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Background: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS., Objective: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors., Methods: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity., Results: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant., Conclusion: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle., (© 2022. The Author(s).)

Patients with hematological diseases often experience cerebrovascular complications including ischemic stroke, intracerebral and subarachnoid hemorrhage, microbleeds, posterior reversible encephalopathy syndrome, and dural sinus and cerebral vein thrombosis (CVT). In this update, we will review recent advances in the management of cerebrovascular diseases in the context of myeloproliferative neoplasms, leukemias, lymphomas, multiple myeloma, POEMS, paroxysmal nocturnal hemoglobinuria (PNH), thrombotic thrombocytopenic purpura (TTP), and sickle-cell disease. In acute ischemic stroke associated with hematological diseases, thrombectomy can in general be applied if there is a large vessel occlusion. Intravenous thrombolysis can be used in myeloproliferative neoplasms and sickle-cell anemia, but in other diseases, a case-by-case evaluation of the bleeding risks is mandatory. Patients with sickle-cell disease and acute stroke need very often to be transfused. In PNH, acute ischemic stroke patients must be anticoagulated. Most patients with CVT can be treated with low-molecular weight heparin (LMWH) acutely, even those with leukemias. Prevention of recurrence of cerebral thrombotic events depends on the control of the underlying disease, combined in some conditions with antithrombotic drugs. The recent introduction of specific monoclonal antibodies in the treatment of PHN and TTP has dramatically reduced the risk of arterial and venous thrombosis., (© 2021. The Author(s).)

Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A-related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged to six pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin. All affected subjects presented with compound heterozygous variants, comprising c.1909 + 22G > A in combination in each pedigree with one of the following novel mutations (Thr596Met, Tyr665LeufsTer11, Glu198Ter, c.646-687_1185 + 844del). The new mutations segregated with the phenotype in all families. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and in some cases also intention tremor. The reportedly characteristic hyperintensity along the superior cerebellar peduncle on MRI was observed in ~ 80% of the cases. Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A-related spastic ataxia. Certain characteristic MRI features may be useful to guide genetic diagnosis.

C-reactive protein (CRP) is a biomarker of systemic inflammation that has been linked to accelerated decline in walking speed in older adults. The aim of the present study was to compare the CRP levels of PD patients with vs patients without freezing of gait (FOG). Patients and controls participating in the COPPADIS-2015 study that performed blood extraction for determining molecular serum biomarkers were included. Patients with FOG were identified as those with a score of 1 or greater on item-3 of the Freezing of Gait Questionnaire (FOG-Q). Immunoassay was used for determining ultrasensitive CRP (US-CRP) level (mg/dL). In the PD group (n = 225; 61.8 ± 9.5 years old, 61.8% males), 32% of the patients presented FOG but none in the control group (n = 65; 60.3 ± 6.1 years old, 56.9% males) (p < 0.0001). Differences in US-CRP level were significant in patients with FOG vs patients without FOG and vs controls (0.31 ± 0.52 vs 0.16 ± 0.21 vs 0.21 ± 0.22; p = 0.04). Significant differences were also observed between patients with vs without FOG (p = 0.001) but not between patients and controls (p = 0.163). US-CRP level was related to FOG (OR = 4.369; 95% CI 1.105-17.275; p = 0.036) along with H&Y (OR = 2.974; 95% CI 1.113-7.943; p = 0.030) and non-motor symptoms burden (NMSS total score; OR = 1.017; 95% CI 1.005-1.029; p = 0.006) after adjusting for age, gender, disease duration, equivalent daily levodopa dose, number of non-antiparkinsonian drugs per day, motor fluctuations, cognition, motor phenotype, and chronic use of anti-inflammatory drugs. The present study suggests that serum US-CRP level is related to FOG in PD patients. Inflammation could be linked to FOG development.

