:Biotin deficiency

• Rashes including red, patchy ones near openings{{Cite web |title=Office of Dietary Supplements - Biotin |url=https://ods.od.nih.gov/factsheets/Biotin-HealthProfessional/ |access-date=2023-06-19 |website=ods.od.nih.gov |language=en}} (e.g. erythematous periorofacial macular rash){{Cite journal |last1=Rajendiran |first1=Ashwin |last2=Sampath |first2=Sowmya |date=2011-09-30 |title=Biotinidase deficiency – clinching the diagnosis rapidly can make all the difference! |journal=BMJ Case Reports |volume=2011 |pages=bcr0720114494 |doi=10.1136/bcr.07.2011.4494 |issn=1757-790X |pmc=3185397 |pmid=22679321}}
• Hair loss (alopecia){{Cite journal |last=Trüeb |first=Ralph M |date=2016 |title=Serum Biotin Levels in Women Complaining of Hair Loss |journal=International Journal of Trichology |volume=8 |issue=2 |pages=73–77 |doi=10.4103/0974-7753.188040 |issn=0974-7753 |pmc=4989391 |pmid=27601860 |doi-access=free }}
• Conjunctivitis
• Brittle nails
• Generalized muscular pains (myalgia){{Cite web |last=LLC |first=HealthMatters io |title=Biotin {{!}} Healthmatters.io |url=https://healthmatters.io/understand-blood-test-results/biotin |access-date=2023-06-19 |website=healthmatters.io |language=en}}
• Paresthesias (pins and needles){{Cite web |date=2017-10-18 |title=Biotin (vitamin B7) for hair growth: Uses, sources, health benefits |url=https://www.medicalnewstoday.com/articles/287720 |access-date=2023-06-19 |website=www.medicalnewstoday.com |language=en}} and numbness in the extemities

• Hallucinations
• Lethargy
• Mild depression{{Cite web |date=2014-04-22 |title=Biotin |url=https://lpi.oregonstate.edu/mic/vitamins/biotin |access-date=2023-06-19 |website=Linus Pauling Institute |language=en}}
• Fatigue, drowsiness{{Cite journal |last1=Abed |first1=Ali-Reza |last2=Abed |first2=Alireza |last3=Banafshe |first3=Hamid Reza |last4=Malekabad |first4=Ebadallah Shiri |last5=Gorgani-firuzjaee |first5=Sattar |last6=Dadashi |first6=Ali-Reza |date=2021-05-12 |title=Effect of biotin supplementation on neuropathic pain induced by chronic constriction of the sciatic nerve in the rat |journal=Research in Pharmaceutical Sciences |volume=16 |issue=3 |pages=250–259 |doi=10.4103/1735-5362.314823 |issn=1735-5362 |pmc=8216157 |pmid=34221058 |doi-access=free }} and somnolence

