Neurogenetics最新文献

Allgrove syndrome (AS) is a rare, multisystem, autosomal recessive disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency. Various and nonspecific neurological symptoms can also develop over time, "blurring" the typical course of this underdiagnosed condition. The incidence of Allgrove syndrome is unknown. Orphanet database reports fewer than 100 published cases, but according to the literature review, at least 206 patients have already been described. The pathogenic variant p.Ser263Pro is one of the most recurrent aberrations affecting the AAAS gene and has been reported in several families of Slavic origin. We investigated genotype-phenotype correlation in 206 patients with AS described in literature (including two novel Polish siblings carrying a homozygous p.Ser263Pro variant in the AAAS gene) and found that neurological symptoms were significantly more common among carriers of p.Ser263Pro variant (33 out of 34, 97.1%) as compared to other AAAS variant carriers (133 out of 172, 77.3%, p = 0.006). While the incidence of the classical clinical triad of AS was similar and observed in 110 out of 206 AS patients (53.4%) and in 18 out of 34 (52.9%) among p.Ser263Pro variant carriers. Furthermore, our report supports the hypothesis of a founder origin of the p.Ser263Pro variant in AAAS gene in a European Caucasian population. Slavic origin was found in 25 out of 36 reported variant carriers (69.4%) and 17 out of 23 (73.9%) who were homozygous for p.Ser263Pro variant. Summarizing, neurological manifestations of AS predominate in patients carrying a potentially founder p.Ser263Pro variant within the AAAS gene.

Microcephaly primary hereditary (MCPH) is a rare neurodevelopmental disorder characterized by a reduced head circumference and variable severity of intellectual disability, typically inherited in an autosomal recessive pattern. Mutations in over 32 genes have been associated with the etiology of MCPH to date, among which ASPM gene is the most frequently mutated, accounting for approximately 68.8% globally. In Pakistan, particularly within the Pashtun population of Khyber Pakhtunkhwa (KP), ASPM mutations are highly prevalent. In this study, we analysed clinical and genetic features of nine consanguineous MCPH families. Among these, six families revealed recurrent nonsense mutation p.Trp1326*(c.3978G > A), increasing the evidence of it being a founder mutation. In addition to this, genetic analysis of other Pashtun origin families found previously reported nonsense mutation in the same ASPM gene, which include p.Arg3244*(c.9730 C > T), p.Tyr3164*(c.9492T > G), and p.Ser1176*(c.3527 C > G). Clinical assessments of patients revealed microcephaly with mild to severe intellectual disability, impaired interpersonal skills, delayed speech, with no evidence of skeletal, muscular, and major organ abnormalities. Protein modeling and conformation analysis suggested less similarity between wild-type and mutated ASPM proteins, which ranged from 0.24% to 0.68%. Further to the current study, a total of 58 families are known to carry the ASPM p.Trp1326* mutation in the Pashtun Population. These findings emphasize the critical role of ASPM in MCPH pathogenesis, strengthening the evidence of recurrent p.Trp1326* mutation as a founder variant in the Pashtun population. The present study signifies the importance of genetic screening and counselling for effective diagnosis of MCPH in high-risk Pashtun origin Pakistani population.

Spastic paraplegia type 11 (SPG11) is a progressive neurological condition with no treatment. Possible involvement of abnormal ganglioside metabolism has been reported in mouse and human cells. Preclinical data in zebrafish and fruit fly models of the disease indicate that miglustat can improve biochemical parameters and locomotion. We assessed the short-term safety of oral miglustat in patients with SPG11. This was an open-label, single center, non-randomized, phase II study. All patients received miglustat orally (4 weeks 100 mg/tid and 8 weeks 200 mg/tid). The primary outcome was the frequency of adverse events (AEs), particularly and severe AEs (SAEs), emerging in the course of the study. As secondary outcomes we measured clinical severity scores, functional tests, and biomarkers at 3 and 6 months. Twelve-week treatment with miglustat was adequately tolerated, with only minor AEs and no SAEs reported. With a few exceptions, the treatment did not seem to impact neuromotor function in patients with SPG11. Although it showed an acceptable safety profile and no SAEs, miglustat did not significantly modify plasma sphingolipid and ganglioside profiles. Its potential therapeutic impact remains low.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by difficulties in social interactions, communication impairments, repetitive behaviors, and restricted interests. A genetic basis for ASD is now well-established. With the availability of high-throughput microarray and sequencing platforms, major advances have been made in our understanding of genetic risk factors. This study assessed the patient records of 62 children diagnosed with ASD or at risk for ASD. Cytogenetics, molecular karyotyping, and whole-exome sequencing (WES) were conducted for these cases. Three likely pathogenic variants were detected in the genes KMT2C, FOXP2, and MAN1B1, each at a rate of 1.6% of total cases. Additionally, variants of uncertain significance (VUS) were found in 13 genes previously associated with ASD. The frequencies of these VUS in total cases were as follows: DLG3-1.6%, MECP2-1.6%, SETD5-1.6%, GRIN1-1.6%, ASXL3-3%, KMT2D - 5%, AP1G1-3%, SPTBN1-3%, TRIP12-1.6%, HCN1-3%, ZNF292-1.6%, and ACSL4-1.6%. We found gene variants in 35% of cases, a rate consistent with previous reports, emphasizing the importance of comprehensive genetic analysis in diagnosing ASD with unclear etiology. This study offers valuable insights into the genetic landscape of ASD within a small cohort and highlights the need for ongoing monitoring and genetic counseling in conditions that present with ASD-like symptoms.