Purpose: To assess the stiffness of hamstring muscles during isometric contractions in healthy individuals, using ultrasound-based shear wave elastography to (1) determine the intra- and inter-day assessment repeatability, (2) characterize the stiffness of semitendinosus (ST) and biceps femoris long head (BFlh) along the contraction intensity, and (3) characterize stiffness distribution among the hamstring muscles and inter-limb symmetry., Methods: Two experiments were conducted. In experiment I (n = 12), the intra-day repeatability in assessing the BFlh and ST stiffness were determined at intensities between 10-60% of maximal voluntary isometric contraction (MVIC) in a single session. In experiment II (n = 11), the stiffness of the hamstring muscles of both thighs was assessed at 20% of MVIC in the first session; and retested (for one randomly chosen thigh) in a second session. Isometric contraction of knee flexors was performed with the knee flexed at 30° and with the hip in a neutral position., Results: Moderate-to-very-high intra- and inter-day repeatability was found (ICC = 0.69-0.93). The BFlh/ST stiffness ratio increased with contraction intensity. At 20% of MVIC, the ST showed the highest stiffness among the hamstring muscles (p < 0.02), with no differences between the remaining hamstring muscles (p > 0.474). No differences were found between limbs (p = 0.12)., Conclusions: The stiffness distribution among the hamstring muscles during submaximal isometric contractions is heterogeneous, but symmetric between limbs, and changes depending on the contraction intensity. Shear wave elastography is a reliable tool to assess the stiffness of hamstring muscles during contraction.

Introduction: To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6., Methods: To assess the functional capacity in daily living, we used the functional assessment (part IV) of the Unified Huntington's Disease Rating Scale (UHDRS-IV), for health-related quality of life the visual analogue scale of the EuroQol Five Dimensions Questionnaire (EQ-5D VAS), and for depressive symptoms the Patient Health Questionnaire (PHQ-9). Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and neurological symptoms other than ataxia with the Inventory of Non-Ataxia Signs (INAS)., Results: UHDRS-IV [SCA1: - 1.35 (0.12); SCA2: - 1.15 (0.11); SCA3: - 1.16 (0.11); SCA6: - 0.99 (0.12)] and EQ-5D [SCA1: - 2.88 (0.72); SCA2: - 1.97 (0.49); SCA3: - 2.06 (0.55); SCA6: - 1.03 (0.57)] decreased linearly, whereas PHQ-9 increased [SCA1: 0.15 (0.04); SCA2: 0.09 (0.03); SCA3: 0.06 (0.04); SCA6: 0.07 (0.04)] during the observational period. Standard response means (SRMs) of UHDRS-IV (0.473-0.707) and EQ-5D VAS (0.053-0.184) were lower than that of SARA (0.404-0.979). In SCA1, higher SARA scores [- 0.0288 (0.01), p = 0.0251], longer repeat expansions [- 0.0622 (0.02), p = 0.0002] and the presence of cognitive impairment at baseline [- 0.5381 (0.25), p = 0.0365] were associated with faster UHDRS-IV decline. In SCA3, higher INAS counts were associated with a faster UHDRS-IV decline [- 0.05 (0.02), p = 0.0212]. In SCA1, PHQ-9 progression was faster in patients with cognitive impairment [0.14 (0.07); p = 0.0396]., Conclusions: In the common SCAs, PROMs give complementary information to the information provided by neurological scales. This underlines the importance of PROMs as additional outcome measures in future interventional trials.