1. Total parenteral nutrition without biotin supplementation: Several cases{{Cite journal |last1=Innis |first1=S. M. |last2=Allardyce |first2=D. B. |date=February 1983 |title=Possible biotin deficiency in adults receiving long-term total parenteral nutrition |url=https://pubmed.ncbi.nlm.nih.gov/6401910/ |journal=The American Journal of Clinical Nutrition |volume=37 |issue=2 |pages=185–187 |doi=10.1093/ajcn/37.2.185 |issn=0002-9165 |pmid=6401910}} of biotin deficiency in patients receiving prolonged total parenteral nutrition (TPN) therapy without added biotin have been reported. Therefore, all patients receiving TPN must also receive biotin at the recommended daily dose, especially if TPN therapy is expected to last more than 1 week. All hospital pharmacies currently include biotin in TPN preparations.
2. Protein deficiency (not certain): A shortage of proteins involved in biotin homeostasis can cause biotin deficiency. The main problems involved in biotin homeostasis are HCS, BTD (biotinidase deficiency) and SMVT{{Cite journal |last1=Zempleni |first1=Janos |last2=Hassan |first2=Yousef I |last3=Wijeratne |first3=Subhashinee SK |date=2008-11-01 |title=Biotin and biotinidase deficiency |journal=Expert Review of Endocrinology & Metabolism |volume=3 |issue=6 |pages=715–724 |doi=10.1586/17446651.3.6.715 |issn=1744-6651 |pmc=2726758 |pmid=19727438}}
3. Anticonvulsant therapy: Prolonged use of certain drugs (especially highly common prescription anti-seizure medications such as phenytoin, primidone, and carbamazepine), may lead to biotin deficiency; however, valproic acid therapy is less likely to cause this condition.Krause et al. 1982, p. 485. Some anticonvulsants (antiepileptic drugs) inhibit biotin transport across the intestinal mucosa. Evidence suggests that these anticonvulsants accelerate biotin catabolism, which means that it's necessary for people to take supplemental biotin, in addition to the usual minimum daily requirements, if they're treated with anticonvulsant medication(s) that have been linked to biotin deficiency.
4. Severe malnourishment{{Cite journal |last1=Velázquez |first1=A. |last2=Martín-del-Campo |first2=C. |last3=Báez |first3=A. |last4=Zamudio |first4=S. |last5=Quiterio |first5=M. |last6=Aguilar |first6=J. L. |last7=Pérez-Ortiz |first7=B. |last8=Sánchez-Ardines |first8=M. |last9=Guzmán-Hernández |first9=J. |last10=Casanueva |first10=E. |date=March 1989 |title=Biotin deficiency in protein-energy malnutrition |url=https://pubmed.ncbi.nlm.nih.gov/2499449/ |journal=European Journal of Clinical Nutrition |volume=43 |issue=3 |pages=169–173 |issn=0954-3007 |pmid=2499449}}{{Citation |last1=Saleem |first1=Fatima |title=Biotin Deficiency |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK547751/ |work=StatPearls |access-date=2023-06-19 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31613531 |last2=Soos |first2=Michael P.}}
5. Prolonged oral antibiotic therapy: Prolonged use of oral antibiotics has been associated with biotin deficiency. Alterations in the intestinal flora caused by the prolonged administration of antibiotics are presumed to be the basis for biotin deficiency.{{Cite journal |last1=Hayashi |first1=Atsushi |last2=Mikami |first2=Yohei |last3=Miyamoto |first3=Kentaro |last4=Kamada |first4=Nobuhiko |last5=Sato |first5=Toshiro |last6=Mizuno |first6=Shinta |last7=Naganuma |first7=Makoto |last8=Teratani |first8=Toshiaki |last9=Aoki |first9=Ryo |last10=Fukuda |first10=Shinji |last11=Suda |first11=Wataru |last12=Hattori |first12=Masahira |last13=Amagai |first13=Masayuki |last14=Ohyama |first14=Manabu |last15=Kanai |first15=Takanori |date=2017-08-15 |title=Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice |journal=Cell Reports |volume=20 |issue=7 |pages=1513–1524 |doi=10.1016/j.celrep.2017.07.057 |issn=2211-1247 |pmid=28813664|doi-access=free }}
6. Genetic mutation: Mikati et al. (2006) reported a case of partial biotinidase deficiency (plasma biotinidase level of 1.3 nm/min/mL) in a 7-month-old boy. The boy presented with perinatal distress followed by developmental delay, hypotonia, seizures, and infantile spasms without alopecia or dermatitis. The child's neurologic symptoms abated following biotin supplementation and antiepileptic drug therapy. DNA mutational analysis revealed that the child was homozygous for a novel E64K mutation and that his mother and father were heterozygous for the novel E64K mutation.{{Cite journal |last1=Mikati |first1=Mohamad A. |last2=Zalloua |first2=Pierre |last3=Karam |first3=Pascale |last4=Habbal |first4=Mohamad-Zuheir |last5=Rahi |first5=Amal C. |date=November 2006 |title=Novel mutation causing partial biotinidase deficiency in a Syrian boy with infantile spasms and retardation |url=https://pubmed.ncbi.nlm.nih.gov/17092467/ |journal=Journal of Child Neurology |volume=21 |issue=11 |pages=978–981 |doi=10.1177/08830738060210110301 |issn=0883-0738 |pmid=17092467|s2cid=26189957 }}

