Clinical Guidance

Genotype-phenotype correlations remain to be determined. Of note, because of the high rate of parental consanguinity most affected individuals are homozygous for a pathogenic variant. Interestingly, for family 3 reported by with a homozygous CA5A of exon 6 in whom carbonic anhydrase VA was absent in liver, the phenotype was not more severe than in the other two families with splice site and missense variants and residual (albeit reduced) carbonic anhydrase VA enzymatic activity.

Source: GeneReviews — "Carbonic Anhydrase VA Deficiency"

Diagnostic Criteria

No consensus clinical diagnostic criteria for carbonic anhydrase VA (CA-VA) deficiency have been published.

Suggestive Findings

Carbonic anhydrase VA (CA-VA) deficiency should be suspected in children with the following clinical and laboratory findings and family history. Clinical findings include neonatal, infantile, or early childhood-onset of metabolic hyperammonemic encephalopathy (like that observed in the urea cycle disorders) with lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma.

Laboratory findings

Source: GeneReviews — "Carbonic Anhydrase VA Deficiency"

Differential Diagnosis

Clinical Findings

Disorders to consider in the differential diagnosis of carbonic anhydrase VA (CA-VA) deficiency are summarized in .

Table 2.

Disorders of Interest in the Differential Diagnosis of CA-VA Deficiency

Gene | Disorder | MOI | Clinical Characteristics

BTD

HLCS | Multiple carboxylase deficiency (biotinidase deficiency holocarboxylase synthetase deficiency) (OMIM 253270) | AR | If untreated, children w/profound defic usually exhibit neurologic abnormalities (seizures, lethargy, muscular hypotonia), cutaneous abnormalities, ataxia, DD, vision problems, hearing loss.

CPS1

Source: GeneReviews — "Carbonic Anhydrase VA Deficiency"

Management Guidelines

No clinical practice guidelines for carbonic anhydrase VA (CA-VA) deficiency have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with carbonic anhydrase VA (CA-VA) deficiency, the following evaluations are recommended:

• Measurement of serum lactate, plasma ammonia, serum glucose, blood gases, plasma amino acids, blood acylcarnitines, urine ketone bodies, and urine organic acid profiles (during periods of illness; when stable for monitoring, preferably fasting)

• Liver function parameters (coagulation, albumin, AST, ALT) as acute liver failure can occur in the urea cycle disorders, which are metabolically similar

• Consideration of:

• Brain MRI to define extent of or to exclude brain edema

• Neurodevelopmental testing

• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CA-VA deficiency in order to facilitate medical and personal decision making

Treatment of Manifestations

During acute episodes. Admit to the hospital children with insufficient intake or refusal to take anything orally and/or signs of metabolic decompensation such as encephalopathy. The following are recommended:

Source: GeneReviews — "Carbonic Anhydrase VA Deficiency"

Clinical Guidance

Acetazolamide should be avoided, as it inhibits carbonic anhydrase activity. If anti-seizure medication is necessary, avoid topiramate based on its action as a carbonic anhydrase inhibitor.

Source: GeneReviews — "Carbonic Anhydrase VA Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Carbonic Anhydrase VA Deficiency"

Surveillance Guidelines

Follow up during infancy and early childhood with a metabolic disease specialist every three to six months for physical and neurologic examinations.

• Consider neurodevelopmental testing and measurement of the following: plasma ammonia and amino acids (to check for chronic hyperammonemia and citrulline deficiency as well as general nutritional state); serum lactate and glucose; blood gases; liver parameters; and urine organic acids.

• If asymptomatic and no further episodes, monitoring can be relaxed during childhood but a sick day regime/emergency plan should be provided and followed.

Source: GeneReviews — "Carbonic Anhydrase VA Deficiency"