The aim of this study was to describe five patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) with chronic cough and preserved limb muscle stretch reflexes. All five patients were in the seventh decade of age, their gait imbalance having been initiated in the fifth decade. In four patients cough antedated gait imbalance between 15 and 29 years; cough was spasmodic and triggered by variable factors. Established clinical picture included severe hypopallesthesia predominating in the lower limbs with postural imbalance, and variable degree of cerebellar axial and appendicular ataxia, dysarthria and horizontal gaze-evoked nystagmus. Upper- and lower-limb tendon jerks were preserved, whereas jaw jerk was absent. Vestibular function testing showed bilateral impairment of the vestibulo-ocular reflex. Nerve conduction studies demonstrated normal motor conduction parameters and absence or severe attenuation of sensory nerve action potentials. Somatosensory evoked potentials were absent or severely attenuated. Biceps and femoral T-reflex recordings were normal, while masseter reflex was absent or attenuated. Sympathetic skin responses were normal. Cranial MRI showed vermian and hemispheric cerebellar atrophy predominating in lobules VI, VII and VIIa. We conclude that spasmodic cough may be an integral part of the clinical picture in CANVAS, antedating the appearance of imbalance in several decades and that sparing of muscle spindle afferents (Ia fibres) is probably the pathophysiological basis of normoreflexia.

Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy with great variety of phenotypes, inheritance patterns, and causative genes. According to median motor nerve conduction velocity (MNCV), CMT is divided into demyelinating (CMT1) with MNCV below 38 m/s, axonal (CMT2) with MNCV above 38 m/s, and intermediate CMT with MNCV between 25 and 45 m/s. In each category, transmission may be autosomal dominant, autosomal recessive, or X-linked. The nosology of intermediate CMT is controversial because of concerns about electrophysiological delimitation. A systematic computer-based literature search was conducted on PubMed, using the following MeSH: (1) intermediate Charcot-Marie-Tooth; (2) X-linked intermediate Charcot-Marie-Tooth; and (3) X-linked Charcot-Marie-Tooth and electrophysiology. We retrieved 225 articles reporting X-linked CMT or intermediate CMT with electrophysiological information. After eligibility, 156 papers were used for this review. In assessing median MNCV, compound muscle action potential (CMAP) amplitudes were taken into account. In cases with attenuated CMAP and wherever possible, proximal median MNCV was used for accurate definition of conduction slowing in the intermediate range. In the vast majority of males with X-linked CMT associated with GJB1 mutation (CMTX1), median MNCV was intermediate. CMT associated with DRP2 mutation is another well-documented X-linked intermediate disorder. Autosomal dominant intermediate CMT (DI-CMT) encompasses 11 different types; six of them with assigned phenotype MIM number and the remaining five being unnumbered. Based on available electrophysiological information, we wonder if DI-CMTA should be reclassified within CMT2. Autosomal recessive intermediate CMT (RI-CMT) covers four numbered MIM phenotypes though, in accordance with reported electrophysiology, two of them (RI-CMTB and RI-CMTD) should probably be reclassified within AR-CMT2. We conclude that intermediate CMT is a complex inherited syndrome, whose characterization requires a specific electrophysiological protocol comprising evaluation of upper limb proximal nerve trunks when distal CMAP amplitudes are reduced, and that an updated version of MIM phenotype numbering is needed.

The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.

The purpose of the study was to describe a pedigree with NEFL E396K mutation associated with a novel dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) phenotype. The pedigree comprised four patients over two generations, aged between 35 and 59 years, who have been serially evaluated since 1993. Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait. Both older patients showed ascending leg weakness to involve pelvic musculature. CMT neuropathy score ranged from 14 to 26 (moderate to severe disease). Electrophysiology showed uniform nerve conduction slowing in the intermediate range, both in distal and proximal nerve segments. Multimodal evoked potential and blink reflex studies revealed abnormalities indicative of central sensorimotor pathway dysfunction. On imaging studies of lower-limb musculature, there was massive atrophy of intrinsic foot muscles and to a lesser degree of calves and thighs predominating in muscles innervated by tibial and sciatic nerves. In both patients exhibiting waddling gait, there was atrophy of pelvic muscles mainly involving gluteus medius, gluteus minimus and piriformis. We conclude that NEFL E396K mutation may manifest with a novel DI-CMT phenotype, characterized by simultaneous involvement of the peripheral and central nervous system.

