A case of infantile Alexander disease diagnosed by magnetic resonance imaging and genetic analysis

We encountered a male infant with infantile Alexander disease presenting with megalencephaly and hydrocephalus as a neonate and subtle seizures at 3 months of age. At 6 months of age, bulbar paralysis appeared. Brain magnetic resonance imaging (MRI) showed abnormal findings with white matter involvement and a characteristic periventricular rim, satisfying the diagnostic criteria proposed by van der Knaap, except for MRI contrast. R239H mutation of glial fibrillary acidic protein gene was identified, representing a common cause of infantile-type Alexander disease.     

Tumor-like enlargement of the optic chiasm in an infant with Alexander disease

We report a patient with infantile Alexander disease (AXD) due to the recurrent p.Arg79Cys GFAP mutation. In addition to typical AXD abnormalities, magnetic resonance imaging demonstrated a tumor-like lesion of the optic chiasm suggestive of a glioma. A transient papilloedema appeared during the follow-up and the lesion partially regressed despite a worsening of white matter involvement. Rare radiological and pathological tumor-like lesions have already been reported in AXD patients. This patient confirms that enlargement of the optic chiasm is a rare feature of AXD, possibly linked to abnormal astrocytic proliferation.     

Alexander disease with mild dorsal brainstem atrophy and infantile spasms

We present the case of a Japanese male infant with Alexander disease who developed infantile spasms at 8 months of age. The patient had a cluster of partial seizures at 4 months of age. He presented with mild general hypotonia and developmental delay. Macrocephaly was not observed. Brain magnetic resonance imaging (MRI) findings fulfilled all MRI-based criteria for the diagnosis of Alexander disease and revealed mild atrophy of the dorsal pons and medulla oblongata with abnormal intensities. DNA analysis disclosed a novel heterozygous missense mutation (c.1154 C>T, p.S385F) in the glial fibrillary acidic protein gene. At 8 months of age, tonic spasms occurred, and electroencephalography (EEG) revealed hypsarrhythmia. Lamotrigine effectively controlled the infantile spasms and improved the abnormal EEG findings. Although most patients with infantile Alexander disease have epilepsy, infantile spasms are rare. This comorbid condition may be associated with the distribution of the brain lesions and the age at onset of Alexander disease.     

TRH therapy in a patient with juvenile Alexander disease

Alexander disease is a rare disorder of the central nervous system caused by a de novo mutation in the glial fibrillary acidic protein (GFAP) gene. Unlike the much more common infantile form, the juvenile form is slowly progressive with bulbar, pyramidal and cerebellar signs. Herein, we report a 9-year old Japanese girl suffering from frequent vomiting, slurred speech and truncal ataxia. Juvenile Alexander disease was diagnosed by genetic analysis, which detected a novel GFAP mutation, D360V. We also describe our clinical success in treating this patient with thyrotropin releasing hormone (TRH).     

Cardio-facio-cutaneous syndrome with infantile spasms and delayed myelination

A girl with cardio-facio-cutaneous (CFC) syndrome due to a BRAF gene mutation (c.1454T→C, p.L485S) experienced repetitive epileptic spasms at the corrected age of 4 months. Electroencephalograms revealed hypsarrhythmia, and magnetic resonance imaging identified delayed myelination and a hypoplastic corpus callosum. Various antiepileptic treatments, including adrenocorticotropic hormone therapy, were ineffective, although transient seizure control was achieved by a ketogenic diet and clorazepate dipotassium. However, seizures with epileptic foci at the bilateral posterior temporal areas re-aggravated and remained intractable; severe psychomotor delay persisted. This case indicated that infantile spasms in CFC syndrome can be difficult to control and may be accompanied by severe psychomotor retardation and abnormal myelination.     

White matter changes mimicking a leukodystrophy in a patient with Mucopolysaccharidosis: characterization by MRI

Mucopolysaccharidosis (MPS) type I (alpha-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome).The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.     

A novel PLP mutation in a Japanese patient with mild Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a rare dysmyelinating disorder due to mutations in the proteolipid protein (PLP) gene. PLP gene mutations are responsible for a broad spectrum of disease, from the most severe form, connatal PMD, to a less severe form, spastic paraplegia 2 (SPG2). We describe here a very mild case of PMD in a patient who presented with nystagmus in early infancy and was unable to walk until 1 year 7 months of age. Brain magnetic resonance imaging (MRI) at 1 year 7 months of age revealed white matter abnormalities typical of PMD. Genetic testing revealed a novel mutation of the PLP gene (Gly197Arg). The patient presented with only mildly ataxic gait and slurred speech at the age of 4 years. Gly197Arg is the first novel mutation located within exon 4 of the PLP gene and associated with mild PMD/SPG2 in a Japanese patient.     

