Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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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.
• 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.
During the late 1970s, inherited isolated deficiencies of the 3 mitochondrial biotin-dependent carboxylases were described (161). 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 3 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 (38). 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 3 mitochondrial carboxylases in his peripheral blood leukocytes and skin fibroblasts (02; 141), as well as deficient activity of acetyl-CoA carboxylase in his fibroblasts (31). 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 (125). 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 (79; 128; 129). This was supported by reports of 2 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 (163). Two patients with presumed intestinal transport defects were subsequently shown to have biotinidase deficiency (130). 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 (21). A common mutation has been identified in many symptomatic individuals (94).
Various aspects of biotinidase deficiency have been reviewed (143). 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 (168; 41). The most common neurologic features of this disorder are seizures and hypotonia (164; 168; 137; 152; 35) or hypertonia (103). 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 (106). 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 (14). Some enzyme-deficient children have exhibited peripheral neuropathy or myelopathy with paraparesis or quadriparesis, which has improved with biotin therapy (142; 62; 15). Some children have had structural brain malformations, including subcortical cysts with Dandy Walker cysts (13; 114). In addition, a child with partial deficiency was reported with autism (179). 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 8 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 (72). The neurologic features of untreated biotinidase deficiency have been reviewed (157).
Older enzyme-deficient children often exhibit ataxia and developmental delay. Sensorineural hearing loss and eye problems, such as optic atrophy and neuropathy (42), have been described in many untreated children (165; 126; 105; 138). One study showed that 76% of symptomatic children with profound biotinidase deficiency have sensorineural hearing loss (174; 36). Frequently, these children have cutaneous symptoms, including skin rash and alopecia (69). The skin lesion can be confused with that of acrodermatitis enteropathica (85). Several patients have had cellular immunologic abnormalities, manifested by fungal infection (23; 107). These immunological aberrations are varied and may represent the effects of abnormal organic acid metabolites or biotin deficiency on normal function (33). Biotin therapy rapidly corrects the immunological dysfunction. A child with hemophagocytic lymphohistiocytosis was found to have biotinidase deficiency; the symptoms of the hemophagocytic syndrome resolved on biotin therapy (59). Some patients with biotinidase deficiency have manifested 1 or 2 of these features, whereas others have exhibited many of the neurologic and cutaneous findings.
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 (102; 101; 68). Within months of biotin treatment, the scotoma resolved and the paraparesis markedly improved. In addition to these 2 enzyme-deficient individuals, 2 others have been described with paresis and eye problems that occurred in early adolescence (132; 172). Mutation analysis has failed to show common mutations in these 4 individuals. Another child with a similar presentation has since been reported (100). Several children with profound biotinidase deficiency have been diagnosed with demyelinating spinal cord disease (176; 20; 99).
There have been multiple reports of older adolescents and adults who exhibited optic neuropathy, especially scotomata, with or without paresis or spastic diplegia (07; 147; 37; 177; 27; 136). Multiple individuals with biotinidase deficiency were initially diagnosed with neuromyelitis optica spectrum disorder (05; 98; 108; 113).
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 (32). Another adult initially presented with respiratory failure (25). 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 (158). In addition, individuals thought to have multiple sclerosis should be tested for biotinidase deficiency because the symptoms of optic neuropathy and/or spastic diplegia/paresis can be seen in both disorders, and biotinidase deficiency is readily treatable (148). 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 (148).
Moreover, 2 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 (171). 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 (04). In those with profound deficiency, only 3 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 (77). The delayed-onset phenotype, with paresis and dyspnea, may appear as early as 4 years of age (57).
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 (71; 121). Clinical consequences of partial deficiency were not known until 1 of these children, who was not treated with biotin, exhibited hypotonia, skin rash, and hair loss at 6 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 (118). It was speculated that other individuals with chronic vaginal candidiasis are carriers and will potentially respond to biotin treatment.
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 (56). A major concern of children as they get older is their compliance with biotin therapy. Two other studies have found similar results (11; 64).
A group of 44 individuals with profound biotinidase deficiency identified by newborn screening, aged from ages 15 to 33 years, have had successful outcomes (156). In addition, the babies born to affected mothers on biotin treatment have all been normal. Compliance was not a major issue in these individuals.
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 2 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 2 weeks, and hair growth returned to the areas of alopecia. The child has had no biochemical, neurologic, or cutaneous abnormalities while on biotin.
Biotin, a water-soluble B-complex vitamin, is the coenzyme for 4 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 (88; 152). Biotinidase also plays a role in the processing of protein-bound biotin, thereby making the vitamin available to the free biotin pool (167). Studies suggest that biotinidase has a role in the transfer of biotin from biocytin to specific proteins (52). Biotinidase and its role in biotin metabolism have been reviewed by Hymes and Wolf (54). The biotinylation of histones by biotinidase and its potential roles in cellular metabolism have been reviewed (149; 180).
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 (60; 163). 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 (43). Heterozygosity can be diagnosed with about 95% accuracy (139). Deficient biotinidase activity has also been demonstrated in extracts of leukocytes and fibroblasts from some of these patients (173). At least 1 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 (44). 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 (21). The genomic organization of the biotinidase gene has also been elucidated (61). The gene that encodes for the serum enzyme has been localized to chromosome 3p25 (22). The biotinidase gene was more finely mapped using radiation hybrids and haplotype analysis of markers within the chromosome 3p25 region (08). The biotinidase gene has been shown to be alternatively spliced (116). 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 (91; 63). 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 (94). A missense mutation, Arg538Cys, is the second most common cause of profound biotinidase deficiency in symptomatic children (92). 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 (82; 83). Mutations among children identified by newborn screening were compared with those of children ascertained by exhibiting symptoms (81). Of the mutations identified in the 2 populations, 4 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 2 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 (89; 93; 53; 78; 34; 170; 149; 65; 76; 80; 73; 74; 127; 131; 66; 58; 97; 112; 16; 17; 51). In one child, biotinidase deficiency was shown to be due to a de novo mutation or gonadal mosaicism (133). The first microdeletion involving only the biotinidase gene that can cause biotinidase deficiency has been described (154).