Purpose: To study the association between the polymorphisms, rs1859962 and rs4430796, from the chromosomes 17q24 and 17q12, respectively, with the risk of prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population., Methods: This study included 33 controls and 167 patients diagnosed with PCa. The polymorphisms, rs1859962 and rs4430796, were analyzed on blood specimens using quantitative PCR. The genetic analysis of the qPCR data was performed using the SNPStats program. A comparison between the clinical characteristics of the prostate cancers from the patients and the presence of the different polymorphism genotypes detected in blood specimens obtained from these patients was performed using the IBM SPSS v20.0 software., Results: We observed no association of the SNPs and the risk of developing PCa (OR 0.84, 95 % CI 0.30-2.38, p = 1.0 to rs1859962 and OR 1.94, 95 % CI 0.57-6.52, p = 0.28 to rs4430796), both sporadic and hereditary. However, patients carrying the genotype G/G from the polymorphism rs4430796 had significantly higher PSA levels than patients carrying the other genotypes (15.05 ng/ml to G/G, 10 and 8.11 ng/ml to genotypes A/G y A/A, respectively, p = 0.01). Furthermore, patients with the genotype G/G of rs4430796 had higher tumor volume than other genotypes (9.45 cc to G/G and 5.22 cc to A/G + A/A, p = 0.04)., Conclusion: The polymorphism rs4430796 of the chromosome 17q12 appears to be a biomarker for cancer aggressiveness, increased PSA and tumor volume of PCa.

The objective of this study was to analyze Charcot-Marie-Tooth disease type 1A (CMT1A) evolution. We conducted a 2-year longitudinal study in 14 CMT1A patients and 14 age- and sex-matched controls. In the patients, we performed neurological examination with hand-held dynamometry, electrophysiology, and lower-limb muscle MRI, both at baseline and 2 years later, while controls were examined at baseline only. Patients' ages ranged from 12 to 51 years. Outstanding manifestations on initial evaluation included pes cavus, areflexia, lower-limb weakness, and foot hypopallesthesia. In evaluating muscle power, good correlation was observed between manual testing and dynamometry. Compared to controls, Lunge, 10-Meter-Walking, and 9-Hole-Peg tests were impaired. Their CMT neuropathy score and functional disability scale showed that patients exhibited mild phenotype and at most slight walking difficulty. Electrophysiology revealed marked nerve conduction slowing and variable compound muscle action potential amplitude reduction. On lower-limb muscle MRI, there was distally accentuated fatty infiltration accompanied by edema in calf muscles. All these clinico-electrophysiological and imaging findings remained almost unaltered during monitoring. Using multivariate analysis, no significant predictors of progression associated to the disease were obtained. We conclude that in the 2-year period of study, CMT1A patients showed mild progression with good concordance between clinico-electrophysiological and imaging findings.

Magnetic resonance imaging (MRI) is an extremely useful technique to diagnose muscle denervation. This report presents an acute motor axonal neuropathy (AMAN) patient in whom, over 2 years, serial clinical-electrophysiological evaluation and MRI examination of lower limb musculature were performed. A 74-year-old patient was admitted with a 24-h history of ascending weakness culminating a few days later in flaccid and areflexic tetraplegia, which was followed by progressive improvement except for severe residual paresis of foot flexors/extensors. Electrophysiological studies showed motor nerve conduction abnormalities characteristic of AMAN, and profuse signs of active denervation in foot and lower leg muscles, and to a much lesser degree in the thigh muscles. On MRI, T2- and T2-fat suppressed (T2FS) images showed an early (up to month 2 after onset) and subtle hypersignal of all four lower leg muscle compartments evolving to an extensive and widespread hypersignal (as of month 6). Progressive hypersignal of lower leg musculature on T1-weighted images, indicative of fatty atrophy, was detected as of the first year. Thigh and pelvic musculature exhibited early and reversible hypersignal on T2 and T2FS images. There was good concordance between clinico-electrophysiological and MRI findings. We conclude that serial MRI may be very useful to evaluate the extent of muscle denervation and to assess clinical course in AMAN.