1. Smoking: Recent studies suggest that smoking can lead to marginal biotin deficiency because it speeds up biotin catabolism (especially in women).{{Cite journal |last1=Sealey |first1=Wendy M |last2=Teague |first2=April M |last3=Stratton |first3=Shawna L |last4=Mock |first4=Donald M |date=October 2004 |title=Smoking accelerates biotin catabolism in women |journal=The American Journal of Clinical Nutrition |volume=80 |issue=4 |pages=932–935 |doi=10.1093/ajcn/80.4.932 |issn=0002-9165 |pmc=1450014 |pmid=15447901}}
2. Excessive alcohol consumption{{Cite journal |last1=Subramanya |first1=Sandeep B. |last2=Subramanian |first2=Veedamali S. |last3=Kumar |first3=Jeyan S. |last4=Hoiness |first4=Robert |last5=Said |first5=Hamid M. |date=March 2011 |title=Inhibition of intestinal biotin absorption by chronic alcohol feeding: cellular and molecular mechanisms |journal=American Journal of Physiology. Gastrointestinal and Liver Physiology |volume=300 |issue=3 |pages=G494–G501 |doi=10.1152/ajpgi.00465.2010 |issn=0193-1857 |pmc=3064116 |pmid=21148397}} (causes a significant reduction in plasma biotin levels)
3. Excessive consumption of antidiuretics or inadequate levels of antidiuretic hormone{{Cite web |last=Hoffman |first=Kristine |date=January 2015 |title=When Vitamin And Nutritional Deficiencies Cause Skin And Nail Changes |url=https://www.hmpgloballearningnetwork.com/site/podiatry/when-vitamin-and-nutritional-deficiencies-cause-skin-and-nail-changes |access-date=2023-06-19 |website=www.hmpgloballearningnetwork.com}}
4. Intestinal malabsorption caused by short bowel syndrome{{Cite journal |last1=Khalidi |first1=N. |last2=Wesley |first2=J. R. |last3=Thoene |first3=J. G. |last4=Whitehouse |first4=W. M. |last5=Baker |first5=W. L. |date=1984 |title=Biotin deficiency in a patient with short bowel syndrome during home parenteral nutrition |url=https://pubmed.ncbi.nlm.nih.gov/6429370/ |journal=Journal of Parenteral and Enteral Nutrition |volume=8 |issue=3 |pages=311–314 |doi=10.1177/0148607184008003311 |issn=0148-6071 |pmid=6429370|hdl=2027.42/141489 |hdl-access=free }}

Biotin is a coenzyme for five carboxylases in the human body (propionyl-CoA carboxylase, methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and 2 forms of acetyl-CoA carboxylase.) Therefore, biotin is essential for amino acid catabolism, gluconeogenesis, and fatty acid metabolism. Biotin is also necessary for gene stability because it is covalently attached to histones. Biotinylated histones play a role in repression of transposable elements and some genes. Normally, the amount of biotin in the body is regulated by dietary intake, biotin transporters (monocarboxylate transporter 1 and sodium-dependent multivitamin transporter), peptidyl hydrolase biotinidase (BTD), and the protein ligase holocarboxylase synthetase. When any of these regulatory factors are inhibited, biotin deficiency could occur.{{cite book|last1=Said|first1=H |title=Water Soluble Vitamins |chapter=Biotin: Biochemical, Physiological and Clinical Aspects |volume=56|pages=1–19|doi=10.1007/978-94-007-2199-9_1|pmid=22116691|series=Subcellular Biochemistry|date=2012 |isbn=978-94-007-2198-2}}

The only reliable method for determining biotin deficiency is the abundance of biotinylated 3-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase in lymphocytes. The level of biotin in urine can be used to identify biotin-supplemented individuals, and the level of 3-hydroxyisovaleric acid in urine can (unreliably) detect biotin-deficient patients.{{Cite journal |last1=Eng |first1=Wei Kay |last2=Giraud |first2=David |last3=Schlegel |first3=Vicki L. |last4=Wang |first4=Dong |last5=Lee |first5=Bo Hyun |last6=Zempleni |first6=Janos |date=2013-07-28 |title=Identification and assessment of markers of biotin status in healthy adults |journal=The British Journal of Nutrition |volume=110 |issue=2 |pages=321–329 |doi=10.1017/S0007114512005065 |issn=0007-1145 |pmc=4743878 |pmid=23302490}}

