RESUMO
Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs due to pyramidal tract dysfunction. REEP2 mutations have been identified as a cause of "pure" HSP, SPG72, with both autosomal dominant and autosomal recessive inheritance. We describe a rare Nepalese family with early-onset pure-type HSP harboring a heterozygous REEP2 missense mutation (c.119T>G, p.Met40Arg). This is only the second SPG72 family with autosomal dominant inheritance. The proband presented slow and spastic gait at age 2 years and the symptoms progressed slowly. The proband's father and uncle presented even milder symptoms of pure spastic paraplegia. Our study may provide an opportunity to further study the genotype-phenotype correlation of SPG72.
Assuntos
Predisposição Genética para Doença , Proteínas de Membrana Transportadoras/genética , Paraplegia Espástica Hereditária/genética , Adulto , Idade de Início , Pré-Escolar , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Nepal/epidemiologia , Linhagem , Paraplegia Espástica Hereditária/epidemiologia , Paraplegia Espástica Hereditária/patologiaRESUMO
BACKGROUND: ALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A. CASE PRESENTATION: A Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine. CONCLUSIONS: Since the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.
Assuntos
Aldeído Desidrogenase/genética , Osso e Ossos/anormalidades , Catarata/complicações , Catarata/genética , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/genética , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Paraplegia Espástica Hereditária/complicações , Paraplegia Espástica Hereditária/genética , Adulto , Povo Asiático/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Proteínas da Mielina/genética , Linhagem , FenótipoRESUMO
We report the first family with a glycyl-tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot-Marie-Tooth disease (DI-CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI-CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Glicina-tRNA Ligase/genética , Adulto , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Condução Nervosa/fisiologia , Linhagem , Nervo Sural/patologia , Adulto JovemRESUMO
We report here a rare case of adult-onset multiloculated hydrocephalus (MLH) after Cryptococcal meningitis. A 63-year-old man had Cryptococcal ventriculitis in 2011, and he recovered with treatment of antimycotic drugs. However, he was admitted again because of disorientation and amnesia, and brain MRI showed dilation of the inferior horn of the left lateral ventricle. He underwent a ventriculoperitoneal shunt (VPS) for noncommunicating hydrocephalus in 2019, and the disorientation and amnesia improved. One year after the VPS, he was admitted because of urinary dysfunction and gait disturbance. Brain MRI showed dilation of the bilateral anterior horns of the lateral ventricles. He underwent an additional VPS into the space in 2020, and urinary dysfunction and gait disturbance improved. This case was supposed that the symptom in agreement with the dilated ventricle by MLH was shown.
Assuntos
Ventriculite Cerebral , Hidrocefalia , Meningite Criptocócica , Amnésia , Ventriculite Cerebral/diagnóstico por imagem , Ventriculite Cerebral/tratamento farmacológico , Ventriculite Cerebral/etiologia , Confusão , Encefalite , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Masculino , Pessoa de Meia-Idade , Mielite , NeoplasiasRESUMO
Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with mutations in the MAPT gene is a hereditary neurodegenerative tauopathy with various clinical phenotypes. We herein report the first Japanese patient with FTDP-17 caused by an IVS10+3G>A mutation in the MAPT gene, which is linked to an H1M haplotype. The present study suggests that the IVS10+3G>A mutation in the MAPT gene can have originated from a non-Caucasian population. In the disease course, myoclonus and respiratory failure can be observed. This study may expand on the clinical and genetic findings for FTDP-17 with mutations in the MAPT gene.
Assuntos
Família , Demência Frontotemporal/genética , Predisposição Genética para Doença , Mutação , Transtornos Parkinsonianos/genética , Fenótipo , Proteínas tau/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 17 , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
We report here the clinical presentation and subsequent autopsy of a 90-year-old man who developed small papules with pain and swelling in his right ear. On admission, he exhibited right facial nerve paralysis, neck stiffness and Kernig's sign. The cell count was elevated and the varicella-zoster virus-PCR was positive in the CSF. Brain magnetic resonance imaging showed hyperintense lesions in the left pons and left temporal lobe, in FLAIR images. We diagnosed the patient with Ramsay Hunt syndrome and meningoencephalitis due to varicella-zoster virus. Although the symptoms of meningitis improved following treatment with intravenous acyclovir (750 mg/day initially, raised to 1,125 mg/day), 16 days after admission, he died suddenly due to gastrointestinal hemorrhage. The autopsy findings included lymphocytic infiltration of the leptomeninges and perivascular space of the cerebrum, and slight parenchyma in the left temporal lobe and insula, as the main histological features. Encephalitis due to varicella zoster virus has been recognized as a vasculopathy affecting large and small vessels. Pathological confirmation is rare in varicella zoster virus meningoencephalitis.