Mitochondrial dysfunction could contribute to the development of spastic paraplegia. Among others, two of the genes implicated in hereditary spastic paraplegia encoded mitochondrial proteins and some of the clinical features frequently found in these patients resemble those observed in patients with mitochondrial DNA (mtDNA) mutations. We investigated the association between common mtDNA polymorphisms and spastic paraplegia. The ten mtDNA polymorphisms that defined the common European haplogroups were determined in 424 patients, 19% with a complicated phenotype. A rare haplogroup was associated with the disease in patients without a SPG3A, SPG4, or SPG7 mutation. Allele 10398G was more frequent among patients with a pure versus complicated phenotype. This mtDNA polymorphism was previously associated with the risk of developing other neurodegenerative diseases. In conclusion, some mtDNA polymorphisms could contribute to the development of spastic paraplegia or act as modifiers of the phenotype.

Forefoot pes cavus is a cardinal sign of Charcot-Marie-Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.

Incomplete penetrance has rarely been reported in Charcot-Marie-Tooth disease. Our aim is to describe reduced penetrance in a hereditary motor neuropathy pedigree due to mutation in the transient receptor potential vallinoid 4 (TRPV4) gene. The pedigree comprised two affected members, the proband aged 44 years and her affected daughter aged 7 years, and seven additional related subjects, three of whom were subclinical gene mutation carriers aged 9, 40 and 70 years. Clinico-electrophysiological studies, MRI of lower-limb musculature and genetic testing of the TRPV4 were performed. The proband presented with a moderate facio-scapulo-peroneal syndrome, whereas her symptomatic daughter suffered from severe congenital spinal muscular atrophy with arthrogryposis, laryngomalacia, and vocal cord paresis. Electrophysiological evaluation revealed a pure motor axonal neuropathy. In the proband, MRI showed extensive and widespread fatty atrophy of lower-leg musculature, whereas in thigh musculature there was just mild distal fatty infiltration of vastus lateralis. Genetic testing revealed a heterozygous Arg269Cys mutation in the TPRV4 gene. In all three mutation carriers results from clinical and electrophysiological examination, and MRI of foot and lower-leg musculature were normal. We conclude that non-penetrance may be an integral feature of neuropathic syndromes associated with TRPV4 gene mutation.

Long-term follow-up studies in Charcot-Marie-Tooth disease type 1 duplication (CMT1A) are scanty. Here we describe a longitudinal study in a CMT1A pedigree. Our CMT1A pedigree comprised 11 examined patients, ages between 13 and 83 (median, 36) years, serially evaluated for up to 26 years. In all 11 patients we carried out electrophysiological evaluation, and in three of them magnetic resonance imaging (MRI) of lower-limb musculature. The 54-year-old proband patient, yearly examined as of age 28, developed at age 48 gradual and progressive distal lower-leg weakness ascending to thigh musculature. His serial electrophysiological studies showed diffuse slowing of motor conduction velocity, absence or severe attenuation of distal compound muscle action potentials, and spontaneous muscle activity in the tibialis anterior and rectus femoris. Two MRI studies of lower limbs, at ages 51 and 54, showed extensive fatty atrophy of lower-leg musculature, and progressive and distally accentuated fatty atrophy of anterior and posterior femoral muscles. An outstanding finding in the first MRI was the presence of marked edema of anterior femoral musculature, which to a great degree was replaced by fatty atrophy in the second study. Muscle edema was also noted in lower-leg and posterior femoral musculature. There was minimal fatty atrophy of the gluteus maximus, the remaining pelvic muscles being preserved. The other ten patients showed mild or moderate phenotype, which remained quiescent over the period of observation. Electrophysiological studies disclosed diffuse and uniform slowing of nerve conduction velocities; in no case was spontaneous muscle activity recorded. MRI showed the CMT1A characteristic pattern of distally accentuated fatty atrophy involving foot and lower-leg musculature with preservation of thigh musculature. We conclude that a small proportion of patients with CMT1A develop a late progression of disease manifested with accentuated distal leg weakness ascending to involve thigh musculature, and that long-term follow-up is essential for its detection.

