RESUMO
INTRODUCTION: Niemann-Pick type C disease (NPC) is a rare genetic disease with an extremely heterogeneous clinical presentation. The adult form of this disease is usually expressed with neurological symptoms; however, non-specific psychiatric disorders are often associated. This article presents a retrospective study on a cohort of NPC patients diagnosed in France with the objectives of researching the presence of psychiatric disorders and qualifying these disorders. METHODS: After carrying out a research within hospital records, a questionnaire was sent to patients or their relatives and their doctors. RESULTS: The cohort was made up of 22 patients. Fifty-two questionnaires were sent to 47 different doctors. We received 67% of answers from the doctors, with 42% of positive answers. The answer rate of the families was 27%. Among the 22 patients, we found the presence of psychiatric disorders in 86% of cases. Seventy-three percent of the patients presented behavior disorders. Among them, 27% exhibited psychomotor excitation or agitation, 23% aggressiveness, 18% intolerance to frustration, 27% sleep disorders and 23% apathy, listlessness and/or clinophilia. Fifty-five percent of patients presented psychotic symptoms, with 45% with delusions and 36% with hallucinations. Seventy-seven percent of patients presented with mood disorders: 36% suffered from depression and 27% from emotional lability or mood swings. Of the 22 patients, a diagnosis of psychiatric disease was made in 50% of cases. The main diagnoses were schizophrenia (27%) and depression (23%). The other diagnoses identified were acute delirium, dysthymia, infantile psychosis, intellectual disharmonic disability and personality disorder. The average age of emergence of the troubles was 17.1 years old for neurological symptoms and 20.9 years old for psychiatric symptoms. The median age was 18 years old for neurological symptoms and 20 years old for psychiatric ones. In 45% of cases, psychiatric occurred after neurological symptoms; in 27%, they occurred before and they were concomitant in 9%. In 50% of cases, psychiatric symptoms existed before the early diagnosis of NPC; in 9%, they occurred after and in 5%, they occurred during the diagnostic process. Fifty-five percent of the patients were followed by a psychiatrist, 50% of patients had been hospitalized at least once in a psychiatric department. Fifty-five percent of the patients received neuroleptics or antipsychotics, 41% received antidepressants, 41% received mood stabilizers or anticonvulsants, 45% received anxiolytics and 23% hypnotics. DISCUSSION: Whilst a small cohort, the low incidence of NPC (1/120,000 to 1/150,000) and the scale of a single-center study make the findings important. In our cohort, we found psychiatric disorders in most of the patients. The symptoms were varied and non-specific, and mainly found in late-onset forms of the disease. This incidence of disorder is much higher than the literature suggests, generally describing psychiatric disorders in approximately one third of NPC adult form. On the other hand, our results on schizophrenia are consistent with the updated recommendations for the diagnosis and management of NPC. According to our results, a retrospective study to develop a suspicion index to aid diagnosis of NPC suggests that psychotic symptoms are underestimated in this disease. In our cohort, we also found a significant rate of psychiatric hospitalizations and psychotropic drugs prescription that had not been previously described in the international literature. We did not have sufficient data on the effectiveness of symptomatic treatment in NPC; the literature was contradictory. It should be noted that despite the high rate of psychiatric patients in our cohort, only half of patients consulted a psychiatrist and a few of them have regular follow-up. To conclude, our study is in line with the current literature that suggests an under-estimation of psychiatric disorders in NPC, but also a likely under-diagnosis of NPC in psychiatric departments. All this data encourage us to keep alerting psychiatrists to identifying this disease in order to promote early and optimal care.
