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Partial Biotinidase Deficiency Revealed Imbalances In International Journal of Environmental Research and Public Health Case Report Partial Biotinidase Deficiency Revealed Imbalances in Acylcarnitines Profile at Tandem Mass Spectrometry Newborn Screening Ilaria Cicalini 1,2 , Damiana Pieragostino 1,3, Cristiano Rizzo 4, Sara Verrocchio 1,2, Daniela Semeraro 1,2, Mirco Zucchelli 1,3, Silvia Di Michele 5 , Carlo Dionisi-Vici 4 , Liborio Stuppia 1,6, Vincenzo De Laurenzi 1,3, Ines Bucci 1,2 and Claudia Rossi 1,6,* 1 Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; [email protected] (I.C.); [email protected] (D.P.); [email protected] (S.V.); [email protected] (D.S.); [email protected] (M.Z.); [email protected] (L.S.); [email protected] (V.D.L.); [email protected] (I.B.) 2 Department of Medicine and Aging Science, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy 3 Department of Innovative Technologies in Medicine & Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy 4 Metabolic Diseases Unit, Bambino Gesù Children Hospital and Research Institute, 00165 Rome, Italy; [email protected] (C.R.); [email protected] (C.D.-V.) 5 Department of Pediatrics, “Spirito Santo” Hospital, 65100 Pescara, Italy; [email protected] 6 Department of Psychological, Health and Territory Sciences, School of Medicine and Health Sciences, “G. d’Annunzio” University, 66100 Chieti, Italy * Correspondence: [email protected]; Tel.: +39-0871-541596; Fax: +39-0871-541598 Citation: Cicalini, I.; Pieragostino, D.; Abstract: Biotinidase (BTD) deficiency is an autosomal recessive inherited neurocutaneous disorder. Rizzo, C.; Verrocchio, S.; Semeraro, D.; BTD recycles the vitamin biotin, a coenzyme essential for the function of four biotin-dependent Zucchelli, M.; Di Michele, S.; carboxylases, including propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate Dionisi-Vici, C.; Stuppia, L.; De carboxylase, and acetyl-CoA carboxylase. Due to deficient activities of the carboxylases, BTD de- Laurenzi, V.; et al. Partial Biotinidase ficiency is also recognized as late-onset multiple carboxylase deficiency and is associated with Deficiency Revealed Imbalances in secondary alterations in the metabolism of amino acids, carbohydrates, and fatty acids. BTD defi- Acylcarnitines Profile at Tandem ciency can be classified as “profound”, with less than 10% of mean normal activity, and as “partial” Mass Spectrometry Newborn with 10–30% of mean normal activity. Newborn screening (NBS) of BTD deficiency is performed Screening. Int. J. Environ. Res. Public Health 2021, 18, 1659. https:// in most countries and is able to detect both variants. Moreover, mild metabolic alterations related doi.org/10.3390/ijerph18041659 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 Academic Editor: Eusebio Chiefari female infant with an initial suspected BTD deficiency at the NBS test, finally confirmed as a partial Received: 28 December 2020 variant by molecular testing. Although BTD deficiency was partial, interestingly her metabolic profile Accepted: 4 February 2021 at birth and during the follow-up tests revealed, for the first time, alterations in specific acylcarnitines Published: 9 February 2021 as a possible result of the deficient activity of biotin-dependent carboxylases. Publisher’s Note: MDPI stays neutral Keywords: biotinidase deficiency; newborn screening; inborn errors of metabolism; metabolic with regard to jurisdictional claims in profiling; mass spectrometry published maps and institutional affil- iations. 1. Introduction Biotinidase (BTD) deficiency is an autosomal recessive inherited disorder of biotin recy- Copyright: © 2021 by the authors. cling and it is associated with neurologic and cutaneous consequences if untreated [1,2]. The Licensee MDPI, Basel, Switzerland. BTD enzyme is encoded by a single gene (BTD) located on chromosome 3p25. Over 150 mu- This article is an open access article tations in the BTD gene have been identified and reported to cause BTD deficiency [1,3,4]. distributed under the terms and The BTD enzyme, a 70–80 kDa glycoprotein, has a dual function: on the one hand, it conditions of the Creative Commons separates the water-soluble vitamin biotin from the biocytin, allowing the recirculation of Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ free biotin, also releasing lysine; on the other hand, BTD also recovers biotin from food 4.0/). sources, by breaking down its bond with other proteins [5], as shown in Figure1. Int. J. Environ. Res. Public Health 2021, 18, 1659. https://doi.org/10.3390/ijerph18041659 https://www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2021, 18, x 2 of 10 Int. J. Environ. Res. Public Health 2021recirculation, 18, 1659 of free biotin, also releasing lysine; on the other hand, BTD also recovers2 of 10 biotin from food sources, by breaking down its bond with other proteins [5], as shown in Figure 1. Figure 1. 