Recovery from neurological deficits following biotin treatment in a biotinidase Km variant.

A 15-year-old boy suffered from progressive bilateral optic neuropathy of acute onset at the age of 10 years. Subsequently he developed spastic paraparesis and a predominantly motor type neuro-axonal neuropathy in all limbs. The basic error has been elucidated to be due to an unusual biotinidase Km variant with biphasic enzyme kinetics causing systemic biotin depletion and consequent multiple biotin-dependent carboxylase deficiency. After daily oral substitution with 10 mg biotin metabolic derangements subsided rapidly. Follow-up studies over one year after substitution with biotin demonstrated remarkable recovery from part of the previously present neuro-ophthalmological, motor and cognitive deficits. The previously extinguished flash-evoked visual potentials now showed clear responses after six months of substitution with biotin. In contrast with reports in literature, these findings indicated that neurological damage associated with biotinidase deficiency, rather than being permanent, is to some extent reversible.

[Juvenile optic neuropathy caused by Km variants of biotinidase]. / Juvenile Optikoneuropathie durch Km-Variante der Biotinidase.

A patient with a newly recognised variant of biotinidase deficiency presented with acute bilateral visual loss at the age of 10 years. A progressive optic neuropathy, a predominantly motor type neuropathy and spastic paraparesis developed over the following 5 years. Metabolic investigations revealed biotin depletion causing multiple biotin dependent carboxylase deficiency. The basic defect was a biotin recycling disorder due to a biotinidase Km variant with residual colorimetric activity of 4.4% of normal. Further investigations on plasma biotinidase showed biphasic kinetics with two different reduced Vmax values and two Km-values, one being almost normal and the other highly elevated. After a period of 2 months of oral substitution with biotin 10 mg per day the visual field defects improved as well as the distal spastic parapareses and motor neuropathy. 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.

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.

[Contrast-enhanced MRT of malignant melanoma of the uvea]. / Kontrastmittelunterstützte MRT maligner Aderhautmelanome.

Twenty-one patients with malignant melanoma of the uvea or iris, some with intra-ocular bleeding, were examined by MRT before and after the administration of Gd/DTPA. In 13 patients, several examinations were performed over a period of 1.5 to 20 months after irradiation of the melanoma. After Gd-DTPA there was an average increase of 13% in the signal intensity from all non-irradiated melanomas (17 cases). Three months following radiation therapy, there was an average increase in signal intensity after Gd-DTPA of 65.7%, and after seven months of 100%. Amelanotic melanomas (two cases) showed a primary increase in intensity of 100%. Two melanomas of the iris were demonstrated by sonography; of these, only one could be shown with certainty by MRT. Small tumours and tumour residues after irradiation were better defined after contrast. In the presence of suspected intra-ocular bleeding, the examination should always be performed after the administration of Gd-DTPA.

[Differential intraocular tumor diagnosis in MRI using gadolinium DTPA: value in comparison with other ophthalmologic examination procedures]. / Differentialdiagnose intraokularer Tumore in der MRT unter Einsatz von Gadolinium DTPA: Wertigkeit im Vergleich mit anderen ophthalmologischen Untersuchungsverfahren.

To improve the tissue characterizing information obtained by MRI we examined 35 patients with 43 different intraocular lesions by applying Gadolinium-DTPA for the first time. Histology was available in seven cases. Twenty patients were diagnosed as having a malignant uveal melanoma, 2 had a melanoma of the ciliary body and the iris, 3 patients were found to have a naevus of the uvea and 3 patients suffered metastatic uveal infiltrates, 4 patients had a senile maculopathy and 10 patients had either a vitreal or a subretinal haemorrhage, 1 patient had an angioma and another a lymphoma of his vitreous. Ruthenium plaques were applied to 13 out of 20 melanoma patients. These patients were followed-up by MRI examinations at regular intervals after therapy. The pretherapeutic signals of melanotic melanomas were high before applying Gadolinium-DTPA and demonstrated a further increase after contrast enhancement. Following ruthenium therapy the drop of the precontrast signal was more pronounced than the postcontrast signal. In complicated clinical situations MRI offers additional information to enable the differentiation between intraocular tumors and haemorrhages.

Microvascular network topology of the human retinal vessels.

A quantitative analysis of blood flow in the human retinal vessels requires a detailed picture of the microvascular network topology. In order to lay the foundation for a quantitative microcirculatory network analysis of the human retina, a novel technique for tissue preparation and network characterization was developed. After injection of hydrogen peroxide into the human bulb, the microvasculature was filled with oxygen produced by endothelial catalase and visualized after embedding in a mixture of cedar oil and gum damar. The vessel topology was documented in the form of photomicrographs, which permitted complete reconstruction of the microvasculature on transparent overlays. By considering the complete capillary system it was possible to divide the retinal network into dichotomous, asymmetric arteriolar and venular trees. The Strahler ordering method, which considers both dichotomous and side branching configurations, was selected and applied to analyze the retinal vascular trees, using the capillaries as the zero order reference vessels. The number of vessel segments was found to be an approximate logarithmic function of the order number, in accordance with Horton's law. Vessel lengths within each order were found to be log-normal distributed, and median lengths for different orders could be approximated by a 2nd degree polynomial curve. Diameters within each order could be approximated by a Gaussian distribution, and the mean values for different orders could be expressed by an exponential curve. These data provide the basis for conductance, pressure and flow computations within the retinal microvessels.

Gadolinium-DTPA-enhanced MRI of intraocular tumors.

The value of gadolinium-enhanced MRI in 30 patients with intraocular lesions has been evaluated. Seventeen patients had a uveal melanoma, two a ciliary body melanoma, three had uveal metastases, one lymphoma, four had senile macula degenerations, and three uveal nevi. Twelve of 17 patients with melanoma were followed up by MRI after ruthenium plaque therapy on 2-4 occasions. Melanomas showed high precontrast signal intensities and only a slight enhancement after intravenous Gd-DTPA was given. After ruthenium plaque therapy precontrast signal intensities (SI) decreased while a moderate signal increase on postcontrast scans was noted. Scars or tumor residues were better delineated on enhanced images. All other tumors than melanotic melanomas showed low SI on precontrast scans and a high signal increase after Gd-DTPA administration. Small amelanotic tumors were better delineated on postcontrast scans. In addition Gd-DTPA-enhanced MRI allowed differentiation between tumor and hemorrhage. No signal increase after Gd-DTPA application was seen in subretinal or vitreous hemorrhages of varying ages.