Assuntos
Transtornos Mentais/psicologia , Doença de Niemann-Pick Tipo C/psicologia , Adulto , Idade de Início , Estudos de Coortes , Comorbidade , Diagnóstico Precoce , Família , Feminino , Aconselhamento Genético , Hospitalização , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Doença de Niemann-Pick Tipo C/complicações , Médicos , Psicotrópicos/uso terapêutico , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Neuropsychiatric signs and MRI abnormalities can occur in patients with phenylketonuria in adulthood. We describe clinical and radiological features of phenylketonuric patients and we discuss the advantage of continuing diet in adulthood. METHOD: We report late onset neuropsychiatric symptoms of four phenylketonuric patients (33-45years) diagnosed in infancy and report the case of a patient (33years) diagnosed with phenylketonuria because of late onset neurological signs. We describe clinical and radiological features of these 5 patients, and their evolution under diet and propose a review of the literature. RESULTS: The main neurological abnormalities in phenylketonuric patients diagnosed in infancy are: brisk reflexes, spastic paraparesis, psychiatric signs that appear 10.5years after the diet arrest. A leukoencephalopathy was present in 93% of cases and 91.7% improve clinically after poor phenylalanine diet reintroduction. In 4 patients, neurological abnormalities (spastic paraparesis, dementia, Parkinsonism) led to the late diagnosis. Two of them had a leukoencephalopathy on brain MRI. Patients had high levels of phenylalanine (above 1500µmol/L) when neuropsychiatric signs occurred. Improvement after diet suggests that hyperphenylalaninemia has a direct toxic effect on the brain. DISCUSSION/CONCLUSION: The long-term follow-up of phenylketonuric patients is mandatory to depict and treat neurological complications in time. Diet reintroduction is efficacious in most cases.
Assuntos
Transtornos Mentais/etiologia , Transtornos Mentais/psicologia , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/psicologia , Fenilcetonúrias/complicações , Fenilcetonúrias/psicologia , Adolescente , Adulto , Idade de Início , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Pré-Escolar , Transtorno Depressivo/etiologia , Transtorno Depressivo/psicologia , Feminino , Humanos , Lactente , Masculino , Doença de Parkinson/etiologia , Doença de Parkinson/psicologia , Fenilcetonúrias/dietoterapia , Adulto JovemRESUMO
We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to α/ß-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to α/ß- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins.
Assuntos
Ácidos Graxos/biossíntese , Erros Inatos do Metabolismo Lipídico/classificação , Fosfolipídeos/biossíntese , Esfingolipídeos/biossíntese , Animais , Humanos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Doenças Metabólicas/classificação , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Modelos Biológicos , Fosfolipídeos/deficiência , Esfingolipídeos/deficiênciaRESUMO
Inborn errors of metabolism (IEM) are caused by mutations in genes coding for enzymes and other proteins involved in cell metabolism. Many IEM can be treated effectively. Although IEM have usually been considered pediatric diseases, they can present at any age, mostly with neurological and psychiatric symptoms, and therefore constitute an integral subspeciality of neurology. However, although they are increasingly being recognized, IEM remain rare, and the care for patients should be optimized in specialized reference centers. Since the number of different diseases is very large, the diagnostic approach needs to be rigorous, starting at the clinics and calling upon the additional help of neuroradiology, biochemistry and molecular biology. In practice, it is important for the neurologist to recognize: (1) when to start suspecting an IEM; and (2) how to correlate a given clinical presentation with one of the five major groups of diseases affecting the nervous system. These five groups may be classified as: (a) energy metabolism disorders such as respiratory chain disorders, pyruvate dehydrogenase deficiency, GLUT1 deficiency, fatty-acid ß-oxidation defects, and disorders involving key cofactors such as electron transfer flavoprotein, thiamine, biotin, riboflavin, vitamin E and coenzyme Q10; (b) intoxication syndromes such as porphyrias, urea-cycle defects, homocystinurias, organic acidurias and amino acidopathies; (c) lipid-storage disorders such as lysosomal storage disorders (Krabbe disease, metachromatic leukodystrophy, Niemann - Pick disease type C, Fabry disease and Gaucher's disease), peroxisomal disorders (adrenomyeloneuropathy, Refsum disease, disorders of pristanic acid metabolism, peroxisome biogenesis disorders), Tangier disease and cerebrotendinous xanthomatosis; (d) metal-storage diseases such as iron, copper and manganese metabolic disorders; and (e) neurotransmitter metabolism defects, including defects of serotonin, dopamine and glycine metabolism.
