Childhood Degenerative & Metabolic Disorders

Updated 11.30.2023
Released 02.07.1994
Expires For CME 11.30.2026

Biotinidase deficiency

Author: Barry Wolf MD PhD

Editor: Barry Wolf MD PhD

Introduction

Overview

The author explains that although all states in the United States and many countries perform newborn screening for biotinidase deficiency, there are still some countries where individuals with the disorder are not identified until they develop major clinical symptoms, some of which are irreversible.

Key points

	• Biotinidase deficiency, an inherited neurocutaneous disorder, usually presents during childhood with neurologic symptoms, metabolic acidosis, mild hyperammonemia, and organic aciduria.
	• Biotinidase deficiency is readily treated with pharmacological doses of the vitamin biotin.
	• Biotinidase deficiency is screened for in most newborn screening programs in the United States and in many other countries.
	• Individuals with biotinidase deficiency who are treated since birth do not appear to develop physical or cognitive problems.
	• The major difficulty in individuals with biotinidase deficiency is compliance with biotin therapy, especially during adolescence, because most of them have never experienced symptoms.

Historical note and terminology

During the late 1970s, inherited isolated deficiencies of the three mitochondrial biotin-dependent carboxylases were described (178). These include (1) pyruvate carboxylase, which converts pyruvate to oxaloacetate, the initial step of gluconeogenesis; (2) propionyl-CoA carboxylase, which catabolizes several branched-chain amino acids and odd-chain fatty acids; and (3) beta-methylcrotonyl-CoA carboxylase, which is involved in the catabolism of leucine. Each deficiency is due to a structural abnormality in one of the mitochondrial enzymes, whereas the activities of the other carboxylases are normal. Children with these disorders usually develop neurologic symptoms and metabolic compromise. Each disorder is treated by dietary restrictions but fails to respond to pharmacologic doses of biotin.

There were children who exhibited symptoms similar to those seen in isolated carboxylase deficiencies, had deficient activities of all three of the mitochondrial carboxylases, and responded to biotin therapy. In 1971, the first patient with such a disorder was reported as having biotin-responsive beta-methylcrotonylglycinuria (42). This individual had metabolic ketoacidosis and elevated concentrations of urinary beta-methylcrotonic acid and beta-methylcrotonylglycine. Several days after starting oral biotin, his symptoms resolved, and the urinary metabolites cleared. The patient had deficient activity of all three mitochondrial carboxylases in his peripheral blood leukocytes and skin fibroblasts (03; 158), as well as deficient activity of acetyl-CoA carboxylase in his fibroblasts (34). These findings prompted the diagnosis of multiple carboxylase deficiency.

Additional children with multiple or combined carboxylase deficiency were reported. Initially, these patients were classified as having either the early-onset (also referred to as neonatal) or the late-onset (also referred to as infantile or juvenile) form of multiple carboxylase deficiency, depending on the age of onset of symptoms (140). Most of the patients with the early-onset form had deficient holocarboxylase synthetase activity. Two children with the late-onset form were reported as having transport defects because they exhibited abnormal responses to oral biotin-loading studies (92; 145; 146). This was supported by reports of two patients with low plasma biotin concentrations whose biotin concentrations failed to increase after the patients were administered an oral dose of the vitamin. In 1983, it was shown that the primary biochemical defect in most patients with late-onset multiple carboxylase deficiency was due to deficient activity of serum biotinidase (180). Two patients with presumed intestinal transport defects were subsequently shown to have biotinidase deficiency (147). When the tissue concentrations in these children were replete in biotin, their plasma biotin concentrations increased normally in response to a dose of biotin. Since then, more than 100 symptomatic individuals have been reported with biotinidase deficiency. Heterozygote detection, neonatal screening, and prenatal diagnosis of the disorder are possible. Human serum biotinidase has been purified and characterized, and the cDNA that encodes for the enzyme has been sequenced (24). A common mutation has been identified in many symptomatic individuals (108).

Clinical manifestations

Presentation and course

Various aspects of biotinidase deficiency have been reviewed (160). The age of onset of symptoms of profound biotinidase deficiency (less than 10% of mean normal serum biotinidase activity) varies from 1 week to 10 years old, with a mean age of presentation between 3 and 6 months old (185; 48). The most common neurologic features of this disorder are seizures and hypotonia (181; 185; 154; 169; 39) or hypertonia (117). The most common type of seizure is myoclonic, but some children have exhibited grand mal and focal types, and a few have had infantile seizures (120). Several patients have exhibited breathing abnormalities such as hyperventilation, laryngeal stridor, and apnea. One child was initially diagnosed with sudden infant death syndrome but was retrospectively found to have biotinidase deficiency (16). Some enzyme-deficient children have exhibited peripheral neuropathy or myelopathy with paraparesis or quadriparesis, which has improved with biotin therapy (159; 74; 17). Some children have had structural brain malformations, including subcortical cysts with Dandy Walker cysts (15; 128). In addition, a child with partial deficiency was reported with autism (196). However, the presumed association of autism with this child is likely coincidental, especially because this child only has partial biotinidase deficiency. A child diagnosed with biotinidase deficiency after she exhibited cutaneous and neurologic symptoms, including seizures, was initially successfully treated with biotin. However, at eight years of age, she developed epilepsy that required anticonvulsive medications in addition to biotin supplementation for adequate control because of the residual neurologic damage caused by failure to identify the disorder and start biotin treatment earlier (85). The neurologic features of untreated biotinidase deficiency have been reviewed (174). There has been a 40-year literature review of the clinical and biochemical features of biotinidase deficiency because the enzyme defect was initially shown to be the cause of late-onset multiple carboxylase deficiency (142).

Older enzyme-deficient children often exhibit ataxia and developmental delay. Sensorineural hearing loss and eye problems, such as optic atrophy and neuropathy (49), have been described in many untreated children (182; 141; 119; 155). One study showed that 76% of symptomatic children with profound biotinidase deficiency have sensorineural hearing loss (191; 40). Frequently, these children have cutaneous symptoms, including skin rash and alopecia (82). The skin lesion can be confused with that of acrodermatitis enteropathica (99). Several patients have had cellular immunologic abnormalities, manifested by fungal infection (26; 121). These immunological aberrations are varied and may represent the effects of abnormal organic acid metabolites or biotin deficiency on normal function (36). Biotin therapy rapidly corrects the immunological dysfunction. The percentages of lymphocyte subsets were similar in newborns with and without biotinidase deficiency (68). A child with hemophagocytic lymphohistiocytosis was found to have biotinidase deficiency; the symptoms of the hemophagocytic syndrome resolved on biotin therapy (69). Some patients with biotinidase deficiency have manifested one or two of these features, whereas others have exhibited many of the neurologic and cutaneous findings.

In locations where newborn screening is not performed, there have been individuals who were ultimately found to have the enzyme deficiency who exhibited nonspecific symptoms, such as loss of consciousness, tetany, failure to thrive, and motor retardation, without severe metabolic compromise (79). One such child had cerebellar hypoplasia and multiple foci of leukodystrophy on brain MRI, and was subsequently found to have elevated 3-hydroxyisovaleric acid in his blood, which led to the diagnosis. These cases further support the usefulness of newborn screening to avoid these cases. Two children were described who were asymptomatic until their teenage years and then developed rapid loss of vision with progressive optic neuropathy and spastic paraparesis (116; 115; 81). Within months of biotin treatment, the scotoma resolved and the paraparesis markedly improved. In addition to these two enzyme-deficient individuals, two others have been described with paresis and eye problems that occurred in early adolescence (149; 189). Mutation analysis has failed to show common mutations in these four individuals. Another child with a similar presentation has since been reported (114). Several children with profound biotinidase deficiency have been diagnosed with demyelinating spinal cord disease (193; 23; 113).

One symptomatic child with biotinidase deficiency exhibited bilateral fornix infarction (stroke) (63). There have been multiple reports of older adolescents and adults who exhibited optic neuropathy, especially scotomata, with or without paresis or spastic diplegia (09; 164; 41; 194; 30; 153; 06). Multiple individuals with biotinidase deficiency were initially diagnosed with neuromyelitis optica spectrum disorder (07; 44; 112; 122; 127; 143). Two adult male siblings with late-onset biotinidase deficiency exhibiting peripheral neuropathy were reported; one also had optic neuropathy (70; 71). The brother with peripheral and optic neuropathy greatly improved with biotin therapy, whereas the older brother with only peripheral neuropathy, who was treated later, did not improve with biotin. These cases exemplify the importance of early diagnosis and treatment.

Although most of these individuals improved on biotin therapy, the symptoms failed to resolve or improve on biotin therapy in one older individual who exhibited symptoms for multiple years prior to diagnosis (35). Another adult initially presented with respiratory failure (28). It has been recommended that adults with untreated metabolic disorders, such as biotinidase deficiency, do not usually exhibit symptoms similar to those of children with the untreated disorder (175). In addition, individuals thought to have multiple sclerosis should be tested for biotinidase deficiency because the symptoms of optic neuropathy or spastic diplegia/paresis can be seen in both disorders, and biotinidase deficiency is readily treatable (165). Biotinidase deficiency should be included in the differential diagnosis of individuals thought to have multiple sclerosis or related disorders. Biotinidase deficiency should be considered in individuals thought to have multiple sclerosis or related disorders (165).

