Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work.

The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40 years of age were included in the prospective, observational study. 80 patients were included over a 2 year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n = 29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n = 9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p < 0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p = 0.001) and more frequently parkinsonism (p < 0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

Is deltoid muscle biopsy useful in isolated camptocormia? A prospective study.

BACKGROUND AND PURPOSE: Camptocormia is a marked anterior curvature of the thoracolumbar spine that may be caused by parkinsonism, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) and muscle disease. The interest of a systematic muscle biopsy has not been evaluated until now. In our study, the aim was to prospectively evaluate the proportion of patients with isolated camptocormia without ALS, MG and parkinsonism who have an underlying myopathy. METHODS: Twenty consecutive patients (75% female, mean age 70 years) with isolated camptocormia were enrolled in a single centre in this 5-year prospective study. ALS, MG and parkinsonism had been excluded in all cases. A left deltoid muscle biopsy was performed in all patients and processed with standard techniques for histology and immunohistochemistry. Additional biochemical and genetic studies were performed when pathological analysis was consistent with myopathy. RESULTS: A myopathy was identified in seven patients (35%). Three patients presented with mitochondrial myopathy, including two patients harbouring a heterozygous POLG gene pathogenic variant and one patient with a heterozygous RRM2B gene pathogenic variant. Two patients presented with an inflammatory myopathy, including one with anti-PM/Scl antibodies. One patient presented with facioscapulohumeral muscular dystrophy and one patient with an MYH7 gene-related myofibrillar myopathy. No obvious myopathy was found in the 13 remaining cases. DISCUSSION: In this prospective study, an underlying myopathy was found in 35% of patients with isolated camptocormia. These results suggest that a muscle biopsy should be systematically performed in patients with isolated camptocormia when ALS, MG and parkinsonism have been excluded.

[HER2 gene amplification assay: is CISH an alternative to FISH?]. / Recherche de l'amplification du gène HER2: la CISH est-elle une alternative à la technique FISH?

The HER2 proto-oncogene encodes a transmembrane protein, which is considered to function as a growth factor receptor. Overexpression of this protein found by immunohistochemistry in about 20% of infiltrating breast carcinomas, has a predictive value of response to treatment by trastuzumab, an anti-HER2 humanized monoclonal antibody. Search for HER2 gene amplification is necessary to adapt the immunohistochemical technique quality and also in the cases of delicate analysis or weak overexpression. It is usually carried out by Fluorescence In Situ Hybridization (FISH). A more recent hybridization technique, named CISH because of its chromogenic revelation is an alternative method, which gives highly correlated results with FISH. We present details of this technique, which may be more familiar for the pathologists than FISH, because reading analysis is similar to that of immunohistochemical staining.

The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain.

We have used the mouse delta-opioid receptor (mDOR) cDNA to isolate the mDOR gene and its human homologue. In both species the coding region is interrupted by two introns with conserved exon-intron boundaries located after transmembrane domains 1 and 4. Using the polymerase chain reaction and primers based on the sequence of the cloned human delta-opioid receptor (hDOR) gene, we have obtained a full length cDNA encoding the hDOR from SH-SY5Y neuroblastoma cells. The cDNA sequence is 100% identical to the cloned human genomic sequence and 94% identical to the mouse sequence at the protein level. When expressed in COS cells, hDOR displays nanomolar affinities for delta-selective ligands, whereas the affinities for mu- and kappa-selective ligands are in the micromolar range. The delta agonists [D-Ala2, D-Leu5]enkephalin, cyclic [D-penicillamine2,D-penicillamine5]enkephalin, and BW373U86 efficiently decrease forskolin-induced cAMP levels in hDOR-expressing COS cells, indicating functional coupling of the receptor. The distribution of hDOR mRNA in human brain was investigated using delta-selective reverse transcription-polymerase chain reaction amplification, followed by Southern hybridization with a delta-specific probe. The transcript is found in cortical areas, including olfactory bulb, hippocampus, and amygdala, as well as in basal ganglia and hypothalamus. No expression is detected in internal globus pallidus, thalamus, any investigated brainstem structure, or pituitary gland. Taken together, our results indicate similar structural, pharmacological, functional, and anatomical properties for the hDOR and the mDOR and therefore support the use of rodent models for the study of these receptors in opioid function.