In the United States, biotin supplements are readily available without a prescription{{Cite web |title=Biotin (Oral Route) Description and Brand Names - Mayo Clinic |url=https://www.mayoclinic.org/drugs-supplements/biotin-oral-route/description/drg-20062359 |access-date=2023-06-19 |website=www.mayoclinic.org}} in amounts ranging from 300 to 10,000 micrograms.{{Cite journal |last1=Katzman |first1=Brooke M. |last2=Lueke |first2=Alan J. |last3=Donato |first3=Leslie J. |last4=Jaffe |first4=Allan S. |last5=Baumann |first5=Nikola A. |date=2018-09-01 |title=Prevalence of biotin supplement usage in outpatients and plasma biotin concentrations in patients presenting to the emergency department |url=https://www.sciencedirect.com/science/article/pii/S0009912018303151 |journal=Clinical Biochemistry |language=en |volume=60 |pages=11–16 |doi=10.1016/j.clinbiochem.2018.07.004 |pmid=30036510 |s2cid=51710689 |issn=0009-9120|url-access=subscription }} 30 micrograms daily is identified as Adequate Intake for men and women 19 years and older. 35 micrograms daily is required for lactating women.{{Cite web |last1=Avenue |first1=677 Huntington |last2=Boston |last3=Ma 02115 |date=2019-07-24 |title=Biotin – Vitamin B7 |url=https://www.hsph.harvard.edu/nutritionsource/biotin-vitamin-b7/ |access-date=2023-06-19 |website=The Nutrition Source |language=en-us}}

Most healthy individuals meet these recommended intakes, however many still take up to 500 to 1,000 micrograms of biotin daily.{{Cite journal |last1=Patel |first1=Deepa P. |last2=Swink |first2=Shane M. |last3=Castelo-Soccio |first3=Leslie |date=August 2017 |title=A Review of the Use of Biotin for Hair Loss |journal=Skin Appendage Disorders |volume=3 |issue=3 |pages=166–169 |doi=10.1159/000462981 |issn=2296-9195 |pmc=5582478 |pmid=28879195}}

Deficiency is rare in locations where egg-white enriched or ketogenic diets are common.{{Citation |last1=Dakshinamurti |first1=Krishnamurti |title=Effects of Biotin Deprivation and Biotin Supplementation |date=2019 |url=https://doi.org/10.1007/978-3-319-55387-0_73 |work=Handbook of Famine, Starvation, and Nutrient Deprivation: From Biology to Policy |pages=1613–1633 |editor-last=Preedy |editor-first=Victor R. |access-date=2023-06-19 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-319-55387-0_73 |isbn=978-3-319-55387-0 |last2=Dakshinamurti |first2=Shyamala |last3=Czubryt |first3=Michael P. |editor2-last=Patel |editor2-first=Vinood B.|url-access=subscription }} Pregnancy, however, alters biomarkers of biotin{{Cite journal |last1=Perry |first1=Cydne A |last2=West |first2=Allyson A |last3=Gayle |first3=Antoinette |last4=Lucas |first4=Lauren K |last5=Yan |first5=Jian |last6=Jiang |first6=Xinyin |last7=Malysheva |first7=Olga |last8=Caudill |first8=Marie A |date=December 2014 |title=Pregnancy and Lactation Alter Biomarkers of Biotin Metabolism in Women Consuming a Controlled Diet123 |journal=The Journal of Nutrition |volume=144 |issue=12 |pages=1977–1984 |doi=10.3945/jn.114.194472 |issn=0022-3166 |pmc=4230210 |pmid=25122647}} and despite a regular biotin intake, approximately half of the pregnant women in the U.S. are marginally biotin deficient.

