Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.

Corrigendum: Remote assessment of cognition in Parkinson's disease and cerebellar ataxia: the MoCA test in English and Hebrew.

[This corrects the article DOI: 10.3389/fnhum.2023.1325215.].

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Telemedicine Versus Traditional In-Person Consultations: Comparison of Patient Satisfaction Rates.

Introduction: Data on patient satisfaction with the provision of genetic consultations using telemedicine are limited, especially those involving children. We compared patient satisfaction rates with telemedicine services versus traditional in-person encounters. Methods: A cross-sectional questionnaire-based study was conducted between January and June 2020. Questionnaires were distributed online to 1,672 consecutive patients who had received genetic counseling at our Genetics Institute in the clinical fields of adult and pediatric genetics, oncogenetics, and prenatal genetics, through in-person and/or telemedicine consultation. We used Likert scale with scores of 4-5 representing "satisfied"-"very satisfied" and 1-2 representing "very unsatisfied"-"unsatisfied." Results: The response rate was 27.3% (400 adults and 57 children <18 years), including 330 who had received in-person consultations (72.2%), 80 telemedicine consultations (17.5%), and 47 both consultations (10.3%). Mean satisfactory scores of 4-5 were reported by 82.1% in the in-person group versus 82.5% in the telemedicine group (p = 0.88). Mean scores of 1-2 were reported by 6.3% in the in-person group versus 11.2% in the telemedicine group (p = 0.31). No pediatric telemedicine group patient (n 12 = ) gave scores of 1-2 compared with 2/33 (6%) patients who had in-person pediatric consultations (p = 0.62). Most responders who had been counseled through telemedicine (n = 127, 84%) indicated willingness to use genetic services through telemedicine again. Conclusions: Users of genetic counseling through telemedicine, especially in the pediatric age group, were very satisfied at rates comparable to those of in-person consultations. Future research should evaluate patient compliance and views according to session type, information provided (e.g., diagnostic vs. negative results), and its nature (good vs. bad news).

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.

Remote assessment of cognition in Parkinson's disease and Cerebellar Ataxia: the MoCA test in English and Hebrew.

There is a critical need for accessible neuropsychological testing for basic research and translational studies worldwide. Traditional in-person neuropsychological studies are inherently difficult to conduct because testing requires the recruitment and participation of individuals with neurological conditions. Consequently, studies are often based on small sample sizes, are highly time-consuming, and lack diversity. To address these challenges, in the last decade, the utilization of remote testing platforms has demonstrated promising results regarding the feasibility and efficiency of collecting patient data online. Herein, we tested the validity and generalizability of remote administration of the Montreal Cognitive Assessment (MoCA) test. We administered the MoCA to English and Hebrew speakers from three different populations: Parkinson's disease, Cerebellar Ataxia, and healthy controls via video conferencing. First, we found that the online MoCA scores do not differ from traditional in-person studies, demonstrating convergent validity. Second, the MoCA scores of both our online patient groups were lower than controls, demonstrating construct validity. Third, we did not find differences between the two language versions of the remote MoCA, supporting its generalizability to different languages and the efficiency of collecting binational data (USA and Israel). Given these results, future studies can utilize the remote MoCA, and potentially other remote neuropsychological tests to collect data more efficiently across multiple different patient populations, language versions, and nations.

Unique Ataxia-Oculomotor Apraxia 2 (AOA2) in Israel with Novel Variants, Atypical Late Presentation, and Possible Identification of a Poison Exon.