Assuntos
Infarto Cerebral/etiologia , Herpes Zoster/etiologia , Meningoencefalite/etiologia , Dissinergia Cerebelar Mioclônica/complicações , Idoso de 80 Anos ou mais , Autopsia , Evolução Fatal , Humanos , MasculinoRESUMO
We report a 40-year-old man who presented with multiple bone pseudofractures after about 20 years from the onset of Wilson's disease (WD). At age 36, he first noticed pain in his left shoulder. At age 39, he had multiple chest pain. On neurologic examinations, dysarthria and dysphagia due to pseudobulbar palsy, rigidity and tremor on right upper lim were observed. WD was confirmed because of low levels of plasma cupper and ceruloplasmin in addition to ATP7B gene mutation. The chest X-ray revealed multiple fractures of the several ribs. We diagnosed osteomalacia due to Fanconi's syndrome because of hypophosphatemia and the impairment of renal tubules for WD. After administration of vitamin D, there happened no new bone pseudofractures. Although bone pseudofractures accompanied by Wilson's disease generally happen in childhood, we should be aware of this symptom even in adulthood.
Assuntos
Síndrome de Fanconi/etiologia , Fraturas Múltiplas/etiologia , Degeneração Hepatolenticular/complicações , Fraturas das Costelas/etiologia , Adenosina Trifosfatases/genética , Adulto , Biomarcadores/sangue , Proteínas de Transporte de Cátions/genética , Ceruloplasmina , Cobre/sangue , ATPases Transportadoras de Cobre , Síndrome de Fanconi/diagnóstico , Fraturas Múltiplas/diagnóstico por imagem , Fraturas Múltiplas/tratamento farmacológico , Degeneração Hepatolenticular/diagnóstico , Humanos , Masculino , Mutação , Osteomalacia/etiologia , Fraturas das Costelas/tratamento farmacológico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Vitamina D/administração & dosagemRESUMO
A 33-year-old woman was admitted due to disturbance of consciousness, dysarthria, dysphagia, sensory disturbances and weakness of the left upper limb after mycoplasma infection. She was treated with intravenous immunoglobulin and intravenous high-dose methylprednisolone as Bickerstaff brainstem encephalitis (BBE). On the 15th hospital day, reflex myoclonus appeared on her face, neck, body and limbs induced by techniques of jaw jerk reflex and patellar tendon reflex. The myoclonus was disappeared after two weeks in accordance with improvement of BBE. The transient reflex myoclonus may be originated from brainstem lesion which was affected by BBE. Reflex myoclonus is thought to be rare symptom in patient with BBE.
Assuntos
Tronco Encefálico , Encefalite/etiologia , Mioclonia/etiologia , Adulto , Autoanticorpos , Encefalite/tratamento farmacológico , Feminino , Gangliosídeos/imunologia , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Metilprednisolona/administração & dosagem , Infecções por Mycoplasma/complicações , Mioclonia/diagnóstico , Miografia , Pulsoterapia , Fatores de TempoRESUMO
A 52-year-old woman developed abnormal behavior and disturbance of consciousness subsequent to several days with a cold. On admission, she was very confused, with incoherent speech, and an inability to recognize family faces. Diffusion weighted MRI showed high intensity signal change in the bilateral medial temporal lobes, including the hippocampus. Cerebrospinal fluid examination was normal. Tests including various viral antibody titers provided no evidence of infection. Several neuronal antibodies including anti-VGKC and -NMDA receptor antibody were absent. Evidence of malignancy was not apparent. She was diagnosed with acute limbic encephalitis complicated by Sjögren's syndrome (SjS), due to the fact that she had a past history of SjS, elevation of anti-SS-A antibody, pleuritis and pericarditis. Her symptoms gradually improved after administration of steroids including pulse therapy; however, her amnesia remained for a long time. In diagnosing acute limbic encephalitis, we should consider SjS as an underlying disease, even though it is rare.
