Clinical Guidance

The pathogenic variant is a founder variant in the native North American Ojibwa, Cree, and Mi'kmaq tribes of the Algonquin-speaking peoples in northwestern Ontario and northeastern Manitoba, Canada . In all 14 affected individuals of Ojibwa and Cree origin, homozygous p.Ala610Thr pathogenic variants were identified. Brain anomalies were identified at age ten days, suggesting that these changes were present in utero . Classes of pathogenic variants. Disease severity has been loosely correlated with the class of PC pathogenic variant. Pathogenic missense and intronic variants are more often associated with PC deficiency types A and C, whereas truncating or nonsense variants are more often associated with PC deficiency type B [, , , ].

Source: GeneReviews — "Pyruvate Carboxylase Deficiency"

Diagnostic Criteria

In some newborns and states in the United States, pyruvate carboxylase (PC) deficiency can be suspected on the basis of elevated levels of citrulline during newborn screening. Since citrulline elevation is not specific to PC deficiency, it is critical to perform additional testing to identify the etiology of the citrulline elevation (see ACMG ACT algorithm). Suggestive Findings Pyruvate carboxylase (PC) deficiency should be suspected in probands with the following clinical and supportive laboratory findings and family history. Clinical Findings Type A (infantile) • Poor feeding, vomiting, failure to gain weight, linear growth failure • Respiratory distress/failure, tachypnea, Kussmaul breathing • Hypotonia, epilepsy (or epileptic encephalopathy), ataxia, dysarthria • Developmental delay • Hepatomegaly (or hepatosplenomegaly) Type B (neonatal) • Poor feeding, vomiting, failure to gain weight • Respiratory distress/failure, tachypnea • Hypotonia, epilepsy, hyporeflexia, hypothermia, lethargy • Hepatomegaly Type C (intermittent/attenuated) • Relatively normal or mildly delayed motor development; intellectual disability and autism • Respiratory distress, tachypnea, Kussmaul breathing • Episodic vomiting • Episodic hypotonia, dystonia, ataxia, dysarthria, transient hemiparesis or acute flaccid paralysis • Hepatomegaly Supportive Laboratory Findings Laboratory abnormalities by analyte. See . Note: For each of the following analytes the abnormal values overlap among PC deficiency types A, B, and C. Normal values differ by laboratory. Table 1. Pyruvate Carboxylase Deficiency: Supportive Biochemical Laboratory Findings in Blood by Phenotype

Source: GeneReviews — "Pyruvate Carboxylase Deficiency"

Differential Diagnosis

Many inborn errors of metabolism have features similar to those of pyruvate carboxylase (PC) deficiency. As listed in , the differential diagnosis includes biotinidase deficiency, holocarboxylase synthase deficiency, pyruvate dehydrogenase deficiency, respiratory chain disorders, tricarboxylic acid cycle disorders, and gluconeogenic defects.

Table 4.

Disorders in the Differential Diagnosis of Pyruvate Carboxylase Deficiency

Gene(s) | Disorder | MOI | Selected Features/ Comments

350 genes1 | Primary mitochondrial disorders | ADARMTXL | Lactate pyruvate concentrations are ; lactate-to-pyruvate ratio is , often 20

Source: GeneReviews — "Pyruvate Carboxylase Deficiency"

Management Guidelines

No clinical practice guidelines for pyruvate carboxylase (PC) deficiency have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PC deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Pyruvate Carboxylase Deficiency: Recommended Evaluations Following Initial Diagnosis in a Neonate/Infant or Child

System/Concern | Evaluation | Comment

Metabolic decompensation

| Consultation w/metabolic physician/ biochemical geneticist specialist metabolic dietitian | • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.

• Hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance emergency treatment, prognosis, risks for metabolic crises)

Laboratory studies

| • Blood lactate pyruvate

• Blood ammonia

• Blood chemistry panel incl glucose liver enzymes

• Arterial or venous blood gas

• Beta-hydroxybutyrate

• Blood amino acids

• Urine organic acids

| Baseline laboratory studies to monitor for metabolic acidosis

Neurologic

| • Neurology consultation

• Brain MRI (and MRS if available)

• Electroencephalogram

Source: GeneReviews — "Pyruvate Carboxylase Deficiency"

Clinical Guidance

Ketogenic diet is contraindicated, as it adds to the metabolic acidosis and ketosis from ketone bodies. Avoid fasting, which induces a catabolic state.

Source: GeneReviews — "Pyruvate Carboxylase Deficiency"

Therapies Under Investigation

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

Source: GeneReviews — "Pyruvate Carboxylase Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to treatment, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 7.

Pyruvate Carboxylase Deficiency: Recommended Surveillance

System/Concern | Evaluation | Frequency

Abnormal growth/ Nutritional deficiencies/ Feeding issues

| • Measurement of growth parameters (incl head circumference)

• Assessment of feeding skills in infants/toddlers

• Assessment by metabolic dietitian

| At each visit

Abnormal biochemical laboratory parameters

| • Plasma ammonia, if clinically warranted

• Plasma lactic acid

• Plasma amino acids

• Comprehensive metabolic panel

• Liver function tests

• CBC, ferritin, urinalysis for ketones

| At each visit dependent on diet mgmt recommendations

Neurologic status

| Neurologic exam, clinical history assessing for new movement disorder or seizures | At each visit

• EEG

• MRI

| As clinically indicated by neurologist

Triheptanoin-related surveillance

| • Monitor for GI adverse reactions.

• If receiving via feeding tube, monitor integrity of feeding tube.

• Monitor plasma acylcarnitine profile.

| At each visit, if affected person is receiving triheptanoin

Development

| Assess developmental milestones educational needs. | At each visit

Supportive care

| Assess need for referrals for social work, palliative care, respite care, home nursing.

CBC = complete blood count; GI = gastrointestinal

Source: GeneReviews — "Pyruvate Carboxylase Deficiency"