1. TheThe Biotin Biotin Cycle. Cycle. The The figure figure shows shows the function the function of the of Biotinidase the Biotinidase (BTD) (BTD)enzyme enzyme in making in making available available the waters- the solublewaters-soluble vitamin vitaminbiotin from biotin biocytin from biocytinand from and dietary from sources. dietary BTD sources. substrates BTD substratescan be ex novo can beprotein-bound ex novo protein-bound biotin, out- sidebiotin, the outside biotin cycle the biotin (as underlined cycle (as underlined by the orange by background) the orange background) or biocytin resulting or biocytin from resulting the biotin from re-cycle the biotin (as underlined re-cycle (as byunderlined the light bygreen the lightbackground). green background). In the case of In BTD the case deficiency, of BTD deficiency,as indicated as by indicated the red by“X”, the free red biotin, “X”, free being biotin, deficient, being cannotdeficient, properly cannot play properly its role play of itscoenzyme role of coenzyme for the four for holocarboxylases, the four holocarboxylases, leading leadingto the accumulation to the accumulation of substrates, of substrates, which causeswhich causestoxicity toxicity and disease and disease signs and signs symptoms. and symptoms. InIn particular, particular, biotin biotin in in the free form acts as a coenzyme, essential for the function of fourfour carboxylases: carboxylases: propionyl-CoA propionyl-CoA carboxylas carboxylasee and and 3-methylcrotonyl-CoA 3-methylcrotonyl-CoA carboxylase in proteinprotein catabolism, pyruvate carboxylase nece necessaryssary for gluconeogenesis, and acetyl-CoA carboxylasecarboxylase in in the the first first step step of of fatty fatty acid acid synt synthesishesis [4,6,7]. [4,6,7]. Therefore, Therefore, an inherited inherited disorder ofof biotin recycling because because of of a deficiency deficiency of BTD is also known as late-onset multiple carboxylasecarboxylase deficiency deficiency and and is is associated associated with with secondary secondary imbalances imbalances in inthe the metabolism metabolism of aminoof amino acids, acids, carbohydrates, carbohydrates, and and fatty fatty acids acids [8]. [Depending8]. Depending on the on theresidual residual enzymatic enzymatic ac- tivity,activity, BTD BTD deficiency deficiency variants variants are are functional functionallyly described described as as “profound” “profound” with with less less than 10% of of mean mean normal normal activity, activity, and “partial” with 10 to to 30% 30% of of mean mean normal normal activity activity [1,4,5]. [1,4,5]. Worldwide, the incidence of BTD deficiency deficiency vari varieses from 1:40,000 to 1:60,000 births, being eveneven higher higher in in countries with with high consanguin consanguinityity rates rates [5]. [5]. Interestingly, Interestingly, a a higher higher inci- inci- dencedence of of 1:6300 1:6300 (cumulative (cumulative for for complete complete or or partial) partial) has has been been recently recently reported reported in in Italy Italy [9]. [9]. TheThe initial clinical symptoms in untreated children might appear between two and five five monthsmonths of of age, even if they may not be evidentevident until severalseveral yearsyears laterlater [[1].1]. Untreated infantsinfants with with profound profound BTD BTD deficiency deficiency can can exhi exhibitbit a variety of neurological and clinical manifestations,manifestations, including including hypotonia, hypotonia, seizures, seizures, feeding problems, ataxia, developmental delay,delay, hearing loss, alopecia, eczema, and skin rash [1,4,5]. [1,4,5]. Biochemically, Biochemically, most untreated patientspatients maymay presentpresent lactic lactic acidosis, acidosis, ketoacidosis, ketoacidosis, and and eventually eventually hyperammonaemia hyperammonaemia [1,4]. [1,4].Other Other metabolic metabolic alterations alterations may include may include the elevation the elevation of lactic of acid lactic and acid alanine and alanine due to defi-due tocient deficient activity activity of pyruvate of pyruvate carboxylase, carboxylas accumulatione, accumulation of propionate, of propionate, 3-hydroxypropionate, 3-hydroxypro- pionate,and methyl and citratemethyl because citrate because of deficient of deficie activitynt activity of propionyl-CoA of propionyl-CoA carboxylase, carboxylase, and in- andcreased increased excretion excretion levels
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