sabato 29 giugno 2013

CHMP positive opinion for LEMTRADA

The positive CHMP opinion for approval of LEMTRADA was based on data from the CARE-MS I and CARE-MS II trials, in which LEMTRADA was significantly more effective than Rebif® (subcutaneous interferon beta-1a 44 mcg three times weekly) at reducing relapse rates. In CARE-MS II, accumulation of disability was significantly slowed in patients given LEMTRADA vs. Rebif, and importantly, patients treated with LEMTRADA were significantly more likely to experience improvement in pre-existing disability.
LEMTRADA has a novel dosing and administration schedule of two annual treatment courses. The first treatment course of LEMTRADA is administered via intravenous infusion on five consecutive days, and the second course is administered on three consecutive days, 12 months later.

The LEMTRADA clinical development program included two randomized Phase III studies comparing treatment with LEMTRADA to Rebif in patients with relapsing-remitting MS who had active disease and were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II), as well as an ongoing extension study. A large randomized Phase II study provided the foundation for the Phase III program.

Safety results were consistent across both the CARE-MS I and CARE-MS II studies. The most common adverse events associated with LEMTRADA were infusion-associated reactions, including headache, rash, fever, nausea and hives. Infections were common in both the LEMTRADA and Rebif groups. Infections more common on LEMTRADA treatment included upper respiratory and urinary tract infections, herpes viral infections, and influenza. Most infusion-associated reactions and infections were mild to moderate in severity and responded to standard treatments.
In both CARE-MS I and CARE-MS II, the incidence of serious adverse events was similar between the two treatment arms. As previously reported, autoimmune disorders were more frequent in patients treated with LEMTRADA, primarily autoimmune thyroid disease which was observed in an estimated 36% of patients during extended follow-up. Immune thrombocytopenia (ITP) developed in 1.4 percent of LEMTRADA-treated patients through extended follow-up and 0.3% developed glomerulonephritis. Autoimmune disorders were detected soon after onset through a monitoring program, and were generally managed using standard treatments.

venerdì 28 giugno 2013

« Io, se potessi, scenderei in campo adesso, su un prato o all'oratorio. Perché io amo il calcio »
(Stefano Borgonovo)


Rest In Peace

giovedì 27 giugno 2013

Discovering strange diseases: Cogan Syndrome

 2013 Jan;12(3):396-400. doi: 10.1016/j.autrev.2012.07.012. Epub 2012 Jul 28.

Cogan's syndrome: an autoimmune inner ear disease.


ENT Department, Policlinico Umberto I, University of Rome Sapienza, Italy.



The objective of our study was to review our current knowledge of the aetiopathogenesis of Cogan's syndrome, including viral infection and autoimmunity, and to discuss disease pathogenesis with relevance to pharmacotherapy. SYSTEMATIC REVIEW METHODOLOGY: Relevant publications on the aetiopathogenesis and pharmacotherapy of Cogan'ssyndrome from 1945 to 2012 were analysed.


Cogan's syndrome is a rare autoimmune vasculitis, and its pathogenesis is unknown. Infection, but primarily autoimmunity, may play contributing roles in the pathogenesis of this disease. It is characterised by ocular and audiovestibular symptoms similar to those of Meniere's syndrome. Approximately 70% of patients have systemic disease, of which vasculitis is considered the pathological mechanism. The immunologic theory is based on the release of auto-antibodies against corneal, inner ear and endothelial antigens, and of anti-nuclear cytoplasmic auto-antibodies (ANCA). Corticosteroids are the first line of treatment, and multiple immunosuppressive drugs have been tried with varying degrees of success. Tumour necrosis factor (TNF)-alpha blockers are a category of immunosuppressive agents representing a recent novel therapeutic option in Cogan's syndrome.

Discovering strange diseases: Bruns - Garland

 2004 Jul-Aug;17(4):200-2.

Diabetic amyotrophy: a brief review.


Department of Medicine, St John's Medical College Hospital, Sarjapur Road, Bangalore 560034, Karnataka, India.

Bruns in 1890 was the first to recognize the main clinical features of 'diabetic amyotrophy'. The term itself was coined by Hugh Garland in 1955 when he reported 12 elderly patients with type 2 diabetes. The aetiology is controversial, and both ischaemic and metabolic hypotheses have been proposed. The current evidence, however, points to a vasculitic aetiology of ischaemia followed by axonal degeneration and demyelination. The main features of diabetic amyotrophy are weakness, wasting and pain, most commonly in the quadriceps muscle. Though the weakness starts on one side, it almost always spreads to the other side in an asymmetrical manner. Patients also complain of sensory symptoms in the thigh such as severe pain, dysaesthesiae and paraesthesiae. On examination, there is weakness in the involved muscles. Tendon jerks, especially the patellar, are absent. Extensor plantar responses may be elicited in some patients. The course of the disease is variable but good functional improvement can be expected in most patients though weakness, sensory symptoms and absent tendon jerks may persist. Some patients experience multiple episodes of the condition commencing mostly on the opposite side. Conservative treatment constitutes optimizing diabetic control along with active physiotherapy and analgesia. Recently, intravenous immunoglobulins have been found to produce dramatic improvement in both clinical and electrophysiological parameters in patients with diabetic polyradiculopathy

