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Metachromatic leukodystrophy (MLD) is a human autosomal recessive lysosomal neurodegenerative disorder that results from the accumulation of sulfatides in the central and peripheral nervous system. It is due to the enzyme deficiency of the sulfatide sulfatase i.e. arylsulfatase A (ASA). During adolescence and/or adulthood, there are 2 clinical presentations. It may be that of a degenerative disease of the central nervous system with mainly spastic manifestations or a spino-cerebellar ataxia, or that of a psychosis. As several lines of evidence indicate that the psychotic form of MLD could be a model of psychosis, we decided to do a pluridisciplinary study on 11 psycho-cognitive cases involving mental and psychiatric testing, in comparison with 5 adult motor cases, a biochemical study with enzyme assays and quantitative mass spectrometry of urinary sulfatides, so as to determine whether there were biochemical particularities related to the psychotic forms. For quantitative mass spectrometry (MS), a non physiological sulfatide with C17:0 fatty acid was synthesized. The major sulfatide isoforms were present in the 2 clinical forms with the following fatty acids and sphingoid bases: C22:1/d18:1, and /or C22:0/d18:2 (m/z 862.5), C22:0 (OH)/d18:1 (m/z 878,5), C24:0/d18:1 and / or C24:0/C23:1(OH)/d18:2 (m/z 890,3), C24:0 (OH)/d18:1(m/z 906.5). We had shown previously that there were different ASA mutations in the psychiatric adult form (heterozygous I179S) versus the adult motor form (homozygous P426L). We show here that there were no relations with the level of ASA and with the mass spectrometric study of the sulfatide isoforms which were identical in the 2 clinical forms.

Lysosomal diseases represent a large group of genetic storage disorders characterized by a defect in the catabolism of complex molecules within the lysosome. Effective treatments are now possible for some of them given progresses in bone-marrow transplantation, enzyme replacement therapy and substrate reduction therapy. Neurologists and psychiatrists are concerned by these diseases because they can present in adolescence or adulthood with progressive neuropsychiatric signs. Here we focus on late-onset clinical forms which can be met in an adult neurology or psychiatric department. Lysosomal diseases were classified into 3 groups: (1) leukodystrophies (metachromatic leukodystrophy, Krabbe's disease and Salla's disease); (2) Neurodegenerative or psychiatric-like diseases (GM1 and GM2 gangliosidoses, Niemann Pick type C disease, sialidosis type I, ceroid-lipofuscinosis, mucopolysaccharidosis type III); (3) multisystemic diseases (Gaucher's disease, Fabry's disease, alpha and B mannosidosis, Niemann Pick disease type B, fucosidosis, Schindler/Kanzaki disease, and mucopolysaccharidosis type I and II. We propose a diagnostic approach guided by clinical examination, brain MRI, electrodiagnostic studies and abdominal echography.

Resume La maladie de Niemann-Pick de type C peut etre detectee dans les services de neurologie adultes meme s’il s’agit de formes infantiles ou juveniles d’evolution prolongee. Cette affection ne peut se manifester qu’a l’adolescence ou a l’âge adulte. Le retard psychomoteur est constant. Dans certains cas, une psychose peut etre la seule manifestation pendant plusieurs annees. Le diagnostic est souvent fait quand des signes extrapyramidaux apparaissent, de meme qu’une ataxie cerebelleuse et une ophtalmoplegie dans le regard vertical. Le traitement par les psychotropes peut poser le probleme d’une neurolipidose induite associee. L’hepatosplenomegalie est souvent discrete, contrairement aux formes classiques infantiles. Des cellules spumeuses de meme que des histiocytes bleu-de-mer dans la moelle osseuse sont classiques. Le test a la filipine met en evidence la surcharge intralysosomale en cholesterol.

RESUME Ce n’est que depuis peu, que l’attention a ete attiree par la revelation tardive, chez l’adolescent et l’adulte, de maladies neurogenetiques d’origine metabolique. Leur presentation clinique et leur evolutivite different de celles de l’enfant. Chez l’enfant, le syndrome neurologique est lie a l’atteinte de plusieurs systemes et l’evolution est rapidement mortelle. Chez l’adulte, le processus est lentement evolutif, et la presentation clinique correspond, selon la maladie, a un syndrome tres systematise qui evoque une maladie degenerative du systeme nerveux. Notre experience nous permet de proposer un arbre de decision.

