Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis.

OBJECTIVE: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing. METHODS: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals. RESULTS: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. CONCLUSIONS: We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.

A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation.

OBJECTIVE: Distal hereditary motor neuropathies (dHMN) form a clinically and genetically heterogeneous group of disorders, characterized by muscle weakness and atrophy predominating at the distal part of the limbs, due to the progressive degeneration of motor neurons in the spinal cord. We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset. We performed a genetic study in this family to identify and characterized the causing mutation. METHODS: Homozygosity mapping strategy and sequencing of the candidate genes were performed. Expression studies were made on patient fibroblasts. Functional experiments were performed on a cellular model of motor neuron disease. RESULTS: We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b. Overexpression of both HSJ1a and HSJ1b reduced inclusion formation induced by the mutated SOD1-A4V in a neuronal cellular model. INTERPRETATION: HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family. Previous studies have shown that HSP40 proteins play a crucial role in protein aggregation and neurodegeneration in several neuronal types, in animal models and human diseases. Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons.

Aggressive familial ALS with unusual brain MRI and a SOD1 gene mutation.

We studied two sisters with rapidly progressing ALS starting at the ages of 46 and 48 years and leading to death after 14 months. Both fulfilled the El Escorial criteria for definite ALS and had marked upper motor neuron (UMN) predominance. Brain MRI, on fluid attenuation recovery (FLAIR) mode, showed outstanding hyperintensities of the precentral gyrus, centrum semiovale, corona radiata and along the corticospinal pathways in the brainstem. Screening for the SOD1 gene disclosed, at codon 140, a base substitution of adenine for thymine (GGT>CCA) known as the A140A 'silent' mutation since it does not change the amino acid (alanine) encoded for at that position. The severe UMN involvement and the fast progression of the disease may correlate with the MRI findings. It is also possible that the A140A mutation is not incidental; the mutated mRNA might be cytotoxic.

Long-lasting cognitive, physiological and hematological effects in rehabilitated, early dietary iron-deficiency adult rats, and improvement by treatment with a mixture of essential fatty acids.

Despite some successful interventions and the large research efforts on this topic, iron deficiency and anemia remain the most common nutritional disorders in the world today. Recently, several researchers indicated that early, induced, iron deficiency produced a long-lasting effect even if the hemoglobin and iron levels returned to normal values. Recent human studies showed that 10-12-year-old children, who were iron deficient at age 1 year, showed lower IQ scores. In this study, we tried to imitate this condition by inducing iron deficiency in rats at age 21 days, for 28 days, and then tested the rats on day 120. The former iron-deficient rats had normal hematological and motor activity values, and normal thermoregulatory response, but they were very slow learners compared to the control rats. Treatment with a mixture of essential fatty acids improved their learning capacity.

Pretreatment with a mixture of essential fatty acids protects rats from anxiogenic effects of REM deprivation.

Rapid eye movements (REM) deprivation induces complex deteriorating effects, which include brain morphological changes such as reduced neurogenesis processes, brain neurochemical and hormonal modifications, and cognitive decline. One of the major effects of REM deprivation is an increased anxiety level. The aim of this study was to examine the effects ofpretreatment with a specific mixture of essential fatty acids on the increased level of anxiety on the behavioral level (elevated plus maze), on the hormonal level (corticosterone level) and on the physiological level (thermoregulation). The results showed that pretreatment with a mixture of essential fatty acids protect the rats from the anxiolytic effects of REM deprivation. The effects of essential fatty acids on sleep mechanisms, on the one hand, and on anxiety levels, on the other hand, may explain the beneficial effects of the pretreatment.

Inspiratory muscle training and the perception of dyspnea in Parkinson's disease.