Moreover, two adults with profound biotinidase deficiency, both of whom are parents of children with profound biotinidase deficiency identified by newborn screening, are and have always been asymptomatic (188). In a group of 32 enzyme-deficient Turkish individuals detected through family studies of symptomatic index cases, 17 had profound deficiency and 15 had partial deficiency (05). In those with profound deficiency, only three were symptomatic, and all of those with partial deficiency were asymptomatic. The reason that some individuals present with symptoms later or not at all remains to be determined. One possible explanation is that individuals with profound biotinidase deficiency, those with less than 1% mean normal serum biotinidase activity, are likely to develop symptoms, whereas those with greater than 1% activity may remain asymptomatic even without biotin treatment (90). The delayed-onset phenotype, with paresis and dyspnea, may appear as early as four years of age (66).

In addition to patients with profound biotinidase deficiency, a group of patients with 10% to 30% of mean normal activity has been identified by neonatal screening (84; 135). Clinical consequences of partial deficiency were not known until one of these children, who was not treated with biotin, exhibited hypotonia, skin rash, and hair loss at six months of age during a bout of gastroenteritis. The patient was started on biotin, and the symptoms resolved. It is possible that partial biotinidase deficiency is a problem only when affected individuals are exposed to stresses, such as starvation or infection. The full clinical spectrum of partial deficiency remains to be determined.

A woman who is heterozygous for biotinidase deficiency had chronic vaginal candidiasis that was successfully treated with oral biotin (132). It was speculated that other individuals with chronic vaginal candidiasis are carriers and will potentially respond to biotin treatment.

Prognosis and complications

All patients develop normally who are diagnosed at birth or before developing symptoms or who do not experience recurrent episodes of metabolic compromise and are treated with biotin. Neurologic problems occur only in those patients who have recurrent symptoms and metabolic compromise. The sequelae include irreversible deafness, optic atrophy, and developmental delay. Compliance with biotin therapy is a potential problem, particularly in families whose children are identified by neonatal screening and have never been symptomatic.

A large cohort of affected children with profound and partial biotinidase deficiency identified by newborn screening over a 25-year period in Michigan had an excellent outcome (64). A major concern of children as they get older is their compliance with biotin therapy. Two other studies have found similar results (13; 76).

A group of 44 individuals with profound biotinidase deficiency identified by newborn screening, aged from ages 15 to 33 years, have had successful outcomes (173). In addition, the babies born to affected mothers on biotin treatment have all been normal. Compliance was not a major issue in these individuals. Newborn screening and early biotin supplementation appears to prevent symptoms of the disorder (198). They found that the development and behaviors of preschool-aged children with the enzyme deficiency identified by newborn screening were not different from their unaffected peers.

Clinical vignette

A 3-month-old female was brought to the emergency department because of the onset of myotonic seizures. On physical examination, the child was found to have a fine eczema-like skin rash, patchy loss of scalp hair, lethargy, and hypotonia. Her mother stated that the child had experienced multiple episodes of vomiting and two occasions of rapid breathing during the last month. Laboratory studies revealed that the child had a mild metabolic acidosis with a bicarbonate concentration of 13 mEq/L. Plasma ammonia concentration was mildly elevated. There was ketonuria, and a urinary organic acid analysis showed increased concentrations of lactate, beta-hydroxyisovalerate, beta-methylcrotonylglycine, and methylcitrate. These findings are consistent with multiple carboxylase deficiency. Serum biotinidase was less than 1% of mean normal activity, confirming that the child had biotinidase deficiency. The child was born in a state where newborn screening for biotinidase deficiency is not performed. She was started on 10 mg of oral biotin. Her seizures, which were poorly controlled with anticonvulsive medications, stopped completely with vitamin supplementation. The child became much more alert over the next few days. Her skin rash disappeared in two weeks, and hair growth returned to the areas of alopecia. The child has had no biochemical, neurologic, or cutaneous abnormalities while on biotin.

Biological basis

Etiology and pathogenesis

Biotin, a water-soluble B-complex vitamin, is the coenzyme for four human carboxylases that have important roles in gluconeogenesis, fatty acid synthesis, and the catabolism of several branched-chain amino acids. Biotin is attached to the various apocarboxylases by the enzyme biotin holocarboxylase synthetase. The carboxyl group of biotin is linked by an amide bond to an epsilon-amino group of a specific lysine residue of the apoenzymes. After the carboxylases are degraded proteolytically to biocytin (biotinyl-lysine) or small biotinyl-peptides, biotinidase cleaves the amide bond, releasing lysine or lysyl-peptides and free biotin, which can then be recycled (102; 169). Biotinidase also plays a role in the processing of protein-bound biotin, thereby making the vitamin available to the free biotin pool (184). Studies suggest that biotinidase has a role in the transfer of biotin from biocytin to specific proteins (59). Biotinidase and its role in biotin metabolism have been reviewed by Hymes and Wolf (61). The biotinylation of histones by biotinidase and its potential roles in cellular metabolism have been reviewed (166; 197).

The primary biochemical defect in most patients with late-onset multiple carboxylase has been shown to be deficient activity of biotinidase in serum. Biotinidase activity is determined by measuring the release of biotin from biocytin or a biocytin analogue, such as N-biotinyl p-aminobenzoate (72; 180). Other assays for biotinidase activity in serum and tissues are available. All patients who have been tested using natural and artificial substrates have been found deficient in both.

Patients with profound biotinidase activity have less than 10% mean normal serum enzyme activity. The parents of these children usually have serum enzyme activities intermediate between those of the patients and those of normal individuals (50). Heterozygosity can be diagnosed with about 95% accuracy (156). Deficient biotinidase activity has also been demonstrated in extracts of leukocytes and fibroblasts from some of these patients (190). At least one patient also had deficient biotinidase activity in his liver. Biotinidase activity in sera of parents of children with partial deficiency is indistinguishable from that of parents of children with profound deficiency (51). There is no correlation between the characteristics of the enzyme protein or lack of protein with the clinical features.

The cDNA that encodes human serum biotinidase has been cloned and sequenced (24). The genomic organization of the biotinidase gene has also been elucidated (73). The gene that encodes for the serum enzyme has been localized to chromosome 3p25 (25). The biotinidase gene was more finely mapped using radiation hybrids and haplotype analysis of markers within the chromosome 3p25 region (10). The biotinidase gene has been shown to be alternatively spliced (130). This may indicate that the enzyme is localized to various subcellular localizations, including the secretory pathway and possibly mitochondria, in different tissues.

Multiple mutations have been described in symptomatic children with profound biotinidase deficiency (105; 75). These mutations include a common 7-base deletion/3-base insertion that occurs in at least one allele of the biotinidase gene in half of symptomatic children (108). A missense mutation, Arg538Cys, is the second most common cause of profound biotinidase deficiency in symptomatic children (106). Two mutations have been found to be common in children with profound biotinidase deficiency who were identified by newborn screening: a Q456H missense mutation and a combination A171T and D444H mutation (95; 96). Mutations among children identified by newborn screening were compared with those of children ascertained by exhibiting symptoms (94). Of the mutations identified in the two populations, four mutations comprise 59% of the abnormal alleles. Two mutations occurred in both populations but occurred in the symptomatic population at a significantly greater frequency. The other two common mutations occurred only in the newborn screening group. It was speculated that children with the mutations that occurred only in the newborn screening population may have mild or no symptoms if left untreated. Additional novel mutations have been reported (103; 107; 60; 91; 38; 187; 166; 77; 89; 93; 86; 87; 144; 148; 78; 67; 111; 126; 18; 19; 58). Because of the high frequency of consanguinity, some countries, such as Turkey, have identified many individuals with biotinidase deficiency and novel mutations (01; 98). In one child, biotinidase deficiency was shown to be due to a de novo mutation or gonadal mosaicism (150). The first microdeletion involving only the biotinidase gene that can cause biotinidase deficiency has been described (171).

In addition, a missense mutation, D444H, appears to be responsible for partial biotinidase deficiency (about 50% of mean normal enzymatic activity) when in combination with a second mutation for profound biotinidase deficiency on the second allele (139). It has been shown that the D444H mutation results in about half of normal activity because of decreased expression of the aberrant enzyme (80). More than 150 mutations causing biotinidase deficiency have been described (101). Mutational and functional studies indicate that the resultant reduced enzymatic activity caused by the D444H mutation is due to decreased protein expression and not to alteration of the enzymatic protein (80). Another study indicates that this variant codes for an enzyme protein with variable activity (08). Mutations causing biotinidase deficiency are currently being collected in a database (110).

Because the D444H variant results in an enzyme with about 50% of mean biotinidase activity from each allele, it is expected that individuals who are homozygous for this variant have about 50% activity. This degree of activity is similar to that of parents of children with profound biotinidase deficiency, are asymptomatic, and do not need biotin therapy. A paper from Turkey reported several individuals who are homozygous with the D444H variant and exhibited symptoms seen in biotin deficiency (138). However, the authors failed to confirm whether these clinical findings resolved with biotin therapy and were not just coincidental in these individuals with this degree of biotinidase activity.

A report indicated that serum biotinidase activity increased over five years in about 50% of children with partial biotinidase deficiency (37). The authors recommend retesting children with partial biotinidase deficiency at five years of age, which obviously has ramifications for biotin treatment in this group of children. This has potential ramifications for continuous biotin therapy in those that have demonstrated increased activities into the heterozygous activity range or more. Additional studies are needed to confirm these results or to change the recommendations for biotin therapy in individuals with partial biotinidase deficiency.

Although mutation analysis by direct sequencing is available, it is now possible to detect several common mutations using real-time PCR of DNA in the blood spots obtained at newborn screening (33). In addition, rapid mutation analysis can be performed using denaturing high-pressure liquid chromatography (62).