mercoledì 26 giugno 2013

Discovering strange diseases: NBIA

 2013 Apr;120(4):695-703. doi: 10.1007/s00702-012-0922-8. Epub 2012 Dec 2.

Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA).


Department of Neurology, University Kiel, Arnold Heller Str. 3, 24105, Kiel, Germany.

Regulation of iron metabolism is crucial: both iron deficiency and iron overload can cause disease. In recent years, our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. These are characterized by excessive iron deposition in the brain, mainly the basal ganglia. Pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2) are the core syndromes, but several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). These conditions show a wide clinical and pathological spectrum, with clinical overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies, and neuronal ceroid lipofuscinosis. Lewy body pathology was confirmed in some clinical subtypes (C19orf12-associated neurodegeneration and PLAN). Research aims at disentangling the various NBIA genes and their related pathways to move towards pathogenesis-targeted therapies. Until then treatment remains symptomatic. Here we will introduce the group of NBIA syndromes and review the main clinical features and investigational findings.

martedì 25 giugno 2013

Discovering strange diseases: Eagle syndrome

 2013 Apr;25(2):87-9. doi: 10.5505/agri.2013.26779.

Eagle syndrome: case report.


Department of Neurology, İzmir Tepecik Training and Research Hospital, İzmir, Turkey.

Eagle syndrome is an aggregate of symptoms caused by an elongated styloid process, most frequently resulting in headache, facial pain, dysphagia and sensation of foreign body in throat. The proper diagnosis is not difficult with clinical history, physical examination and radiographic assessment if there is a sufficient degree of suspicion. The treatment is very effective. We report here a typical case of Eagle syndrome which was misdiagnosed as trigeminal neuralgia for many years and was treated with carbamazepine. We aim to point the place of Eagle syndrome in the differential diagnosis of facial pain. We also re-emphasize the usefulness of the three-dimensional computed tomography in the diagnosis of Eagle syndrome. Even though Eagle syndrome is a rare condition, in cases of facial pain refractory to treatment or unexplained complaints of the head and neck region, it should be considered in the differential diagnosis as it has therapeutic consequences.

Discovering strange diseases: cheiralgia paraesthetica or Wartemberg Syndrome

 2001 Mar;193(3):251-4.

Entrapment of the sensory branch of the radial nerve (Wartenberg's syndrome): an unusual cause.

solated neuropathy of the cutaneous branch of the radial nerve is a rarely recognized pathology. It was described in 1932 byWartenberg, who suggested the name cheiralgia paraesthetica. The syndrome is described as known the entrapment of the superficial branch of the radial nerve. Many different etiologic factors for chronic nerve entrapment have been described, however our case has an unusual cause. A 52 year old man had pain and paresthesia in the area over the lateral aspect of the wrist, thumb and first web six months after Colles' fracture. The patient underwent bony spike resection after five months with ineffective conservative treatment. He has satisfied after this operation. The case was presented because of disappearing his preoperative complaints after the operation with respect to Wartenberg's syndrome constituted a rare cause of bone spike which has not been mentioned in the literature.

Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS).

Human Molecular Genetics Apr 2013

We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinson's disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2-X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells, we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6AP2, c.345C>T (p.S115S), markedly increased exon 4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6AP2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinson's disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology. Another synonymous mutation in the same exon, c.321C>T (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations.

Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confirmed in human beings. We aimed to define novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifically interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis.
In this observational analytical study, we recruited patients with leukoencephalopathies characterised by MRI signal abnormalities in the posterior limbs of the internal capsules, midbrain cerebral peduncles, and middle cerebellar peduncles from our databases of patients with leukoencephalopathies of unknown origin. We used exome sequencing to identify the gene involved. We screened the candidate gene in additional patients by Sanger sequencing and mRNA analysis, and investigated the functional effects of the mutations. We assessed the localisation of ClC-2 with immunohistochemistry and electron microscopy in post-mortem human brains of individuals without neurological disorders.
Seven patients met our inclusion criteria, three with adult-onset disease and four with childhood-onset disease. We identified homozygous or compound-heterozygous mutations in CLCN2 in three adult and three paediatric patients. We found evidence that the CLCN2 mutations result in loss of function of ClC-2. The remaining paediatric patient had an X-linked family history and a mutation in GJB1, encoding connexin 32. Clinical features were variable and included cerebellar ataxia, spasticity, chorioretinopathy with visual field defects, optic neuropathy, cognitive defects, and headaches. MRI showed restricted diffusion suggesting myelin vacuolation that was confined to the specified white matter structures in adult patients, and more diffusely involved the brain white matter in paediatric patients. We detected ClC-2 in all components of the panglial syncytium, enriched in astrocytic endfeet at the perivascular basal lamina, in the glia limitans, and in ependymal cells.
Our observations substantiate the concept that ClC-2 is involved in brain ion and water homoeostasis. Autosomal-recessiveCLCN2 mutations cause a leukoencephalopathy that belongs to an emerging group of disorders affecting brain ion and water homoeostasis and characterised by intramyelinic oedema.

