Partial Biotinidase Deficiency Revealed Imbalances in Acylcarnitines Profile at Tandem Mass Spectrometry Newborn Screening

Abstract

Biotinidase (BTD) deficiency is an autosomal recessive inherited neurocutaneous disorder. BTD recycles the vitamin biotin, a coenzyme essential for the function of four biotin-dependent carboxylases, including propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. Due to deficient activities of the carboxylases, BTD deficiency is also recognized as late-onset multiple carboxylase deficiency and is associated with secondary alterations in the metabolism of amino acids, carbohydrates, and fatty acids. BTD deficiency can be classified as “profound”, with less than 10% of mean normal activity, and as “partial” with 10–30% of mean normal activity. Newborn screening (NBS) of BTD deficiency is performed in most countries and is able to detect both variants. Moreover, mild metabolic alterations related to carboxylase deficiency in profound BTD deficiency could result and possibly be revealed in the metabolic profile by tandem mass spectrometry (MS/MS) NBS. Here, we report the case of a newborn female infant with an initial suspected BTD deficiency at the NBS test, finally confirmed as a partial variant by molecular testing. Although BTD deficiency was partial, interestingly her metabolic profile at birth and during the follow-up tests revealed, for the first time, alterations in specific acylcarnitines as a possible result of the deficient activity of biotin-dependent carboxylases.

High Incidence of Partial Biotinidase Deficiency in the First 3 Years of a Regional Newborn Screening Program in Italy

“…In one newborn, in a repeat follow-up screening test at the age of 16 months, low biotinidase activity was confirmed, while on MS/MS analysis, a higher-than-cutoff value of methylmalonyl-3-hyroxy-isovalerylcarnitine C4DC-C5OH and a significant alteration in its ratio with short and medium chain acylcarnitines were observed. A similar profile was observed in the DBS MS/MS analysis of the proband's father [18].…”

“…Biotin supplementation at pharmacological doses (5-20 mg daily) prevents the development of symptoms in children with profound BD and improves neurological and cutaneous features in symptomatic patients [17]. Treatment of partial BTD is controversial; reports of untreated patients who developed symptoms and the lack of toxicity of the vitamin favor treatment of partial BTD patients with 1-5 mg of oral biotin per day [6,11,18]. The high morbidity and mortality associated with untreated profound BD and the effectiveness of early biotin treatment in preventing most of the symptoms make BD suitable for inclusion in newborn bloodspot screening (NBS) programs.…”