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 (124). It has been shown that the D444H mutation results in about half of normal activity because of decreased expression of the aberrant enzyme (67). More than 150 mutations causing biotinidase deficiency have been described (87). 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 (67). Another study indicates that this variant codes for an enzyme protein with variable activity (06). Mutations causing biotinidase deficiency are currently being collected in a database (96).
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 (30). In addition, rapid mutation analysis can be performed using denaturing high-pressure liquid chromatography (55).
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 (115).
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 (123).
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 (86). Therefore, secondary holocarboxylase synthetase deficiency may develop in patients with biotinidase deficiency, affecting the allocation and/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 (75). 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 (120). 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 (29; 28). 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 (165; 174; 140). 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 (47). 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 (110; 153; 117). 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 (12; 01; 26).
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 (03; 50). 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 3 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 5 symptomatic children with biotinidase deficiency, ages 1 to 5.5 months, leukoencephalopathy and widening of the ventricles and extracerebral cerebrospinal fluid spaces was observed (40). Demyelination was present, but some lesions could not be explained by this mechanism alone. Myelination improved following biotin therapy in all but 1 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 (135; 18).
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 (45). A pilot program was conducted in Virginia to estimate the incidence of this disorder and the feasibility of screening (166; 46). 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 (160; 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 (159).
In addition to the colorimetric assay, some screening programs use a fluorescent enzymatic assay in which biotinyl-6-amidoquinoline is the substrate (84). 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 (175). 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.
Symptoms of biotinidase deficiency are preventable if patients are diagnosed at birth or before symptoms occur and are treated with biotin. Technical standards and guidelines for the diagnosis of biotinidase deficiency have been delineated (119). Children with profound biotinidase deficiency identified by newborn screening and who are treated with biotin remain asymptomatic (138). Delay in follow-up of a positive newborn screen resulted in irreversible neurologic damage in a symptomatic 15-month-old child ultimately confirmed to have the disorder (49). This case exemplifies the importance of universal newborn screening and appropriate follow-up (95).
Biotinidase activity is measurable in cultured amniotic fluid cells and in amniotic fluid (Secor McVoy et al 1984). Therefore, the potential exists for prenatal diagnosis of biotinidase deficiency. Prenatal diagnosis was made in 2 at-risk pregnancies in which amniocenteses were performed because of advanced maternal age. The fetuses were found to be unaffected, and this was confirmed after birth (19). In addition to enzyme determination in amniocytes, a fetus was shown to be a heterozygote by molecular mutation analysis in an at-risk pregnancy (90).
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 (122; 153).
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 1 of the 3 mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts, whereas the activities of the other 2 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 2 disorders. Holocarboxylase synthetase deficiency usually manifests before 3 months of age, whereas biotinidase deficiency usually manifests after 3 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 3 mitochondrial carboxylases in peripheral blood leukocytes prior to biotin treatment. These activities increase to near-normal or normal after biotin treatment (122). Patients with holocarboxylase synthetase deficiency have deficient activities of the 3 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 and/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 (145). 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 (32).
Comprehensive reviews of the diagnostic evaluation of biotinidase deficiency have been published (144; 151). Technical standards and guidelines for the diagnosis of biotinidase deficiency have been established (24). 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 (09). However, some symptomatic patients with the enzyme deficiency do not excrete the characteristic organic acids (134). 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 (163) or biotinyl-6-amidoquinoline (84). 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 (39). 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 (146). The need for an appropriate control serum for successfully confirming the diagnosis was exemplified in the newborn screening experience in Brazil (80).
Markedly elevated serum biotinidase activities have been reported in children with glycogen storage disease type Ia (146). 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 (176; 20; 70; 147).
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 (152). However, a patient is reported to have required higher doses of biotin (104). 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. 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 (77), other evidence indicates biotin treatment should be given to all children with profound biotinidase deficiency, regardless of their residual activity (150).
Most patients with biotinidase deficiency excrete large quantities of biocytin in their urine (10), 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 (109); however, there is also a study that did not find a reduction in biotinidase activity in similarly treated children (178). 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 (155).
A child born to a woman with profound biotinidase deficiency was normal (48).
Barry Wolf MD PhD
Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.See Profile
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Wilson disease is caused by mutations in ATP7B that result in abnormal copper metabolism, and subsequent excess free copper is toxic. The main clinical categories of neurologic Wilson disease have been traditionally divided variably into tremor, dysarthria, pseudosclerosis (tremor +/- dysarthria), parkinsonism, dystonia, or chorea. The aim of treatment is to reduce the amount of toxic free copper.
Jun. 09, 2021
Childhood Degenerative & Metabolic Disorders
Apr. 12, 2021
Childhood Degenerative & Metabolic Disorders
Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital malformation that is associated with intellectual disability. The primary defect
Apr. 09, 2021
Childhood Degenerative & Metabolic Disorders
Mar. 10, 2021
Childhood Degenerative & Metabolic Disorders
Mar. 04, 2021
Childhood Degenerative & Metabolic Disorders
Feb. 21, 2021
Childhood Degenerative & Metabolic Disorders
Feb. 18, 2021