The Lancet Neurology, Volume 12, Issue 7, Pages 659 - 668, July 2013

lunedì 24 giugno 2013

Successful Treatment of Anti-Caspr2 Syndrome by Interleukin 6 Receptor Blockade Through Tocilizumab

Importance  A patient with a Caspr2 autoantibodies–associated syndrome had an unusual clinical triad and an excellent response to B-cell–anergizing therapy using the humanized monoclonal antibody tocilizumab directed against the interleukin 6 (IL-6) receptor.
Observations  A 55-year-old man had an atypical clinical triad of epilepsy, dysarthria, and paroxysmal kinesigenic dystonia, and a high titer of Caspr2 antibodies was detected in his serum and cerebrospinal fluid. Screening for underlying neoplasias was negative. With initial methylprednisolone sodium succinate and alternate treatment using plasma exchange and immunoabsorption as well as subsequent IL-6 receptor blockade through tocilizumab, a complete and stable remission of symptoms has been achieved throughout the follow-up period of 7 months.
Conclusions and Relevance  In our patient, the implementation of a B-cell–anergizing therapy using tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has shown an excellent response. Larger case series or even controlled studies are needed to confirm the efficacy of tocilizumab in autoimmune synaptic or presynaptic diseases.
JAMA Neurol. 2013;():1-4. doi:10.1001/jamaneurol.2013.143.

Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with L-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of L-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a ‘halo’ of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
Brain Volume 136, Issue 6 Pp. 1708-1717.

Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis

Objective: We examined the clinical and pathologic phenotypes of GRN mutation carriers with the pathogenic A9D (g.26C>A) missense mutation.
Methods: Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination.
Results: The clinical diagnoses of patients with GRN A9D mutations were amyotrophic lateral sclerosis, atypical extrapyramidal disorder, and behavioral variant frontotemporal dementia. Immunohistochemistry for TAR DNA-binding protein 43 (TDP-43) revealed variability in morphology and distribution of pathology. One patient had notable involvement of motor neurons in the spinal cord as well as type B TDP-43, whereas 2 other patients had type A TDP-43.
Conclusions: The clinical presentation of the GRN A9D missense mutation is not restricted to behavioral variant frontotemporal dementia and may include aphasia, extrapyramidal features, and, notably, amyotrophic lateral sclerosis.
Neurologyvol. 80 no. 19 1771-1777

domenica 23 giugno 2013

Aquaporin-4 antibody–negative neuromyelitis optica

Objective: To optimize aquaporin-4 (AQP4) antibody (Ab) detection and to assess the influence of the increased sensitivity of the assay on the demographic and disease-related characteristics of a group of AQP4-Ab–negative patients.
Methods: Serum samples were obtained from patients included in the French NOMADMUS database with a definite diagnosis of neuromyelitis optica (NMO) (n 5 87) and were compared with controls (n 5 54). They were tested by indirect immunofluorescence and cell-based assays (CBAs) in various conditions and with several plasmids.
Results: We identified the CBA on live cells transfected with the untagged AQP4-M23 isoform as the best method, with a sensitivity of 74.4% and a specificity of 100%. We demonstrated a direct relationship between improvement of the sensitivity of the detection method and the distinctiveness and characteristics of the AQP4-Ab–negative NMO group. Whereas with the classic indirect immunofluorescence or current AQP4-M1 CBA we found only slight differences between the 2 populations, using the AQP4-M23 CBA, we demonstrated that patients with AQP4-Ab–negative NMO expressed specific demographic and disease-related features. They were characterized by an equal male/female ratio (p , 0.001), a Caucasian ethnicity (p 5 0.029), and an overrepresentation of simultaneous optic neuritis and transverse myelitis at first episode (p 5 0.015). In terms of disability, they experienced a better visual acuity at last follow-up compared with seropositive NMO (p 5 0.007).
Conclusion: This raises the question of a distinct physiopathology for patients with AQP4-Ab–negative NMO and of their place in the spectrum of the disease. Neurology 2013;80:2194–2200

TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis

Objectives: To investigate the roles of 2 polymorphisms of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene, rs1800693 (a common variant) and rs4149584 (a coding polymorphism that results in an amino acid substitution—R92Q), as genetic modifiers of multiple sclerosis (MS), and to evaluate their potential functional implications in the disease.
Methods: The effects of rs1800693 and rs4149584 on 2 measures of disease severity, age at disease onset and Multiple Sclerosis Severity Score, were analyzed in 2,032 patients with MS. In a subgroup of patients, serum levels of the soluble form of TNF-R1 (sTNF-R1) were measured by ELISA; mRNA expression levels of the full-length TNF-R1 and Δ6-TNF-R1 isoform were investigated in peripheral blood mononuclear cells (PBMC) by real-time PCR; cell surface expression of
the TNF-R1 was determined in T cells by flow cytometry.
Results: For rs4149584, R92Q carriers were younger at disease onset and progressed slower compared to noncarriers. However, no association with disease severity was observed for rs1800693. Serum levels of sTNF-R1 and mRNA expression levels of the full-length receptor were significantly increased in patients with MS carrying the R92Q mutation (p 5 0.003 and p 5 0.011, respectively), but similarly distributed among rs1800693 genotypes; cell surface TNF-R1 expression in T cells did not differ between rs4149584 and rs1800693 genotypes. The truncated soluble Δ6-TNF-R1 isoform was identified in PBMC from patients carrying the risk allele for rs1800693.

Placebo-controlled trial of rituximab in IgM- anti MAG neuropathy

Objective: To determine whether rituximab 375 mg/m2
was efficacious in patients with immunoglobulin M (IgM) anti-myelin–associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy).
Methods: Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) $4 and visual analog pain scale .4 or ataxia score $2. The primary outcome was mean change in ISS at 12 months.
Results: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 6 2.7 in the rituximab group, and 1.0 6 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p 5 0.027), the self-evaluation scale (p 5 0.016), and 2 subscores of the Short Form–36 questionnaire.
Conclusions: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis.
Level of evidence: This study provides Class I evidence that rituximab is ineffective in improving
ISS in patients with IgM anti-MAG demyelinating neuropathy.

(Fonts: Neurology 80; 24: June 2013)

sabato 22 giugno 2013


 2013 May 9. pii: S0002-9297(13)00179-1. doi: 10.1016/j.ajhg.2013.04.018. [Epub ahead of print]

Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia.


Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.

domenica 16 giugno 2013



Management of Antithrombotic Therapy in Patients Undergoing Invasive Procedures

Todd H. Baron, M.D., Patrick S. Kamath, M.D., and Robert D. McBane, M.D.
N Engl J Med 2013; 368:2113-2124May 30, 2013DOI: 10.1056/NEJMra1206531

Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

Nejm, june 2013


Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.


In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.


We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.


Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.)

domenica 9 giugno 2013

domenica 2 giugno 2013

 2013 May 23;368(21):1992-2003. doi: 10.1056/NEJMoa1215993. Epub 2013 May 8.

Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.


Department of Neurology, Massachusetts General Hospital, Boston 02115, USA.



The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive.


We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model.


Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis.


The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).


Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis

To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, Pcombined = 2.92 × 10−8, odds ratio (OR) = 1.31) and 22p11 (CABIN1 andSUSD2, rs8141797, Pcombined = 2.35 × 10−9, OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS (Nature Genetics 45; 2013).

Pine-Nut Syndrome

una "chicca neurologica" disponibile nella casella condivisa...

Pinemouth syndrome (PMS), otherwise known as pine nut syndrome, is a relatively new condition. At least several thousand cases have now been described in the literature. The author describes the PMS toxidrome, offers a preliminary case definition, and discusses current best evidence regarding the etiology and risk factors related to the development of PMS. A clinically compatible case of PMSmust include taste disturbance, usually characterized as bitter or metallic, following the ingestion of affected pine nuts by 1 to 3 days. Affected nuts would appear to include all, or some portion, of nuts harvested from species Pinus armandii (Chinese white pine), but could include nuts from other species. The specific toxin that is apparently present in affected nuts has not yet been isolated, and the mechanism of toxicity and factors determining PMS susceptibility need to be further detailed. There are no proven therapies for PMS. The only treatment is to cease ingesting implicated nuts and to wait for symptoms to abate.

ci sono tanto di criteri diagnostici!!!

Linee guida AAN

sono uscite le linee guida su

"Periprocedural Management of Antithrombotic Medications in Patients with Ischemic Cerebrovascular Disease"

sono disponibili in casella condivisa.

buona lettura