27 -Responsive Disorders

Matthias R. Baumgartner, Terttu Suormala

27.1 Clinical Presentation – 333 27.1.1 Holocarboxylase Synthetase Deficiency – 333 27.1.2 Deficiency – 333 27.1.3 Biotin-Responsive Basal Ganglia Disease – 334

27.2 Metabolic Derangement – 334

27.3 Genetics – 334 27.3.1 Holocarboxylase Synthetase Deficiency – 335 27.3.2 – 335 27.3.3 Biotin-Responsive Basal Ganglia Disease – 335

27.4 Diagnostic Tests – 335 27.4.1 Holocarboxylase Synthetase Deficiency – 336 27.4.2 Biotinidase Deficiency – 336 27.4.3 Acquired Biotin Deficiency – 336 27.4.4 Prenatal Diagnosis – 336

27.5 Treatment and Prognosis – 336 27.5.1 Holocarboxylase Synthetase Deficiency – 336 27.5.2 Biotinidase Deficiency – 337 27.5.3 Biotin-Responsive Basal Ganglia Disease – 337

References – 338 332 Chapter 27 · Biotin-Responsive Disorders

The Biotin Cycle and Biotin-Dependent Biotin, a water-soluble vitamin widely present in small is required to generate the active holocarboxylases amounts in natural foodstuffs in which it is mostly (. Fig. 27.2). Recycling of biotin first involves proteo- protein-bound, is the coenzyme of four important lytic degradation of the holocarboxylases, yielding carboxylases, involved in gluconeogenesis, fatty acid biotin bound to lysine (biocytin) or to short biotinyl synthesis, and the catabolism of several amino acids peptides. Biotinidase then releases biotin from the latter (. Fig. 27.1). Binding of biotin to the four inactive apo- compounds, which are derived from either endogenous carboxylases, catalysed by holocarboxylase synthetase, or dietary sources.

V

. Fig. 27.1. Location of the biotin-dependent carboxylases in PC, pyruvate carboxylase; PCC, propionyl-CoA carboxylase; intermediary . ACC, acetyl-CoA carboxylase; CoA, PYR, pyruvate. Full lines indicate one , and dotted lines coenzyme A; HCS, holocarboxylase synthetase; LAC, lactate; indicate that several enzymes are involved. Sites of the enzyme MCC, 3-methylcrotonyl-CoA carboxylase; OAA, oxaloacetate; defects are indicated by solid bars

. Fig. 27.2. The biotin cycle. For definitions of abbreviations, . Fig. 27.1. Sites of the enzyme and transport defects are indicated by solid bars 333 27 27.1 · Clinical Presentation

