D-2-hydroxyglutaric aciduria with cerebral, vascular, and muscular abnormalities in a 14-year-old boy.

D-2-Hydroxyglutaric Aciduria is a rare metabolic disorder that can cause injury to the brain and other organs. This case report concerns a 14-year-old boy showing irritability and typical signs of pyloric stenosis early postnatally. From the age of 3 months he had epilepsy. He was mentally retarded, hypotonic with preserved reflexes, and dystonic. The features were dysmorphic with elongated head and high arched palate. Cardiomegaly with aortic insufficiency was diagnosed. Magnetic resonance imaging of the brain revealed atrophy, reduced periventricular white matter, and multiple bilateral aneurysms of the middle cerebral arteries. The boy died at the age of 14 years. Autopsy confirmed the white-matter reduction of the cerebral hemispheres as well as the arterial aneurysms of the middle cerebral arteries. Lesions of a few leptomeningeal and cerebral microvessels and of the renal and pulmonary arteries were also found. There were bilateral infarcts of the kidneys and signs of cardiomyopathy with noncompensated left ventricular failure. Signs of myopathy were evident. The clinical and postmortem findings imply a disseminated mesenchymal process.

Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome.

The gene encoding the human fatty aldehyde dehydrogenase (FALDH) is located on 17p11.2, causing Sjögren-Larsson syndrome (SLS) when mutated. SLS is an autosomal recessive disorder characterized by a combination of mental retardation, congenital ichthyosis, and spastic di- or tetraplegia. We report here on studies of 16 SLS families from Europe and the Middle East, which resulted in identification of 11 different mutations. The spectrum of mutations characterized in the present study are five nucleotide substitutions resulting in amino acid changes, five frameshift mutations introducing a stop codon, and one in-frame deletion with insertion at the same position. We also observed silent sequence variants in the FALDH gene and a base pair substitution in exon 5 that alters aspartic acid to asparagine, all of which are considered polymorphisms.

Detailed genetic and physical mapping in the Sjögren-Larsson syndrome gene region in 17p11.2.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterised by mental retardation, spasticity, and ichthyosis. In 1994, SLS was linked to chromosome 17 and the gene causing the disorder was recently identified as fatty aldehyde dehydrogenase (FALDH) located in 17p11.2. In this paper we present a detailed genetic and physical map of the region surrounding the SLS/FALDH locus, produced by using new microsatellite markers analysed on the extensive Swedish family material, a radiation hybrid panel, and yeast artificial chromosomes (YACs).

A missense mutation in the FALDH gene identified in Sjögren-Larsson syndrome patients originating from the northern part of Sweden.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by congenital ichthyosis, spastic di- or tetraplegia, and mental retardation. SLS has been reported to occur in many populations but the highest incidence is in the north of Sweden. The gene causing SLS encodes a fatty aldehyde dehydrogenase (FALDH). In the present study, a point mutation in exon 7 of the FALDH gene was found in SLS patients of northern Swedish origin. The mutation consists of a C-to-T exchange at nucleotide position 943 in the cDNA. As a consequence, a highly conserved proline is replaced by a serine. The mutation was found in 49 out of 58 affected chromosomes and could be the most widely spread SLS mutation in the world.

The Sjögren-Larsson syndrome gene is close to D17S805 as determined by linkage analysis and allelic association.

Sjögren-Larsson Syndrome (SLS) is characterized by congenital ichthyosis, spastic dior tetraplegia and mental retardation. It is an autosomal recessive trait that is frequent in the northern part of Sweden. Based on linkage analysis and allelic association, the disorder has now been mapped to chromosome 17. Meiotic recombinations suggest that the gene is flanked by D17S805 on the centromeric and D17S783, D17S959, D17S842 and D17S925 on the telomeric side. These markers map to the same location in reference pedigrees. Strong allelic association (chi-square 60.28, p < 0.0003) to D17S805 suggests that the mutation is located close to this marker.

Monoaminergic dysfunction in Sjögren-Larsson syndrome.

