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Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency(CA5AD)

MedGen UID:
816734
Concept ID:
C3810404
Disease or Syndrome
Synonyms: Carbonic Anhydrase VA Deficiency; Carbonic anhydrase VA deficiency, hyperammonemia due to
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): CA5A (16q24.2)
 
Monarch Initiative: MONDO:0014332
OMIM®: 615751
Orphanet: ORPHA401948

Disease characteristics

Excerpted from the GeneReview: Carbonic Anhydrase VA Deficiency
Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented between day 2 of life and early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Given that fewer than 20 affected individuals have been reported to date, the ranges of initial presentations and long-term prognoses are not completely understood. As of 2021 the oldest known affected individual is an adolescent. Almost all affected individuals reported to date have shown normal psychomotor development and no further episodes of metabolic crisis; however, a few have shown mild learning difficulties or delayed motor skills. [from GeneReviews]
Authors:
Clara van Karnebeek  |  Johannes Häberle   view full author information

Additional descriptions

From NCBI curation
Suggestive Findings: Carbonic anhydrase VA (CA-VA) deficiency should be suspected in children with neonatal, infantile, or early childhood-onset metabolic hyperammonemic encephalopathy (like that observed in the urea cycle disorders) combined with hyperlactatemia and metabolites suggestive of multiple carboxylase deficiency.
From OMIM
Carbonic anhydrase VA deficiency is an autosomal recessive inborn error of metabolism characterized clinically by acute onset of encephalopathy in infancy or early childhood. Biochemical evaluation shows multiple metabolic abnormalities, including metabolic acidosis and respiratory alkalosis. Other abnormalities include hypoglycemia, increased serum lactate and alanine, and evidence of impaired provision of bicarbonate to essential mitochondrial enzymes. Apart from episodic acute events in early childhood, the disorder shows a relatively benign course. Treatment with carglumic acid can result in neurologic improvement (summary by van Karnebeek et al., 2014).  http://www.omim.org/entry/615751
From MedlinePlus Genetics
Carbonic anhydrase VA deficiency is an inherited disorder characterized by episodes during which the balance of certain substances in the body is disrupted (known as metabolic crisis) and brain function is abnormal (known as acute encephalopathy). These potentially life-threatening episodes can cause poor feeding, vomiting, weight loss, tiredness (lethargy), rapid breathing (tachypnea), seizures, or coma.

During an episode, people with carbonic anhydrase VA deficiency have excess ammonia in the blood (hyperammonemia), problems with acid-base balance in the blood (metabolic acidosis and respiratory alkalosis), low glucose in the blood (hypoglycemia), and reduced production of a substance called bicarbonate in the liver. These imbalances lead to the signs and symptoms that occur during the episodes.

People with carbonic anhydrase VA deficiency typically first experience episodes of the disorder by age 2. These episodes may be triggered by going without food (fasting) for longer than usual between meals or when energy demands are increased, such as during illness. Between episodes, children with carbonic anhydrase VA deficiency are generally healthy, and more than half have no further episodes after the first one. Some affected children have mildly delayed development or learning disabilities, while others develop normally for their age.

The risk of metabolic crisis and acute encephalopathy is thought to decrease after childhood. Because of the small number of people with carbonic anhydrase VA deficiency who have come to medical attention, the effects of this disorder in adults are not well understood.  https://medlineplus.gov/genetics/condition/carbonic-anhydrase-va-deficiency

Clinical features

From HPO
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the urine. Ketone bodies are insignificant in the blood and urine of normal individuals in the postprandial or overnight-fasted state.
Elevated urinary 3-hydroxybutyric acid
MedGen UID:
868023
Concept ID:
C4022414
Finding
An increased amount of 3-hydroxybutyric acid in the urine.
Lacticaciduria
MedGen UID:
871116
Concept ID:
C4025585
Finding
An increased concentration of lactic acid in the urine.
Abnormal urine sebacic acid concentration
MedGen UID:
1692932
Concept ID:
C5139636
Finding
Abnormal concentration of sebacic acid in the urine.
3-hydroxyisovaleric aciduria
MedGen UID:
1746334
Concept ID:
C5421619
Finding
Concentration of 3-hydroxyisovaleric acid in the urine above the normal range.
Elevated urine suberic acid level
MedGen UID:
1738538
Concept ID:
C5421685
Finding
The concentration of suberic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Elevated urine acetoacetic acid level
MedGen UID:
1778143
Concept ID:
C5539568
Finding
Elevated amount of acetoacetic acid in the urine.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Respiratory alkalosis
MedGen UID:
1411
Concept ID:
C0002064
Pathologic Function
Alkalosis due to excess loss of carbon dioxide from the body.
Hypernatremia
MedGen UID:
6966
Concept ID:
C0020488
Disease or Syndrome
An abnormally increased sodium concentration in the blood.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Ketoacidosis
MedGen UID:
67434
Concept ID:
C0220982
Disease or Syndrome
Acidosis resulting from accumulation of ketone bodies.
Hyperprolinemia
MedGen UID:
75690
Concept ID:
C0268528
Disease or Syndrome
An increased concentration of proline in the blood.
Hyper-beta-alaninemia
MedGen UID:
75702
Concept ID:
C0268630
Disease or Syndrome
An increased concentration of alanine in the blood.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Low plasma citrulline
MedGen UID:
326522
Concept ID:
C1839532
Finding
A decreased concentration of citrulline in the blood.
Hyperglutaminemia
MedGen UID:
326901
Concept ID:
C1839533
Finding
An increased concentration of glutamine in the blood.
Hypoargininemia
MedGen UID:
892673
Concept ID:
C4025095
Finding
A decreased concentration of arginine in the blood.
Hypoornithinemia
MedGen UID:
1695001
Concept ID:
C5139561
Finding
An abnormal decrease in ornithine in the blood.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
Follow this link to review classifications for Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency in Orphanet.

Recent clinical studies

Diagnosis

Olgac A, Kasapkara CS, Kilic M, Keskin EY, Sandal G, Cram DS, Haberle J, Torun D
J Pediatr Endocrinol Metab 2020 Aug 18;33(10):1349-1352. doi: 10.1515/jpem-2020-0117. PMID: 32809955
Konanki R, Akella RRD, Panigrahy N, Chirla DK, Mohanlal S, Lankala R
Brain Dev 2020 Aug;42(7):534-538. Epub 2020 May 4 doi: 10.1016/j.braindev.2020.04.007. PMID: 32381389

Prognosis

Olgac A, Kasapkara CS, Kilic M, Keskin EY, Sandal G, Cram DS, Haberle J, Torun D
J Pediatr Endocrinol Metab 2020 Aug 18;33(10):1349-1352. doi: 10.1515/jpem-2020-0117. PMID: 32809955

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