27.1.1 Holocarboxylase Synthetase Two inherited defects in biotin metabolism are known: Deficiency holocarboxylase synthetase (HCS) deficiency and bio- tinidase deficiency. Both lead to deficiency of all biotin- Although HCS deficiency was initially termed early-onset dependent carboxylases, i.e. to multiple carboxylase MCD, recent experience shows that the age of onset varies deficiency (MCD). In HCS deficiency, the binding of widely, from a few hours after birth to 8 years of age [2, 3]. biotin to apocarboxylases is impaired. In biotinidase Nevertheless, about half of the patients have presented deficiency, biotin depletion ensues from the inability to acutely in the first days of life with symptoms very similar recycle endogenous biotin and to utilize protein-bound to those observed in other severe organic acidurias, i.e., biotin from the diet. As the carboxylases play an essen- lethargy, hypotonia, vomiting, seizures and hypothermia. tial role in the catabolism of several amino acids, in glu- The most common initial clinical features consist of respira- coneogenesis and in fatty-acid synthesis, their defi- tory difficulties, such as tachypnea or Kussmaul breathing. ciency provokes multiple, life-threatening metabolic Severe metabolic acidosis, ketosis and hyperammonaemia derangements, eliciting characteristic organic aciduria may lead to coma and early death. Patients with a less severe and neurological symptoms. The clinical presentation defect and later onset may also present with recurrent life- is extremely variable in both disorders. Characteristic threatening attacks of metabolic acidosis and typical or- symptoms include metabolic acidosis, hypotonia, sei- ganic aciduria [4, 5]. Early-onset patients that recover with- zures, ataxia, impaired consciousness and cutaneous out biotin therapy and untreated patients with a less severe symptoms, such as skin rash and alopecia. All patients defect may additionally develop psychomotor retardation, with biotinidase and a majority of patients with HCS hair loss and skin lesions. The latter include an erythema- deficiency respond dramatically to oral therapy with tous, scaly skin rash that spreads over the whole body but is pharmacological doses of biotin. Delayed diagnosis particularly prominent in the diaper and intertriginous and treatment in biotinidase deficiency may result in areas; alternatively, the rash may resemble seborrheic der- irreversible neurological damage. A few patients with matitis or ichthyosis [6]. Superinfection with Candida may HCS deficiency show a partial or even no response to occur. Disorders of immune function have been observed biotin and seem to have an impaired long-term out- with decreased T cell count and impaired in vitro and in come. Acquired biotin deficiency, which also causes vivo response to Candida antigen. Episodes of acute illness MCD, is extremely rare. A defect in biotin transport has are often precipitated by catabolism during intercurrent in- been reported in a single child; however the genetic fections or by a higher protein intake. defect remains unresolved to date. Biotin-Responsive Basal Ganglia Disease (BRBGD) is a recently described subacute encephalopathy which disappears within 27.1.2 Biotinidase Deficiency a few days without neurological sequelae if biotin is administered early. Important features are the gradual development of symp- toms and episodes of remission, which may be related to increased free biotin in the diet. The full clinical picture has been reported as early as 7 weeks, but discrete neurological 27.1 Clinical Presentation symptoms may occur much earlier, even in the neonatal period [7]. Neurological manifestations (lethargy, muscular The characteristic manifestation of multiple carboxylase hypotonia, grand mal and myoclonic seizures, ataxia) are deficiency (MCD) is metabolic acidosis associated with the most frequent initial symptoms. In addition, respiratory neurological abnormalities and skin disease. The expres- abnormalities, such as stridor, episodes of hyperventilation sion of the clinical and biochemical features is variable in and apnoea occur frequently; these may be of neurological both inherited disorders [1]. While patients with holocar- origin [8]. Skin rash and/or alopecia are hallmarks of the boxylase synthetase (HCS) deficiency commonly present disease; however, they may develop late or not at all [9, 10]. with the typical symptoms of MCD, those with biotinidase Skin lesions are usually patchy, erythematous/exudative deficiency show a less consistent clinical picture, partic- and typically localized periorificially. Eczematoid dermati- ularly during the early stage of the disease. The onset in tis or an erythematous rash covering large parts of the body biotinidase deficiency may be insidious, and the manifesta- has also been observed, as has keratoconjunctivitis. Hair tion is usually very variable, neurological symptoms often loss is usually discrete but may, in severe cases, become being prominent without markedly abnormal organic-acid complete, including the eyelashes and eyebrows. Immuno- excretion or metabolic acidosis. Later-onset forms of HCS logical dysfunction may occur in acutely ill patients. Some deficiency cannot be clinically distinguished from biotini- children with profound biotinidase deficiency may not dase deficiency, necessitating confirmation of the diagnosis develop symptoms until later in childhood or during ado- by enzyme assay. lescence [11]. Their symptoms usually are less characteristic 334 Chapter 27 · Biotin-Responsive Disorders