Assuntos
Erros Inatos do Metabolismo/terapia , Doenças do Sistema Nervoso/terapia , Adulto , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/terapia , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/terapia , Erros Inatos do Metabolismo/classificação , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo dos Metais/genética , Erros Inatos do Metabolismo dos Metais/terapia , Doenças do Sistema Nervoso/classificação , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/genética , Neurotransmissores/metabolismoRESUMO
INTRODUCTION: The childhood ataxia with central nervous system hypomyelination-vanishing white matter syndrome (CACH-VWM) was first characterized in children (2-5 years) on clinical and MRI criteria: cerebellospastic signs associated with episodes of rapid deterioration following stress and extensive cavitatingleucoencephalopathy. Causative mutations were found in the five genes encoding the subunits of the eukaryotic initiation factor 2B (eIF2B), involved in protein synthesis and its regulation under cellular stresses. A broad clinical spectrum has been subsequently described from congenital to adult-onset forms leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders. METHODS: The inclusion criteria were based on the presence of EIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis was also included. Clinical and MRI findings were retrospectively recorded in all patients. This multicentric study included 24 patients from 22 families. RESULTS: A sex-ratio imbalance was noted (male/female=5/19). The mean age of onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20), psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years, range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients. Magnetic resonance imaging findings consisted of cerebral atrophy (92%), extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found at a homozygous state in 58% of the 24 eIF2B-mutated patients. CONCLUSION: eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by screening for the recurrent p.Arg113His-eIF2Be mutation.
Assuntos
Fator de Iniciação 2B em Eucariotos/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/epidemiologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Adolescente , Adulto , Idade de Início , Criança , Estudos de Coortes , Coleta de Dados , Progressão da Doença , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Estudos Retrospectivos , Adulto JovemRESUMO
In order to identify new metabolic abnormalities in patients with complex neurodegenerative disorders of unknown aetiology, we performed high resolution in vitro proton nuclear magnetic resonance spectroscopy on patient cerebrospinal fluid (CSF) samples. We identified five adult patients, including two sisters, with significantly elevated free sialic acid in the CSF compared to both the cohort of patients with diseases of unknown aetiology (n = 144; P < 0.001) and a control group of patients with well-defined diseases (n = 91; P < 0.001). All five patients displayed cerebellar ataxia, with peripheral neuropathy and cognitive decline or noteworthy behavioural changes. Cerebral MRI showed mild to moderate cerebellar atrophy (5/5) as well as white matter abnormalities in the cerebellum including the peridentate region (4/5), and at the periventricular level (3/5). Two-dimensional gel analyses revealed significant hyposialylation of transferrin in CSF of all patients compared to age-matched controls (P < 0.001)--a finding not present in the CSF of patients with Salla disease, the most common free sialic acid storage disorder. Free sialic acid content was normal in patients' urine and cultured fibroblasts as were plasma glycosylation patterns of transferrin. Analysis of the ganglioside profile in peripheral nerve biopsies of two out of five patients was also normal. Sequencing of four candidate genes in the free sialic acid biosynthetic pathway did not reveal any mutation. We therefore identified a new free sialic acid syndrome in which cerebellar ataxia is the leading symptom. The term CAFSA is suggested (cerebellar ataxia with free sialic acid).
Assuntos
Ataxia Cerebelar/líquido cefalorraquidiano , Ácido N-Acetilneuramínico/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia/líquido cefalorraquidiano , Células Cultivadas , Ataxia Cerebelar/patologia , Cerebelo/patologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transferrina/líquido cefalorraquidianoRESUMO
AIMS: Ornithine delta-aminotransferase (OAT) deficiency causes gyrate atrophy (GA) of the retina, as a consequence of high plasma ornithine concentrations. Because creatine synthesis requires the conversion of arginine and glycine into ornithine and guanidinoacetate, high ornithine concentration inhibits this reaction thus causing secondary creatine deficiency. The aim of this study was to evaluate the neuropsychological features and creatine metabolism in patients with GA. METHODS: The study involved 7 GA patients, aged from 11 to 27 years who underwent neuropsychological evaluation and cerebral proton magnetic resonance spectroscopy (MRS). RESULTS: Neurocognitive impairment was found in 5/7 patients, including mental retardation (3/7), school failure (1/7), major visuospatial dyspraxia (1/7), aggressive behavior (3/7) and epilepsy (2/7). Two patients had normal neuropsychological evaluation. Cerebral proton magnetic resonance spectroscopy revealed a profound creatine deficiency in all patients. MRS data were confirmed by decreased levels of creatine and/or guanidinoacetate in plasma and urine in all patients. CONCLUSIONS: In our group of patients with GA, we found a high prevalence of neurological impairment, not reported so far, and possibly related to secondary creatine deficiency and hyperornithinemia. We propose to treat mentally retarded GA patients with high doses of creatine, as it may normalize brain creatine levels and help to reduce ornithine levels.