Metachromatic leukodystrophy (MLD) is a recessive autosomal disease which is biochemically characterized by an accumulation of sulfatides (sulfogalactosylceramides) mainly in oligodendrocytes and macrophages/microglia. The deficient enzyme is a lysosomal hydrolase, cerebroside sulfate sulfatase (arylsulfatase A). MLD is both a dysmyelinating and a demyelinating disease. The main clinical forms are infantile or juvenile, but some forms appear at adulthood. This disease involves also neuronal cells as sulfatides are also present in neurons in which the defect in degradation occurs also. We have studied 12 cases of adult MLD and clearly distinguished two clinical forms. One of them was characterized by mainly central nervous system motor signs (pyramidal, cerebellar, and seldom dystonia) and a peripheral neuropathy. The other form always started by behavioural abnormalities with modifications of mood, peculiar social reactions; a progressive mental deterioration occurred also. The diagnosis of schizophrenia was often mentioned. Most of these patients remained for many years without any neurological symptoms, and the diagnosis was only made when neurological signs appeared, or when Magnetic Resonance Imaging (MRI) was performed. MRI showed a diffuse demyelination, bilateral and often symmetrical, which could be temporarily limited to the periventricular areas. The diagnosis of adult MLD was biochemical, evidencing the low activity of arylsulfatase A (ASA) and sulfatide accumulation. To determine the respective participation of neurons and glial cells in the physiopathology of both the motor forms and the psycho-cognitive forms, our first approach was to search for mutations differing according to the clinical status. Motor forms involved the major adult ASA mutation P426L in a homozygote form in contrast to psycho-cognitive forms which involved as a compound heterozygote a specific I179S mutation.

Stress is a word that is used very commonly. It is generally employed to design unpleasant phenomena, although it is related to a function necessary to our life. Stress in itself is not a disease. Stress is not an aggression. It is an adaptative response of our body to any demand. Nothing can be done without stress. Stress gives rise to a mobilization of our body to succeed in a group of activities necessary to individual and social life. It favors our dynamism and creativity. But this aptitude can attain its limits, when the solicitations we receive are above what we are able to perform, both in relation to our mental and physical capabilities. The brain controls the systems involved in stress. The main areas are the prefrontal cortex, the limbic system (which comprises the hippocampus and the amygdala) and the hypothalamus. Relations between the prefrontal cortex and the limbic system are important for the planification of action. The main systems of regulation are the sympathetic and parasympathetic systems, the neuro-endocrine system and last but not least the immune system. There is a relation between all our organs and the brain. The genetic aspects and the influences of our past experiences, both during childhood and in adult life, are envisaged.

Leukodystrophies are genetic metabolic diseases which generally occur in early childhood at the time of myelination. Surprisingly, these diseases can also occur during adulthood. Adult forms have various clinical presentations which reflect degenerative diseases of the nervous system. The course may last for decades. This contribution describes the main features of adult leukodystrophies and indicates those for which a biochemical and molecular diagnosis are possible. Other articles deal with their differential diagnosis of leukoencephalopathies and with the diagnostic strategy.

Introduction L’imagerie medicale est une etape importante de l’examen d’un patient dement. L’atteinte de la substance blanche (leucodystrophie), meme isolee, peut etre a l’origine de troubles cognitifs et comportementaux (Filley, 1998). Objectifs Nous avons etudie 8 cas d’adrenoleucodystrophie (ALD) et 8 cas de leucodystrophie metachromatique (LMC) reveles a l’âge adulte, et determine leurs caracteristiques cliniques, neuropsychologiques (tests), et en imagerie par resonance magnetique (IRM). Methodes Le diagnostic a ete etabli, pour l’ALD, par le dosage serique des acides gras a tres longues chaines, et pour la LMC par le dosage d’arylsulfatase A, et par la sulfatidurie qui a ete quantifiee. L’examen neurologique a ete effectue sur une periode de 10 ans. Les tests ont explore le quotient intellectuel, l’attention, les fonctions visuo-spatiales, les memoires declarative et procedurale, le langage, les fonctions du lobe frontal, et le comportement social. Resultats Nous avons observe une absence de troubles du langage et de la memoire procedurale. Il existait des troubles de l’attention, de la memoire declarative, et visuo-spatiaux, et des anomalies du lobe frontal responsables de troubles comportementaux et de l’humeur. Dans la LMC, l’atteinte de la substance blanche etait diffuse, alors que dans l’ALD, la topographie de la demyelinisation entrainait des troubles visuo-spatiaux dans les formes occipitales, des troubles de l’attention dans les formes frontales. Discussion Ces demences different de la maladie d’Alzheimer, car il n’existe ni aphasie, ni agnosie, ni apraxie. Les principaux tests sont axes sur la verbalisation et peuvent donc meconnaitre les alterations specifiques de la substance blanche. La presence de troubles psychiatriques ou comportementaux au premier plan peut faire errer le diagnostic, d’autant que les troubles moteurs sont souvent d’apparition tardive. Conclusion Ces demences de la substance blanche sont liees a des alterations des reseaux neuronaux myelinises. Au debut on peut les reconnaitre ; ulterieurement toutes les fonctions neuro-cognitives sont alterees.

