Spinal muscular atrophy: from rags to riches.

The aim of this paper is to provide a short history of spinal muscular atrophy, from the first descriptions of the disease to the impact of the most recent therapeutical advances on the disease course. The paper provides an overview of how the field has progressed over the years after the availability of care recommendations and, more recently of the new therapies. The paper also highlights the new challenges related to the interpretation of the efficacy of the new therapies and how these are likely to affect several aspects such as the classification of spinal muscular atrophy. We will also discuss the need for further work to better define possible new phenotypes and new methods of assessments and how these should be reflected in the care recommendations. The results in presymptomatic patients will finally highlight the need for neonatal screening.

Gene therapy. The legacy of Waclaw Szybalski.

Seminal demonstration of the possibility of stable genetic modification of mammalian cells performed by Waclaw and Elisabeth Szybalski opened the doors for gene therapy, the term coined by Waclaw Szybalski already in 1962. In the next 60 years, numerous tools for gene delivery have been developed and applied for clinical research, culminating in the registration of several genetic therapies in Europe and the USA. Some of these strategies, aimed to treat severe combined immunodeficiencies, inherited forms of blindness, spinal muscular atrophy, some cancers, and genetic anemias, are the real hope for patients suffering from previously incurable diseases or the ones whose treatment was not effective. On the approaching 60th anniversary of gene therapy, combined with the 100th anniversary of the birth of Professor Waclaw Szybalski (September 9th, 1921), who passed away on December 16, 2020, here I present the summary of the most important aspects of clinical applications of genetic therapies.

[Gene-based therapies of spinal muscular atrophy: a piece of history of medicine]. / Thérapies géniques de l'amyotrophie spinale infantile - Un morceau d'histoire de la médecine.

It is worth stating that a generation is needed to bring about a new family of drugs. After the deciphering of the genetic cause in 1995, two innovative classes of therapeutics are now available for spinal muscular atrophy (SMA): the repeated administration of antisens oligonucleotides and the one-shot administration of a scAAV9-SMN as a gene therapy. By addressing the genetic mechanisms of the disease, these drugs fundamentally change its course. These major advances in an extremely severe disease, often fatal before the age of 18 months in the type 1 form (50% of patients), pave the way for the treatment of other serious pathologies of the nervous or neuromuscular system, and provide unambiguous evidence of the effectiveness of these new classes of drugs called to address a number of genetic or acquired diseases. These breakthroughs raise also new scientific and technological questions (limited production yields of gene therapy drugs) but also ethical issues (access of patients to these innovative therapies) that resonate beyond this disease alone.

TITLE: Thérapies géniques de l'amyotrophie spinale infantile - Un morceau d'histoire de la médecine. ABSTRACT: On convient de dire qu'une génération est nécessaire pour faire émerger une nouvelle famille de médicaments. L'amyotrophie spinale infantile (SMA), après l'élucidation du gène causal en 1995, dispose depuis peu de deux classes innovantes de thérapeutiques : l'administration répétée d'oligonucléotides antisens et l'administration unique d'une thérapie génique par scAAV9-SMN. En s'adressant aux mécanismes génétiques de la maladie, elles en modifient fondamentalement le cours. Ces avancées majeures dans une maladie extrêmement sévère, mortelle souvent avant l'âge de 18 mois dans les formes de type 1 (50 % des malades), ouvrent la voie pour d'autres pathologies graves du système nerveux ou neuromusculaire, et apportent une preuve déterminante de l'efficacité de ces classes nouvelles de produits appelés à s'adresser à de nombreuses maladies génétiques ou acquises. Elles génèrent aussi de nouvelles questions d'ordre scientifique et technologique (capacités limitées de production des quantités nécessaires en thérapie génique) mais également d'ordre éthique (conditions d'accès des malades à ces thérapies innovantes), qui résonnent au-delà de cette seule maladie.

Camptocormia: New Signs in an Old Syndrome.

Camptocormia is defined as an involuntary flexion of the thoracolumbar spine, without fixed kyphosis, which increases during walking and standing, and abates in the supine position. First described during World War 1 in soldiers suffering from war psychoneuroses, camptocormia has progressively come to refer to any cause of trunk forward-flexed posture during standing and ambulation. It is now admitted that camptocormia should be considered as a syndrome related to many etiologies. In this chapter, we present the historical aspects of the syndrome and its main etiologies. We highlight camptocormia in Parkinson disease and its relationships with Pisa syndrome.

How we developed, at the Centre/Institute for Neuromuscular Diseases, differential diagnostics of Spinal Muscle Atrophies / Amyotrophic Lateral Sclerosis (SMA/ALS) and tried to influence the development of the disease.