Assuntos
Creatina/deficiência , Atrofia Girata/complicações , Atrofia Girata/fisiopatologia , Ornitina-Oxo-Ácido Transaminase/deficiência , Adolescente , Adulto , Agressão , Apraxias/etiologia , Apraxias/metabolismo , Encéfalo/metabolismo , Criança , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Atrofia Girata/metabolismo , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/metabolismo , Imageamento por Ressonância Magnética , Masculino , Ornitina-Oxo-Ácido Transaminase/antagonistas & inibidores , Estudos Retrospectivos , Adulto JovemRESUMO
Niemann-Pick disease type C (NP-C) is a devastating genetic disorder characterised by progressive neurological deterioration. However, data on the progression of neurological manifestations, particularly across different patient age-of-disease onsets, are limited. This is an observational retrospective cohort study designed to assess the progression of neurological disease in patients with NP-C. Physicians were asked to retrospectively complete a web-based questionnaire for each patient, at diagnosis and at up to three follow-up visits. An NP-C-specific disability scale was used to measure disease progression. The scale comprised four key parameters of neurological disease progression; ambulation, manipulation, language and swallowing. Disease progression was evaluated based on the annual rate of change in each parameter and the composite score using a linear mixed model analysis, and by classifying patients according to the number of worsened parameters during the observation period. Data were collected from 57 patients. The rate of deterioration was similar across the four individual parameters of the disability scale. The mean (95% CI) annual disease progression was +0.12 (0.09, 0.15) units. Among patients with a time interval of at least 1 year between diagnosis and last visit (n=49), 42 (86%) patients had progressed disease and 7 (14%) patients had stable disease. Disease progression was consistently more rapid in patients diagnosed in early childhood, compared with those diagnosed in late childhood, or with juvenile or adult presentation. In conclusion, our findings showed a progression in all four parameters of the disability scale, representing a continuous, unbroken progression of neurological manifestations.
Assuntos
Doença de Niemann-Pick Tipo C/diagnóstico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Miglustat has been shown to stabilize disease progression in children, juveniles and adults with Niemann-Pick disease type C (NP-C), a rare genetic disorder characterized by progressive neurological deterioration. We report findings from a retrospective observational cohort study assessing the effects of miglustat on neurological disease progression in patients treated in the clinical practice setting. Data from all NP-C patients prescribed miglustat at 25 expert centers were evaluated using a disease disability scale. The scale analyzed four key parameters of neurological disease progression in NP-C (ambulation, manipulation, language, swallowing). Mean individual parameter scores and a composite score were calculated at baseline (time of diagnosis) and up to 4 follow-up visits. Overall, 66 patients were included (mean [SD] age at diagnosis, 9.7 [7.6] years, and at treatment start, 12.8 [9.5] years). The median (range) miglustat exposure was 1.46 (0.05-4.51) years. Mean annual progression was +0.11 score units/year from diagnosis to treatment start, indicating disease progression prior to therapy, and decreasing to -0.01 score units/year from treatment start to last clinic visit, indicating stabilization. Stabilization of neurological disease on miglustat was observed in all age groups, but the magnitude of the effect was greater in patients diagnosed in late childhood and in juveniles and adults. Stabilization of neurological disease was also observed in a subset of 19 patients with extended pre-treatment information. Overall, these data support previous clinical trial findings indicating clinically relevant beneficial effects of miglustat on neurological disease progression in patients with NP-C.