Symptomatic children with profound biotinidase deficiency with null mutations are more likely to develop hearing loss than those with missense mutations. Hearing loss appears to be preventable in children with null mutations if treated soon after birth. This represents the first genotype-phenotype correlation in this disorder (129).

Individuals with untreated biotinidase deficiency develop biotin deficiency, which subsequently results in multiple carboxylase deficiency and the accumulation of abnormal metabolites. These patients also experience renal loss of biotin (137).

Biotinidase deficiency may present with various degrees of metabolic acidosis, ketosis, and hyperammonemia. The metabolic acidosis is usually accompanied by an increased anion gap and lactate elevations. The ketosis is due to the accumulation of abnormal organic acid metabolites of propionate and lactate in blood, and beta-hydroxypropionate, methylcitrate, beta-hydroxyisovaleric acid, beta-methylcrotonylglycine, and beta-hydroxybutyrate in urine. Hyperammonemia plays a major role in causing the lethargy, somnolence, and coma seen in the disorder. The hyperammonemia is due to the secondary inhibition of N-acetylglutamate synthetase, which produces N-acetylglutamate, the activator of carbamyl phosphate synthetase in the urea cycle.

Biotinidase deficiency reduces expression of carboxylases and holocarboxylase synthetase by interfering with the control of the 5’-biotinyl-AMP-dependent transcription (100). Therefore, secondary holocarboxylase synthetase deficiency may develop in patients with biotinidase deficiency, affecting the allocation or distribution of biotin in tissues.

Serum biotinidase activity is not altered by biotin deficiency. This was demonstrated by the fact that several patients who became biotin deficient while being treated with parenteral hyperalimentation lacking biotin had normal serum biotinidase activity (88). Biotinidase appears to play an important role in the processing of protein-bound biotin, either by being secreted into the intestinal tract, where it can release biotin from bound dietary sources that can subsequently be absorbed, or by cleaving biocytin or biotinyl-peptides in the intestinal mucosa or in blood.

Biotinidase activity in cerebrospinal fluid and the brain is low (134). This suggests that the brain may not recycle biotin and must depend on biotin that is transported across the blood-brain barrier. Several symptomatic children who have failed to exhibit peripheral lactic acidosis or organic aciduria have had elevations of lactate or organic acids in their cerebrospinal fluid (32; 31). This compartmentalization of the biochemical abnormalities may explain why the neurologic symptoms usually appear before other symptoms. Peripheral metabolic ketoacidosis and organic aciduria probably occur with severe or prolonged biotin deficiency.

Most patients with biotinidase activity who have hearing loss have had this problem since before beginning biotin therapy (182; 191; 157). Hearing loss is usually irreversible, although several young, affected children have shown some improvement with biotin therapy. It has been speculated that biocytin or biotinyl-peptides accumulate, are toxic, and may even aggravate hearing deficits. This remains to be proven, however. Biotinidase has been localized to discrete regions of the brain and cochlea, including the hair cells and spiral ganglion (54). Lack of biotinidase in these areas likely has a direct role in causing the hearing loss.

EEG findings have ranged from normal to markedly abnormal and are usually nonspecific (124; 170; 131). CT of the head performed in several affected children at different ages has demonstrated abnormalities similar to those seen in isolated carboxylase and holocarboxylase synthetase deficiencies, including cerebral edema, demyelination, low attenuation of white matter, cortical atrophy, and dilated ventricles. Single patients have exhibited a parietal cyst, basal ganglia calcifications, and hypodense areas. In several patients, cerebral atrophy was reversed after biotin therapy (14; 02; 29). One reports recommended that biotinidase deficiency be considered in individuals with atypical or unusual brain imaging studies in those countries where newborn screening is not being performed (43).

Studies of the brains of several children with biotinidase deficiency have revealed a variety of abnormalities. Several patients have had brain lesions suggestive of Leigh disease (04; 57). One patient had cerebral degeneration and atrophy. There was gliosis of the white matter and dentate nucleus, but the brainstem and cerebral peduncles were normal. The presence of focal necrosis with vascular proliferation and infiltration by macrophages suggested a subacute necrotizing myelopathy. In a second child who died at three months of age, the brain revealed defective myelination and focal areas of vacuolization and gliosis in the white matter of the cerebrum and cerebellum. A mild gliosis in the pyramidal cellular layer of the hippocampus was also found, as well as characteristic changes of viral encephalopathy in the putamen and caudate nucleus.

In a series of five symptomatic children with biotinidase deficiency, ages 1 to 5.5 months, leukoencephalopathy and widening of the ventricles and extracerebral cerebrospinal fluid spaces was observed (47). Demyelination or demyelinating leukoencephalopathy was present, but some lesions could not be explained by this mechanism alone (45). Myelination improved following biotin therapy in all but one child who exhibited progressive atrophy and cystic degeneration. Most of these children continued to have some residual neurologic problems. This further supports the implementation of newborn screening. There have been studies that have shown the cost-effectiveness of newborn screening for the disorder (152; 21).

Epidemiology

Because biotinidase deficiency met many of the criteria for inclusion in a neonatal screening program, a colorimetric test for biotinidase activity was developed for determining biotinidase activity in the same blood spots being used for other neonatal screening tests (52). A pilot program was conducted in Virginia to estimate the incidence of this disorder and the feasibility of screening (183; 53). As of December 1990, 142 children had been diagnosed with biotinidase deficiency (76 children with profound biotinidase deficiency and 66 with partial biotinidase deficiency) in neonatal screening programs in essentially all states and 30 countries (177; Wolf unpublished data). These results indicate that the incidence of biotinidase deficiency is 1 in 137,401 for profound biotinidase deficiency; 1 in 109,921 for partial biotinidase deficiency; and 1 in 61,067 for the combined incidence of profound and partial biotinidase deficiency. Although screening for biotinidase deficiency is done in all states of the United States and in many countries, screening is not universally performed. The arguments for screening for both profound and partial biotinidase deficiency are delineated (176). Various countries have added biotinidase deficiency to their newborn screening programs (65). The incidence of the disorder varies greatly in these countries but is usually highest in countries with a high degree of consanguinity.

In addition to the colorimetric assay, some screening programs use a fluorescent enzymatic assay in which biotinyl-6-amidoquinoline is the substrate (97). Although newborn screening for biotinidase deficiency is performed by direct measurement of biotinidase activity in dried blood spots, it is possible to identify appropriate abnormal organic acids or their derivatives by tandem mass spectroscopy in samples from children with biotinidase deficiency who exhibit symptoms earlier than expected or in those who are tested later than in the neonatal period (192). However, direct enzymatic analysis is the most definitive method for making the diagnosis and for ensuring that an affected child is not missed. Care must be taken not to rely on just mass spectroscopy for the diagnosis of biotinidase deficiency.

Differential diagnosis

Nonspecific clinical symptoms, including vomiting, hypotonia, and seizures are often characteristic of treatable disorders such as sepsis, gastrointestinal obstruction, and cardiorespiratory problems. Concomitantly or after exclusion of these conditions, or when these findings are accompanied by metabolic ketoacidosis or hyperammonemia, the presence of an inborn error of metabolism should be considered. Both holocarboxylase synthetase deficiency and biotinidase deficiency may present initially with these clinical features and may, thus, be misdiagnosed as other disorders before they are correctly identified (136; 170).

Other symptoms characteristic of biotin-responsive multiple carboxylase deficiencies, such as skin rash or alopecia, can occur also in children with a deficiency of zinc or essential fatty acids. Frequent viral, bacterial, or fungal infections, owing to immunologic dysfunction, may occur in those with multiple carboxylase deficiency. Children with holocarboxylase synthetase deficiency may have metabolic acidosis and large anion gaps, with elevated concentrations of lactate in the serum and urine. An amino acid analysis may reveal hyperglycinemia, which is also found in other organic acidemias.

Biotin deficiency usually can be excluded unless there is a history of dietary indiscretion, such as the consumption of a diet containing raw eggs or few biotin-containing foods, or a history of protracted parenteral hyperalimentation without biotin supplementation. Low serum biotin concentrations can be useful in differentiating biotin and biotinidase deficiencies from holocarboxylase synthetase deficiency, but it is important to know the method used for the biotin determinations. Only those methods that distinguish biotin from biocytin or bound biotin yield reliable estimates of free biotin concentrations.

Biotinidase deficiency must be differentiated from the isolated carboxylase deficiencies. Organic acid analysis of urine is useful for differentiating isolated carboxylase deficiencies from the biotin-responsive multiple carboxylase deficiencies. Beta-hydroxyisovalerate is the most common urinary metabolite observed in biotinidase deficiency, holocarboxylase synthetase deficiency, and acquired biotin deficiency, but it is also seen in isolated beta-methylcrotonyl-CoA carboxylase deficiency. Elevated concentrations of urinary lactate, methylcitrate, and beta-hydroxypropionate, in addition to beta-hydroxyisovalerate, are indicative of multiple carboxylase deficiency. The isolated carboxylases are not biotin responsive, whereas the multiple carboxylase deficiencies are. A trial of biotin is useful in discriminating the disorders. Isolated carboxylase deficiencies can be excluded by demonstrating deficient enzyme activity of one of the three mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts, whereas the activities of the other two carboxylases are normal.