In our research, we placed the emphasis on delimiting fatal diseases against those that have some similar symptoms, but can be improved, even completely cured. More often we succeeded in differentiating the local compressive factor. In our search for early symptoms, we also found physiological, although quite unusual EMG phenomena. High amplitude neural potentials confirmed the malignant disease diagnosis. The spinal angiography discovered arterial pathology, while CT demonstrated localised hydromyelia. Amyotrophic syndromes caused by chronic led intoxications represented a separate group. Patients would recover significantly on d-penicillamine. We applied it successfully in amyotrophic syndromes with laboratory confirmed copper metabolism disorders. A very significant therapeutic effect was obtained in a patient with SMA without similar laboratory, even in recidivism. Exceptionally, we were able to achieve significant remission with corticosteroids, too. The remaining patients, differentiated as certainly fatal, represented a separate group. We tried to elaborate the special psychosocial and ethical problems connected with its outcome in "round table discussions". The first one was in 1989, at the workshop with King Engel, and the second in 1990, on the Fourth Yugoslav Symposium on Neuromuscular Diseases. In 1990, I visited Cicely Saunders and the St. Christopher's hospice in London, and in 1994 I started to organised hospice movement in Croatia.

Spinal muscular atrophy: a timely review.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord and resultant weakness. The most common form of SMA, accounting for 95% of cases, is autosomal recessive proximal SMA associated with mutations in the survival of motor neurons (SMN1) gene. Relentless progress during the past 15 years in the understanding of the molecular genetics and pathophysiology of SMA has resulted in a unique opportunity for rational, effective therapeutic trials. The goal of SMA therapy is to increase the expression levels of the SMN protein in the correct cells at the right time. With this target in sight, investigators can now effectively screen potential therapies in vitro, test them in accurate, reliable animal models, move promising agents forward to clinical trials, and accurately diagnose patients at an early or presymptomatic stage of disease. A major challenge for the SMA community will be to prioritize and develop the most promising therapies in an efficient, timely, and safe manner with the guidance of the appropriate regulatory agencies. This review will take a historical perspective to highlight important milestones on the road to developing effective therapies for SMA.

[Thoughts on the illness of Hermann von Reichenau (1019-1054)]. / Gedanken zur Krankheit Hermanns von Reichenau (1019-1054).

Hermann from Reichenau--Hermannus contractus--apparently suffered from a disease which led to considerable physical handicap leaving his outstanding intellectual talents undamaged. Various statements about his condition--an epileptic, suffering from spasticity, afflicted by poliomyelits--have never been reconsidered. Using the biography written by this disciple Berthold, the most important contemporary source about Hermanns' life, an approach to a correct diagnosis from a neurologists point of view was the aim of this study. By unbiased analysis of the symptoms described by Berthold a neurologic syndrome is worked out: it comprised a flaccid tetraparesis involving the bulbar area. The sensory as well as the autonomic nervous system were apparently not involved. Intellectual functions were unaffected. Considering this syndrome and other details of Hermanns' life as well as the beginning and course of his illness, a traumatic birth injury, an early childhood disease and a central nervous as well as an infectious disease are ruled out. Muscle disease is considered possible, but motor neuron disease--either amyotrophic lateral sclerosis or spinal muscular atrophy--seems to be the most convincing diagnosis.

[Aran-Duchenne? Duchenne-Aran? The quarrel around progressive muscular atrophy]. / Aran-Duchenne? Duchenne-Aran? La querelle de l'atrophie musculaire progressive.

A description of progressive muscular atrophy, the first item in neuro-muscular nosography, figures in the memoir published by F.A. Aran in 1850. There, all the essential features of the disease can be found: its usual onset at the distal end of the upper limbs, its slowly progressive worsening, with muscular atrophy sparing certain muscles or muscular fascicles, its peculiar "claw hand", its muscular "fasciculations" and cramps, with untouched sensitivity. After praising Aran's "beautiful description", G.B. Duchenne de Boulogne subsequently persisted in claiming paternity, untiringly referring to a memoir on "muscular atrophy with fatty transformation" said to have been submitted to the Académie des Sciences in 1849. There is no trace of this memoir, and while it is true that the "localized electrisation" technique was applied by Duchenne to all the patients in Aran's memoir, and that he was the sole author of two of his observations, it is Aran who must be credited with the clinical description, the synthetic presentation and the appellation of "progressive muscular atrophy". Initially, this term covered a number of disparate facts which were later identified and put in their proper nosological place, even though this dismemberment left standing what Charcot called "Duchenne-Aran disease" before the Aran-Duchenne denomination prevailed. This denomination is now customary, and rightly so.