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/uso terapêutico , Adolescente , Criança , Estudos de Coortes , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Masculino , Doença de Niemann-Pick Tipo C/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Fabry disease (OMIM 301 500) is an X-linked lysosomal storage disease. Neurological symptoms in Fabry disease mainly include stroke, acroparesthesia, cranial nerve palsies and autonomic dysfunction. We report on aseptic meningitis in Fabry patients. METHODS: Clinical analysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, treatment and outcome data were analysed in three cases of meningitis associated with Fabry disease. FINDINGS: Mean age at meningitis onset was 26.6 (24-28) years. Headache was present in all cases and fever in two cases. Meningitis was always diagnosed before Fabry disease. A familial history of Fabry disease was present in two cases. Non-neurological symptoms caused by Fabry disease were present in all cases. All patients also suffered stroke and sensorineural hearing loss. Cerebrospinal fluid (CSF) analysis showed pleocytosis (mean, 36; range: 8-76 cells/mm(3)) and a high protein level (mean, 63; range, 47-70 mg/dl). C-reactive protein blood levels and erythrocyte sedimentation rate were raised. Diagnosis was assessed by low alpha-galactosidase A dosage and/or gene mutation analysis in all cases. All patients were treated with enzyme replacement therapy (ERT). In two cases, lumbar puncture was repeatedly performed and there was no normalisation of CSF under ERT alone, at 9 and 24 months of follow-up, respectively. One patient who suffered intracranial hypertension was treated efficiently with steroids, associated with azathioprine. The fact that Fabry disease could be an auto-inflammatory disorder is discussed. INTERPRETATION: Fabry disease may cause aseptic meningitis.
Assuntos
Isquemia Encefálica/etiologia , Doença de Fabry/complicações , Meningite Asséptica/etiologia , Acidente Vascular Cerebral/etiologia , Adulto , Diagnóstico Precoce , Doença de Fabry/diagnóstico , Cefaleia/etiologia , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
We present a simplified classification of treatable inborn errors of metabolism (IEM) in three groups with a special focus on those disorders observed at adult age. Group 1 includes inborn errors (IE) of intermediary metabolism which give rise to an acute or chronic intoxication. It encompasses aminoacidopathies, organic acidurias (OA), urea cycle disorders (UCD), sugar intolerances, metal storage disorders and porphyrias. Clinical expression can be acute, systemic or involves a specific organ, it can strike in the neonatal period or later and intermittently from infancy to late adulthood. Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins. Group 2 includes IE of intermediary metabolism which affect the cytoplasmic and mitochondrial energetic processes. Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, creatine and pentose phosphate pathways; the latter are untreatable. Mitochondrial defects include respiratory chain disorders, Krebs cycle and pyruvate oxidation defects, mostly untreatable, and disorders of fatty acid oxidation and ketone bodies that are treatable. Group 3 involves cellular organelles and include lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. Among these, some lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies. Physicians can be faced with the possibility of a treatable IE in emergency, either in the neonatal period or late in infancy to adulthood, or as chronic and progressive symptoms, general (failure to thrive), neurological, or specific for various organs or systems. These symptoms and the simplified classification of IEM are summarized in seven tables.
