Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

Prevalence of lower limb deformities among primary school students

Background Lower limb deformities could affect child's quality of life and may worsen with time. This work aims to study the prevalence of lower limb deformities among primary school students in our governorate. Methods This cross-sectional descriptive study was carried out on 4689 students attending 12 public primary schools during the academic year 2019–2020.Complete clinical examination was done for picking of cases of genu varum, genu valgum, genu recurvatum, flat foot, pes cavus, hallux valgus, in-toeing, and lower limb discrepancy, and x-ray on both feet, pelvis, and full-length lower limb was requested. Results This cross-sectional descriptive study included 4689 students. The prevalence of lower limb (LL) deformities was 16.61%. One hundred twenty-three (2.62%) children had a positive history of musculoskeletal pain, 0.09% had genu varum, 0.11% had genu valgum, 0.75% had Genu recurvatum, 0.03% had LL discrepancy, 13.86% had flexible flat foot, 1.22% had rigid flat foot, 0.23% had pes cavus, 1.04 % had in-toeing, 0.06% had hallux varus, and 0.11% had hallux valgus. Conclusions Lower limb deformities are a considerable problem in primary school students that need early diagnosis because it could affect child’s future, health, and career. Further studies are needed to investigate spinal deformity, vit D level, calcium level, foot wear, and school bag weight as hidden factors.

Charcot-Marie-Tooth neuropathy score and ambulation index are both predictors of orthotic need for patients with CMT

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy with an estimated prevalence of 1 person affected on 2500. Frequent symptoms include distal weakness and muscle wasting, sensory loss, reduced deep tendon reflexes, and skeletal deformities, such as hammer toes and pes cavus. CMT is a progressive disease and patients’ needs change over their lifetime. In particular, ambulation aids are increasingly needed to maintain ambulation and reduce the risk of falls. We performed a retrospective analysis of medical records from 149 patients with confirmed CMT to evaluate patients ambulation needs related to the severity of their CMT as measured by the CMT Neuropathy Score (CMTNS) and Ambulation Index (AI). Most patients required some form of orthotics (86.6%). The CMTNS and AI scores both differed significantly between patients with no orthotics compared to those who wore insoles/inserts. The CMTNS and AI also differed significantly between patients wearing insoles and those with ankle foot orthotics (AFOs). CMTNS and the AI were valid predictors of the type and choice of the orthotics. Both the CMTNS and AI can be effective tools to aid in the correct choice of orthotics in patients affected by CMT.

Phenotype of Patients With Charcot-Marie-Tooth With the p.His123Arg Mutation in GDAP1 in Northern Finland

Background and ObjectivesMutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene cause autosomal dominant or autosomal recessive forms of Charcot-Marie-Tooth disease (CMT). Our aim was to study the clinical phenotype of patients with CMT caused by heterozygous p.His123Arg in GDAP1.MethodsTwenty-three Finnish patients were recruited from a population-based cohort and through family investigation. Each patient was examined clinically and electrophysiologically. The Neuropathy Symptom Score and the Neuropathy Disability Score (NDS) were used in clinical evaluation.ResultsThe median age at onset of symptoms was 17 years among patients with p.His123Arg in GDAP1. Motor symptoms were markedly more common than sensory symptoms at onset. All patients had distal weakness in lower extremities, and 17 (74%) patients had proximal weakness. Muscle atrophy and pes cavus were also common. Nineteen (82%) patients had sensory symptoms such as numbness or pain. The disease progressed with age, and the NDS increased 8.5 points per decade. Electrodiagnostic testing revealed length-dependent, sensory and motor axonal polyneuropathy. EDx findings were asymmetrical in 14 patients. Genealogic study of the families suggested a founder effect.DiscussionWe found that CMT in patients with p.His123Arg in GDAP1 is relatively mild and slow in progression.

