An unusual presentation of biotinidase deficiency in infant: High anion gap metabolic acidosis and Burkholderia cepacia sepsis

Biotinidase deficiency (BD) is an inborn metabolic disorder caused by low enzyme activity giving rise to impaired biotin release from dietary proteins. The first symptoms may be seen at first week following birth until 1 year of age. The goal of the therapy is to increase biotin bioavailability by daily 5-20 mg lifelong biotin replacement. Three-month-old girl born to nonconsanguineous parents, admitted to pediatric intensive care with multiple seizures, breathing difficulty and posturing. Blood investigations showed thrombocytopenia and high anion gap metabolic acidosis (HAGMA). Enzyme assay for biotinidase revealed low activities. Urinary organic acid analysis was normal. Enzyme activity is <10% in severe cases whereas between 10-30% in partial deficiency. BD can cause metabolic ketoacidosis, Hyperammonemia and organic Aciduria. BD behaves like immunodeficiency. Rarely bacterial infection can be seen. Treatment is lifelong biotin replacement.

HTRA2 Defect: A Recognizable Inborn Error of Metabolism with 3-Methylglutaconic Aciduria as Discriminating Feature Characterized by Neonatal Movement Disorder and Epilepsy—Report of 11 Patients

Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50). Exome/genome sequencing is a powerful tool for the diagnosis of the clinically and genetically heterogeneous mitochondrial disorders. Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease. All individuals presented a recognizable phenotype with neonatal- or infantile-onset neurodegeneration and death within the first month of life. Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia. Tremor, jitteriness, dystonia, and/or clonus were also common. HTRA2 defect should be grouped under the IEM with 3-MGA-uria as discriminating feature. Clinical characteristics overlap with other disorders of this group suggesting a common underlying pathomechanism. Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing in children with suggestive clinical findings.