A biotinidase Km variant causing late onset bilateral optic neuropathy.

A patient with a newly recognised variant of biotinidase deficiency presented with acute loss of vision at the age of 10 years. Progressive bilateral optic neuropathy, spastic paraparesis, and a predominantly motor type neuropathy developed over the next five years. Metabolic investigations revealed biotin depletion causing multiple carboxylase deficiency. The basic defect was a biotin recycling disorder due to a mutant biotinidase with residual activity of 4.4% assayed routinely. Biocytin excretion in urine was only slightly increased. Further investigations on plasma biotinidase revealed biphasic kinetics with two different reduced values for maximum reaction velocity (Vmax) and two for the Michaelis constant (Km), one being almost normal and the other considerably raised. In contrast to this patient, two age matched children with partial biotinidase deficiency (2.8% and 2.9% of normal), but with a normal Km for biocytin, remained asymptomatic. After six months of oral substitution with 10 mg biotin per day the coecocentral and peripheral scotomata regressed, the pyramidal signs in the lower limbs disappeared, and further progression of the motor neuropathy arrested. We conclude that the differential diagnosis of unexplained bilateral optic neuropathy of juvenile onset, particularly when associated with upper and lower motor neuron disease, should include biotinidase deficiency.

Comparison of patients with complete and partial biotinidase deficiency: biochemical studies.

Seventeen partially biotinidase-deficient patients detected by neonatal screening or family studies were compared with four patients with classical biotinidase deficiency. Using a sensitive HPLC method for biotinidase in plasma (substrate: biocytin) the patients could be divided into two groups: one with residual biotinidase activity, and the second with undetectable biotinidase activity (0-activity). Biocytin excretion, characteristically elevated in 0-activity patients, decreased rapidly with increasing residual biotinidase activity and was almost normal when residual activity exceeded 2-3% of mean normal. In one patient with classical disease (0-activity) biotin deficiency, typical organic aciduria and multiple carboxylase deficiency were found as early as at the second week of life. In contrast, 13 infants with residual activities from 1.2% to 23% had no remarkable clinical or biochemical abnormalities. However, in three 5-, 14- and 15-year-old healthy siblings with residual biotinidase activities between 2.3% and 4.2%, biotin deficiency was proven by decreased activities of the mitochondrial carboxylases in lymphocytes (30-57% of mean normal) and, in the older siblings, also by subnormal plasma biotin concentrations. In biotinidase deficiency, biotin depletion presumably occurs earlier in the brain than in other tissues and may thus first affect the central nervous system. For this reason and because of discrete biochemical abnormalities found in a patient with residual biotinidase activity of 8%, we suggest that at least all patients with residual activities below 10% should be treated with biotin.

[Biotinidase deficiency: a congenital metabolic disease which can be successfully treatment with vitamin H]. / Biotinidasemangel: eine angeborene Stoffwechselerkrankung, die mit Vitamin H erfolgreich behandelt werden kann.

At the age of 13 months a patient developed muscular hypotonia, deafness of the inner ear and cutaneous symptoms (alopecia; skin rash, complicated by superinfection with monilia). Biochemical assays revealed compensated metabolic acidosis, pathologically high lactate and pyruvate concentrations in the blood and cerebro-spinal fluid, as well as increased urinary excretion of 3-OH-isovaleric acid, 3-methylcrotonylglycine and lactate. The patient was diagnosed as suffering from autosomal recessive biotinidase deficiency on the basis of severely reduced biotinidase activity in plasma (0.05 nmol/min/ml). In both his parents and brother heterozygosity was found. Institution of therapy with a daily dose of 10 mg biotin rapidly removed most of the symptoms; after six months of treatment the deafness had improved significantly.

Biotinidase deficiency: a cause of subacute necrotizing encephalomyelopathy (Leigh syndrome). Report of a case with lethal outcome.

An unusual clinical course of a patient with biotinidase deficiency, causing Leigh syndrome, is reported. Laryngeal stridor was the major presenting symptom followed by progressive neurologic deterioration and death at the age of 21.5 mo. Absence of skin and hair abnormalities as well as of organic aciduria delayed the correct diagnosis. Necropsy revealed subacute necrotizing encephalopathy (Leigh syndrome). Carboxylase activities (propionyl CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase) measured in lymphocytes 1 day before death were decreased to 10% of normal values. Propionyl-CoA carboxylase was shown to be the only stable carboxylase in human postmortem tissue; in our patient it was moderately decreased in postmortem liver (29% of control) and kidney (42%), but severely decreased in brain (3%). These findings might explain the severity of neurological symptoms in the absence of marked organic aciduria. They indicate that in biotinidase deficiency the CNS may become biotin depleted earlier and more severely than other organs. Biotinidase deficiency should be included in the differential diagnosis of Leigh syndrome and of unexplained respiratory problems.

Quantitative determination of biocytin in urine of patients with biotinidase deficiency using high-performance liquid chromatography (HPLC).

A specific method for the quantitative determination of biocytin from urine of biotinidase deficient patients is described using HPLC-separation and quantitative determination by an avidin binding method. Partial purification of biocytin from urine was achieved with an anion exchange resin and concentration of the eluate by lyophilization. The recovery of biocytin from urines was 95.3 +/- 5.9 (mean +/- SD). The precision of biocytin estimation in patients urines including the HPLC-sample preparation procedure varied between 5.9% and 10.5% (CV). Biocytin concentrations were measured in urine samples of 5 patients obtained during and/or before biotin therapy. Before treatment biocytin excretion ranged from 6.2-28.8 nmol/mmol creatinine. During therapy biocytin excretion increased to the 1.3 to 4-fold level in 3 out of 4 patients. However, there was no dose-related increase of biocytin excretion when pharmacological doses were administered. Apart from biocytin and biotin, patients excrete additional biotin derivatives. Some of these have been preliminary identified as bisnorbiotin and oxidation products of bisnorbiotin, biocytin and biotin.