Expansion of the first polyalanine tract of the ARX gene in a boy presenting with generalized dystonia in the absence of infantile spasms

Mutations in the Aristaless-related homeobox (ARX) gene are associated with pleiotropic phenotypes including infantile spasms, mental retardation and dystonia. However, relatively consistent genotype-phenotype correlations have been emphasized in prior reports. We report a boy presenting with mental retardation, tonic seizures and dystonia but without infantile spasms. Gene sequencing detected an additional seven GCG repeats in the first polyalanine tract of the ARX gene, a mutation which leads to an expansion of the normal 16 alanine residues to 23. The same ARX gene mutation has been reported in patients with infantile spasms, but was absent in the present case. This finding highlights the diverse phenotypic spectrum that may result from ARX gene mutations.     

Autosomal dominant palatal myoclonus and spinal cord atrophy

We report a new family with palatal myoclonus, pyramidal tract signs, cerebellar signs, marked atrophy of the medulla oblongata and spinal cord, and autosomal dominant inheritance. These findings were almost identical with those in patients previously reported to have histopathologically confirmed adult-onset Alexander disease. Recently, heterozygous point mutations in the coding region of glial fibrillary acidic protein (GFAP) in patients with an infantile form of Alexander disease have been reported. We found a new heterozygous amino acid substitution, Val87Gly in exon 1 of GFAP, in the affected individuals in this family but not in 100 spinocerebellar ataxia (SCA) patients and 100 controls. Therefore, this family might have new clinical entities related to adult-onset Alexander disease and GFAP mutation.     

A novel mutation in an atypical presentation of the rare infantile Farber disease

Background: Farber disease (MIM 228000) is a rare autosomal recessive condition caused by deficiency of lysosomal acid ceramidase (EC 3.5.1.23). The disease presents classically during the infantile period with a characteristic triad of clinical manifestations: (a) painful joints, (b) subcutaneous nodules, and (c) progressive hoarseness due to laryngeal involvement. All cases reported in the literature to date have presented with the above features, except for the neonatal-visceral subtype. Methods: Here we describe a 2-year-old female, a product of a non-consanguineous Emirati union, who was quite well until 8 months of age when presented with failure to thrive, developmental delay with relative sparing of cognitive function, cherry-red spot, painful joint, progressive limitation of joint movement, and hoarseness of voice. The sibling of patient died with similar presentation and the nerve biopsy of deceased sibling showed features consistent with Farber disease. Results: Gene sequencing of the ASAHI gene confirmed the diagnosis of Farber disease. Our patient has two heterozygous novel mutations, one in exon 8 (c.533 T > C) and the other in exon 13 (c.1144 A > C). The carrier status of the parents was confirmed. Conclusions: Farber disease is well known for its striking unique triad of symptoms. This study demonstrates that not all the cases essentially present with subcutaneous nodules which is considered a hallmark of the disease.     

雷帕霉素治疗结节性硬化症合并婴儿痉挛症一例报告并文献复习

目的 探讨雷帕霉素治疗结节性硬化症合并婴儿痉挛症的临床疗效. 方法 对解放军总医院儿童医学中心2011年6月收治的1例结节性硬化症合并婴儿痉挛症患儿应用雷帕霉素治疗前后的临床表现、辅助检查方法、治疗结果等进行回顾性分析. 结果 患儿有明显的皮肤损害,主要表现为色素脱失斑,同时合并婴儿痉挛症,头颅MRI及CT均有异常改变.患儿应用雷帕霉素治疗3个月后可见色素脱失减轻,痉挛发作较前明显减少,头颅MRI显示室管膜下结节较前减小,脑电图较前改善,智能发育进步,且治疗过程中未见明显不良反应. 结论 应用雷帕霉素治疗结节性硬化症合并婴儿痉挛症有显著疗效,安全性好.     

Myeloradiculitis caused by Cryptococcus neoformans infection in a patient with ulcerative colitis: a neuropathological study

Meningitis is the most common feature of cryptococcal infection of the nervous system. We herein describe the case of a 48-year-old man with fulminant cryptococcal myeloradiculitis, whose initial symptoms were impotence, dysuria and weakness of the lower extremities. He had been administered prednisolone and azathioprine for 7years for ulcerative colitis before onset of myeloradiculitis. He finally developed meningoencephalitis and died 2 months after onset despite treatment with amphotericin B and flucytosine. Post-mortem examination revealed numerous infiltrations of cryptococci in the spinal roots as well as in the meninges and subarachnoid space. Inflammatory cells and cryptococci had infiltrated the vessel walls in the spinal cord, and this was accompanied by necrotizing myelopathy. Myeloradiculitis is rare in cryptococcal infection, and this is the first case report to demonstrate direct cryptococcal infection in the spinal roots. Cryptococcal infection should be considered while managing myeloradiculopathy of unknown etiology, especially in immunocompromised patients.     