Biotinidase deficiency must be differentiated also from holocarboxylase synthetase deficiency; because the symptoms of biotinidase deficiency and holocarboxylase synthetase deficiency are similar, clinical differentiation may be difficult. However, the age of onset of symptoms can be useful in discriminating between these two disorders. Holocarboxylase synthetase deficiency usually manifests before three months of age, whereas biotinidase deficiency usually manifests after three months of age. There are exceptions for both disorders, and age of onset alone is not reliable. Both multiple carboxylase deficiencies are characterized by deficient activities of the three mitochondrial carboxylases in peripheral blood leukocytes prior to biotin treatment. These activities increase to near-normal or normal after biotin treatment (136). Patients with holocarboxylase synthetase deficiency have deficient activities of the three mitochondrial carboxylases in fibroblasts incubated in media containing only the biotin contributed by fetal calf serum (low biotin), whereas patients with biotinidase deficiency have normal fibroblast activity. The activities of the carboxylases in holocarboxylase synthetase deficiency become near-normal to normal when cultured in media supplemented with biotin (high biotin). Biotinidase deficiency and holocarboxylase synthetase deficiency can be definitively diagnosed by direct enzymatic assay. Biotinidase activity in patients with isolated carboxylase deficiency or holocarboxylase synthetase deficiency is normal.

Multiple adults with optic neuropathy or spastic diplegia/tetraplegia were ultimately shown to have biotinidase deficiency; however, these individuals were initially thought to have other disorders, such as transverse myelitis, neuromyelitis optica, or multiple sclerosis, and treatment was directed at these diagnoses before the correct diagnosis and biotin treatment was instituted (162). Biotinidase deficiency should be included in the differential diagnosis of these disorders because it is so readily treatable. If an adult with biotinidase deficiency is not readily treated with biotin, the symptoms may become irreversible (35).

Diagnostic workup

Comprehensive reviews of the diagnostic evaluation of biotinidase deficiency have been published (161; 168). Technical standards and guidelines for the diagnosis of biotinidase deficiency have been established (27). The majority of patients with biotinidase deficiency exhibit metabolic ketolactic acidosis and organic aciduria similar to that seen in holocarboxylase synthetase deficiency. Patients with both disorders have elevated concentrations of urinary beta-hydroxyisovalerate and beta-methylcrotonylglycine (11). However, some symptomatic patients with the enzyme deficiency do not excrete the characteristic organic acids (151). Therefore, the presence of normal urinary organic acids, even when the child is symptomatic, does not exclude biotinidase deficiency as the diagnosis. Patients may have mild hyperammonemia. The absence of organic aciduria or metabolic ketoacidosis does not exclude the diagnosis of biotinidase deficiency in a symptomatic child. When neurologic or cutaneous symptoms are suggestive of this deficiency, appropriate enzyme testing should be considered.

Plasma biotin concentrations may be deficient in patients with biotinidase deficiency but may be normal prior to therapy. The methods used to determine the biotin concentration are important because those that use avidin binding do not differentiate among biotin, biocytin, and other biotinyl derivatives.

Definitive diagnosis is made by demonstrating deficient biotinidase activity in serum by measuring the release of biotin from biocytin or a biocytin analogue such N-biotinyl p-aminobenzoate (180) or biotinyl-6-amidoquinoline (97). There is method that measures a 4-methylumbelliferyl product on a digital microfluidic platform that should allow the consolidation of other fluorometric assays onto a single cartridge (46). There has been an increasing problem interpreting the results of quantitative enzyme determinations that are performed without an accompanying control sample obtained at the same time and processed identically as that from the proband (163). The need for an appropriate control serum for successfully confirming the diagnosis was exemplified in the newborn screening experience in Brazil (93).

Markedly elevated serum biotinidase activities have been reported in children with glycogen storage disease type Ia (163). Two of these children were initially thought to have biotinidase deficiency based on their symptoms, but once their enzyme activities were found to be elevated, consideration was given to the diagnosis of glycogen storage disease type Ia, which was confirmed by enzymatic assay.

Because several children with profound biotinidase deficiency have presented with neuropathy and paresis due to spinal cord lesions that can be reversed if biotin treatment is initiated early, biotinidase deficiency should be considered in the differential diagnosis of subacute myelopathy or spinal cord demyelination (193; 23; 83; 164).

Management

Individuals with biotinidase deficiency should be adequately hydrated, especially if there is evidence of dehydration. Large amounts of parenteral fluids help to facilitate the excretion of abnormal organic acid metabolites. Adequate nutrition is essential. In the acute stage of the disorder, protein may be restricted. It is imperative to supply sufficient calories in the form of parenteral glucose or oral polysaccharides. Severe acidosis may initially require bicarbonate supplementation in addition to hydration.

The mainstay of therapy in biotinidase deficiency is biotin supplementation. All symptomatic children with biotinidase deficiency have improved after treatment with 5 to 10 mg of biotin per day. Biotin appears to be required in free form as opposed to bound form because a child fed yeast, in which most of the biotin is in bound form, did not improve. This child did improve, however, when treated with free biotin. Biotin therapy is life-long. Some evidence suggests that the actual requirement for biotin is lower than the 5 to 10 mg per day in some children because several patients have remained asymptomatic while receiving only physiologic doses of the vitamin (169). However, a patient is reported to have required higher doses of biotin (118). Treatment with biotin is essential and sufficient; it is not necessary to treat patients with protein-restricted diets.

The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in the alopecic children. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between the time of diagnosis and the initiation of treatment. Hearing aids or cochlear implants may be effective in children who have developed severe hearing loss that is irreversible with biotin therapy (20). Some treated children have rapidly achieved developmental milestones, whereas others have continued to show deficits. Although there has been the suggestion that biotin therapy may be unnecessary in some patients with greater than 1% residual serum biotinidase activity (90), other evidence indicates biotin treatment should be given to all children with profound biotinidase deficiency, regardless of their residual activity (167).

Most patients with biotinidase deficiency excrete large quantities of biocytin in their urine (12), but there has been no evidence of accumulation of this metabolite in the tissues. It remains to be determined whether biotin therapy is harmful because it may increase the concentration of biocytin in these children.

There is evidence that some anticonvulsive medications, such as valproate, result in decreased serum biotinidase activity in normal individuals (123); however, there is also a study that did not find a reduction in biotinidase activity in similarly treated children (195). Although the mechanism of this effect is not yet understood, these medications may further decrease enzyme activity in children with residual enzyme activity. Fortunately, most symptomatic children with biotinidase deficiency who exhibited seizures no longer require anticonvulsive medications once biotin is initiated.

It has been shown that high doses of biotin, such as that used to treat biotinidase deficiency, can interfere with immunoassays that use biotin-strept(avidin) technologies. Therefore, it is important that health professionals are aware of this when individuals with the disorder are having laboratory tests performed (172).