and may include motor limb weakness, spastic paraparesis involvement of the putamen. All patients diagnosed to date and eye problems such as loss of visual acuity and scotomata are of Saudi, Syrian, or Yemeni ancestry. [11]. Two asymptomatic adults with profound biotinidase deficiency were ascertained after identification of their affected children by newborn screening [12]. Similarly, in 27.2 Metabolic Derangement two asymptomatic adolescent girls and in an asymptomatic adult male, residual plasma biotinidase activity, assessed by In HCS deficiency, a decreased affinity of the enzyme for a sensitive assay, was between 1.2–3.1% of the mean control biotin and/or a decreased maximal velocity lead to reduced value, indicating that the threshold level of biotinidase formation of the four holocarboxylases from their corre- activity needed for normal development is low [13, 14]. sponding inactive apocarboxylases at physiological biotin Alternatively, other factors such as modifying genes or concentrations (. Fig. 27.2) [20–22]. In biotinidase defi- environmental factors may protect some enzyme-deficient ciency, biotin cannot be released from biocytin and short V individuals from developing symptoms. biotinyl peptides. Thus, patients with biotinidase deficiency Because of the variability and nonspecificity of clinical are unable to either recycle endogenous biotin or to use manifestations, there is a great risk of a delay in diagnosis protein-bound dietary biotin (. Fig. 27.2) [1]. Conse quently, [8, 15, 16]. Late-diagnosed patients often have psychomotor biotin is lost in the urine, mainly in the form of biocytin retardation and neurological symptoms, such as leuko- [7, 23], and progressive biotin depletion occurs. Depending encephalopathy, hearing loss and optic atrophy, which may on the amount of free biotin in the diet and the severity of be irreversible [9, 10, 15–18]. The outcome may even be the enzyme defect, the disease becomes clinically manifest fatal. One patient died at the age of 22 months, with features during the first months of life or later in infancy or child- of Leigh syndrome proven by histopathology [8]. hood. Metabolic acidosis and the characteristic organic aci- Deficient activity of carboxylases in both HCS and duria of MCD are frequently lacking in the early stages of biotinidase deficiencies (. Fig. 27.1) results in accumulation the disease. Plasma lactate and 3-hydroxyisovalerate may be of lactic acid and derivatives of 3-methylcrotonyl-coenzyme only slightly elevated, whereas cerebrospinal fluid levels A (CoA) and propionyl-CoA (7 Sect. 27.4). may be significantly higher [19]. This fact and the finding Isolated inherited deficiencies of each of the three of severely decreased carboxylase activities in brain but mitochondrial carboxylases, propionyl-CoA carboxylase moderately deficient activity in liver and kidney in a patient (PCC), 3-methylcrotonyl-CoA carboxylase (MCC); (for with lethal outcome [8] are in accordance with the pre- both, 7 Chap.19), and pyruvate carboxylase (PC; 7 Chap.12), dominance of neurological symptoms and show that, in are also known. A single patient with an isolated defect of biotinidase deficiency, the brain is affected earlier and more acetyl-CoA carboxylase (ACC, cyto solic) has been reported severely than other organs. The threat of irreversible brain [24]. These isolated deficiencies are due to absence or damage demands that biotinidase deficiency should be abnormal structure of the apoenzyme and usually do not considered in all children with neurological problems, even respond to biotin therapy. A patient with isolated partial if obvious organic aciduria and/or cutaneous findings are MCC-deficiency and partial responsiveness to biotin the- not present. Sadly, there seems to have been little improve- rapy has recently been reported [25]. ment in the diagnostic delay over the last 10 years [15, 17]. In BRBGD there is a defective cerebral transport of Therefore, neonatal screening provides the best chance biotin [25a]. of improving outcome in biotinidase deficiency. Impor- Acquired biotin deficiency is rare but may result from tantly, treatment should be instituted without delay, since excessive consumption of raw egg white, malabsorption, patients may become biotin depleted within a few days after long-term parenteral nutrition, hemodialysis, and long- birth [7]. term anticonvulsant therapy. Biotin dependency due to a defect in biotin transport has been suggested in a 3-year-old boy with normal biotinidase and nutritional biotin intake 27.1.3 Biotin-Responsive Basal Ganglia [26], but the genetic defect remains unresolved to date. Disease

Biotin-responsive basal ganglia disease (BRBGD) is an au- 27.3 Genetics tosomal recessive disorder with childhood onset that presents as a subacute encephalopathy with confusion, dys- Both HCS and biotinidase deficiency are inherited as auto- arthria and dysphagia, that progresses to severe cogwheel somal recessive traits. HCS deficiency seems to be rarer rigidity, dystonia, quadriparesis and, if left untreated, to than biotinidase deficiency. The incidences of profound death [19a]. On brain magnetic resonance imaging (MRI) (<10% residual activity) and partial (10–30% residual activ- examination patients display central bilateral necrosis in ity) biotinidase deficiencies are, on average, 1:112 000 and the head of the caudate nucleus with complete or partial 1:129 000, respectively [27]. The incidence of combined 335 27 27.4 · Diagnostic Tests

