[Neurological presentations of lysosomal diseases in adult patients]. / Présentations neurologiques des maladies lysosomales chez l'adulte.

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.

Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults.

Inborn errors of metabolism (IEMs) may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. However, in some cases, psychiatric signs may be apparently isolated. We propose a schematic classification of IEMs into three groups according to the type of psychiatric signs at onset. Group 1 represents emergencies, in which disorders can present with acute and recurrent attacks of confusion, sometimes misdiagnosed as acute psychosis. Diseases in this group include urea cycle defects, homocysteine remethylation defects and porphyrias. Group 2 includes diseases with chronic psychiatric symptoms arising in adolescence or adulthood. Catatonia, visual hallucinations, and aggravation with treatments are often observed. This group includes homocystinurias, Wilson disease, adrenoleukodystrophy and some lysosomal disorders. Group 3 is characterized by mild mental retardation and late-onset behavioural or personality changes. This includes homocystinurias, cerebrotendinous xanthomatosis, nonketotic hyperglycinaemia, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, creatine transporter deficiency, and alpha and beta mannosidosis. Because specific treatments should be more effective at the 'psychiatric stage' before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms or subtle organic signs that are suggestive of an IEM. Here we present an overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood and provide a diagnostic strategy to guide metabolic investigations.

Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.

BACKGROUND: P426L and I179S are the two most frequent mutations in juvenile and adult metachromatic leukodystrophy (late-onset MLD), which, in contrast to infantile MLD, show marked phenotypic heterogeneity. OBJECTIVE: To search for genotype-phenotype correlations in late-onset MLD. METHODS: The authors reviewed the clinical course of 22 patients homozygous for mutation P426L vs 20 patients heterozygous for mutation I179S, in which the second arylsulfatase A (ASA) mutation had also been determined. RESULTS: P426L homozygotes principally presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at the onset of disease but became more apparent as the disease evolved. In contrast, compound heterozygotes for I179S presented with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits were scarce. Reduced peripheral nerve conduction velocities and less residual ASA activity were present in P426L homozygotes vs I179S heterozygotes. CONCLUSION: The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype-phenotype correlation in late-onset metachromatic leukodystrophy.

[Presentation of Niemann-Pick type C disease with psychiatric disturbance in an adult]. / Troubles psychiatriques révélateurs d'une maladie de Niemann-Pick de type C à l'âge adulte.

INTRODUCTION: Niemann-Pick Type C disease (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder. CASE REPORT: A 31-year-old right-handed woman had suffered from schizophrenia for 13 years. At 25 years of age, she developed a gait disorder with a static and kinetic cerebellar syndrome, dysarthria, vertical supranuclear gaze palsy and cognitive impairment. Brain MRI was normal. Abdominal ultrasonography was performed because of hypercholesterolemia and elevated transaminases and revealed hepatosplenomegaly, which in conjunction with other signs and symptoms, suggested the diagnosis of NPC. The diagnosis was confirmed by demonstration of lysosomal storage of unesterified cholesterol (filipin staining) and of a reduced rate of LDL-induced cholesterol esterification. Implication of the NPC1 gene was assessed by genetic complementation analysis. DISCUSSION: The phenotypic presentation of NPC is remarkably variable. The rarer adult-onset form has a slowly progressive course. Psychotic manifestations are often prominent and may precede neurologic symptoms. Exposure to neuroleptics delays the diagnosis of NPC. CONCLUSION: Psychotic manifestations associated with cerebellar syndrome, vertical supranuclear gaze palsy, and splenomegaly are very suggestive of NPC disease which can be reliably diagnosed on cultured skin fibroblasts by filipin staining.

[Presenting psychiatric and cognitive disorders in adult neurolipidoses]. / Manifestations psychiatriques ou cognitives inaugurales dans les neurolipidoses de l'adulte.