Assuntos
Erros Inatos do Metabolismo/classificação , Adulto , Idade de Início , Encefalopatias Metabólicas Congênitas/classificação , Encefalopatias Metabólicas Congênitas/genética , Criança , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/genéticaRESUMO
BACKGROUND: Cobalamin C disease is the most common inborn error of cobalamin metabolism with an autosomal recessive mode of inheritance and mutations within the MMACHC gene. Clinical features, including systemic, haematological and neurological abnormalities, usually occur in the first year of life. Adolescent and adult onset presentations are rare. METHODS: We report on the clinical, molecular and imaging features in three patients aged 40, 42 and 42 years at the last follow-up. We examine these cases together with eight previously described cases to determine the clinical and molecular features of the disease in adults. RESULTS: Mean age at onset of clinical symptoms was 26 years; clinical features included predominant neurological disturbances and thromboembolic complications. White matter abnormalities on brain MRI were sometimes observed. Most patients (eight of nine patients investigated) were compound heterozygotes for the 271dupA mutation and a missense mutation. Intramuscular or intravenous hydroxycobalamin therapy stopped the progression of the disease and resulted in a better clinical outcome and favourable biological status in 7/9 treated cases, while the two untreated patients died quickly. CONCLUSIONS: As cobalamin C disease and related disorders of homocysteine metabolism are treatable conditions, homocysteinaemia should be included in the investigations of patients with progressive neurological deterioration, unexplained psychiatric disturbances or recurrent thromboembolic events.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas Congênitas/genética , Proteínas de Transporte/genética , Aberrações Cromossômicas , Análise Mutacional de DNA , Genes Recessivos/genética , Homocistinúria/genética , Ácido Metilmalônico/urina , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Ventrículos Cerebrais/patologia , Feminino , Seguimentos , Duplicação Gênica , Triagem de Portadores Genéticos , Homocistinúria/diagnóstico , Homocistinúria/tratamento farmacológico , Humanos , Hidroxocobalamina/administração & dosagem , Infusões Intravenosas , Injeções Intramusculares , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Exame Neurológico/efeitos dos fármacos , Oxirredutases , Medula Espinal/patologiaRESUMO
Inborn errors of metabolism (IEMs) may present in adolescence or adulthood with various movement disorders including parkinsonism, dystonia, chorea, tics or myoclonus. Main diseases causing movement disorders are metal-storage diseases, neurotransmitter synthesis defects, energy metabolism disorders and lysosomal storage diseases. IEMs should not be missed as many are treatable. Here we briefly review IEMs causing movement disorders in adolescence and adults and propose a simple diagnostic approach to guide metabolic investigations based on the clinical course of symptoms, the type of abnormal movements, and brain MRI abnormalities.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Transtornos dos Movimentos/diagnóstico , Adolescente , Adulto , Aminoácidos/metabolismo , Cobre/metabolismo , Metabolismo Energético , Gangliosidose GM1/diagnóstico , Humanos , Ferro/metabolismo , Neurotransmissores/biossínteseRESUMO
The discovery of a leukoencephalopathy is a frequent situation in neurological practice and the diagnostic approach is often difficult given the numerous possible aetiologies, which include multiple acquired causes and genetic diseases including inborn errors of metabolism (IEMs). It is now clear that IEMs can have their clinical onset from early infancy until late adulthood. These diseases are particularly important to recognize because specific treatments often exist. In this review, illustrated by personal observations, we give an overview of late-onset leukoencephalopathies caused by IEMs.
Assuntos
Encefalopatias Metabólicas Congênitas/etiologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/etiologia , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/etiologia , Encefalopatias Metabólicas Congênitas/diagnóstico , Transporte de Elétrons , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Homocisteína/metabolismo , Humanos , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/etiologia , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/etiologia , Imageamento por Ressonância Magnética , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/etiologia , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/etiologiaRESUMO
Spastic paraparesis is a general term describing progressive stiffness and weakness in the lower limbs caused by pyramidal tract lesions. This clinical situation is frequently encountered in adult neurology. The diagnostic survey is usually limited to searching for acquired causes (spinal cord compression, inflammatory, metabolic, infectious diseases) and the so-called 'hereditary spastic paraparesis'. Although poorly recognized by neurologists, spastic paraparesis is also one of the multiple presentations of inborn errors of metabolism (IEMs) in children and adults. Pyramidal signs are usually included in a diffuse neurological or systemic clinical picture; however, in some cases spastic paraparesis remains the only symptom for years. Since these metabolic causes are often treatable, it is essential to include them in the general diagnostic approach to spastic paraparesis. Here we review IEMs causing paraparesis in adults.