References

01: Akgun A, Sen A, Onal H. Clinical, biochemical and genotypical characteristics in biotinidase deficiency. J Pediatr Endocrinol Metab 2021;34:1425-33. PMID 34448386
02: Bakker HD, Westra M, Overweg-Plandsoen WC, et al. Normalisation of severe cranial CT scan abnormalities after biotin in a case of biotinidase deficiency (letter). Eur J Pediatr 1994;153:861-2. PMID 7843204
03: Bartlett K, Gompertz D. Combined carboxylase defect: biotin-responsiveness in cultured fibroblasts. Lancet 1976;2(7989):804. PMID 61476
04: Baumgartner ER, Suormala TM, Wick H, Probst A. Biotinidase deficiency: a case of subacute necrotizing encephalomyelopathy (Leigh syndrome). Report of a case with lethal outcome. Pediatr Res 1989;26:260-6. PMID 2587127
05: Baykal T, Gokcay G, Gokdemir Y, et al. Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. J Inherit Metab Dis 2005;28:903-12. PMID 16435182
06: Beck G, Hirozawa D, Honma K, et al. Adult-onset biotinidase deficiency induces acutely progressing leukoencephalopathy. Neurol Clin Pract 2021;11:e383-6. PMID 34484923
07: Bilge N, Yevgi R. Biotinidase deficiency in differential diagnosis of neuromyelitis optica spectrum disorder. Mult Scler Relat Disord 2020;44:102280. PMID 32559702
08: Borsatto T, Sperb-Ludwig F, Blom HJ, Schwartz IVD. Effect of BTD gene variants on in vitro biotinidase activity. Mol Genet Metab 2019;127(4):361-7. PMID 31337602
09: Bottin L, Prud'hon S, Guey S, et al. Biotinidase deficiency mimicking neuromyelitis optica: Initially exhibiting symptoms in adulthood. Mult Scler 2015;21:1604-7. PMID 26203071
10: Blanton SH, Pandya A, Landa BL, et al. Fine mapping of the human biotinidase gene and haplotype analysis of five common mutations. Hum Hered 2000;50:102-11. PMID 10799968
11: Bonafe L, Troxler H, Kuster T, et al. Evaluation of urinary acylglycines by electrospray tandem mass spectrometry in mitochondrial energy metabolism defects and organic acidurias. Mol Genet Metab 2000;69:302-11. PMID 10870848
12: Bonjour JP, Bausch J, Suormala T, Baumgartner ER. Detection of biocytin in urine of children with congenital biotinidase deficiency. Int J Vitam Nutr Res 1984;54:223-9. PMID 6438010
13: Borsatto T, Sperb-Ludwig F, Lima SE, et al. Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients. PLoS One 2017;12(5):e0177503. PMID 28498829
14: Bousounis DP, Camfield PR, Wolf B. Reversal of brain atrophy with biotin treatment in biotinidase deficiency. Neuropediatrics 1993;24:214-7. PMID 8232780
15: Bunch M, Singh A. Peculiar neuroimaging and electrophysiological findings in a patient with biotinidase deficiency. Seizure 2011;20(1):83-6. PMID 21123088
16: Burton B, Roach ES, Wolf B, Weissbecker KA. Sudden death associated with biotinidase deficiency. Pediatrics 1987;79:482-3. PMID 3822661
17: Cabasson S, Rivera S, Mesli S, Dulubac E. Brainstem and spinal cord lesions associated with skin changes and hearing loss: think of biotinidase deficiency. J Pediatr 2015;166:771-1. PMID 25556014
18: Canda E, Yazici H, Er E, et al. Single center experience of biotinidase deficiency: 259 patients and six novel mutations. J Pediatr Endocrinol Metab 2018;31(8):917-26. PMID 29995633
19: Carvalho NO, Del Castillo DM, Januário JN, et al. Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil. Am J Med Genet A 2019;179(6):978-82. PMID 30912303
20: Castellino A, Kurkure R, Rayamajhi P, Kameswaran M. Cochlear implantation in biotinidase enzyme deficiency. Indian J Otolaryngol Head Neck Surg 2022;74(Suppl 1):316-9. PMID 36032817
21: Castilla-Rodríguez I, Vallejo-Torres L, Couce ML, Valcárcel-Nazco C, Mar J, Serrano-Aguilar P. Cost-effectiveness methods and newborn screening assessment. Adv Exp Med Biol 2017;1031:267-81. PMID 29214578
22: Chalmers RA, Mistry J, Docherty PW, Stratton D. First trimester prenatal exclusion of biotinidase deficiency. J Inherit Metab Dis 1994;17:751-2. PMID 7707701
23: Chedrawi AK, Ali A, Al Hassnan ZN, Faiyaz-Ul-Haque M, Wolf B. Profound biotinidase deficiency in a child with predominantly spinal cord disease. J Child Neurol 2008;23(9):1043-8. PMID 18645204
24: Cole H, Reynolds TR, Lockyer JM, et al. Human serum biotinidase: cDNA cloning, sequence and characterization. J Biol Chem 1994a;269(9):6566-70. PMID 7509806
25: Cole H, Weremowicz S, Morton CC, Wolf B. Localization of serum biotinidase (BTD) to human chromosome 3 in band p25. Genomics 1994b;22:662-3. PMID 8001986
26: Cowan MJ, Wana DW, Packman S, et al. Multiple biotin-dependent carboxylase deficiencies associated with defects in T-cell and B-cell immunity. Lancet 1979;2:115-8. PMID 88554
27: Cowan TM, Blitzer MG, Wolf B; Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. Technical standards and guidelines for the diagnosis of biotinidase deficiency. Genet Med 2010;12(7):464-70. PMID 20539236
28: Demirturk Z, Şentürk E, Köse A, Özcan PE, Telci L. A case of biotinidase deficiency in an adult with respiratory failure in the intensive care unit. Balkan Med J 2016;33:563-5. PMID 27761288
29: Desai S, Ganesan K, Hegde A. Biotinidase deficiency: a reversible metabolic encephalopathy. Neuroimaging and MR spectroscopic findings in a series of four patients. Pediatr Radiol 2008;38(8):848-56. PMID 18545994
30: Deschamps R, Savatovsky J, Vignal C, et al. Adult-onset biotinidase deficiency: two individuals with severe, but reversible optic neuropathy. J Neurol Neurosurg Psychiatry 2018;89(9):1009-10. PMID 29025919
31: Diamantopoulos N, Painter MJ, Wolf B, Heard GS, Roe C. Biotinidase deficiency: accumulation of lactate in the brain and response to physiologic doses of biotin. Neurology 1986;36:1107-9. PMID 3736876
32: Dirocco M, Superti-Furga A, Durand P, Cerone R, Romano C. Different organic acid patterns in urine and in cerebrospinal fluid in a patient with biotinidase deficiency. J Inherit Metab Dis 1984;2(Suppl 7):119-20. PMID 6434860
33: Dobrowolski SF, Angeletti J, Banas RA, Naylor EW. Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency. Mol Genet Metab 2003;78:100-7. PMID 12618081
34: Feldman GL, Wolf B. Deficient acetyl-CoA carboxylase activity in multiple carboxylase deficiency. Clin Chim Acta 1981;111:147-51. PMID 6112081
35: Ferreira P, Chan A, Wolf B. Irreversibility of symptoms with biotin therapy in an adult with profound biotinidase deficiency. JIMD Rep 2017;36:117-20. PMID 28220409
36: Fischer A, Munnich A, Saudubray JM. Biotin-responsive immunoregulatory dysfunction in multiple carboxylase deficiency. J Clin Immunol 1982;2:35-8. PMID 6212592
37: Forny P, Wicht A, Rüfenacht V, Cremonesi A, Häberle J. Recovery of enzyme activity in biotinidase deficient individuals during early childhood. J Inherit Metab Dis 2022;45(3):605-20. PMID 35195902
38: Funghini S, Donati MA, Pasquini E, Gasperini S, et al. Two new mutations in children affected by partial biotinidase deficiency ascertained by newborn screening. J Inherit Metab Dis 2002;25:328-30. PMID 12227467
39: Gascon GG, Ozand PT, Brismar J. Movement disorders in childhood organic acidurias. Clinical, neuroimaging, and biochemical correlations. Brain Dev 1994;16(Suppl):94-103. PMID 7726387
40: Genc GA, Sivri-Kalkanoglu HS, Dursun A, et al. Audiologic findings in children with biotinidase deficiency in Turkey. Int J Pediatr Otorhinolaryngol 2007;71(2):333-9. PMID 17161472
41: Girard B, Bonnemains C, Schmitt E, Raffo E, Bilbault C. Biotinidase deficiency mimicking neuromyelitis optica beginning at the age of 4: a treatable disease. Mult Scler 2017;23(1):119-22. PMID 27207447
42: Gompertz D, Draffman GH, Watts JL, Hull D. Biotin-responsive beta-methylcrotonylglycinuria. Lancet 1971;2:22-4. PMID 4103667
43: Gowda VK, Avaragollapuravarga Mathada A, Srinivasan VM, Vamyanmane DK. Biotinidase deficiency in the second decade with atypical neuroimaging findings. Adv Biomed Res 2023;12:148. PMID 37564434
44: Gowda VK, Kerur C, Vamyanmane DK, Kumar P, Nagarajappa VH, Shivappa SK. A treatable cause of myelopathy: biotinidase deficiency presenting as acute flaccid paralysis. J Pediatr Genet 2020a;11(3):257-60. PMID 35990026
45: Gowda VK, Vignesh S, Nagarajan B, et al. Rare treatable cause of demyelinating leukoencephalopathy that one cannot afford to miss. J Pediatr Genet 2020b;11:87-90. PMID 35769961
46: Graham C, Sista RS, Kleinert J, et al. Novel application of digital microfluidics for the detection of biotinidase deficiency in newborns. Clin Biochem 2013;46(18):1889-91. PMID 24036022
47: Grunewald S, Champion MP, Leonard JV, Schaper J, Morris AA. Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics 2004;35(4):211-6. PMID 15328559
48: Haagerup A, Andersen JB, Blichfeldt S, Christensen MF. Biotinidase deficiency: two cases of very early presentation. Dev Med Child Neurol 1997;39:832-5. PMID 9433861
49: Haines SR, Longmuir RA. Optic neuropathy due to biotinidase deficiency in a 19-year-old man. JAMA Ophthalmol 2014;132(2):228-30. PMID 24525934
50: Hart PS, Hymes J, Wolf B. Biochemical and immunological characterization of serum biotinidase in profound biotinidase deficiency. Am J Hum Genet 1992a;50:126-36. PMID 1729884
51: Hart PS, Hymes J, Wolf B. Biochemical and immunological characterization of serum biotinidase in partial biotinidase deficiency. Pediatr Res 1992b;31:261-5. PMID 1561012
52: Heard GS, Secor McVoy Jr, Wolf B. A screening method for biotinidase deficiency in newborns. Clin Chem 1984;30:125-7. PMID 6690118
53: Heard GS, Wolf B, Jefferson LG, et al. Neonatal screening for biotinidase deficiency: results of a 1-year pilot study. J Pediatr 1986;108:40-6. PMID 3944695
54: Heller AJ, Stanley C, Shaia WT, Sismanis A, Spencer RF, Wolf B. Localization of biotinidase in the brain: implications for its role in hearing loss in biotinidase deficiency. Hear Res 2002;173:62-8. PMID 12372635
55: Hendriksz CJ, Preece MA, Chakrapani A. Successful pregnancy in a treated patient with biotinidase deficiency. J Inherit Metab Dis 2005;28:791-2. PMID 16151912
56: Hoffman TL, Simon EM, Ficicioglu C. Biotinidase deficiency: the importance of adequate follow-up for an inconclusive newborn screening result. Eur J Pediatr 2005;164:298-301. PMID 15711955
57: Honavar M, Janota I, Neville BG, Chalmers RA. Neuropathology in biotinidase deficiency. Acta Neuropathol 1992;84:461-4. PMID 1441928
58: Hsu RH, Chien YH, Hwu WL, et al. Genotypic and phenotypic correlations of biotinidase deficiency in the Chinese population. Orphanet J Rare Dis 2019;14(1):6. PMID 30616616
59: Hymes J, Fleischhauer K, Wolf B. Biotinylation of histones by human serum biotinidase: assessment of biotinyl-transferase activity in sera from normal individuals and children with biotinidase deficiency. Biochem Molec Med 1995;56:76-83. PMID 8593541
60: Hymes J, Stanley CM, Wolf B. Mutations in BTD causing biotinidase deficiency. Hum Mutat 2001;18:375-81. PMID 11668630
61: Hymes J, Wolf B. Biotinidase and its roles in biotin metabolism. Clin Chim Acta 1996;255:1-11. PMID 8930409
62: Iqbal F, Item CB, Vilaseca MA, et al. The identification of novel mutations in the biotinidase gene using denaturing high pressure liquid chromatography (dHPLC). Mol Genet Metab 2010;100:42-5. PMID 20083419
63: Izgi E, Ayasli A, Ogul Y, Ogul H. Unusual stroke cause: bilaterally fornix infarction in a patient with biotinidase deficiency. QJM 2023;116(11):944-6. PMID 37522883
64: Jay AM, Conway RL, Feldman GL, Nahhas F, Spencer L, Wolf B. Outcomes of individuals with profound and partial biotinidase deficiency ascertained by newborn screening in Michigan over 25 years. Genet Med 2015;17(3):205-9. PMID 25144890
