Holocarboxylase Synthetase Deficiency

A number sign (#) is used with this entry because holocarboxylase synthetase deficiency is caused by homozygous or compound heterozygous mutation in the HLCS gene (609018) on chromosome 21q22.

Description

Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (summary by Suzuki et al., 2005).

Also see biotinidase deficiency (253260), another form of MCD with a later onset.

Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (Sweetman et al., 1981) or prolonged parenteral alimentation without supplemental biotin (Mock et al., 1981).

Clinical Features

Thoene et al. (1979) described a child with decreased activity of 3 biotin-dependent carboxylases: pyruvate carboxylase (PCC; 608786), propionyl CoA carboxylase (PCCA; 232000), and alpha-methylcrotonyl CoA carboxylase (MCCC1; 609010). The severe manifestations included lactic acidosis, alopecia, keratoconjunctivitis, perioral erosions, and seizures; all symptoms were completely reversed by biotin treatment. Assays of lymphocyte carboxylase activities also rose with biotin. Saunders et al. (1979) demonstrated failure of complementation with other carboxylase mutants and suggested that the defect involved a holocarboxylase synthetase necessary for linking the 3 apoenzymes with biotin.

Feldman et al. (1981) studied cultured fibroblasts from 2 patients with neonatal multiple carboxylase deficiency. Both cell lines were deficient in the 3 biotin-dependent carboxylases and belonged to the 'bio' complementation group. However, the activities of the 3 carboxylases became normal when the cells of 1 line were incubated in medium supplemented with biotin (1 mg per liter) for 24 hours, whereas in the second line a longer time (4 to 6 days) was required to achieve maximal activities at an intermediate level (29 to 57% of normal) with a higher concentration of biotin (10 mg per liter).

Sweetman (1981) recognized that multiple carboxylase deficiency could be classified into early and late forms. The early form showed higher urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxypropionic acid than the late form and was associated with normal plasma biotin concentrations. Sweetman (1981) proposed a defect in holocarboxylase synthetase and intestinal biotin absorption, respectively.

Burri et al. (1981) showed deficiency in holocarboxylase synthetase activity in a patient with early-onset MCD. Munnich et al. (1981) presented evidence suggesting that defective absorption of biotin at the level of the intestinal mucosa underlies some cases of this disorder. Enzyme activities in the MCD patients' fibroblasts cultured in a biotin-free medium were similar to those in controls.

Wolf and Feldman (1982) reviewed the differences between the neonatal and late-onset forms of multiple carboxylase deficiency. Whereas the neonatal form results from deficiency of holocarboxylase synthetase, the findings of Munnich et al. (1981) suggested that biotin absorption or transport may be defective in the form that has its onset at about 3 months of age. A primary or secondary defect in biotin absorption leads to alopecia, an erythematous periorificial dermatitis, and ataxia in babies with infantile-onset disease. The neonatal-onset form presents as congenital lactic acidosis of variable severity with the underlying biochemical lesion in some families identified as an abnormal holocarboxylase synthetase with an elevated Km(biotin) and a decreased Vmax. Packman et al. (1984) concluded, however, that age of onset or severity of clinical presentation may not serve to classify accurately all cases of MCD. They proposed that the patients be classified into 2 categories: type 1 patients have a decline in cytosolic carboxylase activities with biotin deprivation; holocarboxylase synthetase deficiency; and assignment to the 'bio' complementation group. Although most patients in this class show congenital lactic acidosis, milder cases occur. Type 2 patients are characterized by normal fibroblast carboxylase activities at all biotin concentrations; a variable infantile-onset syndrome resembling biotin deficiency states; and a possible primary or secondary absorptive defect. A defect in biotinidase activity has been demonstrated in such patients (Wolf et al., 1983).

Burri et al. (1985) studied holocarboxylase synthetase from fibroblasts of 7 patients with the neonatal form of biotin-responsive multiple carboxylase deficiency. Differences among the values obtained for the Km for biotin and the heat stability of holocarboxylase synthetase suggested that the patients studied represented at least 4 distinct variants at the holocarboxylase synthetase locus. See review of Sweetman and Nyhan (1986).

Fuchshuber et al. (1993) reported a patient with early-onset MCD. Symptoms appeared at day 2 of life, with lactic acidosis, hyperammonemia, and urinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxypropionic acid, and methylcitric acid. Biotin supplementation resulted in marked clinical and biochemical improvement.

The age of onset (2 days to 6 years) as well as the severity of the illness varied considerably in the 5 patients with biotin-responsive holocarboxylase synthesis reported by Suormala et al. (1997). In all patients, diagnosis was established by the finding of organic aciduria typical for multiple carboxylase deficiency in a catabolic state. In 3 patients, clinical symptoms disappeared with 10 to 20 mg biotin/d, whereas normalization of the biochemical parameters required higher doses (20 to 40 mg/d). A fourth patient required a dose of 100 mg/d before her skin rash disappeared; however she remained mentally retarded and showed slightly elevated urinary organic acid excretion. The results of studies of cultured fibroblasts were in accordance with a primary defect of holocarboxylase synthetase due to a decreased affinity for biotin.

Yang et al. (2001) reported multiple Japanese and non-Japanese patients with neonatal MCD. Three patients developed severe acidosis in the first few days of life and died soon after. HLCS activity ranged from 0.7 to 8% of normal. Six patients had later onset of symptoms (1 month to 3 years), were treated with biotin, and showed normal development. HLCS activity in 1 of these patients was 14% of normal.

Molecular Genetics

In sibs with HLCS deficiency reported by Narisawa et al. (1982), Suzuki et al. (1994) demonstrated compound heterozygosity for 2 mutations in the HLCS gene (609018.0001; 609018.0002).

In 9 patients with multiple carboxylase deficiency, Dupuis et al. (1996) identified 6 novel point mutations in the HLCS gene (see, e.g., 609018.0003). Two of the mutations were frequent. Aoki et al. (1999) reported 7 mutations (3 missense, 2 single-bp deletions, a 3-base in-frame deletion, and a 68-bp deletion) identified in the cDNA of 7 holocarboxylase synthetase deficiency patients from Europe and the Middle East. One of the patients was reported by Fuchshuber et al. (1993) (see 609018.0005).

Yang et al. (2001) identified multiple mutations in the HLCS gene in a group of Japanese and non-Japanese patients with biotin-responsive MCD (see, e.g., 609018.0001-609018.0002; 609018.0004-609018.0008). There were no panethnically prevalent mutations.

Suzuki et al. (2005) reviewed the mutations and polymorphisms that have been found in the HLCS gene and their clinical relevance.