Neurology-Genetics最新文献

Background and objectives: Spinocerebellar ataxias are a diverse group of autosomal dominant cerebellar ataxias. SCA2 is a complex ataxia with various extracerebellar symptoms, including parkinsonism, dystonia, hyporeflexia, and cognitive impairment. ATXN2 is a modulator of neurologic disease: Expansions of at least 37 CAG (glutamine) repeats are pathogenic for SCA2, while expansions in the intermediate range (30-32) convey risk for the development of neurodegenerative disorders including Parkinson disease and amyotrophic lateral sclerosis. Homozygous variants are exceedingly rare. This study describes a novel ATXN2 presentation identified in an Acadian family from New Brunswick, Canada: a CAG repeat expansion within the fully penetrant range of SCA2, asymptomatic in the heterozygous state and resulting in a neurodegenerative disorder in homozygous patients.

Methods: Three individuals, 2 siblings and their cousin, were investigated for a neurodegenerative disorder with overlapping phenotypes. The affected individuals and their 5 immediate family members underwent whole-genome sequencing analyzed by ExpansionHunter, repeat-primed PCR and Sanger sequencing.

Results: Sequencing revealed a homozygous 39/39 CAG repeat expansion with 4 CAA interruptions in ATXN2 across all 3 affected individuals. After experiencing childhood intellectual or learning difficulties, the patients developed a pyramidal syndrome with spastic gait and a major neurocognitive disorder characterized by prominent frontal signs during their late twenties. Within a decade, all patients completely lost their autonomy. Shared phenotypic features included ataxia, spasticity, aphasia, dysphagia, myoclonus, atypical parkinsonism, incontinence, diffuse cortical atrophy with frontal predominance, and cerebellar atrophy. The same 39 CAG repeat allele with 4 CAA interruptions was identified in heterozygous state in 4 asymptomatic parents (age 65+) and 1 sibling in their thirties. Three carriers consented to further investigation with a neurologic examination, neuropsychological assessment, and cerebral MRI. Clinical and radiologic signs of disease were absent, despite the carriers' ages and their heterozygous expansion in the fully penetrant range of SCA2.

Discussion: This study describes a novel ATXN2 expansion within the classic pathogenic range for SCA2 that manifests as an early-onset neurodegenerative disorder in the homozygous state, while being asymptomatic into late adulthood in the heterozygous state.

Objectives: Congenital insensitivity to pain (CIP) is a rare sensory neuropathy marked by absent nociception that predisposes patients to injuries and complications. Variants in genes, particularly PRDM12, underlie the condition. We investigated the molecular basis of CIP in 2 unrelated families.

Methods: Trio whole-exome sequencing was performed for 3 CIP patients from 2 unrelated families and their parents; 1 family with negative results subsequently underwent whole genome sequencing. Sanger sequencing and fluorescent PCR confirmed and sized a GCC repeat expansion.

Results: PRDM12 variants explained CIP in both families, each manifesting infantile-onset neuropathic keratopathy and self-mutilation. In Family 1, 2 siblings born to consanguineous parents were homozygous for a 19-GCC repeat expansion in the last exon, resulting in a polyalanine tract of 20 alanines-the largest PRDM12 polyalanine expansion reported to date. In Family 2, the proband carried 2 compound-heterozygous variants c.570+2T > G and c.796A > C (p.Thr266Pro) classified as pathogenic and likely pathogenic, respectively, and both previously undescribed.

Discussion: These data broaden the genetic spectrum of CIP and reinforce PRDM12 as a key gene in pain perception. They also emphasize that diagnostic analysis should target both single-nucleotide variants and polyalanine expansions, which are often underrepresented in whole-exome or whole-genome sequencing data.

Background and objectives: Neuronal ceroid lipofuscinosis type 1 (CLN1) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the PPT1 gene, leading to lipofuscin accumulation, neurodegeneration, psychomotor regression, seizures, and vision loss, with early death in infancy. Currently, no curative treatment exists. Neuroinflammation plays a major role in CLN1 pathophysiology, making anti-inflammatory treatments a potential option. Fingolimod, an immune modulator approved for multiple sclerosis (MS), has shown efficacy in reducing neurodegeneration in CLN1 mouse models. Neurofilament light chain (NfL), a key axonal structural protein, is a biomarker of neuronal damage, with elevated levels indicating axonal injury in various neurologic diseases. We report on 2 pediatric patients with CLN1 treated with fingolimod to assess clinical response and its impact on NfL levels.

