Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). We report the clinical characteristics and the results of molecular studies in 19 SLS patients. Patients 1-17 show the classical triad of severe clinical abnormalities including ichthyosis, mental retardation and spasticity. Most patients were born preterm, and all patients exhibit ocular abnormalities and pruritus. Electro-encephalography shows a slow background activity, without other abnormalities. MRI of the brain shows an arrest of myelination, periventricular signal abnormalities of white matter and mild ventricular enlargement. Cerebral (1)H-MR spectroscopy reveals a characteristic, abnormal lipid peak. The degree of white matter abnormality in the MRIs and the height of the lipid peak in (1)H-MR spectra do not correlate with the severity of the neurological signs. The clinical presentation and the clinical course is strikingly similar in these patients. Patient 18 shows a mild phenotype that essentially contains the same, but less severe, clinical features. Patient 19 exhibits the typical, but very mild, dermatological and ocular abnormalities, without any clinical neurological involvement. The diagnosis of SLS was confirmed by demonstration of the enzyme defect in cultured skin fibroblasts. Furthermore, as might be predicted from the essential role of FALDH in leucotriene B(4) (LTB(4)) metabolism, elevated urinary concentrations of LTB(4) and 20-OH-LTB(4) were found in all patients studied. Molecular studies of the FALDH gene revealed eight different mutations, including three new ones: a large 26-base pair deletion (21-46del), a missense mutation (80C-->T) and an insertion mutation (487-488insA). The vast majority of SLS patients seem to be severely affected independent of their genotype.

Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjögren-Larsson syndrome.

PURPOSE: To report the ocular manifestations associated with the Sjögren-Larsson syndrome in a series of patients with proven fatty aldehyde dehydrogenase deficiency. To emphasize the clinical importance of the ophthalmological features of the Sjögren-Larsson syndrome. To discuss the metabolic disturbances that might give rise to the ophthalmological picture. METHODS: Fifteen patients with Sjögren-Larsson syndrome underwent a standardized ophthalmological examination. In patients of appropriate age, and who were able to cooperate, additional investigations were performed. RESULTS: All patients exhibited bilateral, glistening yellow-white crystalline deposits that were located in the innermost retinal layers and appeared during the first 2 years of life. Repeated fundus photography in individual patients showed that the dots became more numerous as the patients got older. Photophobia, subnormal visual acuity, myopia, and astigmatism were found in most of the patients. Fluorescein angiography was performed in three patients and showed a mottled hyperfluorescence of the retinal pigment epithelium, without leakage. Color vision, electroretinography, and electro-oculography could be performed in only a small number of patients and showed no abnormalities. Visual evoked potentials were found to be abnormal in six of eight patients. CONCLUSIONS: In Sjögren-Larsson syndrome, patients exhibit highly characteristic bilateral, glistening yellow-white retinal dots from the age of 1 to 2 years onward. The number of dots increases with age. The extent of the macular abnormality does not correlate with the severity of the ichthyosis or with the severity of the neurological abnormalities. A high percentage of patients shows additional ocular signs and symptoms, notably marked photophobia.

The role of doctor and patient in the construction of the pseudo-epileptic attack disorder.

Periodic attacks of uncertain origin, where the clinical presentation resembles epilepsy but there is no evidence of a somatic disease, are called Pseudo-Epilepsy or Pseudo-Epileptic Attack Disorder (PEAD). PEAD may be called a 'non-disease', i.e. a disorder on the fringes of established disease patterns, because it lacks a rational pathophysiological explanation. The first aim of this article is to criticize the idea, common in medical science, that diseases are real entities which exist separately from the patient, waiting to be discovered by the doctor. We argue that doctor and patient construct a disease, and that the construction of the disease PEAD includes many normative evaluations. The second aim is to provide insight into the suffering of patients with PEAD. We focus on three aspects of the patient, identity, autonomy and responsibility. We present some characteristic descriptions of (pseudo-)epileptic attacks by Fjodor Dostoevsky, Gustave Flaubert and Thomas Mann. We argue that diagnosing PEAD reduces a meaningful life event into an insignificant, though intriguing, medical phenomenon, and that the patient will not benefit from being diagnosed as having PEAD.

Defective inactivation of leukotriene B4 in patients with Sjögren-Larsson syndrome.

In 6 patients with Sjögren-Larsson syndrome (SLS), the urinary excretion of leukotriene B(4) (LTB(4)) and omega-hydroxy-LTB(4) was found to be highly elevated, whereas omega-carboxy-LTB(4) was absent. This abnormal pattern of urinary excretion of LTB(4) and its metabolites appears to be unique to patients with SLS and offers a new approach to the diagnosis of this disorder. Moreover, defective inactivation of LTB(4) might be of pathophysiologic significance in the disease.

Sjögren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients.