• Biotinidase deficiency
• Holocarboxylase synthetase deficiency
• Multiple carboxylase deficiency

{{Reflist}}

• {{cite journal |vauthors=Adhisivam B, Mahto D, Mahadevan S | title = Biotin responsive limb weakness | journal = Indian Pediatr | volume = 44 | issue = 3 | pages = 228–30 |date=March 2007 | pmid = 17413203 }}
• {{cite journal |vauthors=Baykal T, Gokcay G, Gokdemir Y, Demir F, Seckin Y, Demirkol M, Jensen K, Wolf B | title = Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases | journal = J. Inherit. Metab. Dis. | volume = 28 | issue = 6 | pages = 903–12 | year = 2005 | pmid = 16435182 | doi = 10.1007/s10545-005-0161-3 | s2cid = 22277450 | doi-access = free }}
• {{cite journal | author = Boas MA | title = The Effect of Desiccation upon the Nutritive Properties of Egg-white | journal = Biochem. J. | volume = 21 | issue = 3 | pages = 712–724.1 | year = 1927 | pmid = 16743887 | pmc = 1251968 | doi = 10.1042/bj0210712}}
• {{cite journal |vauthors=Dobrowolski SF, Angeletti J, Banas RA, Naylor EW | title = Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency | journal = Mol. Genet. Metab. | volume = 78 | issue = 2 | pages = 100–7 |date=February 2003 | pmid = 12618081 | doi = 10.1016/S1096-7192(02)00231-7}}
• {{cite journal |vauthors=Forbes GM, Forbes A | title = Micronutrient status in patients receiving home parenteral nutrition | journal = Nutrition | volume = 13 | issue = 11–12 | pages = 941–4 | year = 1997 | pmid = 9433708 | doi = 10.1016/S0899-9007(97)00334-1}}
• {{cite journal |vauthors=Genc GA, Sivri-Kalkanoğlu HS, Dursun A, Aydin HI, Tokatli A, Sennaroglu L, Belgin E, Wolf B, Coşkun T | title = Audiologic findings in children with biotinidase deficiency in Turkey | journal = Int. J. Pediatr. Otorhinolaryngol. | volume = 71 | issue = 2 | pages = 333–9 |date=February 2007 | pmid = 17161472 | doi = 10.1016/j.ijporl.2006.11.001 }}
• {{cite journal |vauthors=González EC, Marrero N, Frómeta A, Herrera D, Castells E, Pérez PL | title = Qualitative colorimetric ultramicroassay for the detection of biotinidase deficiency in newborns | journal = Clin. Chim. Acta | volume = 369 | issue = 1 | pages = 35–9 |date=July 2006 | pmid = 16480705 | doi = 10.1016/j.cca.2006.01.009 }}
• {{cite journal |vauthors=Hassan YI, Zempleni J | title = Epigenetic regulation of chromatin structure and gene function by biotin | journal = J. Nutr. | volume = 136 | issue = 7 | pages = 1763–5 |date=July 2006 | pmid = 16772434 | pmc = 1479604 | doi = 10.1093/jn/136.7.1763}}
• {{cite journal |vauthors=Higuchi R, Mizukoshi M, Koyama H, Kitano N, Koike M | title = Intractable diaper dermatitis as an early sign of biotin deficiency | journal = Acta Paediatr. | volume = 87 | issue = 2 | pages = 228–9 |date=February 1998 | pmid = 9512215 | doi = 10.1080/08035259850157732}}
• {{cite journal |vauthors=László A, Schuler EA, Sallay E, Endreffy E, Somogyi C, Várkonyi A, Havass Z, Jansen KP, Wolf B | title = Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies | journal = J. Inherit. Metab. Dis. | volume = 26 | issue = 7 | pages = 693–8 | year = 2003 | pmid = 14707518 | doi = 10.1023/B:BOLI.0000005622.89660.59| s2cid = 12601233 }}
• {{cite journal | author = Mock DM | title = Biotin status: which are valid indicators and how do we know? | journal = J. Nutr. | volume = 129 | issue = 2S Suppl | pages = 498S–503S |date=February 1999 | pmid = 10064317 | doi = 10.1093/jn/129.2.498S| doi-access = free }}
