Yukiko Yamamoto-Watanabe

A Japanese ALS6 family with mutation R521C in the FUS/TLS gene: A clinical, pathological and genetic report

Here we report a Japanese family with amyotrophic lateral sclerosis (ALS) characterized by very rapid progression, high penetrance and an autosomal dominant mode of inheritance. The phenotype includes atrophy of sternocleidomastoideus muscles, bulbar involvement, weakness of neck muscles and proximal muscle atrophy. These clinical symptoms are reminiscent of myopathy. All patients examined had similar clinical symptoms, age at onset and disease duration. The proband was found to have mutation R521C in the FUS/TLS gene, and was diagnosed as having ALS6. Autopsy material was available from the mother of the proband and FUS-immunoreactive neuronal and glial cytoplasmic inclusions were observed in the anterior horn of the spinal cord. While atrophy and weakness of the sternocleidomastoideus muscle is not emphasized in previous reports, this symptom may be a clinical hallmark of ALS6.

Quantification of cystatin C in cerebrospinal fluid from various neurological disorders and correlation with G73A polymorphism in CST3

Cystatin C (CC) is a cysteine protease inhibitor abundantly expressed in the central nervous system. Bunina bodies, small eosinophilic intraneuronal inclusions, are stain positive for CC and are the most specific histological hallmark of amyotrophic lateral sclerosis (ALS). In this study, employing a latex turbidimetric immunoassay, levels of CC in cerebrospinal fluid (CSF) were quantified in 130 age-matched individuals with either a neurological disorder [ALS, Alzheimers disease (AD), Parkinsons disease (PD), tauopathy (TP), multiple system atrophy (MSA), chronic inflammatory demyelinating polyneuropathy (CIDP)] or no known neurological condition (normal control, NC). The CC level in CSF was found to be correlated with the age during the investigation but not the protein concentration. There was no difference in CC levels between NC and ALS or CIDP cases, whereas CC levels were significantly lower in MSA compared with NC. Of the 130 cases, 96 were genotyped, and G/A or A/A polymorphism at +73 within the CST3 gene was found in 28 individuals. The CC level was significantly lower in the combined group of G/A and A/A genotypes compared with G/G. The present data demonstrate that the level of CC in CSF should not be considered as a biomarker of ALS, but there is a correlation between CC levels and the CST3 genotype.

Amyloid β accelerates phosphorylation of tau and neurofibrillary tangle formation in an amyloid precursor protein and tau double-transgenic mouse model

In Alzheimers disease, Aβ deposits are considered the initial cardinal events that induce tauopathy secondarily. However, the relationship between Aβ amyloidosis and tauopathy has not been determined in detail. We produced double transgenic mice, 2×TgTau+/–APP+/–, by mating Tg2576 mice that exhibit Aβ amyloidosis and TgTauP301L mice that show tauopathy, and statistically analyzed the effect of Aβ accumulation on tauopathy. There was no significant difference in theprogression of Aβ accumulation among 2×TgTau+/–APP+/– and 1×TgTau−/–APP+/–, and tau accumulation among 2×TgTau+/−APP+/− and 1×Tg Tau+/–APP−/–. The appearance rates of phosphorylated tau developing in neurons and processes were significantly accelerated in 2×TgTau+/–APP+/– mice compared with those in 1×TgTau+/–APP−/– mice at 23 months of age. Accumulation of phosphorylated and confomationally altered tau and GSK3β in neuronal processes was accelerated in the white matter in 2×TgTau+/–APP+/–. The level of phosphorylated tau in the sarkosyl‐insoluble fraction was increased in 2×TgTau+/–APP+/– brains compared with that in 1×TgTau+/–APP−/– brains. Thus, Aβ amyloid partially enhances tauopathy through accumulation of insoluble, phosphorylated, and conformationally changed tau in neuronal cytoplasm and processes in the late stage.

Factors responsible for neurofibrillary tangles and neuronal cell losses in tauopathy

TgTauP301L mice that overexpress the mutant human tauP301L present in FTDP‐17 reproduce neurofibrillary tangles (NFTs), neuronal cell losses, memory disturbance, and substantial phenotypic variation. To demonstrate factors responsible for NFT formation and neuronal cell losses, sets of TgTauP301L for comparison with or without NFTs and neuronal cell losses were studied with oligonucleotide microarrays. Gene expressions were altered in biological pathways, including oxidative stress, apoptosis, mitochondrial fatty acid betaoxidation, inflammatory response pathway, and complement and coagulation cascade pathways. Among 24 altered genes, increased levels of apolipoprotein D (ApoD) and neuronal PAS domain protein 4 (Npas4) and decreased levels of doublecortin (DCX) and potassium channel, voltage‐gated, shaker‐related subfamily, β member 1 (Kcnab1) were found in the TgTauP301L with NFTs and neuronal cell losses, Alzheimers brains, and tauopathy brains. Thus, many biological pathways and novel molecules are associated with NFT formation and neuronal cell losses in tauopathy brains.

An Unusual Case of Elderly-Onset Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) With Multiple Cerebrovascular Risk Factors

Here we report a female patient with elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). At age 71, she developed gait disturbance, followed by memory disturbance 1 year later. She had been treated for hypertension and diabetes mellitus for 19 years. There apparently was low penetrance of disease. Magnetic resonance imaging (MRI) findings showed typical features of CADASIL, and the R607C mutation was detected in exon 11 in NOTCH3. This case strongly indicates that CADASIL should be considered when typical findings are observed on MRI even in cases of elderly onset with multiple cerebrovascular risk factors.

A novel mutation in the arylsulfatase A gene associated with adult-onset metachromatic leukodystrophy without clinical evidence of neuropathy.

! 45 and 47, respectively. His parents were not consanguineous and there is no previous history of similar neurological diseases in the family. Examination of the optic fundi showed no abnormal findings. He had no numbness, paresthesia, muscle weakness, muscle atrophy, abnormal involuntary movements or ataxia. Superficial sensation was normal, but vibratory sense was very slightly impaired in the lower limbs. The deep tendon reflexes were normal in the upper limbs. The patellar tendon reflexes were bilaterally increased, and the bilateral Achilles tendon reflexes were mildly diminished. The plantar responses were bilaterally extensor, but no spasticity was observed. Brain MRI revealed severe symmetrical white matter hyperintensities in the periventricular area on T2-weighted images and cerebral atrophy. Results from nerve conduction studies Dear Sir, Metachromatic leukodystrophy (MLD, MIM 250100) is an autosomal recessive hereditary disease characterized by neurological symptoms such as cognitive and behavioral abnormalities, ataxia and seizures [1] . MLD results from deficiency of arylsulfatase A (ASA), resulting in sulfatide accumulation in the central and peripheral nervous system [1] . A number of mutations in the ASA gene associated with decreased activity of ASA have been reported in patients with MLD [1] . Here we report a male patient with adult-onset MLD who is compound heterozygous for a novel nonsense mutation (C38X) (TGC ] TGA) and a known missense mutation (T409I) (ACT ] ATT) [2, 3] . Of note, this patient showed severely decreased nerve conduction velocities without obvious external clinical signs of neuropathy, normally a characteristic feature of MLD. The absence of clear external signs contributed to initial misdiagnosis. The 33-year-old male developed irritability and disorientation and visited a hospital department of psychiatry. There he was diagnosed with schizophrenia and, although he continued to take medications Received: November 21, 2007 Accepted: January 28, 2008 Published online: October 3, 2008