OBJECTIVE: To determine the spectrum of clinical and MRI/1H MRS features of patients with fatty aldehyde dehydrogenase (FALDH) deficiency. BACKGROUND: The Sjogren-Larsson syndrome (SLS) was originally defined as a clinical triad consisting of ichthyosis, spastic di- or tetralegia, and mental retardation, with autosomal recessive inheritance. By now, both the deficiency of the enzyme FALDH, and the genetic mutations on chromosome 17 responsible for this deficiency, have been identified. SLS, defined by fibroblast FALDH deficiency, seems to be a much broader syndrome. METHODS: The clinical findings of 11 FALDH-deficient patients of different ages and one patient with the characteristic SLS-like ichthyosis, but without FALDH deficiency, were evaluated in relation to their cerebral MRI, and to 1H MRS in six patients. RESULTS: The severity of neurologic symptoms showed considerable variation. Fundoscopic perifoveal glistening dots and the characteristic SLS-like ichthyosis were present in all patients. Serial MRI findings showed evidence of retarded myelination and a variable degree of dysmyelination. 1H MRS showed an accumulation of free lipids in the periventricular white matter, even before the stage of visible dysmyelination. CONCLUSIONS: The neurologic consequences of FALDH deficiency show considerable variation. The characteristic pattern of ichthyosis and retinal degeneration are seen consistently, yet they are not pathognomonic. MRI and 1H MRS findings suggest an accumulation of long-chain fatty alcohol intermediates, resulting in retarded myelination and dysmyelination.

Preterm birth in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) was originally described as a triad of spasticity, mental retardation and congenital ichthyosis. The syndrome reflects an underlying deficiency of microsomal fatty aldehyde dehydrogenase (FALDH). We report on clinical data concerning pregnancy, labor and neonatal period in 15 patients. Pregnancies were uncomplicated, except for preterm rupture of membranes in three pregnancies, and the occurrence of preterm birth. Mean gestational age was 35.3 weeks (S.D. 2.4 weeks), and preterm birth was found in 73% of the children, while all children were born before or in the 38th week of gestation. Birth weight was normal for gestational age in all patients. The neonatal period was free from serious complications, apart from hemolytic disease in two patients. Preterm birth was found in 7% of the healthy siblings, reflecting the normal population. Prematurity and spasticity are intrinsic and concurrent parts of SLS, without causal relation. SLS should be considered in every neonate with congenital ichthyosis, especially if the child is born preterm. A possible explanation for preterm birth in SLS could be the defective inactivation of leukotriene B4 (LTB4), which recently has been demonstrated in patients with SLS.

Akinetic mutism with bithalamic infarction. Neurophysiological correlates.

A 42-year-old man presented with akinetic mutism, caused by bilateral thalamic infarction, resulting in a temporary amnesic syndrome and, finally, selective downgaze palsy. Electroencephalographic recording in the initial phase showed generalized spike- and-wave discharges, similar to those found in animal studies after lesion or stimulation of specific thalamic nuclei. Analysis of magnetic resonance images (MRI) of the head showed that the centre of ischemic necrosis particularly involved the intralaminar thalamic nuclei and a small part of the rostral mesencephalon. The findings support the previously suggested involvement of cortico-thalamo-mesencephalic circuitry in the initiation of motor responses, and the association of the non-specific thalamic nuclei with the appearance of generalized epileptiform phenomena in cases of reduced vigilance.

Mitochondrial cytopathy presenting as hereditary sensory neuropathy with progressive external ophthalmoplegia, ataxia and fatal myoclonic epileptic status.

We present six adult patients from three separate families, with a remarkably uniform heredo-ataxic syndrome, developing in three stages and ending in early death. The initial stage is determined by severe sensory neuropathy. The second stage is characterized further by progressive external ophthalmoplegia (PEO), probably caused by ocular myopathy, and progressive ataxia. During a short last stage there is epilepsia, and particularly myoclonic status epilepticus, of which four patients died unexpectedly. Sural nerve biopsies showed severe loss of myelinated fibres in a rather early stage of disease. Skeletal muscle biopsies (and a specimen of ocular muscle) revealed ragged-red fibres. Autopsy examination in two patients revealed multisystemic involvement of the nervous system, with, in particular, degeneration of spinal dorsal columns and spinocerebellar tracts. Pedigree data were compatible with an autosomal recessive disorder. Additional findings, particularly elevation of CSF lactate, suggested mitochondrial cytopathy as an essential feature of the multisystem degeneration in these patients.

Cell loss in the nucleus raphes dorsalis in Alzheimer's disease.

Marked neuron loss in the predominantly serotonergic nucleus raphes dorsalis (NRd) in Alzheimer's disease (AD) has repeatedly been reported in the literature. However, most of these studies quantitated only part of the NRd and data were expressed as numerical density. Applying a 3-dimensional sampling scheme throughout the entire rostrocaudal extent of the NRd and sampling neurons regardless of their size and staining characteristics, an overall neuron loss of 39.4% was demonstrated and a tendency for cell shrinkage was likely to be present. No rostrocaudal gradient in neuron loss could be shown. These NRd data are in accordance with neuron loss in other subcortical structures in AD.