Assuntos
Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Paraparesia Espástica/complicações , Paraparesia Espástica/diagnóstico , Idade de Início , Árvores de Decisões , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Masculino , Metilação , Neurônios Motores/metabolismo , Paraparesia Espástica/genética , Medula Espinal/patologia , SíndromeRESUMO
Inborn errors of metabolism (IEMs) represent poorly known causes of epilepsy in adulthood. Although rare, these are important to recognize for several reasons: some IEMs respond to specific treatments, some antiepileptic drugs interfering with metabolic pathways may worsen the clinical condition, and specific genetic counselling can be provided. We review IEMs potentially revealed by epilepsy that can be encountered in an adult neurology department. We distinguished progressive myoclonic epilepsies (observed in some lysosomal storage diseases, respiratory chain disorders and Lafora disease), from other forms of epilepsies (observed in disorders of intermediary metabolism, including porphyrias, creatine metabolism defects, glucose transporter (GLUT-1) deficiency, Wilson disease or succinic semialdehyde dehydrogenase deficiency). We propose a diagnostic approach and point out clinical, radiological and electrophysiological features that suggest an IEM in an epileptic patient.
Assuntos
Epilepsia/diagnóstico , Epilepsia/etiologia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Adulto , Árvores de Decisões , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/complicações , Convulsões/complicações , SíndromeRESUMO
Although they are classically viewed as paediatric diseases, it is now recognized that inborn errors of metabolism (IEMs) can present at any age from childhood to adulthood. IEMs can involve the peripheral nervous system, mostly as part of a more diffuse neurological or systemic clinical picture. However, in some cases, the neuropathy can be the unique initial sign. Here, based on our personal experience and on a comprehensive literature analysis, we review IEMs causing neuropathies in adults. Diseases were classified according to the predominant type of neuropathies into (1) acute neuropathies, (2) mononeuropathy multiplex, (3) chronic axonal polyneuropathies, (4) chronic demyelinating polyneuropathies, (5) small-fibre neuropathies, and (6) lower motor neuron disease.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Doenças do Sistema Nervoso Periférico/etiologia , Doença Aguda , Adolescente , Adulto , Idade de Início , Doença Crônica , Árvores de Decisões , Doenças Desmielinizantes/etiologia , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Humanos , Erros Inatos do Metabolismo/classificação , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/epidemiologia , Pessoa de Meia-Idade , Mononeuropatias/etiologia , Doença dos Neurônios Motores/etiologia , Polineuropatias/etiologia , Terminologia como AssuntoRESUMO
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.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Doenças do Sistema Nervoso/etiologia , Adolescente , Adulto , Cognição , Árvores de Decisões , Diagnóstico Diferencial , Feminino , Humanos , Erros Inatos do Metabolismo/classificação , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/psicologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/psicologia , Testes Neuropsicológicos , Guias de Prática Clínica como Assunto , Terminologia como AssuntoRESUMO
INTRODUCTION: Homocysteine lies at an important metabolic branch point; it may be either converted to cystathionine through the transsulfuration pathway, or methylated to form methionine. Hyperhomocysteinemia may result from hereditary defects affecting one of these reactions. STATE OF ART: Cystathionine beta synthase or 5,10-methylenetetrahydrofolate deficiency can both result in homocystinuria. Current knowledge about biochemical mechanisms leading to hyperhomocysteinemia, clinical and radiological features, pathogenesis and treatment are reviewed, focusing on late onset forms of these diseases which can be diagnosed in adulthood. CBS deficiency is characterized by lens dislocation, skeletal abnormalities, neurologic disturbances and thromboembolism. MTHFR deficiency leads to various neurological symptoms, ranging from developmental delay to encephalopathy, including motor and gait abnormalities, seizures, psychiatric manifestations and rarely strokes. The treatment of CBS deficiency depends on vitamin B6, whereas MTHFR deficiency can be efficiently treated by vitamin B12, folic acid, and betaine. PERSPECTIVES: Homocysteinemia should be measured in patients with unexplained neurological manifestations or thromboembolism.
Assuntos
Homocistinúria/terapia , Tetra-Hidrofolato Desidrogenase/deficiência , Animais , Ácido Fólico/sangue , Homocisteína/sangue , Homocisteína/metabolismo , Homocistinúria/diagnóstico , Homocistinúria/genética , Homocistinúria/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/terapia , Tetra-Hidrofolato Desidrogenase/genéticaRESUMO
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.