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27 Biotin-Responsive Disorders 27 Biotin-Responsive Disorders Matthias R. Baumgartner, Terttu Suormala 27.1 Clinical Presentation – 333 27.1.1 Holocarboxylase Synthetase Deficiency – 333 27.1.2 Biotinidase 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 Biotinidase Deficiency – 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 Enzymes 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 metabolism. ACC, acetyl-CoA carboxylase; CoA, PYR, pyruvate. Full lines indicate one enzyme, 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]. Consequently, [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
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