Assuntos
Encefalite Límbica/etiologia , Síndrome de Sjogren/complicações , Doença Aguda , Feminino , Hipocampo/patologia , Humanos , Encefalite Límbica/diagnóstico , Encefalite Límbica/tratamento farmacológico , Encefalite Límbica/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/patologia , Lobo Temporal/patologiaAssuntos
Hipotensão Ortostática/genética , Doença por Corpos de Lewy/genética , Doença de Parkinson/genética , alfa-Sinucleína/deficiência , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Feminino , Duplicação Gênica , Humanos , Hipotensão Ortostática/fisiopatologia , Japão , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Linhagem , Penetrância , alfa-Sinucleína/genéticaRESUMO
A 54-year-old man was admitted due to progressive gait disturbance and cognitive impairment. On MRI, a hyperintense region was observed in the periventricular white matter on FLAIR imaging, with Gd-enhancement in the choroid plexus and periventricular wall. Cerebrospinal fluid (CSF) examination showed marked abnormalities including a high white blood cell count (WBC, 360â cells/mm(3). 83% lymphocytes), an elevated protein level (1,416â mg/dl), a low glucose level (12â mg/dl), and elevated cryptococcal antigen with positive Indian ink staining. Cryptococcal ventriculitis was diagnosed. The patient was initially treated with liposomal amphotericin B, fluconazole, voriconazole, and flucytosine for 38 weeks, followed by administration of itraconazole and fluconazole with some improvement. The brain MRI after one month showed septum formation in the posterior horn, which was suggestive of ventriculitis. Although ventriculitis is rare, we should pay attention to the presence of ventriculitis due to cryptococcal infection in the central nervous system.
Assuntos
Ventriculite Cerebral/diagnóstico , Ventriculite Cerebral/microbiologia , Criptococose , Cryptococcus neoformans , Transtornos Neurológicos da Marcha/etiologia , Transtornos da Memória/etiologia , Antifúngicos/administração & dosagem , Antígenos de Fungos/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Ventriculite Cerebral/complicações , Ventriculite Cerebral/tratamento farmacológico , Cryptococcus neoformans/imunologia , Progressão da Doença , Quimioterapia Combinada , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Creutzfeldt-Jakob disease (CJD) presents with rapidly progressive dementia associated with several symptoms including pyramidal, extrapyramidal, and cerebellar signs. In Japan, patients with PRNP gene mutations comprise 18.3% of CJD cases. In the present study, we report a 74-year-old man with a double mutation in the PRNP gene. He showed dysarthria, gait disturbance, and cognitive impairment. High signal intensity was observed in the bilateral cortex on brain MRI in diffusion-weighted images. There were high total Tau protein and 14-3-3 protein levels in the cerebrospinal fluid. We diagnosed him as having CJD clinically, and analyzed the PRNP gene, which revealed a V180I mutation and a M232R one, i.e., a compound heterozygous status. In our patient, the disease has very slowly progressive (total disease course, 37 months). The V180I and M232R mutations are specific mutations to Japanese CJD patients. For patients with a double PRNP gene mutation, only V180I and M232R have been known. Patients with a double mutation (V180I /M232R) in the PRNP gene might show an atypical disease course with a slow progression.
Assuntos
Síndrome de Creutzfeldt-Jakob/genética , Mutação , Príons/genética , Idoso , Humanos , Masculino , Proteínas PriônicasRESUMO
OBJECTIVE: In amyotrophic lateral sclerosis (ALS), not only impairment of motor neurons but also impairment of the autonomic nervous system has been demonstrated by previous physiological studies. Several investigators have reported a correlation between autonomic dysfunction and respiratory dysfunction in ALS. This study analyzed the relation between parameters of respiratory function and muscle sympathetic nerve activity (MSNA) in a large number of ALS patients. METHODS: In 50 patients with ALS (mean age (SD): 62.1 (11.7) years), MSNA, heart rate (HR), and blood pressure (BP) were recorded simultaneously. The arterial oxygen content (PaO2), arterial carbon dioxide content (PaCO2), and forced vital capacity expressed as a percentage of the predicted value for healthy controls (%VC) were determined as parameters of respiratory function. RESULTS: There were no significant correlations between MSNA and PaO2, PaCO2, %VC, or the disability score. Analysis of chronological changes in 14 patients examined twice showed that the disability score and PaCO2 were significantly increased, and %VC was significantly more decreased at the second examination compared with the first examination (p<0.01 and p<0.05, respectively). In contrast, HR, BP, burst rate of MSNA, and age-adjusted MSNA exhibited no significant changes between the first and second examinations. CONCLUSIONS: These findings show that gradual deterioration of respiratory function in ALS patients is not associated with changes of quantitative MSNA parameters, which may suggest that abnormality of the autonomic nervous system is a primary feature of ALS.