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Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by a complex interaction of genetic and environmental factors. Recently, a polymorphic intronic CA repeat in STMN2 gene has been proposed as risk factor for ALS. The presence of long/long CA genotype, especially if one allele had 24 CA, was reported to be significantly associated with the disease in a cohort of sporadic ALS patients. We tested an Italian cohort of 366 ALS patients and 353 healthy controls and we found no association between CA length and ALS risk. [ABSTRACT FROM AUTHOR]

Background Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1. It was mainly described in children. Methods A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood. Results Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1. All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited. Conclusions Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures. [ABSTRACT FROM AUTHOR]

Background: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1 . It was mainly described in children., Methods: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood., Results: Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1 . All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited., Conclusions: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)