Neuronal ceroid lipofuscinoses (NCLs) are rare, inherited lysosomal storage disorders (LSDs) of the brain and retina. Gastrointestinal (GI) manifestations are reported in clinical practice but remain largely underexplored. Lysosomal dysfunction affects both the central and the peripheral nervous systems, including the enteric nervous system (ENS) where accumulation of storage material and neuronal loss may directly contribute to GI dysmotility. These insights, combined with emerging gene therapies targeting both brain and ENS pathology, underscore the need for validated GI endpoints in NCL research. We present a cross-sectional study assessing prevalence, progression, and clinical impact of GI symptoms in an Italian NCL cohort. Using caregiver-reported data and standardized tools - including the PedsQL™ GI Symptoms Scales and the Hamburg rating Scale - we evaluated GI burden and its correlation with neurological severity. Over 60% of caregivers reported GI disturbances, with constipation as the most prevalent and earliest onset symptom. Nutritional issues, such as dysphagia, were common but tended to appear later. GI symptoms correlated well with decline in quality of life, especially for Trouble Swallowing (p_adj <0.000001), Food and Drink Limits (p_adj <0.000001), and Constipation (p_adj = 0.026006). Problems with food and drink and swallowing problems correlated with the Hamburg rating Scale, while constipation did not, suggesting distinct underline mechanisms. Our findings support the importance of routine screening of GI symptoms in NCLs and their potential inclusion as extra-CNS endpoints in future therapeutic trials.

A 1 year 11 months-old female patient displayed focal seizures symptoms with good response to oxcarbazepine. Her brain magnetic resonance imaging (MRI) showed white-matter, bilateral and symmetrical hyperintense foci in periventricular parietal and frontal regions with U-fiber sparing. A gene panel requested for the study of leukodystrophies and subsequent segregation reported compound heterozygous variants in LAMB1 gene: c.3659_3660delTG (p.Val1220Glyfs*31), maternally inherited, and c.2942 A > T (p.Asn981Ile), paternally inherited. Published cases with biallelic, loss-of-function LAMB1 variants displayed a broad phenotype that depends on the deleteriousness of the variants, ranging from mildly affected individuals to severely affected ones with multiple other anomalies. Also, monoallelic, presumably toxic gain-of-function LAMB1 variants can also cause leukoencephalopathy but whose onset of manifestations is in adulthood. The cases affected by the dominant condition also exhibit a broad range of manifestations and brain imaging anomalies, some of them overlap to those seen in the recessive LAMB1-related leukoencephalopathy. This work unveils the relevance of performing a comprehensive literature review for a better comprehension of overlapping conditions caused by variants in the same gene.

Spinocerebellar ataxia type 32 (SCAR32) is a rare autosomal neurodegenerative disorder caused by mutations in the peroxiredoxin 3 (PRDX3) gene, which encodes a mitochondria-specific antioxidant enzyme critical for maintaining cellular redox homeostasis. Here, we reported a case of a homozygous nonsense mutation (c.619 C > T; p.Arg207*) in PRDX3 of a 12-year-old Chinese boy. This mutation was predicted to result in premature termination of protein translation. Consequently, the patient presented with slowly progressive gait ataxia and cerebellar vermis atrophy. Mild cognitive impairment was also observed, with deficits in perceptual reasoning and processing speed. Additionally, he showed increased thyroid autoantibodies and thyroid enlargement. This case broadens the phenotypic spectrum of PRDX3-related disease, highlights its genetic and clinical heterogeneity, and reinforces the importance of early genetic testing in paediatric ataxia.

Dopa-responsive dystonia (DRD) is a rare disorder in children and is notable for the fact that it can be effectively treated. The diagnosis of DRD assumes significant importance when there is a notable improvement in the patient's psychomotor and neurological development as a result of early intervention. The present case report aims to share two distinct clinical presentations, both firstly misdiagnosed as cerebral palsy and both had diurnal fluctuating of dystonia. In clinical presentations such as diurnal fluctuation suggestive of DRD, we aimed to emphasize that instead of waiting up to two years for genetic test results, evaluating the response to low-dose L-DOPA may support the patient's daily and vital functions during this period. Moving from treatment to diagnosis may still be a valid approach.