The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4.

PURPOSE: Hereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset. METHODS: We performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553). RESULTS: We found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel-Cox test, P < .0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients. CONCLUSION: SARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy.

The Myelic Limited Dorsal Malformation: Prenatal Ultrasonographic Characteristics of an Intermediate Form of Dysraphism.

OBJECTIVES: The aim of the study was to report a subtype of dysraphism designated as myelic limited dorsal malformation (MyeLDM) and to describe its characteristics at prenatal ultrasound (US). METHODS: It was a retrospective study from 2014 to 2020 based on second-line US evaluation of patients referred to our institution for myelomeningocele (MMC). Magnetic resonance imaging and acetylcholine esterase evaluation in the amniotic fluid were also offered. Major and minor criteria for open and closed dysraphism were defined and recorded for each patient. Patients were included as MyeLDM when both criteria of closed and open dysraphism were observed in the same fetus. Correlations were obtained with the postpartum data. RESULTS: Twenty patients fulfilled the inclusion criteria, some of them being very close to MMC, others very close to limited dorsal myeloschisis (LDM), and others lying in between. There were 13 live-born neonates and 7 terminations of pregnancy. Correlations between prenatal and postpartum data were overall very good. CONCLUSION: Our series describe the ultrasonographic characteristics of an intermediate type of dysraphism and suggest that there is a continuum between MMC and LDM with numerous possibilities of hybrid forms (MyeLDM) sharing characteristics of both open and closed dysraphisms.

The upper limb in children with cerebral palsy. Evaluation and treatment.

Management of the upper limb in children with cerebral palsy is often complex and must be carried out by a team experienced in this field. Several clinical parameters must be taken into consideration, such as higher functions, visual problems, overall upper limb function, motor control, sensitivity, presence of hemineglect or synkinesis, limb position at rest and during walking. And last but not least, a complete analysis of the upper limb is required. It is only after this exhaustive assessment - which often includes occupational therapy, physiotherapy and in some cases, video and electromyography evaluations - that a treatment indication can be discussed with the patient's family. Other than baseline treatment consisting of rehabilitation, occupational therapy and bracing, botulinum toxin injections could be an option, targeting specific muscle groups. Surgical treatments, which are often indicated in severe forms with contractures, are proposed after the patient's case is presented at a multidisciplinary meeting. These include selective neurotomy, muscle-tendon release, transfer or lengthening, and procedures on bone and joints (osteotomy, arthrodesis). LEVEL OF EVIDENCE: Expert opinion.

[Urinary incontinence in children]. / Incontinence urinaire de l'enfant.

URINARY INCONTINENCE IN CHILDREN. Urinary incontinence in children and adolescents is most often of functional origin. Questioning and clinical examination with a bladder diary should look for underlying urological or neurological causes. The type of incontinence, daytime or nocturnal, must be specified to adapt treatments. Renal and bladder ultrasound is recommended, and urodynamic studies are not routinely used. Lifestyle advice and bowel management are prerequisites for treatment. Depending on the type of symptoms, drug treatment, pelvic floor treatment, behavioral measures or stimulation of the posterior tibial nerve can be proposed. The evolution can sometimes be slow with a significant impact on quality of life, and neurocognitive aspects need to be considered.

INCONTINENCE URINAIRE DE L'ENFANT. L'incontinence urinaire de l'enfant et de l'adolescent est le plus souvent d'origine dite fonctionnelle. L'interrogatoire et l'examen clinique, comprenant un catalogue mictionnel, doivent rechercher des causes urologiques ou neurologiques sous-jacentes. Le type d'incontinence, diurne ou nocturne, doit être précisé car les traitements en dépendent. L'échographie rénale et vésicale est recommandée, et le bilan urodynamique n'est pas systématique. Les mesures hygiéno-diététiques et le traitement de la constipation constituent la première étape de la prise en charge. Selon le type de symptômes, un traitement médicamenteux, la rééducation périnéale, des mesures comportementales ou la stimulation du nerf tibial postérieur peuvent être proposés. L'évolution peut être parfois lente, avec un retentissement important sur la qualité de vie, et les aspects neurocognitifs nécessitent d'être pris en compte.

Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3.

BACKGROUND AND OBJECTIVES: In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. METHODS: We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. RESULTS: We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. DISCUSSION: READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03487367.

Individual perception of environmental factors that influence lower limbs spasticity in inherited spastic paraparesis.

BACKGROUND: Phenotypic variability is a consistent finding in neurogenetics and therefore applicable to hereditary spastic paraparesis. Identifying reasons for this variability is a challenge. We hypothesized that, in addition to genetic modifiers, extrinsic factors influence variability. OBJECTIVES: Our aim was to describe the clinical variability in hereditary spastic paraparesis from the person's perspective. Our goals were to identify individual and environmental factors that influence muscle tone disorders and derive interventions which could improve spasticity. METHODS: This study was based on self-assessments with questions on nominal and ordinal scales completed by participants with hereditary spastic paraparesis. A questionnaire was completed either in-person in the clinic or electronically via lay organization websites. RESULTS: Among the 325 responders, most had SPG4/SPAST (n = 182, 56%) with a mean age at onset of 31.7 (SD 16.7) years and a mean disease duration of 23 (SD 13.6) years at the time of participation. The 2 factors identified as improving spasticity for > 50% of the responders were physiotherapy (193/325, 59%), and superficial warming (172/308, 55%). Half of the responders (n = 164, 50%) performed physical activity at least once a month and up to once a week. Participants who reported physiotherapy as effective were significantly more satisfied with ≥ 3 sessions per week. Psychologically stressful situations (246/319, 77%) and cold temperatures (202/319, 63%) exacerbated spasticity for most participants. CONCLUSION: Participants perceived that physiotherapy reduced spasticity and that the impact of physiotherapy on spasticity was much greater than other medical interventions. Therefore, people should be encouraged to practice physical activity at least 3 times per week. This study reported participants' opinions: in hereditary spastic paraparesis only functional treatments exist, therefore the participant's expertise is of particular importance.