Methods: This study involved 2 patients with CLN1 who were treated with fingolimod under a compassionate use program at Great Ormond Street Hospital. Inclusion criteria required a molecular diagnosis of CLN1. Patient 1 was monitored over a 36-month period, while patient 2 was followed for 15 months. Fingolimod was administered daily, with dosing adjusted based on age and weight. Lymphocyte counts and NfL levels were regularly measured throughout the study to assess treatment response. The primary outcome was the evaluation of the safety profile following the SOP for fingolimod administration at GOSH. Secondary outcomes included clinical assessments to monitor disease progression and lymphocyte count. As an exploratory outcome, we measured NfL levels, which serve as a biomarker of neuroinflammation and axonal injury.

Results: Two patients with CLN1 were treated with fingolimod under compassionate use. Patient 1 showed a >50% reduction in NfL levels after 14 months, approaching normal results after 2 years, while patient 2 had limited NfL data but generally lower levels, possibly due to later disease onset. No major safety concerns were observed. No clinical improvements were seen, although some stabilization was observed despite expected disease progression.

Discussion: The significant reduction in NfL levels observed suggests reduced neuroaxonal damage secondary to immune modulation. This finding highlights the potential role of immune modulation in addressing underlying inflammatory processes in CLN1, even if it does not fully halt disease progression.

Objectives: This series reports 3 unrelated individuals with features of neurofibromatosis type 1 (NF1) and/or schwannomatosis (SWN) in whom variants of uncertain significance (VUSs) were resolved through RNA testing and tissue analysis, highlighting the clinical impact of these tests.

Methods: Each patient's genetic testing identified a VUS that could have explained their clinical presentation. Because diagnostic criteria were not met, we performed VUS resolution. For patient 1, we conducted tissue analysis and RNA-based Sanger sequencing. For patients 2 and 3, RNA-based Sanger sequencing was pursued.

Results: Tissue analysis and RNA testing reclassified the NF1 c.8050 + 93A>T VUS in patient 1 as pathogenic, confirming diagnosis of NF1. RNA testing of the NF2 c.448-5T>C VUS in patient 2 reclassified the variant as likely benign, ruling out diagnosis of germline neurofibromatosis type 2 (NF2). RNA testing of the SPRED1 c.377-13T>A VUS in patient 3 reclassified the variant as likely benign, ruling out diagnosis of germline Legius syndrome.

Discussion: Because diagnostic criteria for NF1 and SWN include genetic testing, resolving VUSs in those who do not meet criteria is crucial for clinical care. In this article, we report 3 cases in which RNA testing and tissue analysis clarified pathogenicity of VUSs, thereby affecting clinical care, and in one case providing a definitive diagnosis.

Background and objectives: Pathogenic variants in the SCN2A gene, encoding the α-subunit type 2 of the voltage-gated sodium channel Na_V1.2, cause a phenotypic spectrum including 4 major disorders as benign familial infantile seizures, developmental and epileptic encephalopathy, intellectual disability, and autism. Gain-of-function variants resulting phenotypes may be treated with sodium channel blockers, while loss-of-function (LoF) conditions are non-respondent. We focused on the effects of the pathogenic SCN2A variant c.4976C>T (p.A1659V) found in heterozygosity in 3 patients affected by DEE non responsive to SCB. We functionally investigated this previously uncharacterized SCN2A variant.

Methods: Three individuals with the SCN2A c.4976C>T (p.A1659V) variant were studied. This variant was detected by next-generation sequencing (NGS). The nucleotide substitution was inserted by site-directed mutagenesis in a stabilized SCN2A plasmid encoding Na_V1.2. Expression and functional characterization of the Na_V1.2 A1659V variant was performed in HEK293 cells by western blotting, confocal microscopy, and patch clamp electrophysiology.

