Anti-TNF-α therapy in the management of severe neurosarcoidosis: a report of five cases from a single centre and literature review.

Neurologic manifestations are found in 5-15 % of patients with sarcoidosis. This granulomatous disease may affect any part of the peripheral or the central nervous system, being potentially severe and difficult to treat. Corticosteroids are the cornerstone of therapy in sarcoidosis. However, some patients become resistant or experience side effects to corticosteroids. In these patients, second line therapies including immunosuppressive drugs such as methotrexate, azathioprine, mycophenolate, cyclophosphamide and leflunomide have been used. Anti-TNF-α drugs have been proposed as a therapeutic option for those who are refractory to immunosuppressive drugs or initially in cases of severe sarcoidosis. We report on 5 patients with neurosarcoidosis treated with anti-TNF-α drugs in our center. A literature review of patients with neurosarcoidosis treated with anti-TNF-α drugs was conducted. In our series successful response to anti-TNF-α therapy was achieved. However, the high frequency of relapses following anti-TNF-α discontinuation makes necessary a close follow-up of these patients when the biologic agent is stopped.

Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

Reduced serum progranulin level might be associated with Parkinson's disease risk.

BACKGROUND AND PURPOSE: Common genetic variants (rs5848 and rs646776) have been reported as regulators of blood progranulin (GRN) levels in healthy individuals. METHODS: To assess the influence of rs5848 and rs646776 polymorphisms in both serum GRN level and risk for common neurodegenerative diseases, we studied 304 patients with Parkinson's disease (PD), 217 individuals with Alzheimer's disease, 131 subjects with mild cognitive impairment, and 126 controls. RESULTS: The mean concentration of GRN in the serum of patients with PD (319.6 ng/ml) was significantly lower than that of controls (371.5 ng/ml; P = 0.009), whereas there were no significant differences between other groups. Rs646776 minor allele carriers had lower serum GRN levels in each of the four subgroups. There was no correlation between rs5848 genotypes and serum GRN concentrations. Genotype frequencies of both polymorphisms did not differ between groups. CONCLUSION: Reduced circulating GRN levels might be associated with PD risk by pathogenic factors different from rs5848 and rs646776 polymorphisms.

[Guidelines for molecular diagnosis of Charcot-Marie-Tooth disease]. / Guía diagnóstica en el paciente con enfermedad de Charcot-Marie-Tooth.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy. In accordance with the inheritance pattern and degree of slowing of motor conduction velocity (MCV) of the median nerve, CMT encompasses five main forms: CMT1 (autosomal dominant [AD] or X-linked transmission and MCV < 38 m/s); CMT2 (AD or X-linked transmission and MCV > 38 m/s); CMT4 (autosomal recessive [AR] and severe slowing of MCV); AR-CMT2 (AR transmission and MCV > 38 m/s); and DI-CMT (intermediate form with AD transmission and MCV between 30 and 40 m/s). In spite of its stereotyped semiological repertoire (basically, symptoms and signs of sensory-motor polyneuropathy and pes cavus), CMT seems to be one of the most complex hereditary neurodegenerative syndromes, 31 causative genes having been cloned. DEVELOPMENT: This paper is aimed at performing a nosological review of the disease, emphasising the guidelines for its molecular diagnosis. Genetic epidemiological studies and genotypes reported in Spanish patients are revised. CONCLUSIONS: In the great majority of CMT cases, mutations involve a reduced number of genes, namely: for CMT1, PMP22, GJB1 and MPZ; for CMT2, MFN2 and GJB1; for CMT4, GDAP1, and NDRG1, HK1 and SH3TC2 (gypsies); for AR-CMT2, GDAP1; and for DI-CMT, GJB1 and MPZ. Given their low prevalence, mutations in other pathogenic genes should be investigated after discarding the previous ones. There is no place for the indiscriminate use of diagnostic CMT genetic panels.

Axonal pathology in early stages of Guillain-Barré syndrome.

