Hereditary spastic paraplegias

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en fr Hereditary spastic paraplegias : clinical spectrum in Sudan, further deciphering of the molecular bases of autosomal recessive forms and new genes emerging Paraplégies spastiques héréditaires : exploration clinique au Soudan, études des origines moléculaires des formes autosomiques récessives et identification de nouveaux gènes en cause

64 Key Words: Hereditary Spastic Paraplegia, SPG57/TFG, SPG11, SACS, ATL1, ALS2. 65 Introduction: 66 Pure Hereditary Spastic Paraplegias (HSP) and Hereditary ataxias (HA) represent the 67 extremes of the spectrum of spinocerebellar neurodegenerative disorders. They are often 68 correlated and impose diagnostic difficulty specially with other neurodegenerative 69 disorders with close clinical presentation as motor neurone disease (MND).1 They can 70 be transmitted by 70 all modes of inheritance.1–5 HSP is a group of disorders with the core 71 defining clinical features of insidiously progressive weakness and spasticity of the lower 72 extremities. It is the second most important motor neuron disease with a prevalence of 73 3-10 per 100000 in most populations.6 Prevalence of autosomal dominant (AD) HSP 74 ranges between 0.5-5.5 per 100000 individuals and that of autosomal recessive (AR) 75 HSP between 0.3-5.3 per 100000 individuals.7 HSP can be pure (uncomplicated) or 76 complex according to the absence or presence of additional neurological and non 77 neurological manifestations. To date there are more than 67 known HSP genes.1 AD 78 HSP forms are the most frequent in western populations. SPG4, SPG3A, SPG10 and 79 SPG31 account for up to 50% of AD HSP. SPG3A (ATL1) alone accounts for 10% of 80 AD HSP, with a frequency depending on the age at onset.8 On the contrary, AR HSP 81 predominates in highly consanguineous communities.7,9,10 Thin corpus callosum (TCC)- 82 associated HSP represents a distinct subgroup of HSP accounting for approximately a 83 third of AR HSP.11 At least nine genes have been identified to be responsible for this 84 category. They include SPG1, SPG11, SPG15, SPG18, SPG21, SPG32, SPG46 and 85 SPG49/56 (SPG49 according to HUGO and SPG56 according to OMIM nomenclature) 86 and in rare cases, SPG7. Mutations in SPG11 (also known as KIAA1840 and FLJ21439) 87 (OMIM gene *: 610844) constitute the most frequent cause of TCC-associated HSP 88 (41-77%).12 SPG11 is responsible for 10-20% of all AR HSP [Spastic Paraplegia 11; 89 OMIM phenotype #: 604360], particularly in the Mediterranean basin.6,10,13–16 Next 90 generation sequencing aided the identification of rare genes causing HSP.1,17
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Recent advances in understanding hereditary spastic paraplegias and emerging therapies

Recent advances in understanding hereditary spastic paraplegias and emerging therapies

Abstract Hereditary spastic paraplegias (HSPs) are a group of rare, inherited, neurological diseases characterized by broad clinical and genetic heterogeneity. Lower-limb spasticity with first motoneuron involvement is the core symptom of all HSPs. As spasticity is a syndrome and not a disease, it develops on top of other neurological signs (ataxia, dystonia, and parkinsonism). Indeed, the definition of genes responsible for HSPs goes beyond the 79 identified SPG genes. In order to avoid making a catalog of the different genes involved in HSP in any way, we have chosen to focus on the HSP with cerebellar ataxias since this is a frequent association described for several genes. This overlap leads to an intermediary group of spastic ataxias which is actively genetically and clinically studied. The most striking example is SPG7, which is responsible for HSP or cerebellar ataxia or both. There are no specific therapies against HSPs, and there is a dearth of randomized trials in patients with HSP, especially on spasticity when it likely results from other mechanisms. Thus far, no gene-specific therapy has been developed for HSP, but emerging therapies in animal models and neurons derived from induced pluripotent stem cells are potential treatments for patients.
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Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology

Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology

Abstract Hereditary spastic paraplegias (HSP) are rare neurodegenerative diseases sharing the degeneration of the corticospinal tracts as the main pathological character- istic. They are considered one of the most heterogeneous neurological disorders. All modes of inheritance have been described for the 84 different loci and 67 known causative genes implicated up to now. Recent advances in molecu- lar genetics have revealed clinico-genetic heterogeneity of these disorders including their clinical and genetic overlap with other diseases of the nervous system. The systematic analysis of a large set of genes, including exome sequenc- ing, is unmasking unusual phenotypes or inheritance modes associated with mutations in HSP genes and related genes involved in various neurological diseases. A new nosology may emerge after integration and understanding of these new data to replace the current classification. Collectively, functions of the known genes implicate the disturbance of intracellular membrane dynamics and trafficking as the consequence of alterations of cytoskeletal dynamics, lipid
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Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting

Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting

Abstract Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, which are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and, due to the recent technological revolution in molecular genetics, 76 different spastic gait disease-loci (SPG) with 59 corresponding spastic paraplegia genes (SPG) have been identified. Autosomal recessive HSP are usually associated with diverse additional features (referred as complicated forms) contrary to autosomal dominant HSP, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged of the clinical spectra and has revealed a huge clinical variability for almost all HSP, and complicated forms have been described for primary pure HSP subtypes, making therefore genotype-phenotype more complex. In addition, the introduction of next generation sequencing (NGS) in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias…) or neurodevelopmental disorders including intellectual disability. This review aims to describe the most recent advances in the field and to provide genotype- phenotype correlations that could help making clinical diagnoses of this heterogeneous group of disorders.
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Update on the genetics of spastic paraplegias

Update on the genetics of spastic paraplegias

2 Recent findings Our perception of the intricate connections between clinical, genetic and molecular aspects of neurodegenerative disorders has radically changed in recent years, thanks to improvements in genetic approaches. This is particularly true for hereditary spastic paraplegias, for which >60 genes have been identified, highlighting (i) the considerable genetic heterogeneity of this group of clinically diverse disorders, (ii) the fuzzy border between recessive and dominant inheritance for several mutations and (iii) the overlap of these mutations with other neurological conditions in terms of their clinical effects. Several hypotheses have been put forward concerning the pathophysiological mechanisms involved, based on the genes implicated and their known function, and based on studies on patient samples and animal models. These mechanisms include mainly mitochondrial impairment, abnormal intracellular trafficking, changes to endoplasmic reticulum shaping and defects affecting lipid metabolism, lysosome physiology, autophagy, myelination and development. Several causative genes affect multiple of these functions, which are, most of the time, interconnected.
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Spastic co-contraction is directly associated with altered cortical beta oscillations after stroke

Spastic co-contraction is directly associated with altered cortical beta oscillations after stroke

6. Conclusion These results suggest that cortical beta oscillation alterations may reflect an important neural mechanism underlying with spastic co-contraction of elbow muscles during movement following a stroke. The present findings extend the current concept of cortical oscillations toward an underlying neural mechanism associated with the motor impairment after a stroke. Movement-related beta desynchronization is increasingly being used to investigate the functional role of cortical oscillations in motor function, making cortical beta oscillations a potential marker for motor recovery in stroke subjects. Our study pleads for an EEG-based assessment of cortical oscillatory activity as a target to understand and characterize
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Acute pancreatitis as initial presentation for hereditary spherocytosis: A case report

Acute pancreatitis as initial presentation for hereditary spherocytosis: A case report

Introduction Hereditary spherocytosis is one of the most common cause for hemolytic anemia and is due to a red cell membrane defect. The incidence is likely to be underestimate, as mild cases are often not diagnosed. 18/07/2015 19/07/2015 20/07/2015 22/07/2015 27/07/2015

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Association between hereditary predisposition to common cancers and congenital multimalformations

Association between hereditary predisposition to common cancers and congenital multimalformations

To the best of our knowledge, no research has been published on the incidence of congenital malformations in the offspring of parents with hereditary cancer risk. Sources of data on both conditions were available in the Auvergne region of France and were extensive enough to enable research regarding this issue. We crossed the information available in two large databases, the first used by the oncogenetic ser- vice of Centre Jean Perrin Comprehensive Cancer Center containing pedigrees of cancer-prone families and the second from the regional register of congenital malformations that includes all children born with a congenital malformation. The study period corresponded to 26 years, from January 1986 to December 2011.
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Benign hereditary chorea, not only chorea: a family case presentation

Benign hereditary chorea, not only chorea: a family case presentation

Conclusions This family presented a broad spectrum of hyperkinetic movements with chorea as the most prominent symp- tom in the youngest generation, but with combinations of dystonia, myoclonus, mild ataxia and stuttering in the older generations. At the time of examination, all af- fected subjects exhibited unsteadiness, and were unable to walk in consecutive tandem steps. The affected index family member was originally diagnosed with hereditary ataxia, due to family history and mild ataxia. The pre- dominant feature, chorea, was probably overseen in this family and delayed the identification of the correct eti- ology. In addition neither progression nor atrophy of the cerebellum on MRI scans were observed in this family. The diagnosis was therefore revised. This emphasizes the importance of accurate phenomenology and the im- portance of examination of more family members due to intrafamiliar clinical heterogeneity, which is commonly seen in monogenetic disorders, Table 1 [30].
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Finding good 2-partitions of digraphs I. Hereditary properties

