Psychiatric Presentation of Frontotemporal Dementia Associated with Inclusion Body Myopathy due to the VCP Mutation (R155H) in a French Family.

INTRODUCTION: Inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare late-onset autosomal dominant disorder due to a mutation of the valosin-containing protein (VCP) gene. CASE REPORT: We report the case of a patient who developed progressive weakness of the limbs in his fifties, until he was confined to a wheelchair. At that time, he developed acute behavioural changes including irritability, severe anxiety and major depression, which led to him being hospitalised in a psychiatric hospital. He also suffered from aphasia and executive function impairment, which helped us to diagnose a behavioural form of frontotemporal dementia (FTD). The diagnosis of IBMPFD due to a mutation in the VCP gene was confirmed by a genetic study of the VCP gene (R155H mutation). DISCUSSION: THE CLINICAL DIAGNOSIS OF IBMPFD IS SUGGESTED BY THE PRESENCE OF AT LEAST ONE OF THREE MAJOR MANIFESTATIONS AS FOLLOWS: inclusion body myopathy (mean onset at 42 years of age), Paget's disease of the bone and FTD (mean onset at 55 years of age). It is mostly the behavioural form of FTD (behavioural changes, executive dysfunction and aphasia). One interesting finding in our report is the predominance of the psychiatric symptoms at the beginning of the behavioural changes, which led to the diagnosis of FTD. The diagnosis of IBMPFD was confirmed by the genetic study: the R155H mutation found on exon 5 domain CDC48 is the most frequent of the 18 known mutations in the VCP gene.

A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is the most common cause of inherited peripheral neuropathy, with an estimated frequency of 1/2500. We studied a large family with 17 patients affected by the axonal form of CMT (CMT2). Analysis of the 15 genes or loci known to date was negative. Genome-wide genotyping identified a CMT2 locus in 16q21-q23 between D16S3050 and D16S3106. The maximum two-point LOD score was 4.77 at theta = 0 for marker D16S3050. Sequencing of candidate genes identified a unique mutation, c.986G>A (p.Arg329His), affecting a totally conserved amino acid in the helical domain of cytoplasmic alanyl-tRNA synthetase (AlaRS). A second family with the same mutation and a different founder was then identified in a cohort of 91 CMT2 families. Although mislocation of mutant Arg329His-AlaRS in axons remains to be evaluated, experimental data point mostly to a quantitative reduction in tRNA(Ala) aminoacylation. Aminoacylation and editing functions closely cooperate in AlaRS, and Arg329His mutation could also lead to qualitative errors participating in neurodegeneration. Our report documents in 18 patients the deleterious impact of a mutation in human cytoplasmic AlaRS and broadens the spectrum of defects found in tRNA synthetases. Patients present with sensory-motor distal degeneration secondary to predominant axonal neuropathy, slight demyelination, and no atypical or additional CNS features.

Spatial relationships between lingual nerve and mandibular ramus: original study method, clinical and educational applications.

Lingual nerve damage complicating oral surgery would sometimes require electrographic exploration. Nevertheless, direct recording of conduction in lingual nerve requires its puncture at the foramen ovale. This method is too dangerous to be practiced routinely in these diagnostic indications. The aim of our study was to assess spatial relationships between lingual nerve and mandibular ramus in the infratemporal fossa using an original technique. Therefore, ten lingual nerves were dissected on five fresh cadavers. All the nerves were catheterized with a 3/0 wire. After meticulous repositioning of the nerve and medial pterygoid muscle reinsertion, CT-scan examinations were performed with planar acquisitions and three-dimensional reconstructions. Localization of lingual nerve in the infratemporal fossa was assessed successively at the level of the sigmoid notch of the mandible, lingula and third molar. At the level of the lingula, lingual nerve was far from the maxillary vessels; mean distance between the nerve and the anterior border of the ramus was 19.6 mm. The posteriorly opened angle between the medial side of the ramus and the line joining the lingual nerve and the anterior border of the ramus measured 17 degrees . According to these findings, we suggest that the lingual nerve might be reached through the intra-oral puncture at the intermaxillary commissure; therefore, we modify the inferior alveolar nerve block technique to propose a safe and reproducible protocol likely to be performed routinely as electrographic exploration of the lingual nerve. What is more, this original study protocol provided interesting educational materials and could be developed for the conception of realistic 3D virtual anatomy supports.