Neurolipidoses may present as psychiatric illness or dementia which may be isolated for a long time without neurological manifestations. Thus the relation with a metabolic disease may be difficult to establish. In this survey, we wish to present our clinical and biological experience in relation with lysosomal or peroxisomal disorders giving rise to neurolipidoses, a review of the literature, as well as the elements which allow to present a diagnostic strategy. We report mainly on metachromatic leukodystrophy, GM2 gangliosidosis, Fabry's disease, Niemann-Pick type C, Kufs disease, adrenoleukodystrophy, cerebro-tendinous xanthomatosis. Psychiatric symptoms may overshadow subtle signs of cognitive and motor dysfunction. Careful and persistent neurodiagnostic evaluation must be performed even in cases when CT and MRI scans are considered normal. Resistance to psychotropic drugs may be an element of orientation. The biological diagnosis is mainly biochemical. Although most of the genes involved have been cloned, many of the mutations are private, except for metachromatic leukodystrophy for which specific mutations may be related to adult cases and either with predominantly motor or predominantly cognitive and psychiatric manifestations. This review discusses also other metabolic diseases which may present as isolated or predominant cognitive and psychiatric manifestations.

Adult-onset leukodystrophies.

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.

Variable number tandem repeat dopamine transporter gene polymorphism and Parkinson's disease: no association found.

We studied a variable number of tandem repeat polymorphisms in the dopamine transporter gene in search of an association with Parkinson's disease in a French population. Five alleles were detected, consisting of 7, 8, 9, 10 and 11 copies of the 40-base pair repeat sequence, of which the 10-copy allele was the most common. There was no significant difference between the patients and the control subjects in the distribution frequencies of the alleles or genotypes, or in ages at onset in patients between the main allelic classes.

Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

[2 familial cases of metachromatic leukodystrophy of late onset]. / Deux cas familiaux de leucodystrophie métachromatique à expression tardive.

We report here a familial observation of metachromatic leukodystrophy (MLD) in 2 sisters. The very beginning, with only psychiatric manifestations at adolescence, could be precisely established. The evolution towards a dementia, and the evidence of a pyramidal syndrome oriented later towards a clearly organic disease. A very wide bilateral and symmetrical demyelination was shown by Magnetic Resonance imaging. The deficiency in arylsulfatase A activity oriented towards MLD which was confirmed by metachromatic deposits in the nerve biopsy. Molecular biology evidenced in the two, compound heterozygoty with both the classical mutation of the infantile form with loss of a splicing site at the level of intron 2, and the ileu > Ser 179 mutation frequent in adult forms.

[Juvenile GM2 gangliosidosis with progressive spinal muscular atrophy onset]. / Gangliosidose à GM2 juvénile débutant par une amyotrophie spinale progressive.

GM2 gangliosidosis are caused by a beta-hexosaminidase A enzyme deficiency. Mutations in the gene leaving residual enzyme activity give rise to juvenile and adult forms of the disease which have a great clinical heterogeneity. We report three cases which have been considered for some time as Kugelberg-Welander disease. beta-hexosaminidase A was determined with the sulfated synthetic substrate, 4-méthylumbelliferyl-N-acetylglucosamine 6-sulfate (4-MUGS), which allowed the diagnosis. Two of these cases from one family had normal values of hexosaminidase A in serum as found in the B1 variant. Compound mutations were detected. The B1 variants had a classical B1 mutation (G533-->A) and a new mutation located on exon 11. The patient of the second family had the classical mutation of adult GM2 gangliosidosis (Gly269-->Ser) and a new mutation on exon 1, at the initiation codon.

Trinucleotide GAA repeat expansions in seven French Friedreich ataxia families.

We collected 7 Friedreich ataxia (FRDA) pedigrees from France. All cases but one family were homozygous for an unstable GAA trinucleotide expansion in the first intron of the frataxin gene. In this peculiar pedigree absence of the GAA expansion supports the notion of possible genetic heterogeneity of FRDA.

Mutation frequencies of the cytochrome CYP2D6 gene in Parkinson disease patients and in families.

The frequencies of five mutations of the debrisoquine 4-hydroxylase (CYP2D6) gene (mutations D6-A, B, C, D, and T), corresponding to poor metabolizer (PM) phenotypes, were determined by restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) in 47 patients with Parkinson disease, and compared with the findings in 47 healthy controls. These mutant alleles were about twice as frequent among patients as in controls, with an approximate relative risk ratio of 2.12 (95% confidence interval, 1.41-2.62). There seem to be no significant differences in frequencies of mutant genotypes in patients among gender and modalities of response with levodopa therapy; but frequency of the mutations was slightly enhanced after age-at-onset of 60 years. Mutations D6-B, D, and T were detected in 7 patients belonging to 10 Parkinson pedigrees.

Methyl bromide intoxication during grain store fumigation.