Finding good 2-partitions of digraphs I. Hereditary properties

Lemma 2.1 Let D be a digraph. If S is a set of vertices such that DhSi is out-branchable and Reach + D (S) = V (D), then D has an out-branching with root in S. 2.1 Hereditary, checkable and enumerable properties Recall the definitions of the two classes of properties H, E : H ={acyclic, complete, arcless, oriented, semicomplete, symmetric, tournament} and E ={strongly connected, connected, minimum out-degree at least 1, minimum in-degree at least 1, minimum semi-degree at least 1, minimum degree at least 1, out-branchable, in-branchable}. A property P is checkable if there is a polynomial-time algorithm deciding whether a given digraph has the property P. Observe that the fifteen properties in E ∪ H are all checkable.
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MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

The absence of familial antecedents in more than 65% of individuals, as well as the paternal transmission identified in 3 pedigrees, further supports previous suggestions of a paternal mode of transmission (13). This mode of inher- itance, with its consequence of generation skipping, com- plicates identification of candidate mutation carriers. In general, the phenotypic characteristics of MAX mutant patients overlap with clinical features observed for other PCC/PGL-related hereditary disorders. For example, the presence of a significant proportion of bilateral/multiple PCC cases among MAX germline mutation carriers, repre- senting 21% (13 of 63) of patients included in this cohort (Table 1), is in agreement with the high percentage (35%– 60%) of bilateral tumors found in patients with mutations in VHL, RET, or TMEM127 (7, 29, 33, 34). The age at diagnosis of PCCs in MAX mutation carriers (34 years) was clearly lower than in negative cases (48 years), also lower than the reported on average in patients with TMEM127, RET, and NF1 mutations (38–42 years), but higher to that for VHL and SDH mutation carriers (27–32 years; refs. 19, 20, 29, 33–35).
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Finding good 2-partitions of digraphs I. Hereditary properties

Finding good 2-partitions of digraphs I. Hereditary properties

2.1 Hereditary, checkable and enumerable properties Recall the definitions of the two classes of properties H, E: H ={acyclic, complete, arcless, oriented, semicomplete, symmetric, tournament} and E ={strongly connected, connected, min- imum out-degree at least 1, minimum in-degree at least 1, minimum semi-degree at least 1, minimum degree at least 1, out-branchable, in-branchable}. A property P is checkable if there is a polynomial-time algorithm deciding whether a given digraph has the property P. Observe that the fifteen properties in E ∪ H are all checkable.

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The strong global dimension of piecewise hereditary algebras

The strong global dimension of piecewise hereditary algebras

H 0 [ℓ − 1], respectively). It then follows from 3.4.3, parts (2) and (3), and from the fact that T ends in H 0 [ℓ] that the conclusion of the proposition holds true for T  4.2.4. When T starts in a one-parameter family of pairwise orthogonal tubes but does not end in a suitable suspension of that family (unlike 4.2.3) then less can be told about the indecomposable direct summands of T . Yet there exists a relevant hereditary abelian generating subcategory associated with T as explained in the following result. This will be sufficient to determine the strong global dimension of T in that case.
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On-line computation and maximum-weighted hereditary subgraph problems

On-line computation and maximum-weighted hereditary subgraph problems

Abstract. In this paper, we study the on-line version of maximum- weighted hereditary subgraph problems. In our on-line model, the final instance-graph (which has n vertices) is revealed in t clusters, 2 ≤ t ≤ n. We first focus on the on-line version of the following problem: finding a maximum-weighted subgraph satisfying some hereditary property. Then, we deal with the particular case of the independent set. For all these problems, we are interested in two types of results: the competitivity ratio guaranteed by the on-line algorithm and hardness results that account for the difficulty of the problems and for the quality of algorithms developed to solve them.
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Algorithms for Symmetric Submodular Function Minimization under Hereditary Constraints and Generalizations

Algorithms for Symmetric Submodular Function Minimization under Hereditary Constraints and Generalizations