Regressive changes of astroglia in white matter lesions in cerebrovascular disease and Alzheimer’s disease patients

The pathogenesis of white matter lesions, which are frequently found in ischemic cerebrovascular disease and Alzheimer’s disease, remains unclear. Using light and electron microscopic immunohistochemistry for glial fibrillary acidic protein (GFAP) as a marker, the present study focused on the role of astroglia which show characteristic morphological alterations. Of 29 brains of patients with cerebrovascular disease and Alzheimer’s disease, 4 brains showed extensive swelling and vacuolation of white matter astroglia with their processes disintegrated and beaded (termed clasmatodendrosis). No such cells were observed in 6 control patients. Clasmatodendritic astroglia were not intensely eosinophilic using hematoxylin and eosin staining and included large lipophilic granules in their perikarya. These astroglia were immunoreactive for serum proteins such as immunoglobulins, fibrinogen and complement C3, C1q and C3d, as well as for proteins which are known to increase in reactive astroglia, such as vimentin, α-B crystallin, apolipoprotein-E and laminin. Double labeling for GFAP and microglial cell markers indicated that these cells were of astroglial lineage. Immunoelectron microscopy for GFAP revealed that clasmatodendritic astroglia had condensed chromatin, lysosomes and large membrane-bound osmiophilic cytoplasmic inclusions, which corresponded to the lipophilic granules observed with light microscopy. These cytochemical features collectively suggest that clasmatodendritic astroglia incorporate edema fluid and phagocytose cellular debris, and eventually degenerate as a result of cerebral edema. Received: 3 December 1996 / Revised, accepted: 24 January 1997     

Spontaneous tension pneumocephalus in a patient with subdural empyema

We report a 45-year old male who developed subdural empyema (SE) with tension pneumocephalus. The patient was admitted unconscious with tonic extensor response to pain. A “gas-forming” organism, Escherichia coli, was detected. Surgical evacuation of the pus and treatment with the appropriate antibiotic did not result in amelioration of his symptoms and the patient died. We identified a rare clinical situation when the SE cavity had a relatively large air loculus that was clearly related to gas-forming bacteria. It appeared that the patient had developed tension pneumocephalus related to the air produced by the pathogen. To our knowledge, this is the first report of a gas-forming organism in an abscess cavity that resulted in tension pneumocephalus and related symptoms.     

H型高血压患者血清B族维生素水平以及脑影像学变化的研究

目的 观察H型高血压患者血浆同型半胱氨酸(Hcy)及血清叶酸、维生素B12和患者脑白质的变化,为临床干预脑白质病变提供参考依据. 方法 选择大连市友谊医院神经内科、心内科自2010年4月至2011年3月收治的高血压患者110例(其中H型高血压组78例,单纯高血压组32例),选择同期健康体检者50例作为对照组,采用放射免疫分析法检测血浆Hcy及血清叶酸、维生素B12的水平,MRI检查并评价脑白质病变的级别. 结果 H型高血压患者m浆Hcy、血清叶酸、维生素B12水平高于单纯高血压组和对照组,差异有统计学意义(P＜0.05);3组受试者脑白质病变级别的差异有统计学意义(P＜0.05),由平均秩次判断,脑白质病变在H型高血压组表现明显,其次为单纯高m压组、对照组. 结论 H型高血压患者血中叶酸、维生素B12水平下降,脑白质病变损害严重,可能与高Hcy血症有关.     

Tangier disease phenotype diversity in dizygous twin sisters

Introduction

Tangier disease (TD) is a rare autosomal recessive disorder characterized by a deficiency or absence of high-density lipoprotein (HDL) caused by mutations in the adenotriphosphate-binding cassette transporter-1 gene (ABCA1). Mutations of ABCA1 lead to a defect in cellular cholesterol removal and to deposition of cholesterol esters throughout the body.

Observation

We report here on the case of a 53-year-old woman with a severe phenotype of TD. The patient had a dizygous twin sister who had only asymptomatic corneal opacities and thrombopenia.

Conclusion

This family demonstrates the wide intrafamilial phenotype diversity of TD.     