We report here the results of a simple and reproducible technique which can be used in semi-routine analysis of peripheral nerve biopsy specimens, so as to have a quantitative analysis of the major lipid classes, i.e. cholesterol, cerebrosides, ethanolamine phospholipids, phosphatidyl-choline, phosphatidyl-serine + phosphatidyl-inositol, sphingomyelin and gangliosides. Glycolipid hexoses, cholesterol and total phospholipids have been compared in different age groups. Although all lipid classes increased from the younger to the older age group, the molar ratio of cholesterol to phospholipid differed less than the glycolipid to phospholipid ratio. Both increased significantly, even between age group 10–16 and older patients (36, 54, 61, 68, 72 and 73 years old). Although individual variations in lipid content are noteworthy, it must be emphasized that evolution with age of the lipid composition must be taken into account. Furthermore, this study confirms and extends earlier findings of increased ganglioside levels in some cases of peripheral neuropathies observed during perhexiline maleate therapy where characteristic lipid-like polymorphous inclusions have been demonstrated.

Artificial substrates are being used routinely for the diagnosis of lipidosis. In the case of metachromatic leukodystrophy (MLD), p.nitrocatechol-sulfate (p.NCS) at acidic pH is the substrate for arylsulfatase A (ASA). Complete analogy of elution profile on column chromatography between ASA and cerebroside sulfate sulfatase (1) has secured in the use of the artificial substrate for MLD diagnosis. Although an activator protein is necessary for enzyme action on the natural substrate (2), only the ASA enzyme itself is deficient in MLD variant B (3). Another enzyme arylsulfatase B (ASB) reacts with p.NCS at less acidic pH; together with ASA and other sulfatases, it is deficient in another type of sulfatidosis, Austin’s disease or MLD variant O (3).

Gaucher’s disease is normally characterized according to the clinical phenotype. The form which is discovered at adult age is classically called type 1 and is devoid of neurological symptomatology. Nevertheless, several cases have been described with neurological symptoms appearing at adulthood. Among those, cases have been reported with atypical Parkinsonian symptomatology (Bogaert et al., 1939; Davidson, 1942; Neil et al., 1979; Sack, 1980; Soffer et al., 1980; McKeran et al., 1985). The diagnosis was based on the discovery of a splenomegaly and of Gaucher cells in the bone marrow, on the excess of glucocerebrosides in tissues and on the deficiency of glucocerebrosidase. We report here another case of type 1 Gaucher’s disease with extra-pyramidal symptomatology, in which the multiple mulecular forms of β-glucocerebrosidase were investigated according to Ginns et al. (1982).

• We performed a lipid analysis on nerve biopsy specimens in two cases of degenerative hypertrophic neuropathy. Quantitative analysis of the major lipid classes, ie, cholesterol, cerebrosides, sulfatides, ethanolamine phospholipids, phosphatidyl-choline, phosphatidyl-serine, phosphatidyl-inositol, sphingomyelin, and gangliosides, were performed. The two cases exhibited extreme decreases in levels of lipids that could be related to the very low myelin content of these nerves. Cholesterol and phospholipid levels were especially reduced. Cerebrosides and sulfatides were not modified in the same proportion, as could have been predicted from the degree of demyelination. This relative glycolipid increase could be due to the very high Schwann cell proliferation.

• A variant of metachromatic leukodystrophy (MLD), Austin disease, is characterized by a multiple isozyme deficiency of arylsulfatase. A 31/2-year-old girl with progressive mental and physical deterioration had decreased activities of arylsulfatases A and B in the leukocytes, shown by acrylamide gel electrophoresis. Under the electron microscope, biopsy specimens of the brain and the peripheral nerve showed lamellar structures with socalled zebra bodies in the cytoplasmic processes of glial cells, granulomembranous inclusions with fingerprint configurations in neurons, and myelinlike material in Schwann cells. Results from our study suggest an intricate nature of this dysmetabolic disorder, which shows ultrastructural changes usually seen in classic MLD, a deficiency of arylsulfatase A only, concomitant with those seen in mucopolysaccharidoses such as Hurler and Sanfilippo syndromes.