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.
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Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic gain-of function (GOF) disorder provoked by mutations in the TTR gene. Until recently, ...therapeutic options were limited and consisted mainly in liver transplantation and TTR-stabilizers. In the last few years, ATTRv has been at the center of major therapeutic breakthroughs, including development of effective small interfering RNA (siRNA) and antisense oligonucleotide (ASO) treatments targeting liver TTR mRNA. Both siRNA (patisiran) and ASO (inotersen) treatments are now commercially available and have dramatically improved ATTRv neurological outcome. Ongoing clinical trials currently evaluate another siRNA, vutrisiran and a novel ASO formulation, eplontersen. A CRISPR-Cas9-based TTR gene editing treatment is also currently evaluated, with encouraging preliminary results. These recent therapeutic developments demonstrate the shifting paradigm of ATTRv, a previously untreatable and lethal disorder and provide a proof-of-concept for developing siRNA, ASO and CRISPR-Cas9 treatments for other GOF genetic disorders.
Molecular studies have created a paradigm shift in our perception of Charcot-Marie-Tooth disease (CMT). Indeed, CMT has evolved from the concept of a rather homogeneous hereditary disease exclusively ...involving peripheral nerves to the concept of a highly heterogeneous clinical and genetic syndrome mainly – but sometimes not exclusively – involving the peripheral nervous system. The phenotypic spectrum of CMT overlaps with other inherited neuropathies such as distal hereditary motor neuropathy (dHMN), hereditary sensory and autonomic neuropathy (HSAN), spinal muscular atrophy (SMA) subtypes, and the neuropathies of mitochondrial disorders. At a molecular level, mutations in one given gene may alternatively provoke CMT, HSAN, dHMN or SMA variants. Over the last years, there have been dramatic advances in deciphering the molecular basis for many CMT subtypes and more than 900 different mutations in more than 60 causative genes are now described. However, as 75% of CMT causative genes apparently remain unknown and as disease-specific therapies are not available, major advances are yet to come in the field of CMT.
La biologie moléculaire a radicalement modifié notre vision de la maladie de Charcot-Marie-Tooth (CMT). Ainsi, la notion de CMT a évolué d’un concept de polyneuropathie héréditaire homogène vers un concept de syndrome clinique et génétique hétérogène impliquant de manière prédominante, mais pas toujours exclusive, le système nerveux périphérique. Le spectre phénotypique des CMT recoupe en partie le spectre phénotypique des neuropathies motrices distales héréditaires (dHMN), des neuropathies sensitives et dysautonomiques héréditaires (HSAN), des neuropathies des maladies mitochondriales et de plusieurs sous-groupes d’amyotrophie spinale. Sur le plan moléculaire, des mutations sur un même gène peuvent provoquer une CMT, une dHMN, une HSAN ou une amyotrophie spinale scapulopéronière. Ces dernières années, les avancées de la génétique moléculaire ont permis d’identifier plus de 900 mutations responsables de CMT sur plus de 60 gènes différents. Néanmoins, dans la mesure où 75 % des gènes responsables de CMT pourraient être inconnus et dans la mesure où aucune thérapie spécifique de la CMT n’est actuellement disponible, d’importants progrès restent à faire dans le domaine des CMT.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare autoimmune disorder of the peripheral nervous system, primarily affecting the myelin sheath. The pathophysiology of CIDP is ...complex, involving both humoral and cellular immunity. The diagnosis of CIDP should be suspected in patients with symmetrical proximal and distal motor weakness and distal sensory symptoms of progressive onset, associated with decreased/abolished tendon reflexes. Treatments include intraveinous immunoglobulins, steroids and plasma exchange, with usually an induction phase followed by a maintenance therapy with progressive weaning. Treatment should be rapidly initiated to prevent axonal degeneration, which may compromise recovery. CIDP outcome is variable, ranging from mild distal paresthesiae to complete loss of ambulation. There have been several breakthroughs in the diagnosis and management of CIDP the past ten years, e.g. discovery of antibodies against the node of Ranvier, contribution of nerve ultrasound and magnetic resonance imaging to diagnosis, and demonstration of subcutaneous immunoglobulins efficiency. This led us to elaborate French recommendations for the management of adult & pediatric CIDP patients. These recommendations include diagnosis assessment, treatment, and follow-up.
Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic ...homeostasis. Using a mouse model of the disease (SOD1G86R), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1G86R mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.
Synopsis
Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.
The early alteration of muscle metabolic equilibrium between glucose and lipid use impacts on the capacity for muscle to efficiently adapt to increased energetic demands in the SOD1G86R ALS mouse model.
PDK4 is central to these metabolic changes, being upregulated at early asymptomatic stages and increasing throughout disease progression in the SOD1G86R model, as well as in ALS patients.
The metabolic alterations described are specific to glycolytic muscle (TA) in the SOD1G86R model.
Regulation of the glycolytic pathway presents as a potential therapeutic strategy as a drug targeting of PDK4 improves muscle function and overall metabolic status in the SOD1G86R model.
Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.
Magnetic resonance imaging (MRI) and ultrasonographic (US) investigations have recently became prominent tools for the investigation of peripheral nerve injuries. MRI is the most valuable for the ...study of proximal nervous structures, i.e. roots and plexi, whereas US is better suited for the investigation of distal nerves, including entrapment syndromes. However, as nerve conduction studies and electromyographic studies still have a better sensitivity and specificity than MRI and US, they remain the gold standard for the evaluation of the peripheral nervous system.
L’analyse de la littérature en 2013 révèle que les techniques d’imagerie par résonance magnétique (IRM) et par ultrasonographie (US) occupent une place croissante dans l’exploration des neuropathies ...périphériques. L’exploration IRM est particulièrement indiquée dans l’exploration des structures nerveuses proximales (racines et plexi) alors que l’exploration US semble plus prometteuse dans l’exploration des troncs nerveux distaux, en particulier dans les syndromes canalaires. L’exploration électroneuromyographique reste néanmoins encore aujourd’hui l’examen de référence pour l’exploration du système nerveux périphérique, avec une meilleure sensibilité et une meilleure spécificité que les explorations IRM et US.
Magnetic resonance imaging (MRI) and ultrasonographic (US) investigations have recently became prominent tools for the investigation of peripheral nerve injuries. MRI is the most valuable for the study of proximal nervous structures, i.e. roots and plexi, whereas US is better suited for the investigation of distal nerves, including entrapment syndromes. However, as nerve conduction studies and electromyographic studies still have a better sensitivity and specificity than MRI and US, they remain the gold standard for the evaluation of the peripheral nervous system.
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.
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