profound and partial deficiency is about 1 in 60 000. The mutations in children detected by newborn screening with cDNAs for human HCS [28, 29] and biotinidase [30] have mutations in symptomatic children revealed four mutations been cloned, and the corresponding genes have been comprising 59% of the mutant alleles studied [42]. Only mapped to human chromosomes 21q22.1 [29] and 3p25 two of these mutations occurred in both populations [42]. [31], respectively. In both genes, multiple disease causing Thus it is possible that individuals with certain mutations mutations have been identified. in the newborn screening group may have a decreased risk of developing symptoms. Almost all individuals with partial biotinidase deficiency have the D444H mutation in com- 27.3.1 Holocarboxylase Synthetase bination with a mutation causing profound biotinidase Deficiency deficiency on the second allele [39].

More than 20 different disease causing mutations have been reported [32–35]. About 2/3 of them are within the putative 27.3.3 Biotin-Responsive Basal Ganglia biotin-binding region of HCS and result in decreased Disease affinity of the enzyme for biotin [20, 22, 32, 34, 36]; this probably accounts for the in vivo responsiveness to biotin BRBGD is due to mutations in SLC19A3, a gene coding for therapy of these patients. The degree of abnormality of the a cerebral biotin transporter related to the reduced folate Km values of HCS for biotin correlates well with the time and thiamine transporters [25a]. Different missense muta- of onset and severity of illness, i.e. highest Km with early tions have been identified. onset and severe disease [21]. Other mutations, located outside the biotin-binding site in the N-terminal region, are associated with normal Km but decreased Vmax [22]. 27.4 Diagnostic Tests Most patients with this type of mutation also respond to biotin, although higher doses may be required and residual A characteristic organic aciduria due to systemic deficiency biochemical and clinical abnormalities may persist. Biotin of the carboxylases is the key feature of MCD. In severe responsiveness in such patients may derive from a positive cases, an unpleasant urine odour (cat’s urine) may even effect of biotin on HCS mRNA transcription and thus be suggestive of the defect. MCD is reflected in elevated on HCS protein, which has recently been suggested [37]. urinary and plasma concentrations of organic acids as However, since this mechanism involves HCS protein itself, follows: it requires the presence of residual HCS activity in order 4 Deficiency of MCC: 3-hydroxyisovaleric acid in high to work. Only one mutant allele, L216R, when present in concentrations, 3-methylcrotonylglycine in smaller the homozygous state, has been associated with a biotin- amounts; unresponsive, severe clinical phenotype [32]. This mutation 4 Deficiency of PCC: methylcitrate, 3-hydroxypropionate, seems to be highly prevalent in Polynesian patients of propionylglycine, tiglylglycine, propionic acid in small Samoan origin (David Thorburn and Callum Wilson, per- to moderate amounts; sonal communication). 4 Deficiency of PC: lactate in high concentrations, pyru- vate in smaller amounts.

27.3.2 Biotinidase Deficiency There is no metabolic marker in BRBGD. The majority of HCS-deficient patients excrete all of the At least 79 different mutations have been identified in pa- typical organic acids in elevated concentrations, provided tients with profound or partial biotinidase deficiency [35, that the urine sample has been taken during an episode 38, 39]. The two most common mutations detected in of acute illness. In contrast, in biotinidase deficiency ele- symptomatic patients with profound deficiency in the vated excretion of only 3-hydroxyisovalerate may be found, U.S.A., accounting for about one third of the alleles, are especially in early stages of the disease. 20 % of untreated 98-104del7ins3 and R538C [38, 40]. In contrast, in patients biotinidase-deficient children had normal urinary organic with profound biotinidase deficiency detected by newborn acid excretion when symptomatic [10]. screening, three mutations – Q456H, the double-mutant The measurement of carboxylase activities in lympho- allele A171T + D444H, and D252G – accounted for about cytes provides direct evidence of MCD. These activities are half of the mutant alleles detected [38]. Strikingly, these low in HCS deficiency but may be normal in biotinidase mutations were not detected in any of the symptomatic deficiency, depending on the degree of biotin deficiency patients [38, 40]. Furthermore, none of the symptomatic [3, 14]. The two inherited disorders can easily be distin- children had detectable serum biotinidase biotinyl-trans- guished by assay of biotinidase activity in serum. Today, this ferase activity while two thirds of the children identified assay is included in the neonatal screening programs in by screening had detectable activity [41]. A comparison of many countries worldwide. 336 Chapter 27 · Biotin-Responsive Disorders