AOA2 is a rare progressive adolescent-onset disease characterised by cerebellar vermis atrophy, peripheral neuropathy and elevated serum alpha-fetoprotein (AFP) caused by pathogenic bi-allelic variants in SETX, encoding senataxin, involved in DNA repair and RNA maturation. Sanger sequencing of genomic DNA, co-segregation and oxidative stress functional studies were performed in Family 1. Trio whole-exome sequencing (WES), followed by SETX RNA and qRT-PCR analysis, were performed in Family 2. Sanger sequencing in Family 1 revealed two novel in-frame SETX deletion and duplication variants in trans (c.7009_7011del; p.Val2337del and c.7369_7371dup; p.His2457dup). Patients had increased induced chromosomal aberrations at baseline and following exposure to higher mitomycin-C concentration and increased sensitivity to oxidative stress at the lower mitomycin-C concentration in cell viability test. Trio WES in Family 2 revealed two novel SETX variants in trans, a nonsense variant (c.568C > T; p.Gln190*), and a deep intronic variant (c.5549-107A > G). Intronic variant analysis and SETX mRNA expression revealed activation of a cryptic exon introducing a premature stop codon (p.Met1850Lysfs*18) and resulting in aberrant splicing, as shown by qRT-PCR analysis, thus leading to higher levels of cryptic exon activation. Along with a second deleterious allele, this variant leads to low levels of SETX mRNA and disease manifestations. Our report expands the phenotypic spectrum of AOA2. Results provide initial support for the hypomorphic nature of the novel in-frame deletion and duplication variants in Family 1. Deep-intronic variant analysis of Family 2 variants potentially reveals a previously undescribed poison exon in the SETX gene, which may contribute to tailored therapy development.

Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations.

Genetic alterations in COL4A2 are less common than those of COL4A1 and their fetal phenotype has not been described to date. We describe a three-generation family with an intragenic deletion in COL4A2 associated with a prenatal diagnosis of recurrent fetal intracerebral hemorrhage (ICH), and a myriad of cerebrovascular manifestations. Exome sequencing, co-segregation analysis, and imaging studies were conducted on eight family members including two fetuses with antenatal ICH. Histopathological evaluation was performed on the terminated fetuses. An intragenic heterozygous pathogenic in-frame deletion; COL4A2, c.4151_4168del, (p.Thr1384_Gly1389del) was identified in both fetuses, their father with hemiplegic cerebral palsy (CP), as well as other family members. Postmortem histopathological examination identified microscopic foci of heterotopias and polymicrogyria. The variant segregated in affected individuals demonstrating varying degrees of penetrance and a wide phenotypic spectrum including periventricular venous hemorrhagic infarction causing hemiplegic CP, polymicrogyria, leukoencephalopathy, and lacunar stroke. We present radiographic, pathological, and genetic evidence of prenatal ICH and show, for what we believe to be the first time, a human pathological proof of polymicrogyria and heterotopias in association with a COL4A2 disease-causing variant, while illustrating the variable phenotype and partial penetrance of this disease. We highlight the importance of genetic analysis in fetal ICH and hemiplegic CP.

Evaluation of Dorsal Midline Discolorations with Physical Examination and Ultrasound.

OBJECTIVE: To assess the association between dorsal midline skin discolorations, tethering of the spinal cord, and the role of ultrasound screening of these stigmata, focusing specifically on vascular lesions. STUDY DESIGN: We conducted a prospective observational study of infants <6 months of age with suspicious dorsal midline skin stigmata. All were evaluated by physical examination and ultrasound scan. A subset also had a magnetic resonance imaging examination. We examined the association between small, red-shaded discolorations and their respective imaging findings. RESULTS: Among 100 cases with discolorations of vascular types, either isolated or combined with low-risk simple dimples or deviated gluteal folds, none had clinically significant pathologic findings requiring surgical intervention. CONCLUSIONS: Midline lumbar discolorations are more benign than previously thought. Despite the very low association of this group of stigmata with surgical implications, we still recommend the routine use of ultrasound scanning.

Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.

Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.