65: Jezela-Stanek A, Suchoń L, Sobczyńska-Tomaszewska A, et al. Molecular background and disease prevalence of biotinidase deficiency in a Polish population-data based on the national newborn screening programme. Genes (Basel) 2022;13(5):802. PMID 35627187
66: Kalkanoglu HS, Dursun A, Tokatli A, Coskun T, Karasimav D, Topaloglu H. A boy with spastic paraparesis and dyspnea. J Child Neurol 2004;19(5):397-8. PMID 15224716
67: Karaca M, Özgül RK, Ünal Ö, et al. Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening. Eur J Pediatr 2015;174(8):1077-84. PMID 25754625
68: Karaoglan M, Nacarkahya G, Keskin M, Keskin O. Immunophenotypic analysis of lymphocyte subsets in newborns with biotinidase deficiency. Pediatr Allergy Immunol 2021;32:586-598. PMID 33217065
69: Kardas F, Patiroglu T, Unal E, Chiang SC, Bryceson YT, Kendirci M. Hemophagocytic syndrome in a 4-month-old infant with biotinidase deficiency. Pediatr Blood Cancer 2012;59(1):191-3. PMID 22605457
70: Kellom E, Stepien K, Rice G, Wolf B. Biotinidase deficiency is a rare, potentially treatable cause of peripheral neuropathy with or without optic neuropathy in adults. Mol Genet Metab Rep 2020;26:100696. PMID 33364171
71: Kellom ER, Wolf B, Rice GM, Stepien KE. Reversal of vision loss in a 49-year-old man with progressive optic atrophy due to profound biotinidase deficiency. J Neuroophthalmol 2021;41:e27-30. PMID 32235217
72: Knappe J, Brommer W, Biederbick K. Reinigung und Eigenschaften der Biotinidase aus Schweinenieren und Lactobacillus casei. Biochem Z 1963;228:599-613. PMID 14087327
73: Knight HC, Reynolds TR, Meyers GA, Pomponio RJ, Buck GA, Wolf B. Structure of the human biotinidase gene. Mamm Genome 1998;9:327-30. PMID 9530634
74: Komur M, Okuyaz C, Ezgu F, Atici A. A girl with spastic tetraparesis associated with biotinidase deficiency. Eur J Paediatr Neurol 2011;15(6):551-3. PMID 21571559
75: Küry S, Ramaekers V, Bézieau S, Wolf B. Clinical utility gene card for: Biotinidase deficiency-update 2015. Eur J Hum Genet 2016;24(7). PMID 26577040
76: Landau YE, Waisbren SE, Chan LM, Levy HL. Long-term outcome of expanded newborn screening at Boston children's hospital: benefits and challenges in defining true disease. J Inherit Metab Dis 2017;40(2):209-18. PMID 28054209
77: Laszlo A, Schuler EA, Sallay E, et al. Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. J Inherit Metab Dis 2003;26(7):693-8. PMID 14707518
78: Li H, Spencer L, Nahhas F, et al. Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene. Mol Genet Metab 2014;112:242-6. PMID 24797656
79: Liu S, Zhang Y, Deng Z, et al. Delayed biotin therapy in a child with atypical profound biotinidase deficiency: late arrival of the truth and a lesson worth thinking. Int J Mol Sci 2023;24(12):10239. PMID 37522883
80: Liu Z, Zhao X, Sheng H, et al. Clinical features, BTD gene mutations, and their functional studies of eight symptomatic patients with biotinidase deficiency from Southern China. Am J Med Genet A 2018;176(3):589-96. PMID 29359854
81: Lott IT, Lottenberg S, Nyhan WL, Buchsbaum MJ. Cerebral metabolic changes after treatment in biotinidase deficiency. J Inherit Metab Dis 1993;16:399-407. PMID 8412000
82: Lunnemann L, Vogt A, Blume-Peytavi U, Garcia Bartels N. Hair-shaft abnormality in a 7-year-old girl. Trichorrhexis nodosa due to biotinidase deficiency. JAMA Dermatol 2013;149(3):357-63. PMID 23552716
83: Mc Sweeney N, Grunewald S, Bhate S, Ganesan V, Chong WK, Hemingway C. Two unusual clinical and radiological presentations of biotinidase deficiency. Eur J Paediatr Neurol 2010;14(6):535-8. PMID 20153672
84: McVoy JR, Levy HL, Lawler M, et al. Partial biotinidase deficiency: clinical and biochemical features. J Pediatr 1990;116:78-83. PMID 2295967
85: Mico SI, Jiménez RD, Salcedo EM, Martínez HA, Mira AP, Fernández CC. Epilepsy in biotinidase deficiency after biotin treatment. JIMD Rep 2012;4:75-8. PMID 23430899
86: Mikati MA, Zalloua P, Karam P, Habbal MZ, Rahi AC. Novel mutation causing partial biotinidase deficiency in a Syrian boy with infantile spasms and retardation. J Child Neurol 2006;21(11):978-81. PMID 17092467
87: Milankovics I, Kamory E, Csokay B, Fodor F, Somogyi C, Schuler A. Mutations causing biotinidase deficiency in children ascertained by newborn screening in Western Hungary. Mol Genet Metab 2007;90(3):345-8. PMID 17185019
88: Mock DM, Baswell DL, Baker H, Holman RT, Sweetman L. Biotin deficiency complicating parenteral alimentation: diagnosis, metabolic repercussions and treatment. Ann N Y Acad Sci 1985;447:314-34. PMID 3925860
89: Moslinger D, Muhl A, Suormala T, Baumgartner R, Stockler-Ipsiroglu S. Molecular characterisation and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies. Eur J Pediatr 2003;162 Suppl 1:S46-9. PMID 14628140
90: Moslinger D, Stockler-Ipsiroglu S, Scheibenreiter S, et al. Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr 2001;9:277-82. PMID 11388594
91: Muhl A, Moslinger D, Item CB, Stockler-Ipsiroglu S. Molecular characterisation of 34 patients with biotinidase deficiency ascertained by newborn screening and family investigation. Eur J Hum Genet 2001;9:237-43. PMID 11313766
92: Munnich A, Saudubray JM, Carre G, et al. Defective biotin absorption in multiple carboxylase deficiency. Lancet 1981;2:263. PMID 6114319
93: Neto EC, Schulte J, Rubim R, et al. Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. Braz J Med Biol Res 2004;37(3):295-9. PMID 15060693
94: Norrgard KJ, Pomponio RJ, Hymes J, et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res 1999;46:20-7. PMID 10400129
95: Norrgard KJ, Pomponio RJ, Swango KL, et al. Mutation (Q456H) is the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Biochem Mol Med 1997a;61:22-7. PMID 9232193
96: Norrgard KJ, Pomponio RJ, Swango KL, et al. Double mutation (A171T and D444H) is a common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Hum Mutat 1997b;11:410. PMID 10206677
97: Ohlsson A, Guthenberg C, Holme E, von Döbeln U. Profound biotinidase deficiency: a rare disease among native Swedes. J Inherit Metab Dis 2010;33 Suppl 3:S175-80. PMID 20224900
98: Oz O, Karaca M, Atas N, Gonel A, Ercan M. BTD gene mutations in biotinidase deficiency: genotype-phenotype correlation. J Coll Physicians Surg Pak 2021;30:780-5. PMID 34271776
99: Patra S, Senthilnathan G, Bhari N. Acrodermatitis enteropathica-like skin eruption with neonatal seizures in a child with biotinidase deficiency. Clin Exp Dermatol 2020;45(2):266-7. PMID 31323123
100: Perez-Monjaras A, Cervantes-Roldan R, Meneses-Morales I, et al. Impaired biotinidase activity disrupts holocarboxylase synthetase expression in late onset multiple carboxylase deficiency. J Biol Chem 2008;283(49):34150-8. PMID 18845537
101: Pindolia K, Jordan M, Wolf B. Analysis of mutations causing biotinidase deficiency. Hum Mutat 2010;31(9):983-91. PMID 20556795
102: Pispa J. Animal biotinidase. Ann Med Exp Biol Fenn 1965;43(Suppl 5):1-39. PMID 5867120
103: Pomponio RJ, Coskun T, Demirkol M, et al. Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis 2000a;23:120-8. PMID 10801053
104: Pomponio RJ, Hymes J, Pandya A, et al. Prenatal diagnosis of heterozygosity for biotinidase deficiency by enzymatic and molecular analyses. Prenat Diagn 1998;18:117-22. PMID 9516011
105: Pomponio RJ, Hymes J, Reynolds TR, et al. Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediatr Res 1997a;42:840-8. PMID 9396567
106: Pomponio RJ, Norrgard KJ, Hymes J, et al. Arg538 to Cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of profound biotinidase deficiency in symptomatic children. Hum Genet 1997b;99:506-12. PMID 9099842
107: Pomponio RJ, Ozand PT, Al Essa M, Wolf B. Novel mutations in children with profound biotinidase deficiency from Saudi Arabia. J Inherit Metab Dis 2000b;23:185-7. PMID 10801060
108: Pomponio RJ, Reynolds TR, Cole H, Buck GA, Wolf B. Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency. Nat Genet 1995;11(1):96-8. PMID 7550325
109: Porta F, Pagliardini V, Celestino I, et al. Neonatal screening for biotinidase deficiency: a 30-year single center experience. Mol Genet Metab Rep 2017;13:80-2. PMID 28971021
110: Procter M, Wolf B, Crockett DK, Mao R. The Biotinidase Gene Variants Registry: a paradigm public database. G3 (Bethesda) 2013;3(4):727-31. PMID 23550138
111: Procter M, Wolf B, Mao R. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab 2016;117(3):369-72. PMID 26810761
112: Radelfahr F, Riedhammer KM, Keidel LF, et al. Biotinidase deficiency: a treatable cause of hereditary spastic paraparesis. Neurol Genet 2020;13:6(6):e525. PMID 33134520
113: Raha S, Udani V. Biotinidase deficiency presenting as recurrent myelopathy in a 7-year-old boy and a review of the literature. Pediatr Neurol 2011;45(4):261-4. PMID 21907891
114: Rahman S, Standing S, Dalton RN, Pike MG. Late presentation of biotinidase deficiency with acute visual loss and gait disturbance. Dev Med Child Neurol 1997;39:830-1. PMID 9433860
115: Ramaekers VT, Brab M, Rau G, Heimann G. Recovery from neurological deficits following biotin treatment in a biotinidase Km variant. Neuropediatrics 1993;24:98-102. PMID 8352834
116: Ramaekers VT, Suormala TM, Brab M, Duran R, Heimann G, Baumgartner ER. A biotinidase Km variant causing late onset bilateral optic neuropathy. Arch Dis Child 1992;67:115-9. PMID 1739323
117: Rathi N, Rathi M. Biotinidase deficiency with hypertonia as unusual feature. Indian Pediatr 2009;46:65-7. PMID 19179722
118: Riudor E, Vilaseca MA, Briones P, et al. Requirement of high biotin doses in a case of biotinidase deficiency. J Inherit Metab Dis 1989;12:338-9. PMID 2515382
119: Salbert BA, Astruc J, Wolf B. Ophthalmological findings in biotinidase deficiency. Ophthalmologica 1993a;206:177-81. PMID 8278163
120: Salbert BA, Pellock JM, Wolf B. Characterization of seizures associated with biotinidase deficiency. Neurology 1993b;43:1351-4. PMID 8327137
121: Sander JE, Malamud N, Cowan MJ, Packman S, Ammann AJ, Wara DW. Intermittent ataxia and immunodeficiency with multiple carboxylase deficiencies: a biotin-responsive disorder. Ann Neurol 1980;8:544-7. PMID 7436398
122: Santoro JD, Paulsen KC. Biotinidase deficiency as a mimic of neuromyelitis optica spectrum disorder in childhood. JAMA Neurol 2020;78(1):118-20. PMID 33016994
123: Schulpis KH, Karikas GA, Tjamouranis J, Regoutas S, Tsakiris S. Low serum biotinidase activity in children with valproic acid monotherapy. Epilepsia 2001;42:1359-62. PMID 11737173
124: Schulz PE, Weiner SP, Belmont JW, Fishman MA. Basal ganglia calcifications in a case of biotinidase deficiency. Neurology 1988;38:1326-8. PMID 3399084
125: Secor McVoy JR, Heard GS, Wolf B. The potential for the prenatal diagnosis of biotinidase deficiency. Prenat Diagn 1984;4:317. PMID 6483793
126: Seker Yilmaz B, Mungan NO, et al. Twenty-seven mutations with three novel pathologenic variants causing biotinidase deficiency: a report of 203 patients from the southeastern part of Turkey. J Pediatr Endocrinol Metab 2018;31(3):339-43. PMID 29353266
127: Shah S, Khan N, Lakshmanan R, Lewis B, Nagarajan L. Biotinidase deficiency presenting as neuromyelitis optica spectrum disorder. Brain Dev 2020;42(10):762-6. PMID 32741581
128: Singhi P, Ray M. Ohtahara syndrome with biotinidase deficiency. J Child Neurol 2011;26(4):507-9. PMID 21115748