27.4.1 Holocarboxylase Synthetase 27.4.4 Prenatal Diagnosis Deficiency Prenatal diagnosis of HCS deficiency is possible by enzy- 4 Biotin concentrations in plasma and urine are normal; matic studies in cultured chorionic villi or amniotic fluid 4 Carboxylase activities in lymphocytes are deficient and cells or by demonstration of elevated concentrations of cannot be activated by in vitro preincubation with metabolites by stable isotope dilution techniques in amni- biotin [1]; otic fluid. Organic acid analysis in milder forms of HCS 4 Direct measurement of HCS activity requires a protein, deficiency may fail to show an affected fetus, necessitating e.g. an apocarboxylase or an apocarboxyl carrier pro- enzymatic investigation in these cases [5]. Prenatal diag- tein of ACC as one of the substrates [21, 43]; therefore, nosis allows rational prenatal therapy, preventing severe it is not routinely performed; metabolic derangement in the early neonatal period [5, 45]. 4 HCS deficiency can be diagnosed indirectly by de- Biotinidase can be measured in chorionic villi or cultured V monstrating severely decreased carboxylase activities in amniotic fluid cells but, in our opinion, this is not warranted, fibroblasts cultured in a medium with low biotin con- because prenatal treatment is not necessary. centration (10–10 mol/l) and by normalization (or, at least an increase) of the activities in cells cultured in media supplemented with high biotin concentrations 27.5 Treatment and Prognosis (10–6–10–5 mol/l) [3, 21]. It must be noted that fibro- blasts of some late-onset patients may exhibit normal With the exception of some cases of HCS deficiency, both levels of carboxylase activities when cultured in stan- inherited disorders can be treated effectively with oral dard media supplemented with 10% fetal calf serum, biotin in pharmacologic doses. No adverse effects have which results in a final biotin concentration of about been observed from such therapy over a more than 20-year 10–8 mol/l [3, 5]. experience of treating biotinidase deficiency [39] and, importantly, there is no accumulation of biocytin in body fluids [23], which was previously suspected to be a possible 27.4.2 Biotinidase Deficiency risk. Restriction of protein intake is not necessary except 4 Biotinidase activity in plasma is absent or decreased in very severe cases of HCS deficiency. Acutely ill patients [14, 27]. Many patients have measurable residual activity with metabolic decompensation require general emergency and should be evaluated for the presence of a Km defect treatment in addition to biotin therapy (7 Chap. 4). (7 below); 4 Symptomatic patients usually have decreased biotin concentrations in plasma and urine [7, 14], provided 27.5.1 Holocarboxylase Synthetase that an assay method that does not detect biocytin is Deficiency used [44]. In addition, carboxylase activities in lym- phocytes are usually decreased but are normalized The required dose of biotin is dependent on the severity of within hours after either a single dose of oral biotin [7] the enzyme defect and has to be assessed individually [1]. or in vitro preincubation with biotin [1, 14]; Most patients have shown a good clinical response to 10– 4 Patients excrete biocytin in urine [23], the concentra- 20 mg/day, although some may require higher doses, i.e. tion being dependent on the level of residual biotinidase 40-200 mg/day [1, 3, 45–47]. In spite of apparently complete activity [14]; clinical recovery, some patients continue to excrete ab- 4 Carboxylase activities in fibroblasts cultured in low- normal metabolites (particularly 3-hydroxyisovalerate), a biotin medium are similar to those in control fibro- finding that correlates inversely with the actual level of blasts, and are always normal in fibroblasts cultured in carboxylase activity in lymphocytes. Exceptionally, per- standard medium. sistent clinical and biochemical abnormalities have been observed despite treatment with very high doses of biotin [1, 32, 45–47]. All patients with HCS deficiency have at 27.4.3 Acquired Biotin Deficiency least partially responded to pharmacological doses of biotin with the exception of those homozygous for the missense 4 Biotinidase activity is normal in plasma; mutation L216R [32]. 4 Biotin concentrations are low in plasma and urine; To date, the prognosis for most surviving, well-treated 4 Carboxylase activities in lymphocytes are decreased patients with HCS deficiency seems to be good, with the and are promptly normalized after a single dose of exception of those who show only a partial or no response oral biotin or after preincubation with biotin in to biotin [1, 32, 45–47]. Careful follow-up studies are needed vitro [1]. to judge the long-term outcome. In one patient, followed for 337 27 27.5 · Treatment and Prognosis