OBJECTIVE: To present the clinical, molecular, and cell biological findings in a family with an autosomal recessive form of hereditary spastic paraplegia characterized by a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN). METHODS: We used a combination of whole-genome linkage analysis and exome sequencing to map the disease locus and to identify the responsible gene. To analyze the physiologic consequences of the disease, we used biochemical and cell biological methods. RESULTS: Ten members of a highly consanguineous family manifested a childhood-onset SPOAN-like phenotype with slow progression into late adulthood. We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor splice-site mutation in the IBA57 gene, previously implicated in 2 infants with lethal perinatal encephalomyopathy. This gene encodes the mitochondrial iron-sulfur (Fe/S) protein assembly factor IBA57. In addition to a severely decreased amount of normal IBA57 messenger RNA, a patient's cells expressed an aberrantly spliced messenger RNA with a premature stop codon. Lymphoblasts contained 10-fold-lower levels of wild-type, but no signs of truncated IBA57 protein. The decrease in functional IBA57 resulted in reduced levels and activities of several mitochondrial [4Fe-4S] proteins, including complexes I and II, while mitochondrial [2Fe-2S] proteins remained normal. CONCLUSIONS: Our findings reinforce the suggested specific function of IBA57 in mitochondrial [4Fe-4S] protein maturation and provide additional evidence for its role in human disease. The less decreased IBA57 protein level in this family explains phenotypic differences compared with the previously described lethal encephalomyopathy with no functional IBA57.

International survey on the management of skin stigmata and suspected tethered cord.

OBJECTIVES: We designed a survey to investigate current international management trends of neonates with lumbar midline skin stigmata suspicious of tethered cord, among pediatric neurosurgeons, focusing on the lower risk stigmata, simple dimples, deviated gluteal folds, and discolorations. Our findings will enable physicians to assess their current diagnosis routine and aid in clarifying management controversies. STUDY DESIGN: A questionnaire on the proposed diagnostic evaluation of seven case reports, each accompanied by relevant imaging, was distributed by e-mail to members of the International Society for Pediatric Neurosurgery, the European Society for Pediatric Neurosurgery, and via the PEDS server list between March and August 2008. RESULTS: Sixty-two questionnaires, completed by experienced professionals with a rather uniform distribution of experience levels, were analyzed. Forty-eight percent do not recommend any imaging of simple dimples, 30% recommend US screening and 22% recommend MR. Seventy-nine percent recommend imaging of deviated gluteal fold with 30% recommending MR. Ninety-two percent recommend imaging infants with hemangiomas with 74% recommending MR. MR for sinus tracts is recommended by 90% if sacral and by 98% if lumber. Eighty-four percent recommend MR for filar cyst. CONCLUSIONS: Our survey demonstrates that management of low-risk skin stigmata, simple dimple, deviated gluteal fold, and discolorations lacks consensus. In addition, a significant sector of the professional community proposes a work-up of simple dimples, sacral tracts, and filar cysts that contradicts established recommendations. A simple classification system is needed to attain a better approach, enabling correct diagnosis of tethered cord without exposing neonates to unnecessary examinations.

Low-risk lumbar skin stigmata in infants: the role of ultrasound screening.

OBJECTIVE: To reassess the utility and validity of ultrasound (US) screening in infants with lumbar midline skin stigmata (MSS) that may be associated with tethering of the spinal cord. STUDY DESIGN: We conducted a prospective observational study of 254 infants under age 6 months with suspicious dorsal MSS between 2005 and 2007. All infants were examined by US and neurosurgical clinical evaluation, and 50 infants also underwent magnetic resonance imaging (MRI). The US and MRI findings were analyzed for correlation. Associations between the imaging findings and the presence of the low-risk skin lesions simple dimple (113 cases) and deviated gluteal fold (DGF; 44 cases) also were evaluated. RESULTS: Analysis of US and MRI results for the cohort of 50 neonates in whom both examinations were performed showed high concordance. The low-risk group of infants with simple dimple and DGF constituted 157 US procedures, 96% of which were of high quality, providing clear visualization of spinal components. None demonstrated any clinically significant pathological findings. CONCLUSIONS: Our data reaffirm the reliability of US as a screening tool for tethered cord syndrome. Infants with low-risk lesions, such as simple dimple and DGF, may be absolved from US screening, because these findings alone do not indicate underlying pathological lesions. We propose a simplified diagnostic classification system for MSS.