White matter changes in dementia with Lewy bodies and Alzheimer's disease: a tractography-based study

Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are different types of dementia. However, their clinical symptoms partially overlap and differential diagnosis is occasionally difficult. There is need for additional diagnostic criteria to reliably differentiate between these two conditions. Meanwhile, several imaging studies have showed inconsistent results between DLB and AD. The aim of this study was to use a tractography-based analysis to elucidate white matter alterations in subjects with DLB compared to those with AD and to controls. An understanding of the white matter connectivity differences between AD, DLB and controls will be helpful for differential diagnosis and an understanding of the pathophysiology. Twenty-six subjects with DLB, 26 with AD and 26 controls underwent magnetic resonance diffusion tensor imaging and neuropsychological assessment. Diffusion tensors were computed and fiber-tract maps were created using “dTV II” software. We measured mean fractional anisotropy (FA) values along the uncinate fasciculus (UNC), the inferior occipitofrontal fasciculus (IOFF) and the inferior longitudinal fasciculus (ILF). Both subjects with DLB and AD had lower FA values for the bilateral UNC than controls. Subjects with DLB exhibited significantly lower FA values on both sides of the IOFF and the left side of the ILF than those of controls. Although there were no significant differences between subjects with DLB and AD for any measurements, those with DLB exhibited lower FA values especially in visual-related white matter. These different changes in white matter tracts among groups could be helpful for differential diagnosis and an understanding of the pathophysiology.     

A novel method for evaluating brain function and microstructural changes in Parkinson's disease

In this study,microstructural brain damage in Parkinson’s disease patients was examined using diffusion tensor imaging and tract-based spatial statistics.The analyses revealed the presence of neuronal damage in the substantia nigra and putamen in the Parkinson’s disease patients.Moreover,disease symptoms worsened with increasing damage to the substantia nigra,confirming that the substantia nigra and basal ganglia are the main structures affected in Parkinson’s disease.We also found that microstructural damage to the putamen,caudate nucleus and frontal lobe positively correlated with depression.Based on the tract-based spatial statistics,various white matter tracts appeared to have microstructural damage,and this correlated with cognitive disorder and depression.Taken together,our results suggest that diffusion tensor imaging and tract-based spatial statistics can be used to effectively study brain function and microstructural changes in patients with Parkinson’s disease.Our novel findings should contribute to our understanding of the histopathological basis of cognitive dysfunction and depression in Parkinson’s disease.     

PRRT2 mutation in Japanese children with benign infantile epilepsy

Mutations in PRRT2 genes have been identified as a major cause of benign infantile epilepsy and/or paroxysmal kinesigenic dyskinesia. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We explored PRRT2 mutations in Japanese children who had had unprovoked infantile seizures or convulsion with mild gastroenteritis. The probands included 16 children with benign infantile epilepsy, 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. Statistical analyses were performed to identify differences in probands with benign infantile epilepsy according to the presence or absence of PRRT2 mutation. Among a total of 24 probands, PRRT2 mutations was identified only in 6 probands with benign infantile epilepsy. A common insertion mutation, c.649_650insC, was found in 5 families and a novel missense mutation, c.981C>G (I327M), in one. The family history of paroxysmal kinesigenic dyskinesia was more common in probands with PRRT2 mutations than in those without mutations. Our study revealed that PRRT2 mutations are common in Japanese patients with benign infantile epilepsy, especially in patients with a family history of paroxysmal kinesigenic dyskinesia.     

阿尔茨海默病合并白质病变患者的认知功能障碍特点分析

目的探讨阿尔茨海默病(AD)合并白质病变(WML)患者危险因素和认知功能障碍特点。方法临床收集轻度阿尔茨海默病患者77例,根据MRIT2加权像是否合并WML分为单纯AD组34例和阿尔茨海默病合并WML组43例,以78名年龄和教育程度相匹配的认知正常老年人为对照组,分别进行MMSE、数字广度测验、词语延迟回忆测验、词语流畅性测验、积木测验和画钟测验。结果 (1)与对照组和单纯AD病组相比,AD合并WML组高血压病和房颤的比例明显升高(P<0.05)。(2)与对照组相比,单纯AD组和AD合并WML组MMSE、数字广度测验、词语延迟回忆测验、词语流畅性测验、积木测验和画钟测验评分均明显降低(P<0.05)。(3)与单纯AD组相比,AD合并WML组词语流畅性测验、积木测验和画钟测验评分均显著降低(P<0.05)。结论高血压病、糖尿病和房颤可能是AD合并WML的危险因素;WML可加重AD患者视空间和执行功能障碍。