9 years and treated prenatally and from the age of 3.5 months lectual impairment and ataxia have been observed as long- with 6 mg biotin/day, some difficulties in fine motor tasks term complications [9, 15, 17, 18]. were obvious at the age of 9 years [48]. In five Japanese Patients with residual activity up to 10%, usually de- patients (four families), the intelligence quotient (IQ) at the tected by neonatal screening or family studies, may remain age of 5–10 years varied between 64 and 80 [45]. Four of asymptomatic for several years or even until adulthood these patients had a severe neonatal onset form, and one of [12–14]. According to our experience with 61 such patients them (IQ=64) was treated prenatally. Three of these patients (52 families), however, they show a great risk of becoming showed recurrent respiratory infections, metabolic acidosis biotin deficient and should be treated with, e.g., 2.5 mg of and organic aciduria despite high-dose (20–60 mg/day) biotin per day [14, 27, 39]. biotin therapy. However, irreversible neurological auditory- visual deficits, as described for biotinidase deficiency, have Group 2 not been reported. Prenatal biotin treatment (10 mg/day) Patients with partial biotinidase deficiency (10–30% re- has been reported in a few pregnancies [5, 45]. It is unclear sidual activity) are mostly detected by neonatal screening whether prenatal treatment is essential; treatment of at-risk and in family studies and usually remain asymptomatic. children immediately after birth may be sufficient. One infant with about 30% enzyme activity developed hypotonia, skin rash and hair loss during an episode of gastroenteritis at 6 months of age. This was reversed by 27.5.2 Biotinidase Deficiency biotin therapy [50]. We showed that among 24 patients with 14–25% serum biotinidase activity studied at the age of Introduction of neonatal screening programs has resulted 8 months to 8 years, 16 patients had a subnormal biotin in the detection of asymptomatic patients with residual concentration in at least one plasma sample, with a ten- biotinidase activity [27]. Based on measurement of plasma dency toward lower values with increasing age [51]. There- biotinidase activity, the patients are classified into three fore, it seems necessary to regularly control patients with main groups. 10-30% of residual activity and to supplement patients 1. Patients with profound biotinidase deficiency, with less with borderline abnormalities with small doses of biotin, than 10% of mean normal serum biotinidase activity. e.g., 2.5–5 mg/week. Using a sensitive method with the natural substrate bio- cytin, we classify these patients further into those with Group 3 complete deficiency (undetectable activity, limit of Among 201 patients (176 families), we found ten patients detection a0.05% of the mean normal value) and those (eight families) with a Km defect. In the routine colorimetric with residual biotinidase activity up to 10% [14]. biotinidase assay with 0.15 mmol/l biotinyl-p-amino- 2. Patients with partial biotinidase deficiency, with 10– benzoate as substrate, six of these patients (five families) 30% residual activity. showed profound deficiency (0.94–3% residual activity), 3. Patients with decreased affinity of biotinidase for bio- whereas four patients (three families) showed partial defi- cytin, i.e. Km variants [49]. ciency (18–20% residual activity). The index patient in all five families with profound deficiency presented with a Group 1 severe clinical illness [16, 49], and one of the patients with In early-diagnosed children with complete biotinidase de- partial deficiency, although apparently asymptomatic, had ficiency, 5–10 mg of oral biotin per day promptly reverse marginal biotin deficiency at the age of 2 years [49]. These or prevent all clinical and biochemical abnormalities. For results show the importance of testing all patients with chronic treatment, the same dose is recommended. Under residual biotinidase activity for a Km defect. They all seem careful clinical and biochemical control, it may be possible to have a high risk of becoming biotin deficient and, there- to reduce the daily dose of biotin to 2.5 mg. However, biotin fore, must be treated with biotin. has to be given throughout life and regularly each day, since biotin depletion develops rapidly [7]. Neonatal screening for biotinidase deficiency [27] 27.5.3 Biotin-Responsive Basal Ganglia allows early diagnosis and effective treatment. In such pa- Disease tients, the diagnosis must be confirmed by quantitative measurement of biotinidase activity. Treatment should be All clinical symptoms of BRBGD disappear within a few instituted without delay, since patients may become biotin days with the administration of high doses of biotin (5– deficient within a few days after birth [7]. 10 mg/kg/day) if the patient is treated early. They reappear In patients who are diagnosed late, irreversible brain within 1 month if biotin is discontinued. Patients diagnosed damage may have occurred before the commencement of late, or who have had repeated episodes, suffer from residual treatment. In particular, auditory and visual deficits often symptoms such as paraparesis, mild mental retardation or persist in spite of biotin therapy [9, 10, 17–19], and intel- dystonia [19a]. 338 Chapter 27 · Biotin-Responsive Disorders

