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A large kindred, in which either Leber's hereditary optic atrophy, or a hereditary spastic dystonia, or a combination of both manifested over many generations was restudied after the first report on it in 1964. NMR scans revealed bilateral, and, in two patients with hemidystonia, unilateral necrosis with shrinkage of the putamen, in one case associated with total disappearance of the head of the caudate nucleus. Except for age-appropriate cortical atrophy in one instance, no other changes were observed in the brain, brainstem, and cerebellum. The putaminal necrosis appears as typical "striatal slits" on the NMR scans. It is argued that this rare disease, since the princeps description in 1964 only reported in England (1986) and the U.S.A (1986), is most likely a singular type of mitochondrial encephalopathy: it is associated with Leber's optic atrophy, and the NMR changes observed have been signalled in other mitochondrial encephalomyelopathies, such as Leigh's disease and MELAS.

A minor haemoglobin variant in a Dutch family has been characterized as Hb A2-NYU:α2δ212Asn→-Lys. Arguments are presented, based partially on dat

It was investigated whether the protoporphyrin that can be extracted from red blood cells of erythropoietic protoporphyria (E.P.P.) patients is present in the cells as free molecules or protein-bound. With isoelectric focusing and with starch gel electrophoresis it could be shown that virtually all protoporphyrin in the erythrocytes is protein-bound. It is very likely that the protoporphyrin is bound to hemoglobin at heme-binding sites. This was indicated by several observations: 1. 1. With isoelectric focusing the protoporphyrin-protein complex is focused at a pH only slightly higher than the isoelectric point of hemoglobin. 2. 2. With chromatography on Sephadex columns it appeared that hemoglobin and the protoporphyrin-protein complex have the same molecular weight. 3. 3. A heme-protoporphyrin exchange occurred when the heme-globin bond was labialized by conversion to hemiglobin. The resulting protoporphyrinhemoglobin complex had the same electrophoretic mobility with starch gel electrophoresis as the protoporphyrin-protein complex, extracted from red blood cells of E.P.P. patients.

The preliminary results obtained with stabilized and non-stabilized β-carotene in the oral treatment of photohypersensitivity in 25 protoporphyria patients are reported. β-Carotene appeared to have a beneficial effect in a majority of these patients. Carotinodermia was the only side-effect. Difficulties with regard to the evaluation of the results are discussed.

A large family has been studied, in which a heredo-degenerative disease occurs in association with hereditary optic atrophy. In 7 generations with 549 members, at least 18 individuals were affected, only one of these being a female; of these 14 were examined clinically and 12 are still living. Of the 18, six presented with both optic atrophy and neurological signs; six with optic atrophy only, and six with only neurological manifestations. The optic atrophy seemed to conform with all the diagnostic criteria of Leber's disease. The neurological condition was extremely uniform and has not been described hitherto. It seems to occupy a position intermediate between hereditary spastic paraplegia (Strumpell-Lorrain) and Hallervorden-Spatz disease. The only female patient in the family was atypical in this respect, and had been repeatedly diagnosed as a case of multiple sclerosis. The validity of this diagnosis is discussed. Also included is the case history of a patient belonging to another family with typical Leber's atrophy with an identical clinical picture. The inheritance of both the optic atrophy and the neurological disorder seems to be linked to the X-chromosome.

Irradiation of erythrocytes of patients with erythropoietic protoporphyria with light of about 410 nm wavelength in the presence of oxygen, causes hemolysis. In a nitrogen atmosphere photohemolysis was inhibited completely, indicating that an oxidative step is involved in the process. Several redox reagents inhibited the photohemolytic response. Similar photohemolysis could be observed with normal red cells, after adding protoporphyrin-IX-dimethyl ester to the medium. The hemolytic process itself could be characterized as a colloid osmotic hemolysis.

The photodynamic action of protoporphyrin on erythrocytes of patients with erythropoietic protoporphyria and on sensitized normal red blood cells leads to K + loss and Na + gain, resulting finally in colloid osmotic hemolysis. To elucidate the pathochemical background of this process, the ATP and glutathione-producing metabolic systems and the activity of other cellular enzymes was studied during irradiation, in the prelytic period. The glucose consumption, intracellular ATP level and catalase activity were not influenced by the photochemical process, whereas the cellular glutathione concentration decreased during irradiation. The activity of cellular acetylcholinesterase and of membrane ATPase decreased in the prelytic period, the (Na + + K + )-dependent ATPase being more sensitive than the Mg 2+ -stimulated ATPase. Measurements of 86 Rb + uptake demonstrated a decreasing active Rb + transport with a concomitant increase of passive Rb + permeability during irradiation. The results indicated that the cellular membrane is presumably the primary target of the protoporphyrin-induced photodynamic process.