• {{cite journal | author = Mock DM | title = Skin manifestations of biotin deficiency | journal = Semin Dermatol | volume = 10 | issue = 4 | pages = 296–302 |date=December 1991 | pmid = 1764357 }}
• {{cite journal |vauthors=Möslinger D, Mühl A, Suormala T, Baumgartner R, Stöckler-Ipsiroglu S | title = Molecular characterisation and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies | journal = Eur. J. Pediatr. | issue = Suppl 1 | pages = S46–9 | volume = 162 |date=December 2003 | pmid = 14628140 | doi = 10.1007/s00431-003-1351-3 | s2cid = 6490712 }}
• {{cite journal |vauthors=Neto EC, Schulte J, Rubim R, Lewis E, DeMari J, Castilhos C, Brites A, Giugliani R, Jensen KP, Wolf B | title = Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations | journal = Braz. J. Med. Biol. Res. | volume = 37 | issue = 3 | pages = 295–9 |date=March 2004 | pmid = 15060693 | doi = 10.1590/S0100-879X2004000300001| doi-access = free | hdl = 10183/21194 | hdl-access = free }}
• {{cite journal |vauthors=Schulpis KH, Gavrili S, Tjamouranis J, Karikas GA, Kapiki A, Costalos C | title = The effect of neonatal jaundice on biotinidase activity | journal = Early Hum. Dev. | volume = 72 | issue = 1 | pages = 15–24 |date=May 2003 | pmid = 12706308 | doi = 10.1016/S0378-3782(02)00097-X}}
• {{cite book |author1=Thompson, J |author2=Manore M |author3=Sheeshka J |veditors=Bennett G, Swieg C | title = Nutrition: A functional Approach | publisher = Pearson Canada | location = Toronto | year = 2010 | pages = 353 | isbn = 9780321740212 | chapter = Nutrients involved in energy metabolism and blood health |display-editors=etal}}
• {{cite journal | author = Velázquez A | title = Biotin deficiency in protein-energy malnutrition: implications for nutritional homeostasis and individuality | journal = Nutrition | volume = 13 | issue = 11–12 | pages = 991–2 | year = 1997 | pmid = 9433719 | doi = 10.1016/S0899-9007(97)00345-6}}
• {{cite journal |vauthors=Weber P, Scholl S, Baumgartner ER | title = Outcome in patients with profound biotinidase deficiency: relevance of newborn screening | journal = Dev Med Child Neurol | volume = 46 | issue = 7 | pages = 481–4 |date=July 2004 | pmid = 15230462 | doi = 10.1111/j.1469-8749.2004.tb00509.x| doi-access = free }}
• {{cite journal | author = Welling DB | title = Long-term follow-up of hearing loss in biotinidase deficiency | journal = J. Child Neurol. | volume = 22 | issue = 8 | pages = 1055 |date=August 2007 | pmid = 17761663 | doi = 10.1177/0883073807305789 | s2cid = 39911504 }}
• {{cite journal |vauthors=Wiznitzer M, Bangert BA | title = Biotinidase deficiency: clinical and MRI findings consistent with myelopathy | journal = Pediatr. Neurol. | volume = 29 | issue = 1 | pages = 56–8 |date=July 2003 | pmid = 13679123 | doi = 10.1016/S0887-8994(03)00042-0}}
• {{cite book | author = Wolf B |veditors=Scriver CR, Beaudet AL | title = The metabolic & molecular bases of inherited disease | publisher = McGraw-Hill | location = New York | year = 2001 | pages = 3935–62 | isbn = 978-0-07-913035-8 | chapter = Disorders of biotin metabolism |display-editors=etal}}

• [https://www.ncbi.nlm.nih.gov/books/NBK1322/ GeneReviews/NCBI/NIH/UW entry on Biotinidase deficiency]
• [https://www.ncbi.nlm.nih.gov/omim/253260,253260,609019,253260,609019 OMIM entries on Biotinidasa deficiency]

{{Medical resources

| DiseasesDB =

| ICD11 = {{ICD11|5B5G}}

| ICD10 = {{ICD10|E|53|8|e|50}}

| ICD9 = {{ICD9|266.2}}

| ICDO =

| OMIM =

| MedlinePlus =

| eMedicineSubj = ped

| eMedicineTopic = 238

| MeshID =

}}

{{Nutritional pathology}}

Category:Vitamin deficiencies