There have been over 300 cases of methyl bromide poisoning reported in the literature. The first objective of this case report was to bring out an experience with the false belief that work in a closed space is safe when accompanied by the use of a cartridge respirator with activated charcoal. The second objective of this article was to demonstrate the marked toxicity of methyl bromide with the potential to cause long-term neurological damage. Two experienced fumigation workers (equipped with rapidly saturable respiratory cartridges) entered a building where the concentration of methyl bromide was 17g x m-3 instead of the advised 20mg x m-3. They felt rapidly unwell and complained of nausea and shortness of breath, followed for one them by generalized convulsions. Five months later this last man was still bedridden. The other worker had almost no after-effects. The highest bromide level was found in the blood and also in the activated charcoal cartridge of the most injured worker. There was a relationship between methyl bromide level exposure and neurological damage importance.

Allele doses of apolipoprotein E type epsilon 4 in sporadic late-onset Alzheimer's disease.

Apoliprotein E, type epsilon 4 allele (ApoE-epsilon 4) is associated with late-onset sporadic Alzheimer's disease (AD). We have found that the cumulative probability of remaining unaffected over time decreases for each dose of ApoE-epsilon 4 in sporadic, late-onset French AD. The effect of genotypes on age at onset of AD was analyzed using the product limit method, to compare unaffected groups during aging.

A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype.

We describe two adult siblings who had had mild GM2 gangliosidosis since childhood. They presented with spinal muscular atrophy and dysarthria, and one sibling also had mental disturbances. Laboratory studies established the diagnosis of the B1 variant of GM2 gangliosidosis, because the hexosaminidase (Hex) A deficiency was not present upon testing with the unsulfated synthetic substrate 4-methylumbelliferyl N-acetylglucosaminide. HEXA gene analysis proved that the patients are compound heterozygotes for the previously identified G533-->A mutation and for a new mutation, G1171-->A, at exon 11. This new mutation affects a conserved amino acid and results in a Val-->Met substitution at position 391 of the HEXA gene. Full sequence of the alpha-subunit cDNA of Hex A revealed no other mutation. Assays for Hex A activities in patients suspected of having GM2 gangliosidosis should be performed with the sulfated substrate 4-methylumbelliferyl N-acetylglucosamine 6-sulfate.

[Fibrodysplasia ossificans progressiva. Apropos of a case]. / Myosite calcifiante progressive. A propos d'une observation.

PURPOSE OF THE STUDY: Fibro-dysplasia ossificans progressive is a rare inherited disease, presumably transmitted as an autosomal dominant defect. The high level of spontaneous mutations explains the sporadic cases. Pre symptomatic diagnosis could be actually evoked by the association of progressive ossification of soft tissues with congenital anomalies of bones (metacarpal and metatarsal). The purpose of this study is to report a clinical case with a very severe course. CASE REPORT: A 10-year-old boy developed progressive ossification of muscles and soft tissues in multiple sites neck, back, shoulders, elbows, hips and knees. The clinical course was severe due to the ankylosis of all the joints and the decrease of pulmonary reserve with fixation of the chest wall. A malformation of the great toes facilitated the diagnosis. DISCUSSION: This pattern of heterotopic ossification together with the congenital malformations of the great toes defines the developmental phenotype for fibrodysplasia ossificans. A slow course with successive thrusts occurs. Ossification progressively involves tendons, ligaments and the connective tissue of skeletal muscles. Excision of heterotopic bone is futile as the trauma of the operation can lead to the stimulation of new heterotopic ossification at the operative site. Surgery is only useful for biopsy and histological study reveals bone metaplasia. The mature heterotopic bone is histologically indistinguishable from mature skeletal bone. The non skeletic muscles are characteristically spared from ossification. Premature death often results from respiratory failure due to fixation of the thoracic cage. The pathogenesis and the treatment of the disorder are unknown.

Molecular characterization of Charcot-Marie-Tooth patients in 15 pedigrees from France.

Molecular characterization of Charcot-Marie-Tooth patients in 15 pedigree from France: We collected 15 Charcot-Marie-Tooth (CMT) pedigrees from France. DNA polymorphisms analysis by Southern blotting with probes at the D17S122 locus demonstrated 17p duplication in three CMT1a families and in one sporadic case. Two families affected by CMT2 showed no evidence of the duplication.