The anteroposterior distribution of monoamine and monoamine metabolite concentrations was determined in subcortical brain nuclei of two cases of Sjögren-Larsson syndrome (SLS) and was compared to two control cases. The brains were divided into halves and sectioned coronally. For biochemical analyses, caudate nucleus, putamen, globus pallidus, substantia nigra, nucleus accumbens, amygdala, and hippocampus were dissected macroscopically. Monoamine and its metabolites were determined by reverse-phase liquid chromatography with electrochemical detection. The other hemisphere was studied neuropathologically. The SLS cases revealed cell loss in substantia nigra and putamen and a widespread white-matter destruction. Biochemically, most pronounced alterations were seen in the dopamine system in putamen with severely reduced concentrations of dopamine (DA; 14% of control values) and the catabolic metabolites 3-methoxytyramine (3-MT; 9% of control values) and homovanillic acid (HVA; 20% of control values). In substantia nigra and the other striatal regions studied, a general decrease of 3-MT and HVA concentrations was observed in the SLS subjects compared to the controls, although the decrease was less pronounced than in putamen. Generally, somewhat reduced noradrenaline and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were seen in the SLS cases, whereas serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were increased compared to the controls in most regions studied. These data suggest a specific monoaminergic dysfunction in patients with SLS. The severe decline in the dopaminergic system in putamen suggests that supplementation of dopamine agonists may ameliorate the symptoms of SLS patients.

Sjögren-Larsson syndrome: inherited defect in the fatty alcohol cycle.

We investigated fatty alcohol metabolism in eight patients with Sjögren-Larsson syndrome, and in nine obligate heterozygotes. Fatty alcohol: nicotinamide-adenine dinucleotide oxidoreductase (FAO) activity was deficient in cultured skin fibroblasts (mean 18% of normal, n = 8) and peripheral blood leukocytes (mean 22% of normal, n = 3) from patients with Sjögren-Larsson syndrome. The palmitoyl coenzyme A-inhibitable component of FAO activity was decreased to 10% and 15% of normal in fibroblasts and leukocytes, respectively, of patients with Sjögren-Larsson syndrome. Most affected patients accumulated long-chain fatty alcohol in plasma, with a greater relative accumulation of octadecanol (mean threefold greater than normal) than hexadecanol (mean twofold greater than normal). Erythrocyte lipid alkyl ether linkages derived from hexadecanol were slightly increased in three of four patients. Fibroblasts and leukocytes from heterozygotes with Sjögren-Larsson syndrome showed mean FAO activities that were intermediate between those seen in homozygotes and in normal control subjects. The heterozygotes had normal fatty alcohol concentrations in plasma. These studies demonstrate FAO deficiency in patients with Sjögren-Larsson syndrome, and suggest that accumulation of fatty alcohol or its metabolic products may be important in the pathogenesis of this disorder.

Sjögren-Larsson syndrome in Sweden: distribution of the gene.

The distribution of carriers of the gene for Sjögren-Larsson syndrome in Sweden suggests a center of dispersion in the county of Västerbotten in Northern Sweden. The origin of the spread of the gene can be traced back at least 700 years.

Oral function in the physically handicapped with or without severe mental retardation.

Neuromotor handicaps and mental retardation have been associated with various types of dental malocclusions and oral dysfunction. In this study the specific role of mental status on oral functions was examined. For this, oral function capacity was compared between two groups of physically handicapped children and young adults, one with a physical handicap alone, the other with mental retardation. The latter were found not only to be significantly more motor-impaired in general, but also were found to have significantly more deficient oral functions (speech, swallowing and chewing). Mentally retarded also showed significantly more frequent involvement with regard to some other characteristics of oral function and oral conditions, such as lip seal, tongue posture and drooling. As oral dysfunction may cause dental malocclusion, it seems likely that the deviating or immature oral functions in the mentally retarded group may explain earlier observations of a higher prevalence and often more severe malocclusion in these individuals, compared to those who are handicapped.

Lipofuscin and melanin content of the retinal pigment epithelium in a case of Sjögren-Larsson syndrome.