INTRODUCTION: Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disease of the peripheral nervous system. It may be classified into 2 main subtypes: demyelinating (AIDP) and axonal (AMAN). This study aims to analyse the mechanisms of axonal damage in the early stages of GBS (within 10 days of onset). DEVELOPMENT: We analysed histological, electrophysiological, and imaging findings from patients with AIDP and AMAN, and compared them to those of an animal model of myelin P2 protein-induced experimental allergic neuritis. Inflammatory oedema of the spinal nerve roots and spinal nerves is the initial lesion in GBS. The spinal nerves of patients with fatal AIDP may show ischaemic lesions in the endoneurium, which suggests that endoneurial inflammation may increase endoneurial fluid pressure, reducing transperineurial blood flow, potentially leading to conduction failure and eventually to axonal degeneration. In patients with AMAN associated with anti-ganglioside antibodies, nerve conduction block secondary to nodal sodium channel dysfunction may affect the proximal, intermediate, and distal nerve trunks. In addition to the mechanisms involved in AIDP, active axonal degeneration in AMAN may be associated with nodal axolemma disruption caused by anti-ganglioside antibodies. CONCLUSION: Inflammatory oedema of the proximal nerve trunks can be observed in early stages of GBS, and it may cause nerve conduction failure and active axonal degeneration.

Multimodal neurophysiological study of SCA2 and SCA3 autosomal dominant hereditary spinocerebellar ataxias.

BACKGROUND: The spinocerebellar ataxias (SCA) are a group of genetic neurodegenerative diseases, clinically and pathologically heterogeneous, characterized by slowly progressive cerebellar ataxia. OBJECTIVE: To identify the neural pathways affected neurophysiologically, correlate the findings with the size of CAG expansion and determine the contribution of neurophysiological studies in the differential diagnosis of the two most prevalent genotypes in Spain, SCA2 and SCA3. METHOD: We examined 10 SCA2 and 12 SCA3 patients by electromyography, electroneurography motor and sensory, multimodal evoked potentials, transcranial magnetic stimulation, blink reflex and masseter reflex. In the statistical analysis linear regression studies were performed, and the, Spearman correlation coefficient and nonparametric test U of Mann-Whitney calculated. RESULTS: We detected the presence of a predominantly sensory neuropathy in most SCA2 patients and in a minority of SCA3 patients; the central somatosensory pathway showed significant defects in both populations. We recorded a high incidence of brain-stem electrophysiological abnormalities in SCA2 patients; in particular, the masseter reflex was abnormal in all SCA2 patients, remaining intact in all SCA3 patients. The study of cortico-spinal pathway showed a greater percentage of abnormalities in both populations than in previous studies. CONCLUSION: SCA2 is a model of sensory neuronopathy with central and peripheral axonopathy. Studies of brain-stem pathways show a higher incidence of abnormalities in SCA2 patients. SCA3 patients show major changes in the central somatosensory pathway with relative normality of the electroneurography. The masseter reflex was the most useful test in the differential diagnosis between both genotypes.

Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3ß) on the risk of Parkinson's disease.

BACKGROUND: Oxidative stress is a central factor in the pathogenesis of Parkinson's disease (PD). Heme oxygenase-1 (HO-1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase-3beta (GSK3beta) activity. Underexpression of HO-1 in concert with an upregulation of GSK3beta would result in a less effective antioxidant response and might increase the risk of PD. METHODS: We examined two functional polymorphism in the promoter regions of HO-1 (-413, rs2071746) and GSK3beta (-157, rs6438552) in a group of 251 Spanish patients with PD and 234 controls. RESULTS: Subjects carrying both the HO-1 (-413, rs2071746) TT genotype and the GSK3beta (-157, rs6438552) TT genotype had a four times higher risk of developing PD than subjects without these genotypes (adjusted by age and sex OR = 4.12; 95% CI = 1.45-11.71; Bonferroni corrected P = 0.024). CONCLUSIONS: Considering synergistic effects between polymorphisms in oxidative stress-related genes may help in determining the risk profile for PD.

Serum heme oxygenase-1 levels are increased in Parkinson's disease but not in Alzheimer's disease.

OBJECTIVE: Oxidative stress is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD), and heme oxygenase-1 (HO-1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up-regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO-1 in peripheral blood of PD and AD patients remains unresolved. METHODS: We measured serum HO-1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. RESULTS: The median serum concentration of HO-1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO-1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO-1 did not differ significantly between AD patients and AD controls. CONCLUSION: The increase of serum HO-1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.

Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK-3beta) and Alzheimer's disease risk.

OBJECTIVE: Glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK-3beta genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. METHODS: In a case-control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3'-UTR, rs735555) and GSK-3beta (-50, rs334558) polymorphisms on susceptibility to AD. RESULTS: Subjects carrying both the CDK5R1 (3'-UTR, rs735555) AA genotype and the GSK-3beta (-50, rs334558) CC genotype had a 12.5-fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01-0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. CONCLUSION: These data support a role for tau phosphorylation regulating genes in risk for AD.

Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis. / ¿Por qué degeneran las motoneuronas? Actualización en la patogenia de la esclerosis lateral amiotrófica.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. DEVELOPMENT: This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration. CONCLUSIONS: ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established.

Autosomal-dominant distal myopathy with a myotilin S55F mutation: sorting out the phenotype.

OBJECTIVE: To describe the clinical phenotype of an autosomal-dominant pedigree with myotilinopathy. METHODS: Two symptomatic patients and six asymptomatic gene mutation carriers were examined. We performed serum chemistry, electrophysiological assessments, magnetic resonance imaging (MRI) of lower limb musculature, histochemical and immunohistochemical studies of a muscle biopsy and mutation analysis of the myotilin gene. RESULTS: Both symptomatic patients, aged 76 and 61 years, presented with late-onset, distal lower-limb weakness involving the ankle and toe flexo-extensor muscles extending up to the thigh muscles; there was mild weakness of the intrinsic hand musculature in the eldest patient. Electromyography revealed a myopathic pattern. Serum creatine kinase levels were slightly elevated. Muscle biopsy revealed myopathic changes with myotilin- and desmin-positive aggregates. Gene sequencing identified a myotilin S55F mutation. In both patients, MRI showed moderate to severe fatty atrophy of all four leg muscle compartments, extending up to the thigh musculature, mainly involving the biceps, femoris, semimembranosus, vasti and glutei muscles; intrinsic foot musculature was involved but to a lesser degree. In all six gene mutation carriers, aged from 21 to 63 years, clinical examinations showed no myopathic signs. MRI was normal in the youngest individual, whereas in the remaining five individuals the outstanding finding was fatty infiltration of the soleus muscles. CONCLUSIONS: Myotilin S55F mutations may cause a clinically distinct autosomal-dominant late-onset and lower-limb distal myopathic syndrome involving all four leg muscle compartments. MRI helps to reliably depict the topography of fatty muscle atrophy and to detect early leg muscle changes in asymptomatic gene mutation carriers.

Gene-gene interaction between 14-3-3 zeta and butyrylcholinesterase modulates Alzheimer's disease risk.

A loss in the regulatory mechanism that controls tau phosphorylation in normal brain is suggested to cause tau hyperphosphorylation in Alzheimer's disease (AD) brain and the development of neurofibrillary tangles (NFT). 14-3-3 zeta protein and butyrylcholinesterase (BCHE) are associated with NFT in AD brain and stimulate tau phosphorylation. In a case-control study in 231 AD patients and 221 healthy controls, we examined whether the combined effects between 14-3-3 zeta (rs964917 and rs983583) and BCHE (K variant) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the BCHE K allele and the 14-3-3 zeta rs964917 G/G genotype (OR = 0.44, 95% CI = 0.20-0.95, P = 0.03), or 14-3-3 zeta rs983583 G/G genotype (OR = 0.46, 95% CI = 0.21-1.00, P = 0.05) had a lower risk of developing AD than subjects without these risk genotypes. Considering synergistic effects between polymorphisms in tau phosphorylation relate-genes may help in determining the risk profile for AD.

Inflammation-related genes and the risk of Parkinson's disease: a multilocus approach.

For the first time, the multilocus approach by the set-association method has been applied for the analysis of a cluster of five genes [tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-8, IL-1alpha and IL-10] involved in the brain neuroinflammatory pathway in Parkinson's disease (PD), in a well-defined group of 197 PD patients and 173 control subjects from Spain. Set-association analysis did not reveal an independent or an interactive effect of these inflammatory genes on the PD risk.

Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer's disease.