Evaluation of the Foot Arch in Partial Weightbearing Conditions

Background: Weightbearing plain radiography or computed tomography (CT) is used for diagnosis or treatment selection in foot disorders. This study compared foot alignment between full weightbearing (50% body weight [BW] per foot) plain radiography and nonweightbearing (0% BW) or partial weightbearing (10% BW per foot) CT scans. Methods: Subjects had both full (50% BW per foot) weightbearing plain radiographs and either a nonweightbearing (0% BW) or a partial weightbearing (20% BW or 10% BW per foot) CT scan. Feet (n = 89) had been previously classified as pes cavus (n = 14/17 [subjects/feet]), neutrally aligned (NA; 20/30), asymptomatic pes planus (APP; 18/24), and symptomatic pes planus (SPP; 15/18). Lateral talometatarsal angle (LTMA) and calcaneal pitch angle were compared between weightbearing radiography and maximum-intensity projection images generated from CT. Results: Significant differences in LTMA were found between nonweightbearing CT scans and full (50% BW per foot) weightbearing plain radiographs: the mean difference was 6.6 degrees in NA, 9.2 degrees in APP, and 11.3 degrees in SPP ( P < .0001); no significant difference in LTMA was found for pes cavus. Although the interaction of foot type ( P = .084) approached statistical significance, pairwise differences between 10% weightbearing and 50% weightbearing images by foot type were significant but small. The 50% weightbearing condition resulted in calcaneal pitch angles the same or slightly lower or higher than those of the 10% weightbearing and nonweightbearing images. LTMA and calcaneal pitch angle measurements made on full (50% BW per foot) weightbearing plain radiographs and non- (0%) or partial (10% BW per foot) weightbearing angles from CT scans were strongly correlated. Conclusion: Different foot types have similar 2-dimensional sagittal plane morphologies with partial weightbearing (10% BW per foot) CT scans and, to a lesser degree, nonweightbearing (0%) neutral-position CT scans when compared to full weightbearing (50% BW per foot) plain radiographs. Level of Evidence: Level III Retrospective case control study.

Neuro-Ophthalmological Findings in Friedreich’s Ataxia

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a severe autosomal recessive genetic disorder of the central nervous (CNS) and peripheral nervous system (PNS), affecting children and young adults. Its onset is before 25 years of age, with mean ages of onset and death between 11 and 38 years, respectively. The incidence is 1 in 30,000–50,000 persons. It is caused, in 97% of cases, by a homozygous guanine-adenine-adenine (GAA) trinucleotide mutation in the first intron of the frataxin (FXN) gene on chromosome 9 (9q13–q1.1). The mutation of this gene causes a deficiency of frataxin, which induces an altered inflow of iron into the mitochondria, increasing the nervous system’s vulnerability to oxidative stress. The main clinical signs include spinocerebellar ataxia with sensory loss and disappearance of deep tendon reflexes, cerebellar dysarthria, cardiomyopathy, and scoliosis. Diabetes, hearing loss, and pes cavus may also occur, and although most patients with FRDA do not present with symptomatic visual impairment, 73% present with clinical neuro-ophthalmological alterations such as optic atrophy and altered eye movement, among others. This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.

An 88.8-kb Novel Deletion of 19q13.2 Encompassing the ATP1A3Gene Detected by Array CGH in a Patient with Delayed Psychomotor Development, Generalized Hypotonia and Macrocephaly

Many neurodevelopmental disorders are caused by the presence of CNVs. Chromosome microarray technology is widely used to accurately detect CNVs. We report the case of a male, aged 3 years, presenting with delayed psychomotor development, generalized hypotonia, encephalopathy, delayed myelination in the central nervous system, and poor motor coordination. The array CGH revealed an interstitial deletion of chromosome 19q13.2 with a size of 88.8 kb involving 3 OMIM genes: <i>RABAC1</i>, <i>ARHGEF1</i>, and <i>ATP1A3</i>. Heterozygous mutations in the <i>ATP1A3</i> gene are associated with delayed psychomotor development, alternating hemiplegia of childhood type 2 (AHC2), dystonia type 12, and cerebellarataxia-areflexia–pes cavus-optic atrophy-sensorineural hearing loss syndrome, also called CAPOS syndrome. The phenotypic expression of partial <i>ATP1A3</i> deletion is, however, poorly described in the literature. The deletion was confirmed by MLPA, and we identified a hitherto undescribed novel deletion of exons 3b–21 of the <i>ATP1A3</i> gene. Our data suggest that the deletion of the <i>ATP1A3</i> gene is a causative factor of the AHC2 phenotype in the patient.