The most pronounced biochemical characteristic in erythropoietic protoporphyria (EPP), an inherited disorder of heme biosynthesis, is the greatly increased protoporphyrin concentration in the red blood cell, which leads to photohemolysis when the cells are irradiated with visible light (9). Isoelectric focusing and protoporphyrin-hemoglobin binding experiments indicate that protoporphyrin is bound to hemoglobin at heme-binding sites (5). Experimental data of Schwartz et al. (10) were interpreted as indicating that the erythroid cell itself is the source of the protoporphyrin in the red blood cell. The increased protoporphyrin content can be explained by a decreased activity of heme synthetase or by an increased production of protoporphyrin in the heme metabolic pathway, both of which are indicated in the literature (7, 10). During systematic studies in the pathogenesis and the biochemical aspects of EPP, the activity of heme synthetase and the total porphyrin biosynthesis in blood cells of EPP patients were compared to the activities in normal blood cells.

Virtually all protoporphyrin in erythrocytes of patients vith erythropoietic protoporphyria is bound to hemoglobin. The maximum of the fluorescence excitation spectrum of this protoporpliy-rin-hemoglobin complex shifted, with increasing concentration, from 405 nm to 389 nm. A similar shirt was observed wlien titrating a solution of free protoporphyrin with hemoglobin. The Soret maximum of free protoporphyrin itself. on the other hand, was not concentration-dependent. These observations indicate that spectrofluorometric measurements do not allow conclusions coticerning the mode of protoporphyrin binding to hemoglobin.Experiments on protoporphyrin exchange between the hemoglobins A, F and S reinforced the previously drawn conclusion that protoporphyrin is bound to hemoglobin at the heme-binding sites.

Eleven patients belonging to two generations of a Dutch family with cerebral and cerebellar haemorrhage, haemorrhagic infarction and infarction are described. Their ages varied from 44 to 58 years. The principal clinical characteristic was recurring cerebral haemorrhages, sometimes preceded by a history of migrainous headaches or mental changes. In 4 of the 6 autopsied cases, old and new multiple cerebral haemorrhagic infarcts and infarcts were found, in one case a single cerebral haemorrhage and in another a cerebellar haemorrhage. In 5 cases this resulted in secondary subarachnoid haemorrhage. In one case the infarcts were only slightly haemorrhagic and did not result in subarachnoid haemorrhage. This patient presented as dementia. Microscopically, in these 6 cases and in one biopsy specimen hyaline thickening of the walls of cortical arterioles was found. The arteries of the arachnoid showed marked tortuosity, concentric proliferation, and focal hyalinization of the walls. Amyloid was found in the hyalinized vessels in 5 cases, but not outside the central nervous system. We believe that we are dealing with an inherited disorder with an autosomal dominant mode of inheritance, in which microangiopathy leads to cerebral haemorrhage and (haemorrhagic) infarction. It seems likely that amyloidosis underlies the angiopathy, and that this family suffers from a condition similar to the one described by Gudmundsson in 1972.

Three sibs are described suffering from hereditary non-progressive spinal muscular atrophy with non-progressive mental retardation. One of them had in addition signs of pyramidal tract involvement. Muscular weakness was more pronounced proximally than distally and the neck muscles were severely involved. They all had small skulls and several associated congenital malformations were observed including syndactyly of the left hand in 1 patient. The patients belong to a small inbred community in the Netherlands. Erythropoietic protoporphyria was also present in the family but segregated independently. This combination of “congenital” mental retardation with “congenital” non-progressive spinal muscular atrophy is believed to represent a new syndrome, caused by a rare recessive gene.

The photodynamic effect of protoporphyrin on red blood cells of patients with erythropoietic protoporphyria and on sensitized normal erythrocytes leads primarily to increased passive cation permeability of the membrane. This increased permeability appeared to be caused by photo-oxidation of a cellular target, localized in the red cell membrane. Both unsaturated fatty acids and sulfhydryl, methionyl, histidyl, tyrosyl and tryptophan residues in membrane proteins appeared to be sensitive to protoporphyrin-induced photo-oxidation. It was shown that the increased cation permeability can not be attributed to peroxidation of unsaturated fatty acids in the membrane. Therefore the observed damage of the permeability barrier is presumably caused by photo-oxidation of amino acid residues in membrane proteins. The experimental results are discussed in relation to data in recent literature, concerning the significance of amino acid residues in the maintenance of functional and structural integrity of cellular membranes.