129: Sivri HS, Genc GA, Tokatli A, et al. Hearing loss in biotinidase deficiency: genotype-phenotype correlation. J Pediatr 2007;150(4):439-42. PMID 17382128
130: Stanley CM, Hymes J, Wolf B. Identification of alternatively spliced human biotinidase mRNAs and putative localization of endogenous biotinidase. Mol Genet Metab 2004;81(4):300-12. PMID 15059618
131: Stigsby B, Yarworth SM, Rahbeeni Z, et al. Neurophysiologic correlates of organic acidemias: a survey of 107 patients. Brain Dev 1994;16(Suppl):125-44. PMID 7726377
132: Strom CM, Levine EM. Chronic vaginal candidiasis responsive to biotin therapy in a carrier of biotinidase deficiency. Obstet Gynecol 1998;92:644-6. PMID 9764646
133: Strovel ET, Cowan TM, Scott AI, Wolf B. ERRATUM: Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med 2018;20(2):282. PMID 29240078
134: Suchy SF, Secor McVoy Jr, Wolf B. Neurologic symptoms of biotinidase deficiency: possible explanation. Neurology 1985;35:1510-1. PMID 4033935
135: Suormala T, Baumgartner ER, Wick H, Scheibenreiter S, Schweitzer S. Comparison of patients with complete and partial biotinidase deficiency: biochemical studies. J Inherit Metab Dis 1990;13:76-92. PMID 2109151
136: Suormala T, Wick H, Bonjour JP, Baumgartner ER. Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin responsiveness in a single blood sample. Clin Chim Acta 1985a;145:151-62. PMID 3918814
137: Suormala T, Wick H, Bonjour JP, Baumgartner ER. Intestinal absorption and renal excretion of biotin in patients with biotinidase deficiency. Eur J Pediatr 1985b;144:21-6. PMID 3926500
138: Sürücü K, Köse E, Koç Yekedüz M, Eminoğlu FT. A different approach to the evaluation of the genotype-phenotype relationship in biotinidase deficiency: repeated measurement of biotinidase enzyme activity. J Pediatr Endocrinol Metab 2023;36(11):1061-71. PMID 37725148
139: Swango KL, Demirkol M, Huner G, et al. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet 1998;102:571-5. PMID 9654207
140: Sweetman L. Two forms of biotin-responsive multiple carboxylase deficiency. J Inherit Metab Dis 1981;4:53-4. PMID 6790844
141: Taitz LS, Leonard JV, Bartlett K. Long-term auditory and visual complications of biotinidase deficiency. Early Hum Dev 1985;11:325-31. PMID 4054050
142: Tankeu AT, Van Winckel G, Elmers J, et al. Biotinidase deficiency: What have we learned in forty years? Mol Genet Metab 2023;138(4):107560. PMID 37027963
143: Teive HAG, Camargo CHF, Pereira ER, Coutinho L, Munhoz RP. Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment. Neurogenetics 2022;23:167-77. PMID 35397036
144: Thodi G, Schulpis KH, Molou E, et al. High incidence of partial biotinidase deficiency cases in newborns of Greek origin. Gene 2013;524(2):361-2. PMID 23644139
145: Thoene J, Baker H, Yoshino M, Sweetman L. Biotin responsive carboxylase deficiency associated with subnormal plasma and urinary biotin. N Engl J Med 1981;304:817-20. PMID 6782477
146: Thoene J, Lemons R, Baker H. Impaired intestinal absorption of biotin in juvenile multiple carboxylase deficiency. N Engl J Med 1983;308:639-42. PMID 6828095
147: Thoene J, Wolf B. Biotinidase deficiency in juvenile multiple carboxylase deficiency. Lancet 1983;2:398. PMID 6135890
148: Tiar A, Mekki A, Nagara M, et al. Biotinidase deficiency: novel mutations in Algerian patients. Gene 2014;536(1):193-6. PMID 23481307
149: Tokatli A, Coskun T, Ozalp I. Biotinidase deficiency with neurological features resembling multiple sclerosis. J Inherit Metab Dis 1997;20:707-8. PMID 9323568
150: Tonin R, Caciotti A, Funghini S, et al. Biotinidase deficiency due to a de novo mutation or gonadal mosaicism in a first child. Clin Chim Acta 2015;18;445:70-2. PMID 25795614
151: Tsao CY, Kien CL. Complete biotinidase deficiency presenting as reversible progressive ataxia and sensorineural deafness. J Child Neurol 2002;17:146. PMID 11952077
152: Vallejo-Torres L, Castilla I, Couce ML, et al. Cost-effectiveness analysis of a national newborn screening program for biotinidase deficiency. Pediatrics 2015;136(2):e424-32. PMID 26169436
153: Van Winckel G, Ballhausen D, Wolf B, et al. Severe distal motor involvement in a non-compliant adult with biotinidase deficiency: the necessity of life-long biotin therapy. Front Neurol 2020;11:516799. PMID 33192963
154: Wastell HJ, Bartlett K, Dale G, Shein A. Biotinidase deficiency: a survey of 10 cases. Arch Dis Child 1988;63:1244-9. PMID 3196050
155: Weber P, Scholl S, Baumgartner ER. Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. Dev Med Child Neurol 2004;46:481-4. PMID 15230462
156: Weissbecker KA, Nance WE, Eaves LJ, Piussan C, Wolf B. Detection of heterozygotes for biotinidase deficiency. Am J Hum Genet 1991;39:385-90. PMID 1877614
157: Welling DB. Long-term follow-up of hearing loss in biotinidase deficiency. J Child Neurol 2007;22(8):1055. PMID 17761663
158: Weyler W, Sweetman L, Maggio DC, Nyhan WL. Deficiency of propionyl-CoA carboxylase and methylcrotonyl-CoA carboxylase in a patient with methylcrotonylglycinuria. Clin Chim Acta 1977;76:321-8. PMID 858206
159: Wiznitzer M, Bangert BA. Biotinidase deficiency: clinical and MRI findings consistent with myelopathy. Pediatr Neurol 2003;29(1):56-8. PMID 13679123
160: Wolf B. Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". Genet Med 2012;14(6):565-75. PMID 22241090
161: Wolf B. Biotinidase deficiency. In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 2010a.
162: Wolf B. Biotinidase deficiency masquerading as multiple sclerosis? Mult Scler 2018a;24(2):237-8. PMID 28337933
163: Wolf B. Biotinidase deficiency: new directions and practical concerns. Curr Treat Options Neurol 2003;5:321-8. PMID 12791199
164: Wolf B. Biotinidase deficiency should be considered in individuals exhibiting myelopathy with or without and vision loss. Mol Genet Metab 2015a;116(3):113-8. PMID 26358973
165: Wolf B. Biotinidase deficiency should be considered in individuals thought to have multiple sclerosis and related disorders. Mult Scler Relat Disord 2019b;28:26-30. PMID 30551056
166: Wolf B. Biotinidase: its role in biotinidase deficiency and biotin metabolism. J Nutr Biochem 2005;16:441-5. PMID 15992688
167: Wolf B. Children with profound biotinidase deficiency should be treated with biotin regardless of their residual enzyme activity or genotype. Eur J Pediatr 2002;161:167-8. PMID 11998918
168: Wolf B. Clinical issues and frequent questions about biotinidase deficiency. Mol Genet Metab 2010b;100:6-13. PMID 20129807
169: Wolf B. Disorders of biotin metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 1992b:2083-103.
170: Wolf B. Disorders of biotin metabolism: treatable neurological syndromes. In: Rosenberg R, Prusiner SB, DiMauro S, Barchi RL, Kunkel LM, editors. The Molecular and Genetic Basis of Neurological Disease. Stoneham (MA): Butterworth, 1992a:569-81.
171: Wolf B. First microdeletion involving only the biotinidase gene that can cause biotinidase deficiency: A lesson for clinical practice. Mol Genet Metab Rep 2016;6:74-6. PMID 27014582
172: Wolf B. High doses of biotin can interfere with immunoassays that use biotin-strept(avidin) technologies: implications for individuals with biotin-responsive inherited metabolic disorders. Mol Genet Metab 2019a;127(4):321-4. PMID 31320189
173: Wolf B. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med 2017a;19(4):396-402. PMID 27657684
174: Wolf B. The neurology of biotinidase deficiency. Mol Genet Metab 2011;104(1-2):27-34. PMID 21696988
175: Wolf B. "Think metabolic" in adults with diagnostic challenges: biotinidase deficiency as a paradigm disorder. Neurol Clin Pract 2017b;7(6):518-22. PMID 29431165
176: Wolf B. Why screen newborns for profound and partial biotinidase deficiency? Mol Genet Metab 2015b;114:382-7. PMID 25638506
177: Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis 1991;14:923-7. PMID 1779651
178: Wolf B, Feldman GL. The biotin-dependent carboxylase deficiencies. Am J Hum Genet 1982;34:699-716. PMID 6127031
179: Wolf B, Freehauf CL, Thomas JA, Gordon PL, Greene CL, Ward JC. Markedly elevated serum biotinidase activity may indicate glycogen storage disease type Ia. J Inherit Metab Dis 2003;26(8):805-9. PMID 14739685
180: Wolf B, Grier RE, Allen RJ, Goodman SI, Kien CL. Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. Clin Chim Acta 1983a;131:273-81. PMID 6883721
181: Wolf B, Grier RE, Allen RJ, et al. Phenotypic variation in biotinidase deficiency. J Pediatr 1983b;103:233-7. PMID 6875714
182: Wolf B, Grier RE, Heard GS. Hearing loss in biotinidase deficiency. Lancet 1983c;2:1365. PMID 6139700
183: Wolf B, Heard GS, Jefferson LG, Proud VK, Nance WE, Weissbecker KA. Clinical findings in four children with biotinidase deficiency detected through a statewide neonatal screening program. N Engl J Med 1985a;313:16-9. PMID 4000223
184: Wolf B, Heard GS, McVoy JR, Raetz HM. Biotinidase deficiency: the possible role of biotinidase in the processing of dietary protein-bound biotin. J Inherit Metab Dis 1984;7(Suppl 2):121. PMID 6434861
185: Wolf B, Heard GS, Weissbecker KA, McVoy JR, Grier RE, Leshner RT. Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann Neurol 1985b;18:614-7. PMID 4073853
186: Wolf B, Jensen K, Barshop B, et al. Biotinidase deficiency: novel mutations and their biochemical and clinical correlates. Hum Mutat 2005;25:413. PMID 15776412
187: Wolf B, Jensen K, Huner G, et al. Seventeen novel mutations that cause profound biotinidase deficiency. Mol Genet Metab 2002a;77:108-11. PMID 12359137
188: Wolf B, Norrgard K, Pomponio RJ, et al. Profound biotinidase deficiency in two asymptomatic adults. Am J Med Genet 1997;73:5-9. PMID 9375914
189: Wolf B, Pomponio RJ, Norrgard KJ, et al. Delayed-onset profound biotinidase deficiency. J Pediatr 1998;132:362-5. PMID 9506660
190: Wolf B, Secor McVoy J. A sensitive radioassay for biotinidase activity: deficient activity in tissues of serum biotinidase-deficient individuals. Clin Chim Acta 1984a;135:275-81. PMID 6661819
191: Wolf B, Spencer R, Gleason T. Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. J Pediatr 2002b;140:242-6. PMID 11865279
192: Xie LJ, Zhu JX, Zhu XD, Li HJ, Han LS, Gu XF. Combined use of tandem mass spectrometry with urine gas chromatography/mass spectrometry is useful for diagnosis of inborn errors of metabolism in children. Zhongguo Dang Dai Er Ke Za Zhi 2008;10(1):31-4. PMID 18289467
193: Yang Y, Li C, Qi Z, et al. Spinal cord demyelination associated with biotinidase deficiency in 3 Chinese patients. J Child Neurol 2007;22(2):156-60. PMID 17621476
194: Yilmaz S, Serin M, Canda E, et al. A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency. Metab Brain Dis 2017. PMID 28281033
195: Yilmaz Y, Tasdemir HA, Paksu MS. The influence of valproic acid treatment on hair and serum zinc levels and serum biotinidase activity. Eur J Paediatr Neurol 2009;13(5):439-43. PMID 18922714
196: Zaffanello M, Zamboni G, Fontana E, Zoccante L, Tato L. A case of partial biotinidase deficiency associated with autism. Neuropsychol Dev Cogn Sect C Child Neuropsychol 2003;9(3):184-8. PMID 13680408
197: Zempleni J. Uptake, localization, and noncarboxylase roles of biotin. J. Annu Rev Nutr 2005;25:175-96. PMID 16011464
198: Zengin Akkus P, Ciki K, Mete Yesil A, et al. Developmental and behavioral outcomes of preschool-aged children with biotinidase deficiency identified by newborn screening. Eur J Pediatr 2021;180:217-224. PMID 32683535