20. Aoki Y, Suzuki Y, Li X et al (1997) Characterization of mutant holo- References carboxylase synthetase (HCS): a Km for biotin was not elevated in a patient with HCS deficiency. Pediatr Res 42:849-854 1. Baumgartner ER, Suormala T (1997) Multiple carboxylase deficiency: 21. Burri BJ, Sweetman L, Nyhan WL (1985) Heterogeneity in holo- inherited and acquired disorders of biotin metabolism. Int J Vit Nutr carboxylase synthetase in patients with biotin-responsive multiple Res 67:377-384 carboxylase deficiency. Am J Hum Genet 37: 326-337 2. Sakamoto O, Suzuki Y, Li X et al (2000) Diagnosis and molecular 22. Sakamoto O, Suzuki Y, Li X et al (1999) Relationship between analysis of an atypical case of holocarboxylase synthetase defi- kinetic properties of mutant enzyme and biochemical and clinical ciency. Eur J Pediatr 159:18-22 responsiveness to biotin in holocarboxylase synthetase deficiency. 3. Suormala T, Fowler B, Duran M et al (1997) Five patients with a Pediatr Res 46:671-676 biotin-responsive defect in holocarboxylase formation: evaluation 23. Suormala TM, Baumgartner ER, Bausch J et al (1988) Quantitative of responsiveness to biotin therapy in vivo and comparative stud- determination of biocytin in urine of patients with biotinidase ies in vitro. Pediatr Res 41:666-673 deficiency using high-performance liquid chromatography (HPLC). 4. Sherwood WG, Saunders M, Robinson BH et al (1982) Lactic acidosis Clin Chim Acta 177:253-270 in biotin-responsive multiple carboxylase deficiency caused by 24. Blom W, de Muinck Keizer SM, Scholte HR (1981) Acetyl-CoA car- V holocarboxylase synthetase deficiency of early and late onset. boxylase deficiency: An inborn error of de novo fatty acid synthesis. J Pediatr 101:546-550 N Engl J Med 305:465-466 5. Suormala T, Fowler B, Jakobs C et al (1998) Late-onset holocarbo- 25. Baumgartner MR, Dantas MF, Suormala T et al (2004) Isolated xylase synthetase-deficiency: pre- and post-natal diagnosis and 3-methylcrotonyl-CoA carboxylase deficiency: Evidence for an evaluation of effectiveness of antenatal biotin therapy. Eur J Pediatr allele-specific dominant negative effect and responsivness to 157:570-575 biotin therapy. Am J Hum Genet 75:790-800 6. Seymons K, De Moor A, De Raeve H, Lambert J (2004) Dermato- 25a. Zeng WQ, Al-Yamani E, Acierno JS Jr et al (2005) Biotin-responsive logic signs of biotin deficiency leading to the diagnosis of multiple basal ganglia disease maps to 2q36.3 and is due to mutations in carboxylase deficiency. Pediatr Dermatol 21:231-235 SLC19A3. Am J Hum Genet 77:16-26 7. Baumgartner ER, Suormala TM, Wick H, Bausch J, Bonjour JP (1985) 26. Mardach R, Zempleni J, Wolf B et al (2002) Biotin dependency due Biotinidase deficiency associated with renal loss of biocytin and to a defect in biotin transport. J Clin Invest 109:1617-1623 biotin. 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