Results: The same de novo pathogenic SCN2A variant was detected in 3 patients with DEE characterized by early onset, severe ID, and seizures unresponsive to SCB. In 2 patients, the variant is in a mosaic state. The Na_V1.2 A1659V variant did not affect channel protein expression while exhibiting significant effects on its function as shown by the reduced Na⁺ currents, a shift of the activation curve toward more negative potentials, a shift of the inactivation curve to more negative voltages, and slower kinetics of inactivation compared with native Na_V1.2 in HEK293 cells. Simulations suggested that the variant increases excitability in neurons.

Discussion: These results revealed the multifaceted functional effect of A1659V variant on channel activity and highlighted the complex genotype-phenotype correlation underlying significant clinical and pharmacological variability in SCN2A-related encephalopathies.

Background and objectives: Hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are rare neurologic disorders that often represent opposite ends of a shared clinical spectrum. Spastic ataxia, defined by the co-occurrence of cerebellar syndrome and overt spasticity, remains comparatively underexplored and is associated with relatively few genetic causes. The aim of this study was to characterize the clinical and genetic features of spastic ataxia in a large HCA cohort and compare them with those of nonspastic HCA.

Methods: A prospective HCA cohort was initiated in 2017, incorporating annual assessments following a structured and standardized protocol. Spastic ataxia was defined as ataxia occurring in conjunction with spasticity grade ≥2 on the Modified Ashworth Scale. Patients meeting this criterion were identified; their clinical and genetic data were analyzed and compared with those of patients with nonspastic forms of HCA. The Movement Disorder Society's nomenclature for genetic disorders was adopted, using dual-prefix notation for combined phenotypes (e.g., HSP/ATX for spastic ataxia), except for entities such as MJD/SCA3 or ARSACS, which are more readily recognized by their original designations.

Results: Of 249 patients assessed (164 families), 56 (22.5%; from 46 families) exhibited a spastic ataxia phenotype. Compared with nonspastic HCA, these patients had earlier onset and longer disease duration. Spastic ataxia was significantly associated with autosomal recessive inheritance and conventional (nonrepeat expansion) variants. Thirty-eight probands (80.8%) had a definite genetic diagnosis, involving 22 causal genes. The most frequent diagnoses were ARSACS (17.4%), ATX-SYNE1 (6.5%), ATX-ANO10, HSP/ATX-KIF1C, HSP/ATX-PGN, HSP-ZFYVE26, MxMD-ATP13A2, and ATX/HSP-KCNA2 (4.3% each). A noncerebellar presentation was observed in 30 patients with spastic ataxia (53.6%) while 26 (46.6%) had cerebellar onset. After adjustment for disease duration, patients with spastic ataxia had significantly higher baseline scores on the Scale for the Assessment and Rating of Ataxia, reflecting a greater disease burden. In addition, falls were more frequent in this group.

Discussion: Spastic ataxia represented a clinically and genetically distinct subgroup within HCA, marked by recessive inheritance, large genetic heterogeneity, and more severe motor impairment. Greater awareness of its heterogeneous presentations and progressive disability over time is crucial for timely diagnosis, genetic counseling, and development of tailored management strategies for these patients.

Background and objectives: SYNE1 deficiency is an autosomal recessive disorder with a broad phenotypic spectrum, most commonly presenting as adult-onset cerebellar ataxia with or without motor neuron dysfunction. We aimed to expand this spectrum by describing the clinical and genetic findings in 2 unrelated families with early-onset motor neuron disease and virtually no cerebellar signs over time.

Methods: We performed detailed clinical, neurophysiologic, and genetic studies of 2 unrelated families with juvenile amyotrophic lateral sclerosis (ALS) and biallelic variants in SYNE1.

Results: The phenotypes of both families showed onset of symptoms in childhood or adolescence, with signs of upper and lower motor neuron dysfunction in multiple territories suggestive of juvenile ALS. Patients developed progressive muscle weakness, eventually leading to respiratory distress and bulbar signs. Whole-exome sequencing identified SYNE1 biallelic truncating variants in both families: a homozygous nonsense variant, c.23131C>T (p.Gln7711*), in Family 1, and a novel homozygous splice-site variant, c.17851-1G>A, in Family 2. Notably, mild or no cerebellar manifestations were observed during the follow-up.