The purpose of the present study was to describe clinico-electrophysiological features and lower limb muscle MRI findings in a CMT2J pedigree due to MPZ Thr124Met mutation. We examined the proband, aged 56 years, and her affected daughter and son, aged 30 and 29 years. Disease severity in terms of ability to walk and run was established using a nine-point functional disability scale (FDS). We administered the CMT neuropathy score (CMTNS) based on patient's symptoms, neurologic examination and neurophysiologic testing. All three patients had non-symptomatic Adie's pupil. The proband and her son presented with late-onset lower limb sensorimotor neuropathy and pes cavus; the proband's daughter had no signs of polyneuropathy. FDS score was 4 in the proband, 2 in her son, and 0 (normal) in her daughter. In both symptomatic patients, electrophysiological study showed a pattern of length-dependent axonal neuropathy mainly involving lower limb nerves; this was normal in the other patient. CMTNS was 18 in the proband, 12 in her son, and 0 (normal) in her daughter. MRI of foot and leg musculature was normal in the proband's daughter, whereas the other two patients showed massive fatty atrophy of intrinsic foot musculature, extensive and diffuse fatty atrophy of leg muscles in the proband, and mild distally accentuated fatty infiltration of calf muscles in her son. Muscle edema, detected only in the proband's son, was present in 7 out of 22 (33%) of visualized leg muscles, whereas contrast enhancement occurred in 6 of them. The reported mutation may manifest with either isolated Adie's pupil or pupil abnormalities with late-onset sensorimotor length-dependent axonal polyneuropathy, though the presence of pes cavus might indicate an earlier onset. MRI examination helps to delineate an accurate extent of muscle involvement in the disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene together represent the most common genetic determinant of Parkinson's disease (PD) identified to date. The vast majority of patients with LRRK2-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the LRRK2 region. Nine of the patients were of Basque origin and 20 were non-Basques. We inferred haplotypes using a Bayesian approach and utilized a maximum-likelihood method to estimate the age of the most recent common ancestor. Significant but incomplete allele sharing was observed over a distance of 6.0 Mb and a single, rare ten-marker haplotype 5.8 Mb in length was seen in all mutation carriers. We estimate that the most recent common ancestor lived 1,350 (95% CI, 1,020-1,740) years ago in approximately the seventh century. We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain.

A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). Estrogen could protect the brain from neurodegeneration by augmenting the secretion of the anti-inflammatory interleukin (IL)-10 from microglial cells. In a case-control study in 231 AD patients and 194 healthy controls, we examined whether the combined effects between the genes coding for aromatase (a critical enzyme in the peripheral synthesis of estrogens) and IL-10 might be responsible for susceptibility to AD. Subjects carrying both the aromatase (5 -UTR) GG and the IL-10 (-1082) GG genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR = 0.17, 95% CI = 0.04-0.77, P = 0.02).

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.

Interleukin (IL)-1 is a potent proinflammatory cytokine that is markedly overexpressed in the brains of patients with Alzheimer's disease (AD). The IL-1A [-889] allele 2 has been shown to increase AD risk, probably by upregulating the inflammatory cascade in the disease process. A case-control study utilizing a clinically well-defined group of 298 sporadic AD patients and 306 control subjects was performed to test this association. Our data show that the IL-1A allele 2 is a risk factor in a dose-dependent manner, the risk of developing AD with two copies of the IL-1A allele 2 (odds ratio 3.1, 95 % CI 1.30-7.45) being approximately double that of one copy of the IL-1A allele 2 (odds ratio 1.4, 95 % CI 0.99-1.94, P for trend = 0.0004). Furthermore, the risk associated with the IL-1A allele 2 was not restricted to AD patients of a particular age, and we could confirm this association in our early-onset and late-onset AD patients.