BACKGROUND: Pulmonary and respiratory muscle function impairment are common in patients with Parkinson's disease (PD). Inspiratory muscle training may improve strength, dyspnea and functional capacity in healthy subjects and in those with chronic obstructive pulmonary disease. This study investigated the effect of specific inspiratory muscle training (SIMT) on pulmonary functions, inspiratory muscle performance, dyspnea and quality of life, in patients with PD. PATIENTS AND METHODS: Twenty patients with PD (stage II and III Hoehn and Yahr scale) were recruited for the study and were divided into two groups: (a) ten patients who received SIMT and (b) ten patients who received sham training, for three months. Pulmonary functions, the respiratory muscle strength and endurance, the perception of dyspnea (POD) and the quality of life were studied before and within one week after the training period. All subjects trained daily, six times a week, each session consisting of 1/2 hour, for 12 weeks. RESULTS: Following the training period, there was a significant improvement, in the training group but not in the control group, in the following parameters: inspiratory muscle strength, (PImax, increased from 62.0 +/- 8.2 to 78.0 +/- 7.5 cm of H2O (p < 0.05), inspiratory muscle endurance (increased from 20.0 +/- 2.8 to 29.0 +/- 3.0 cm of H2O (p < 0.05), and the POD (decreased from 17.9 +/- 3.2 to 14.0 +/- 2.4 units (p < 0.05). There was a close correlation between the increase in the inspiratory muscle performance and the decrease in the POD. CONCLUSIONS: The inspiratory muscle performance may be improved by SIMT in patients with PD. This improvement is associated with a significant decrease in their POD.

A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32.

We updated the clinical features of a consanguineous Arab Israeli family, in which four of seven children were affected by spastic paraplegia complicated by skin pigmentary abnormalities. A genomewide linkage screen performed for the family identified a new locus (SPG23) for this form of hereditary spastic paraplegia, in an approximately 25cM region of chromosome 1q24-q32, with a peak logarithm of odds score of 3.05.

The role of polyunsaturated fatty acids in restoring the aging neuronal membrane.

In addition to a gradual loss of neurons in various brain regions, major biochemical changes in the brain affect the neuronal membrane that is the "site of action" for many essential functions including long-term potentiation (LTP), learning and memory, sleep, pain threshold, and thermoregulation. Normal physiological functioning includes the transmission of axonal information, regulation of membrane-bound enzymes, control of ionic channels and various receptors. All are highly dependent on membrane fluidity, where rigidity is increased during aging. The significantly higher level of cholesterol in aging neuronal membrane, the slow rate of cholesterol turnover, and the decreased level of total polyunsaturated fatty acids (PUFA) may result from poor passage rate via the blood-brain barrier, or from a decreased rate of incorporation into the membrane, or a decrease in the activities of delta-6 and delta-9 desaturase enzymes. The added oxidative stress, which leads to an increase of free radicals leading to a decrease in membrane fluidity, may respond to a restricted diet, and thereby overcome the damaging effects of the free radicals. A central focus of this review is that a specific ratio of n-3/n-6 PUFA can restore many of these age-related effects.

Respiratory muscle performance and the Perception of dyspnea in Parkinson's disease.

BACKGROUND: Pulmonary and respiratory muscle function impairment are common in patients with Parkinson's disease (PD). However, dyspnea is not a frequent complaint among these patients, although it is well documented that the intensity of dyspnea is related to the activity and the strength of the respiratory muscles. PATIENTS AND METHODS: We studied pulmonary function, respiratory muscle strength and endurance and the perception of dyspnea (POD) in 20 patients with PD (stage II and III Hoehn and Yahr scale) before and after their first daily L-dopa dose. Respiratory muscle strength was assessed by measuring the maximal inspiratory and expiratory mouth pressures (PImax and PEmax), at residual volume (RV) and total lung capacity (TLC) respectively. The POD was measured while the subject breathed against progressive load and dyspnea was rated using a visual analog scale. RESULTS: Respiratory muscle strength and endurance were decreased and the POD was increased during the off medication period compared to normal subjects. There was a nonsignificant trend to an increase in Plmax, PEmax and endurance after L-dopa intake. The POD of PD patients decreased (p<0.05) following medication, although, it remained increased (p<0.01) as compared to the normal subjects. Even if patients had spirometry data showing a mild restrictive pattern, before medication, both forced vital capacity (FVC) and forced expiratory volume (FEV)1 remained almost identical after L-dopa intake. CONCLUSIONS: Patients with PD have higher POD, compared to normal subjects and this increased perception is attenuated when the patients are on dopaminergic medication. The change in the POD is not related to changes in respiratory muscle performance or pulmonary functions. A central effect or a correction of uncoordinated respiratory movements by L-dopa may contribute to the decrease in POD following L-dopa treatment.