Discussion: This report highlights a novel phenotype of SYNE1 deficiency characterized by early-onset motor neuron disease and virtually no cerebellar manifestations, broadening the phenotypic spectrum of this complex neurodegenerative disease. These findings support investigating SYNE1 variants in juvenile ALS and including SYNE1 in motor neuron disease gene panels.

A recent explosion in genomic testing has led to the identification of several genetic disorders that mimic CNS-specific autoimmune disorders. Such monogenic disorders, although rare, represent a diagnostic challenge because of their diverse phenotypes and overlapping features. Early recognition of these disorders is crucial not only to prevent overtreatment with immunotherapy but also to ensure that targeted treatments are available for many of these disorders. This review explores some of the monogenic disorders that can masquerade as neuroinflammatory phenotypes. These clinical vignettes are stratified according to neuroanatomical localization along the neuroaxis: supratentorial white matter, gray matter, brainstem, and spinal cord involvement. Through these cases, we discuss how clinical, laboratory, and neuroimaging red flags, such as early onset, relentless progression despite immunotherapy, and lack of CSF markers of inflammation, can guide specific diagnostic workup. In the next section, we highlight the approach to genetic testing in identifying monogenic mimickers. Finally, we discuss a selected list of currently available and emerging therapeutic strategies for some of these disorders. These include JAK inhibitors for Aicardi-Goutières syndrome, anti-TNF therapy for adenosine deaminase 2 deficiency (DADA2), and gene replacement therapy for X-linked adrenoleukodystrophy. By providing a comprehensive and systematic clinical approach, this review aims to equip neurologists with a framework to navigate diagnostic evaluations for such monogenic disorders.

Dominant pathogenic variants in ATP1A3 can occur anywhere in the coding sequence and can cause a wide range of clinical presentations. A practical problem is that sequencing services use one of 3 different mRNA transcripts with different lengths to number the candidate variants. Genetic reports often identify an ATP1A3 variant as a VUS when it is actually well validated. Only 1 transcript, the MANE Select transcript that encodes a protein of 1,013 amino acids, is well supported by evidence. Misidentification of variants in ATP1A3 is disadvantageous when it prevents a confident diagnosis. We illustrate the differences among the 3 transcripts and their merits. Sequencing services should use the MANE Select transcript.

Background and objectives: PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome due to pathogenic germline variants in the PTEN gene. PHTS harbors a diverse range of clinical manifestations including an associated neurodevelopmental (ND) and neurologic phenotype, requiring a multidisciplinary approach to care. There are no clinical practice guidelines for the management of ND or neurologic comorbidities. The objective of these clinical guidelines was to use the latest knowledge to generate a resource for providers, researchers, and patients on the best practices in the practical management of neurologic and ND challenges in PHTS.

Methods: The PHTS Consensus Guidelines Working Group was established, comprising a core group of seven experts in the diagnosis and management of PHTS, including genetics, neurology, neuropsychology, and neurodevelopment (including psychiatry and psychology). The Working Group held joint meetings with a Patient Advisory Group (PTEN Foundation), comprising patients with PHTS and their advocates. Informed by a comprehensive literature review, the Working Group met regularly between 2022 and 2024 to produce guideline statements, refined through iterative feedback. A modified Delphi approach was used with an independent extended panel of neurologists, neuropsychologists, and psychiatrists, to establish final consensus guidelines.

Results: The first iteration of the clinical consensus recommendations for the management of ND and neurologic features in patients with PHTS was formed. Guidelines encompass ND challenges, mood disorders, ND screening, neuroimaging abnormalities, neurologic comorbidities, and tumors affecting the CNS.

Discussion: While multiple efforts are ongoing to better characterize the natural history of PHTS, the clinical management of individuals with PHTS is complex and remains challenging because of variable expressivity and age-related specificities. As part of a comprehensive effort to develop consensus management guidelines, which cover all manifestations of PHTS, we present the first iteration of guidelines for the ND and neurologic manifestations of PHTS, aimed at improving care for affected individuals and families.