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Biotinidase deficiency

Associated Disorders

Infantile combined carboxylase deficiency
Infantile multiple carboxylase deficiency
Juvenile combined carboxylase deficiency
Juvenile multiple carboxylase deficiency
Late-onset combined carboxylase deficiency
- Late-onset multiple carboxylase deficiency
- Partial biotinidase deficiency
- Demyelinating spinal cord disease

Differential Diagnosis

sepsis
gastrointestinal obstruction
cardiorespiratory problems
inborn error of metabolism
zinc deficiency
- essential fatty acids deficiency
- immunologic dysfunction
- multiple carboxylase deficiency
- isolated carboxylase deficiency
- isolated beta-methylcrotonyl-CoA carboxylase deficiencies
- holocarboxylase synthetase deficiencies

Also Relevant

Biotin holocarboxylase synthetase deficiency
Isolated beta-methylcrotonyl-CoA carboxylase deficiency
Leigh syndrome
Nondominant hereditary ataxias
Propionyl-CoA carboxylase deficiency
- Pyruvate carboxylase deficiency

Clinical Categories

Childhood Degenerative & Metabolic Disorders

Biotinidase deficiency …

Biotinidase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

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Also in This Category

Abnormalities of tetrahydrobiopterin metabolism

Carnitine palmitoyltransferase II deficiency

Aicardi-Goutieres syndrome

Cockayne syndrome

Methylmalonic acidemia

HHH syndrome

Citrullinemias types 1 and 2

Hyperargininemia

Biotinidase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Abnormalities of tetrahydrobiopterin metabolism

Carnitine palmitoyltransferase II deficiency

Aicardi-Goutieres syndrome

Cockayne syndrome

Methylmalonic acidemia

HHH syndrome

Citrullinemias types 1 and 2

Hyperargininemia

This is an article preview.
Start a Free Account
to access the full version.