BACKGROUND: Variants in genes encoding enzymes involved in production, aggregation or degradation of beta-amyloid are potential risk factors for sporadic Alzheimer's disease (AD). METHODS: Meta-analyses on AD association with BACE1 exon 5, BACE1 intron 5, FE65 intron 13, CYP46 intron 2, alpha(1)-antichymotrypsine Ala17Thr, bleomycin hydrolase I443V, lectin-like oxidized low-density lipoprotein receptor (OLR1) 3'-UTR (+1071) and (+1073), and very-low-density lipoprotein receptor (VLDLR) 5'-UTR (CGG-repeat) polymorphisms. RESULTS: In BACE1 exon 5, genotype CC+CT acts as a protective factor in Apolipoprotein E (ApoE) epsilon 4 carriers [odds ratio (OR) = 0.57; 95% confidence interval (CI): 0.38-0.88], and as a risk factor in ApoE epsilon 4 non-carriers (OR = 1.33; 95% CI: 1.00-1.78). OLR1 3'-UTR (+1073) allele C is associated with increased risk (OR = 1.23; 95% CI: 1.01-1.50). VLDLR 5'-UTR genotype 2 is associated with increased risk (OR = 1.70; 95% CI: 1.09-2.63) in the Asian population and is protective (OR = 0.48; 95% CI: 0.26-0.86) in the non-Asian population. Other studied polymorphisms are not associated with AD. CONCLUSIONS: The overall impact on AD risk of the genes for which meta-analyses are now available is rather limited. Additional meta-analyses of other different genes encoding for A beta production, aggregation and degradation mediators might help in determining the risk profile for AD.

Acute motor conduction block neuropathy pattern occurring in the course of an acute inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To describe the case of a young woman with the diagnosis of acute inflammatory demyelinating polyradiculoneuropathy (AIDP), who during the course of the disease developed an electrophysiologic pattern of acute motor conduction block neuropathy (AMCBN). METHODS: Electrophysiologic techniques including needle EMG, standard motor and sensory nerve conductions studies, and somatosensory evoked potentials were carried out over the four months after symptom onset. RESULTS: The results of four neurophysiological studies, performed on Days 14, 26, 35 and 125 after symptomatic onset are reported. All immunological determinations including antiganglioside antibodies (GM1, GM2, GM3, asialoGM1, GD1a, GD1b, GD3, GQ1b and GT1b) were negative. The patient had a favorable evolution following treatment with intravenous immunoglobulins (IVIg). CONCLUSIONS: We conclude that the electrophysiologic hallmark of AMCBN may occur in the course of AIDP. Serial investigation including proximal, intermediate and distal segments of all nerves from upper and lower limbs is essential for its detection.

Axonal pathology in early stages of Guillain-Barré syndrome. / Patología axonal en la fase precoz del síndrome de Guillain-Barré.

INTRODUCTION: Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disease of the peripheral nervous system. It may be classified into 2 main subtypes: demyelinating (AIDP) and axonal (AMAN). This study aims to analyse the mechanisms of axonal damage in the early stages of GBS (within 10days of onset). DEVELOPMENT: We analysed histological, electrophysiological, and imaging findings from patients with AIDP and AMAN, and compared them to those of an animal model of myelin P2 protein-induced experimental allergic neuritis. Inflammatory oedema of the spinal nerve roots and spinal nerves is the initial lesion in GBS. The spinal nerves of patients with fatal AIDP may show ischaemic lesions in the endoneurium, which suggests that endoneurial inflammation may increase endoneurial fluid pressure, reducing transperineurial blood flow, potentially leading to conduction failure and eventually to axonal degeneration. In patients with AMAN associated with anti-ganglioside antibodies, nerve conduction block secondary to nodal sodium channel dysfunction may affect the proximal, intermediate, and distal nerve trunks. In addition to the mechanisms involved in AIDP, active axonal degeneration in AMAN may be associated with nodal axolemma disruption caused by anti-ganglioside antibodies. CONCLUSION: Inflammatory oedema of the proximal nerve trunks can be observed in early stages of GBS, and it may cause nerve conduction failure and active axonal degeneration.

Patología axonal en la fase precoz del síndrome de Guillain-Barré / Axonal pathology in early stages of Guillain-Barré syndrome

