The Invitae Multiple Carboxylase Deficiency Panel analyzes the BTD and HLCS genes, which are associated with multiple carboxylase deficiency. This test is useful for the diagnosis of patients who are suspected to have multiple carboxylase deficiency from clinical symptoms, abnormal newborn-screening results, or biochemical findings. This test may help determine the genetic cause (biotinidase deficiency or holocarboxylase synthetase deficiency) of multiple carboxylase deficiency.
The Invitae Organic Acidemias Panel and the Invitae Elevated C5-OH Panel have been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. They can be ordered at no additional cost.
Multiple carboxylase deficiency, which includes biotinidase deficiency and holocarboxylase synthetase deficiency
Multiple carboxylase deficiency can be caused by two inherited metabolic disorders: biotinidase deficiency and holocarboxylase synthetase deficiency. Profound biotinidase deficiency and holocarboxylase synthetase deficiency are fully penetrant disorders. The clinical and biochemical symptoms of multiple carboxylase deficiency are variable but can include metabolic acidosis, neurological abnormalities, skin changes, and abnormal elevations on urine organic acids, including 3-hydroxyisovaleric acid, lactic acid, 3-hydroxypropionic acid, methylcitric acid, 3-methylcrotonylglycine, propionylglycine, and tiglylglycine. Patients with biotinidase deficiency will also have low serum biotinidase activity. In addition to clinical and biochemical findings, patients can be identified through abnormal newborn-screening results. Newborns with biotinidase deficiency may have low biotinidase enzyme activity, whereas newborns with holocarboxylase synthetase deficiency may have elevated C3 or C5-OH acylcarnitines. Biotinidase deficiency and most holocarboxylase synthetase deficiency can be treated successfully with pharmacologic doses of biotin. Because patients with biotinidase deficiency can have a wide variability in clinical and biochemical symptoms, molecular testing may be warranted in suspected patients who lack the classic organic aciduria.
Partial biotinidase deficiency is generally seen in patients with 10%–30% of residual biotinidase activity. Many patients with partial biotinidase deficiency have been identified through newborn screening and remain asymptomatic. Those with symptoms may have intermittent hypotonia, skin rashes, and alopecia during times of intercurrent illness. These patients are still at risk of becoming biotin dependent, so biotin therapy is recommended.
Profound biotinidase deficiency is generally seen in patients with less than 10% of residual biotinidase activity. Symptom onset ranges from one week to 10 years, with an average age of onset at 3.5 months. Untreated patients with profound biotinidase deficiency can have hypotonia, seizures, alopecia, eczema, and developmental delay. Over time, untreated patients may develop sensorineural hearing loss, candidiasis, ataxia, conjunctivitis, and visual problems such as optic atrophy. Early treatment with pharmacologic doses of biotin is important to prevent irreversible neurologic damage.
Patients with holocarboxylase synthetase typically have a more severe clinical picture than patients with biotinidase deficiency. At least half of patients present with a severe organic aciduria during the first few days of life. Symptoms may include metabolic acidosis, ketosis, hyperammonemia, lethargy, vomiting, hypotonia, seizures, respiratory difficulties, and hypothermia. Untreated patients may suffer coma and early death. Patients with a milder enzyme deficiency and later onset may have recurrent attacks of metabolic acidosis. Overtime, untreated patients can develop psychomotor delay, a characteristic skin rash, and alopecia.
For patients with symptoms consistent with multiple carboxylase deficiency and a biochemical diagnosis of biotinidase deficiency (low serum biotinidase activity and elevated 3-hydroxyisovaleric acid and lactic acid (with or without 3-hydroxypropionic acid), methylcitric acid, 3-methylcrotonylglycine, propionylglycine, and tiglylglycine in urine), approximately 100% will have two pathogenic variants in the BTD gene.
For patients with symptoms consistent with multiple carboxylase deficiency and a biochemical diagnosis of holocarboxylase synthetase deficiency (normal serum biotinidase activity and elevated 3-hydroxyisovaleric acid, lactic acid, 3-hydroxypropionic acid, methylcitric acid, 3-methylcrotonylglycine, propionylglycine, and tiglylglycine in urine), approximately 100% will have two pathogenic variants in the HLCS gene.
Both causes of multiple carboxylase deficiency—biotinidase deficiency and holocarboxylase synthetase deficiency—are inherited in an autosomal recessive pattern.
The worldwide prevalence for biotinidase deficiency is 1 in 60,000. Partial biotinidase deficiency has birth incidence of roughly 1 in 129,500 and profound biotinidase deficiency has a birth incidence of 1 in 112,271. The birth incidence of both partial and profound biotinidase deficiency has been estimated in several subpopulations as follows:
The incidence of holocarboxylase synthetase deficiency is estimated at 1 in 87,000 live births.
Testing for multiple carboxylase deficiency should be considered in patients with some or all of the following symptoms: feeding difficulties, breathing problems, skin changes, alopecia, lethargy, metabolic acidosis, hypotonia, lethargy, seizures, and rash.
For considerations for testing please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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