The human substantia nigra and ventral tegmental area. A neuroanatomical study with notes on aging and aging diseases.

The present study comprises a cytoarchitectonic analysis of the human substantia nigra (SN) and ventral tegmental area (VTA); a discussion of their chemoarchitecture and fiber connections (mainly based on tract-tracing studies in primates) preceded by an overview of the wealth of tract-tracing data in rodents; a discussion of the involvement of the SN/VTA complex in Parkinson's disease (PD) and related disorders and in Alzheimer's disease (AD), including some quantitative data; and finally, some functional and pathophysiological considerations, relating nigral organization to pathophysiology and hypotheses on the etiology and distribution of AD and PD. DAergic cell populations in the mesencephalon (SN pars compacta, VTA, and the retrorubral area A8) which give rise to well-developed, DAergic, mesotelencephalic pathways, including a distinct mesostriatal system, and a substance P-immunoreactive striatotegmental system which projects to the SN pars reticulata and VTA appear to be common to reptiles, birds, and mammals (Sect. 3.1). The extensive literature on the organization of the SN/VTA complex in rats is summarized in Sect. 3.2. The mesotelencephalic projection is organized along inverted dorsal to ventral, medial to lateral, and rostral to caudal topographies. A dense DAergic innervation is characteristic of the entire striatal complex, including the caudate-putamen (the dorsal striatum), the nucleus accumbens, and the olfactory tubercle (the ventral striatum). This mesostriatal projection is compartmentally organized with distinct sets of DAergic neurons projecting to striosomes and extrasriosomal matrix, respectively, suggesting specialized channels directed at DAergic modulation of sensorimotor processing in the striatal matrix and limbic related mechanisms represented in the striosomal system. The VTA and medial part of the SN give rise to the DAergic mesolimbocortical system with extensive projections to limbic, allocortical, and neocortical structures. The striatonigral output pattern in rats is organized in such a way that the dorsal striatum mainly innervates the SN pars reticulata, whereas the ventral striatum projects predominantly to the VTA and medial part of the SN. Within the striatonigral projections in rats some interesting channels can be recognized, relating the sensorimotor cortex, via its corticostriatal projections, to that region of the SN giving rise to the nigrothalamic projection, and the visual cortex to the nigrotectal component of the SN pars reticulata.(ABSTRACT TRUNCATED AT 400 WORDS)

Core and paracores; some new chemoarchitectural entities in the mammalian neuraxis.

A study of the recent neuromorphological, neurophysiological and neuroethological literature, and data from the current research in our own laboratory have led us to a new classification of entities in the mammalian neuraxis. This classification comprises the core and the median and lateral paracores. The core of the neuraxis may be considered as a caudally extended limbic system. It extends throughout the central nervous system and, as its name implies, most of it is situated close to the ventricular cavity. This entity is characterized by the presence of (1) numerous diffuse grisea, (2) enormous amounts of thin, unmyelinated, varicose axons, many of which are arranged in diffuse fibre systems, (3) large numbers of different neuromediators, particularly neuropeptides, and (4) large numbers of neurons which concentrate estrogen and androgen hormones. Ethophysiological studies have shown that the core region contains numerous loci from which on stimulation quite characteristic behavioral patterns, like eating, drinking, fear, attack, reproductive behavior etc., can be elicited. The core region appears to be involved most directly in the organization of behavior and is of paramount importance for the regulation of processes aimed at the survival of the individual (organism) and of the species. The median and lateral paracores represent extensions of the core at the level of the brain stem. The median paracore includes the raphe nuclei, whereas the (bilateral) lateral paracore is constituted by a ventrolaterally extending lamella of tissue. Both paracores contain sets of monoaminergic cells giving rise to networks of fibres that pervade virtually all grisea of the neuraxis, i.e. the serotoninergic neurons in the median paracore and the catecholaminergic cells in the lateral paracore. The lateral paracore contains a series of grisea, including the substantia nigra, the ventral tegmental area, the nucleus reticularis parvocellularis, the tegmental pedunculopontine nucleus and the catecholaminergic cell groups A1, A2, A5, A7 and C1 and C2. It harbours a large bundle of loosely arranged, thin fibres, which forms a direct caudal continuation of the hypothalamic medial forebrain bundle. This lateral paracore bundle contains numerous catecholaminergic and peptidergic fibres. Three typical core centres, viz. the nucleus centralis amygdalae, the bed nucleus of the stria terminalis and the lateral hypothalamic area contribute substantially to this bundle. The lateral paracore contains, just like the core region, a large number of functionally defined centres related to integrated somatomotor and visceromotor responses. It is postulated that non-synaptic interneuron