Introducción: El síndrome de Guillain-Barré (SGB) es un trastorno agudo e inmuno-mediado del sistema nervioso periférico. Sus dos subtipos básicos son el desmielinizante (AIDP) y el axonal (AMAN). El objetivo de este trabajo es abordar los mecanismos de daño axonal en la fase precoz del síndrome (≤ 10 días del inicio sintomático). Desarrollo: Se han revisado aspectos histológicos, neurofisiológicos y de imagen descritos tanto en la AIDP como en la AMAN. Los hallazgos en la patología humana han sido contrastados con lo reportado en la neuritis alérgica experimental inducida por el componente P2 de la mielina. El edema inflamatorio de las raíces raquídeas y de los nervios espinales constituye la lesión inicial en el SGB. En los nervios espinales de casos fatales de AIDP se ha demostrado la presencia de lesiones isquémicas endoneurales, lo cual sugiere que la inflamación puede condicionar un incremento de su presión con reducción del flujo sanguíneo transperineural, que puede desencadenar fallo de la conducción y eventualmente degeneración axonal secundaria. En la AMAN con anticuerpos antigangliósido el bloqueo de la conducción por disfunción de los canales del sodio nodales puede afectar a troncos nerviosos proximales, intermedios y distales. Además de los mecanismos que operan en la AIDP, la degeneración axonal activa en la AMAN puede ir ligada a la disrupción del axolema nodal inducida por los anticuerpos anti-gangliósido. Conclusión: En la fase precoz del SGB hay edema inflamatorio de los troncos nerviosos proximales, que puede condicionar fallo de la conducción nerviosa y degeneración axonal activa. (AU)

Introduction: Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disease of the peripheral nervous system. It may be classified into 2 main subtypes: demyelinating (AIDP) and axonal (AMAN). This study aims to analyse the mechanisms of axonal damage in the early stages of GBS (within 10 days of onset). Development: We analysed histological, electrophysiological, and imaging findings from patients with AIDP and AMAN, and compared them to those of an animal model of myelin P2 protein-induced experimental allergic neuritis. Inflammatory oedema of the spinal nerve roots and spinal nerves is the initial lesion in GBS. The spinal nerves of patients with fatal AIDP may show ischaemic lesions in the endoneurium, which suggests that endoneurial inflammation may increase endoneurial fluid pressure, reducing transperineurial blood flow, potentially leading to conduction failure and eventually to axonal degeneration. In patients with AMAN associated with anti-ganglioside antibodies, nerve conduction block secondary to nodal sodium channel dysfunction may affect the proximal, intermediate, and distal nerve trunks. In addition to the mechanisms involved in AIDP, active axonal degeneration in AMAN may be associated with nodal axolemma disruption caused by anti-ganglioside antibodies. Conclusion: Inflammatory oedema of the proximal nerve trunks can be observed in early stages of GBS, and it may cause nerve conduction failure and active axonal degeneration. (AU)

Charcot-Marie-Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study.

OBJECTIVE: To describe a large pedigree with Charcot-Marie-Tooth disease type 1A (CMT1A) duplication in which severe pelvic and thigh musculature weakness occurred in two patients, detected by analysing the leg muscle atrophy pattern on magnetic resonance imaging (MRI). METHODS: The pedigree comprised 18 patients, aged between 15 and 85 (median 46) years, who were serially evaluated for up to three decades. All 18 patients and 13 non-affected at-risk people underwent electrophysiological examination. An MRI study of lower limb musculature was carried out in four patients. Three patients underwent sural-nerve biopsy. Genetic testing was carried out in 17 patients and in all 13 at-risk normal people. RESULTS: Fourteen patients were asymptomatic or slightly disabled. The two oldest patients, aged 84 and 80, showed a moderate phenotype. Two other patients, aged 70 and 53, showed late-onset and gradually progressive peroneal paresis extending up to the thigh and pelvic musculature, resulting in waddling gait. MRI scans of all three patients with a mild phenotype showed subtle and subclinical fatty infiltration of calf anterolateral muscle compartments, with thigh muscle involvement in one patient, and extensive atrophy of intrinsic foot muscles. In the youngest patient with proximal leg weakness, the MRI scan showed massive fatty atrophy of all the calf muscles, posteromedial thigh muscle compartments, and internal and external hip rotator muscles. Sural-nerve biopsy specimens showed hypertrophic neuropathy with no superimposed inflammation. Good correlation was seen between electrophysiological and genetic testing. CONCLUSIONS: Late in the clinical course, a small proportion of patients with CMT1A develop severe proximal leg weakness, and long-term follow-up is essential for its detection. MRI scans may show subclinical involvement of the thigh musculature.

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE epsilon4 allele.

Cholesterol regulates the production of amyloid beta (Abeta), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Abeta in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C-629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) epsilon4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE epsilon4 carriers, homozygous for the CETP (-629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01-5.37), than homozygous and heterozygous carriers of the CETP (-629) C allele (odds ratio 7.12, 95% CI 4.51-11.24, P for APOE epsilon4/CETP (-629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE epsilon4 allele, possibly through modulation of brain cholesterol metabolism.