Recent advances in understanding hereditary spastic paraplegias and emerging therapies.

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.

Upper limb kinematics after Latissimus Dorsi transfer in children with brachial plexus birth palsy.

BACKGROUND: Brachial plexus birth palsy remains a frequent condition and one of its treatments is to transfer the Latissimus Dorsi tendon to the infraspinatus muscle. The aim of this study was to analyse, for the first time, the three-dimensional kinematic effects of this operation on the upper limb joints during the five Mallet tasks and their correlation with clinical parameters. METHODS: Kinematic analysis was performed using an electromagnetic device. An Index of Improvement taking into account the angle in preop and postop, the reproducibility and the angle of a control group was developed. Three groups of patients were analysed: sixteen patients (mean: 10,5 years) for the reproducibility, thirty children (mean: 9,5 years) for the control group and ten patients (mean: 8 years 7 months) who were operated. FINDINGS: The humerothoracic and glenohumeral external rotations improved during the external rotation, the neck and the abduction tasks and worsened during the spine task. The glenohumeral external rotation worsened during the mouth task. The Humerothoracic abduction improved during the abduction and the neck tasks. The elbow flexion improved for the neck task. Differences were observed between patients and correlations were obtained between the Index of Improvement and clinical parameters. INTERPRETATION: Using kinematics allows to better analyse the evolution of joint angles after the latissimus dorsi transfer. The Index of Improvement allows to quickly analyse the effect of the operation for each angle and each patient. This effect depends on clinical parameters.

Ultrasound shearwave elastography to characterize muscles of healthy and cerebral palsy children.

Shear wave elastography (SWE) is an ultrasound technique to obtain soft tissue mechanical properties. The aim of this study was to establish the reliability of SWE in young children, define reference data on healthy ones and compare the shear modulus of healthy and spastic muscles from cerebral palsy (CP). The reproducibility is evaluated: at rest, on 7 children without any musculoskeletal pathology by 3 different operators, on 2 muscles: biceps brachii long head and medial gastrocnemius. The comparison study was made, on the same 2 muscles, at rest and under passive stretching, with a control group (29 healthy children), a spastic group (spastic muscles of 16 children from CP) and a non-spastic group (non-spastic muscles of 14 children from CP). The intra-operator reliability and inter-operator reliability, in terms of standard deviation, were 0.6 kPa (11.2% coefficient of variation (CV)) and 0.8 kPa (14.9% CV) for the biceps, respectively, and 0.4 kPa (11.5% CV) and 0.5 kPa (13.8% CV) for the gastrocnemius. At rest, no significant difference was found. Under passive stretching, the non-spastic CP biceps were significantly stiffer than the control ones (p = 0.033). Spastic gastrocnemius had a higher shear modulus than in the control muscles (p = 0.0003) or the non-spastic CP muscles (p = 0.017). CP stretched medial gastrocnemius presented an abnormally high shear moduli for 50% of patients.

Diagnosis, follow-up and management of sleep-disordered breathing in children with osteogenesis imperfecta.

OBJECTIVES: Osteogenesis imperfecta (OI) is the most common genetic skeletal disorder. Extraskeletal findings are common but an association with sleep-disordered breathing (SDB) has never been described. The aim of this study was to investigate clinical features of children with OI and suspected SDB. METHODS: A retrospective study of clinical records, signs of SDB and polysomnographic recordings of children with OI was performed. We paid particular attention to symptoms that could be associated with SDB in this population - scoliosis, kyphosis, vertebral arthrodesis, chest wall deformities, basilar impression, autonomy - as well as data already known to be associated with obstructive sleep apnea such as body mass index and upper-airway impairment. RESULTS: We reviewed the clinical charts of 188 patients referred to our genetic skeletal disorders reference center for OI. Among the 15 patients (8%) with polysomnographic recordings, 12 (6.4%) had sleep-disordered breathing. We found a negative correlation between the Brief Assessment of Motor Function score and Apnea Hypopnea Index (r=-0.68; p=0.01) and Desaturation Index (r=-0.62; p=0.02). The Apnea Hypopnea Index was higher for non-walkers than walkers (mean [SD]: 6.5 [3.6] vs. 2.4 [1.5]; p=0.02) and with type III versus IV OI. Two patients were started on continuous positive airway pressure ventilation, with clinical improvement. CONCLUSION: For OI children, symptoms suggesting obstructive sleep disorders should be searched for systematically, especially in children with compromised autonomy, high body mass index, trunk deformations, and severe OI type.