Finally, we show how to extend our methods to return all the extreme subsets of certain classes of set functions, where a set is called extreme if its function value is strictly smaller than any one of its nontrivial subsets. In particular, the minimal minimizers of a set function over any hereditary family are extreme subsets. For our methods to work, we further require the family of extreme subsets of f to form a simple structure known as a laminar family. This is the case for most of the strongly PP- admissible functions we consider. The general versions of our results about minimal minimizers and extreme sets are stated as Theorems 18 and 24 in sections 5 and 6, respectively.
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Combined spastic paresis of both gastrocnemius and femoral quadriceps muscles in Belgian blue calves

Combined spastic paresis of both gastrocnemius and femoral quadriceps muscles in Belgian blue calves

Faculté Médecine Vétérinaire, Université de Liège - Belgium Institute Spastic paresis of the hindlimb muscles is a well-known neuro-muscular disease. Frequent occurrence of an atypical form of the disease in Belgian Blue (BB) calves led us to perform a retrospective study in order to establish a differential diagnosis.

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Hereditary multiple exostoses of the ribs as an uncommon cause of pneumothorax

Hereditary multiple exostoses of the ribs as an uncommon cause of pneumothorax

[9] Assefa D, Murphy RC, Bergman K, et al. Three faces of costal exostoses: case series and review of literature. Pediatr Emerg Care 2011;27: 1188 –91. [10] Pollitzer RC, Harrell GT, Postlethwait RW. Recurrent pneumothorax associated with hereditary deforming chondrodysplasia; report of a case apparently due to puncture of the lung by an exostosis of a rib. N C Med J 1952;13:668–73.

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Linear Rank-Width of Distance-Hereditary Graphs I. A Polynomial-Time Algorithm

Linear Rank-Width of Distance-Hereditary Graphs I. A Polynomial-Time Algorithm

It turns out that by applying local complementations on the marked vertices having a neighbor in B, in the right way depending on the type of B, we can avoid the difficulties showed in Figures 3 and 4, and indeed obtain the wanted character- ization. We now define the notion of limb and prove some technical lemmas that will be used in the subsequent sections. In this section let us fix D the canonical decomposition of a connected distance-hereditary graph G. We recall from Theo- rems 2.8 and 2.9 that each bag of D is of type K or S, and marked edges of types KK or S p S c do not occur.

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View of The Genetics of Leber’s Hereditary Optic Neuropathy: A Literature Review

View of The Genetics of Leber’s Hereditary Optic Neuropathy: A Literature Review

MOLECULAR MECHANISM The causative factor for disease in LHON is a missense mutation in NADH dehydrogenase, a co-enzyme responsible for the production of ATP and cellular energy (7). This results in decreased ATP synthesis, elevated oxidative stress, and disruptions to the transport of glutamate, ultimately leading to Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by a painless, acute loss of central vision, with 95% of affected individuals harbouring one of three pathogenic mutations (G11778GA, G3460A, or T14484C). The purpose of this review is to highlight the distinguishing clinical presentations of the disease with respect to the mutation subtype and present our recent understanding of two unique features of the disease: male predominance and incomplete penetrance. We also review recent advancements made in the diagnosis and treatment of this rare mitochondrial disease and their implications for genetic counselling.
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Controlling for lesions, kinematics and physiological noise: impact on fMRI results of spastic post-stroke patients

Controlling for lesions, kinematics and physiological noise: impact on fMRI results of spastic post-stroke patients

During the fMRI examination, patients were in a supine position in the scanner, with their eyes closed. Before each scanning session, they were given instructions and familiarized with the fMRI paradigm. We administered a passive wrist extension task. Task instructions and auditory stimuli indicating movement frequency were provided to the patients through headphones. The auditory stimuli continued across the activation (A) and rest (R) trials of the blocked design paradigm. Each functional run lasted 5 minutes and consisted of 10 30-s trials, alternating between R and A trials. During the R trials, patients were instructed to rest and not to think about the movement, whereas during the A trials, the examiner, who was present in the fMRI room, mobilized the patients’ wrist by raising and lowering their hand from 0 ° to its maximum amplitude with a frequency of 0.5 Hz. Fifteen passive movements were performed per A trial. Each functional run was performed twice, once using the unaffected wrist and once the affected (i.e. spastic) one. Movement amplitudes were monitored and recorded with homemade MR-compatible goniometers attached to the patients’ wrists ( Fig. 1 ). These goniometers, which did not restrict their movements, were connected to a PC located in the console room. The recording was paced by the MRI trigger. The data were stored digitally, using NI Labview 2009 software (National Instruments Corp., Austin, TX, USA) [28] installed on the PC, and subsequently analyzed offline.
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