onset can be in the newborn (protein intolerance, vomiting, diarrhea, failure to thrive, hepatomegaly, diffuse cirrhosis, low blood urea, hyperammonemia, and leukopenia) but also in adulthood (protein intolerance in people who refuse to eat protein-rich food)
  • Hyperammonemia-hyperornithinemia-homocitrullinuria (HHH): caused by mutations in the SLC25A15 gene, autosomal recessive inheritance, it is characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or chronic liver dysfunction.

Carbonic anhydrase VA deficiency

Carbonic anhydrase VA deficiency (also known as CA-VA deficiency) is an autosomal recessively inherited conditions which have been described in just four children so far. It is caused by mutations in the CA5A gene. The disorder can be suspected in children with neonatal, infantile, or early-childhood metabolic hyperammonemic encephalopathy (similar to that described in urea cycle disorders) combined with hyperlactatemia and metabolites suggestive of multiple carboxylase deficiency. Besides hyperammonemia, biochemical findings include increase of lactate and ketones in plasma, respiratory alkalosis and metabolic acidosis, plasma elevation of glutamine and alanine and low-to-normal citrulline, and urine elevation of high 3-OH propionate, propionylglycine, methylcitrate, lactate, beta-hydroxybutyrate and acetoacetate.

Recommended testing workflow

Panel testing recommended at Breda Genetics for this condition:

Urea cycle and hyperammonemia disorders (ACADM, ACADS, ACADVL, ARG1, ASL, ASS1, BCKDHA, BCKDHB, CPS1, CPT1A, CPT2, DBT, DLD, ETFA, ETFB, ETFDH, GLUD1, HADHA, HADHB, HCFC1, HLCS, HMGCL, HMGCS2, IVD, MCCC1, MCCC2, MMAA, MMAB, MMACHC, MMADHC (C2ORF25) , MUT, NAGS, OTC, PC, PCCA, PCCB, SLC22A5, SLC25A13, SLC25A15, SLC25A20, SLC7A7, SUCLA2, SUCLG1, TMEM70)

References

Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy. Widhalm K, Koch S, Scheibenreiter S, Knoll E, Colombo JP, Bachmann C, Thalhammer O. Pediatrics. 1992 Jun;89(6 Pt 2):1182-4. PMID: 1594374

Propionyl-CoA carboxylase – A review. Wongkittichote P, Ah Mew N, Chapman KA. Mol Genet Metab. 2017 Dec;122(4):145-152. PMID: 29033250

Oxidative stress in urea cycle disorders: Findings from clinical and basic research. Parmeggiani B, Vargas CR.  Clin Chim Acta. 2018 Feb;477:121-126. PMID: 29203429

Inborn Errors of Metabolism with Acidosis: Organic Acidemias and Defects of Pyruvate and Ketone Body Metabolism. Schillaci LP, DeBrosse SD, McCandless SE. Pediatr Clin North Am. 2018 Apr;65(2):209-230. PMID: 29502910

Respiratory chain deficiencies. Delonlay P, Rötig A, Sarnat HB. Handb Clin Neurol. 2013;113:1651-66. PMID: 23622386

Pyruvate Carboxylase Deficiency. Wang D, De Vivo D. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2009 Jun 2 [updated 2018 Mar 1]. PMID: 20301764

Lysinuric Protein Intolerance. Nunes V, Niinikoski H. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2006 Dec 21 [updated 2018 Apr 12]. PMID: 20301535

Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome. Camacho J1, Rioseco-Camacho N1. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2012 May 31. PMID: 22649802

Systemic Primary Carnitine Deficiency. El-Hattab AW1. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2012 Mar 15 [updated 2016 Nov 3]. PMID: 22420015

Hum Mutat. 2001 Sep;18(3):169-89. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Gregersen N, Andresen BS, Corydon MJ, Corydon TJ, Olsen RK, Bolund L, Bross P. PMID: 11524729

OMIM: 237310207900311250215700605814603471243500222700238970615751

Hyperammonemia on Medscape: Emedicine.medscape: 1174503-overview

Orphanet: ORPHA33

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