[Botulism has not disappeared]. / Le botulisme est toujours d'actualité

INTRODUCTION: Botulism is a potentially fatal infectious disease induced by a neurotoxin secreted by Clostridium botulinum, a sporulated species of obligate anaerobic bacteria. This neurotoxin inhibits the normal release of acetylcholine in the synaptic cleft, inducing presynaptic neuromuscular blockade. The diagnosis is often difficult because of the range and the lack of specificity of the symptoms. CASE: We report two cases of human botulism. The first case was easy to diagnose, with dysphagia, dysphonia, blurred vision, and xerostomia, associated with potentiation on electromyogram and B botulinum toxin in the serum. Symptoms in the second case included diplopia, blurred vision, dysphagia, dysphonia, with potentiation on electromyogram but no botulinum toxin. DISCUSSION: These two cases remind us of the necessity to keep botulism in mind when systemic atropinic symptoms are found together with generalized, progressive and extensive paralysis. The diagnosis is confirmed by electromyogram and serology. There is no specific treatment for botulism; only intensive care surveillance and symptomatic treatment improve survival.

Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene.

We report on a patient with a severe, rare neonatal form of non-dystrophic myotonia. The patient presented with facial dysmorphism, muscle hypertrophy, severe constipation, psychomotor delay, and frequent cold-induced episodes of myotonia and muscle weakness leading to severe hypoxia and loss of consciousness. Muscle biopsy was non-specific and electromyography revealed intense generalized myotonia. The myotonic episodes improved after introducing oral mexiletine and maintaining room temperature at 28 degrees C. The patient died at 20 months of age following a bronchopulmonary infection. A previously undescribed de novo heterozygous c.3891C > A change, which predicts p.N1297K in the SCN4A gene. Mutations within the voltage-gated sodium channel alpha-subunit gene (SCN4A) have been described in association with several phenotypes including paramyotonia congenita, hyperkalemic or hypokalemic periodic paralysis, and potassium-aggravated myotonias. The cold-sensitive episodes of stiffness followed by weakness suggested the diagnosis of channelopathy in our patient. However, her neonatal onset, the triggering of severe episodes by exposure to modest decreases in temperature, involvement of respiratory muscles with prolonged apnea, early-onset muscle hypertrophy, psychomotor retardation, and fatal outcome are evocative of a distinct clinical subtype. Our observation expands the phenotypic spectrum of sodium channelopathies.

Clinicopathological aspects of the neuropathy of neurogastrointestinal encephalomyopathy (MNGIE) in four patients including two with a Charcot-Marie-Tooth presentation.

We report on four patients with severe polyneuropathy associated with intestinal pseudoobstruction (MNGIE). Three patients presented characteristic supranuclear ophthalmoplegia, and hyperdense signals on T2 weighted cerebral MRI and dystrophic mitochondria in Schwann cells and in endothelial cells in nerve biopsy specimens. Two of these patients had a Charcot-Marie-Tooth (CMT) presentation. All three were heterozygous for a recessively transmitted double substitution in the TP gene: Glu286Lys/Glu289Ala, Asp156Gly/Leu177Pro and Glu289Ala/Gly387Asp. The fourth patient, who was the only patient of this series with an affected sib, had no oculomotor manifestations, nor T2 hyperdense signals on brain MRI, and no TP gene mutation and or morphological abnormalities of mitochondria on electron microscopic examination. He was the only patient of this series with an affected sib. The three patients with the full MNGIE syndrome died before the age of 30 years. Detailed results of nerve pathology show that severe axonal degeneration is associated with segmental abnormalities of the myelin sheath in this syndrome which appears genetically heterogeneous. Our findings suggest that only ophthalmoplegia and hyperdense signals on cerebral MRI are directly related to the mitochondriopathy.