Necropsy material from the eye of a 23-year-old male known to have suffered from the Sjögren-Larsson syndrome, characterised by mental retardation, spastic diplegia or tetraplegia, congenital ichthyosis, and so-called glistening dots in the foveal and parafoveal areas of the fundus of the eye, was investigated ultrastructurally. The retinal pigment epithelium in the macular area showed a significant increase in lipofuscin granules, most likely because of a reduced capacity for digestion of phagocytosed material, and a significant decrease in melanin and melanolipofuscin granules in comparison with a normal control material. The ophthalmoscopically visible glistening dots and the pigment epithelial 'windows' seen on fluorescein angiography may possibly be explained by a further progression of these changes. No retinal changes were found in the macular area, the midperiphery, or the periphery that could be attributed with certainty to any other origin than post-mortem autolysis. More material would be needed, however, to elucidate further the fundal changes in the Sjögren-Larsson syndrome.

Congenital ichthyosis with alopecia, eclabion, ectropion and mental retardation--a new genetic syndrome.

A syndrome with severe generalized congenital ichthyosis, alopecia, eclabion, ectropion and mental retardation without neurological symptoms or macular changes in the eyes was seen in two sibs and in two aunts and uncles in an inbred North-Swedish family. The clinical picture of the patients in the present family strongly deviated from that seen in the Sjögren-Larsson syndrome found in the same area. This could be a new syndrome with autosomal recessive inheritance.

Malocclusions in physically and/or mentally handicapped children.

The purpose of this work was to study the morphological characteristics of dental occlusion in groups of physically and/or mentally handicapped children, taking into consideration the need of a detailed classification of medical diagnosis and degree of mental capacity. The material consisted of physically handicapped children with normal intelligence, including the subgroups Cerebral palsy and Others (other medical diagnoses), and severely mentally retarded children with or without a physical handicap, including the subgroups Down's syndrome, Cerebral palsy and Others. Totally 115 children (3-17 years) were studied with respect to occlusion, space conditions, hypodontia and received orthodontic treatment, and compared to matched control groups of healthy children. The severely mentally retarded children in all of the handicap groups had the highest prevalence of, and often the most severe, malocclusions compared to their controls. The results indicate that the mental status is more important for the orthodontic status than the medical diagnosis.

Lethal and non-lethal diastrophic dysplasia. A study of 14 Swedish cases.

A clinical study was performed on 14 patients with diastrophic dysplasia (DD), including three pairs of sibs. Six of these patients, including two pairs of sibs, died shortly after birth of respiratory and circulatory insufficiency. We consider these six patients to represent a special lethal variant of DD. In all infants with the lethal variant of DD the birth weight was lower than in those with the non-lethal variant. There were also roentgenological differences between these two groups. Overlapping in joints and dislocation of the cervical spine were seen in all the lethal cases. In addition, four of the six patients with lethal DD cases had a congenital heart defect, and none in the non-lethal group.

Sjögren-Larsson syndrome: delta 5-and delta 6-fatty acid desaturases in skin fibroblasts.

Cultured skin fibroblasts from two patients with Sjögren-Larsson syndrome (SLS) and from a normal control were analyzed for trienoic and tetraenoic fatty acids. In addition, we assayed desaturation of [1-14C]linoleic acid in cells from four patients and four controls. There was no significant effect of the disease on the composition of polyunsaturated fatty acids or on the rate of linoleic acid desaturation in fibroblasts. The results indicate the presence of delta 5- and delta 6-fatty acid desaturases in cells from SLS patients.

Dental health and dental care in severely mentally retarded children.

Dental health of 103 children with severe mental retardation living in the north of Sweden, has been surveyed and compared with that of a control group of healthy children of normal intelligence. Data has been related to medical diagnosis, medication, type of residence and previous dental care. The children with severe mental retardation had been offered dental care to the same extent as the control children. Lack of cooperation in treatment and treatment under general anaesthesia was common among the SMR-children. The SMR-children who lived in institutions had a lower prevalence of caries than either those SMR-children not living in institutions or the control group. The SMR-children had a considerably higher frequency of inflamed gingival surfaces and pathological gingival pockets than the control children. The highest frequency was found among children with Down's syndrome. Gingival hyperplasias were recorded in 21% of the SMR-children. The study showed that the children with SMR had shared the generally improved dental care resources and that regular dental care had ensured that there was no neglected need for caries treatment. Periodontal health was poor and the need for stronger and appropriate preventive measures against gingivitis and periodontitis was considerable.