Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

NFIA haploinsufficiency: case series and literature review.

Background: NFIA-related disorder (OMIM #613735) is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment and non-specific dysmorphic features. To date, fewer than thirty patients affected by this disorder have been described. Methods: Our study included three children with NFIA haploinsufficiency recruited from three medical genetics centers. Clinical presentations were recorded on a standardized case report form. Results: All patients presented a variable degree of intellectual disability. None of the individuals in our cohort had urinary tract malformations. Three novel mutations, c.344G>A, c.261T>G, and c.887_888del are reported here. Conclusion: NFIA haploinsufficiency can be suspected through careful observation of specific dysmorphisms, including macrocephaly and craniofacial abnormalities. Instrumental tests such as MRI and renal ultrasound provide further diagnostic clues, while genetic testing can confirm the diagnosis.

Aromatic L-Amino-Acid Decarboxylase Deficiency Screening by Analysis of 3-O-Methyldopa in Dried Blood Spots: Results of a Multicentric Study in Neurodevelopmental Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.

Chromosome Microarray Analysis for the Investigation of Deletions in Pediatric Movement Disorders: A Systematic Review of the Literature.

Background: Chromosome microarray analysis (CMA) can detect copy number variants (CNV) beyond the resolution of standard G-banded karyotyping. De novo or inherited microdeletions may cause autosomal dominant movement disorders. Objectives: The purpose of this study was to analyze the clinical characteristics, associated features, and genetic information of children with deletions in known genes that cause movement disorders and to make recommendations regarding the diagnostic application of CMA. Methods: Clinical cases published in English were identified in scientific databases (PubMed, ClinVar, and DECIPHER) from January 1998 to July 2019 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Cases with deletions or microdeletions greater than 300 kb were selected. Information collected included age, sex, movement disorders, associated features, and the size and location of the deletion. Duplications or microduplications were not included. Results: A total of 18.097 records were reviewed, and 171 individuals were identified. Ataxia (30.4%), stereotypies (23.9%), and dystonia (21%) were the most common movement disorders. A total of 16% of the patients demonstrated more than one movement disorder. The most common associated features were intellectual disability or developmental delay (78.9%) and facial dysmorphism (57.8%). The majority (77.7%) of microdeletions were smaller than 5 Mb. We find no correlation between movement disorders, their associated features, and the size of microdeletions. Conclusions: Our results support the use of CMA as an investigational test in children with movement disorders. As the majority of identified articles were case reports and small case series (low quality), future efforts should focus on larger prospective studies to examine the causation of microdeletions in pediatric movement disorders.

Status Epilepticus in Chromosomal Disorders Associated with Epilepsy: A Systematic Review.

Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to prolonged seizures. The International League Against Epilepsy (ILAE) identified 13 chromosomal disorders associated with epilepsy (CDAE); data regarding SE occurrence in these patients is lacking. A systematic scoping review was conducted to outline current literature evidence about clinical features, treatments, and outcomes of SE in pediatric and adult patients with CDAE. A total of 373 studies were identified with the initial search; 65 of these were selected and regarded as SE in Angelman Syndrome (AS, n = 20), Ring 20 Syndrome (R20, n = 24), and other syndromes (n = 21). Non-convulsive status epilepticus (NCSE) is frequently observed in AS and R20. No specific, targeted therapies for SE in CDAE are available to date; anecdotal reports about SE treatment are described in the text, as well as various brief- and long-term outcomes. Further evidence is needed to precisely portray the clinical features, treatment options, and outcomes of SE in these patients.

Cognitive, Behavioral, and Sensory Profile of Pallister-Killian Syndrome: A Prospective Study of 22 Individuals.

BACKGROUND: Developmental delay and intellectual disability are two pivotal elements of the phenotype of Pallister-Killian Syndrome (PKS). Our study aims to define the cognitive, adaptive, behavioral, and sensory profile of these patients and to evaluate possible correlations between the different aspects investigated and with the main clinical and demographic variables. METHODS: Individuals of any age with genetically confirmed PKS were recruited. Those ≤ 42 months were administered the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III), and those > 42 months the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II). Stereotyped behaviors (Stereotypy Severity Scale, SSS) and aggressive behaviors (Behavior Problems Inventory-Short Version, BPIs) were assessed in all subjects > 1 year; sensory profile (Child Sensory Profile 2, C-SP2) in all aged 2-18 years. RESULTS: Twenty-two subjects were enrolled (11 F/11 M; age 9 months to 28 years). All subjects ≤ 42 months had psychomotor developmental delay. Of the subjects > 42 months, 15 had low IQ deviation, and 1 in the normal range. Stereotypies were frequent (median SSS-total score 25/68). Lower Vineland-II values corresponded to greater intensity and frequency of stereotypies (p = 0.004 and p = 0.003), and self-injurious behaviors (p = 0.002 and p = 0.002). Patients with severe low vision had greater interference of stereotypies (p = 0.027), and frequency and severity of aggressive behaviors (p = 0.026; p = 0.032). The C-SP2, while not homogeneous across subjects, showed prevalence of low registration and sensory seeking profiles and hypersensitivity to tactile and auditory stimuli. Lower Vineland-II scores correlated with higher Registration scores (p = 0.041), while stereotypies were more frequent and severe in case of high auditory sensitivity (p = 0.019; p = 0.007). Finally, greater sleep impairment correlated with stereotypies and self-injurious behaviors, and lower Vineland-II scores. CONCLUSIONS: The present study provides a further step in the investigation of the etiopathogenesis of the syndrome. Furthermore, these aspects could guide rehabilitation therapy through the identification of targeted protocols.

Neurological Phenotype of Mowat-Wilson Syndrome.

Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to ZEB2 gene defects (heterozygous mutation or deletion). The ZEB2 gene is a widely expressed regulatory gene, extremely important for the proper prenatal development. MWS is characterized by a specific facial gestalt and multiple musculoskeletal, cardiac, gastrointestinal, and urogenital anomalies. The nervous system involvement is extensive and constitutes one of the main features in MWS, heavily affecting prognosis and life quality of affected individuals. This review aims to comprehensively organize and discuss the neurological and neurodevelopmental phenotype of MWS. First, we will describe the role of ZEB2 in the formation and development of the nervous system by reviewing the preclinical studies in this regard. ZEB2 regulates the neural crest cell differentiation and migration, as well as in the modulation of GABAergic transmission. This leads to different degrees of structural and functional impairment that have been explored and deepened by various authors over the years. Subsequently, the different neurological aspects of MWS (head and brain malformations, epilepsy, sleep disorders, and enteric and peripheral nervous system involvement, as well as developmental, cognitive, and behavioral features) will be faced one at a time and extensively examined from both a clinical and etiopathogenetic point of view, linking them to the ZEB2 related pathways.

Sleep in Children With Pallister Killian Syndrome: A Prospective Clinical and Videopolysomnographic Study.

Objectives: Pallister-Killian syndrome (PKS) is a rare genetic disorder with multi-organ involvement caused by mosaic tetrasomy of chromosome 12p. Although many caregivers report the presence of impaired sleep in their children, there are no clear data in the literature on this issue and no systematic study has ever been performed. With this study, we aimed to characterize the features of sleep in Pallister-Killian syndrome and identify the possible influence of clinical and demographic features. Moreover, our aim was to verify the effectiveness of conventional screening questionnaires in this particular group of patients. Methods: We prospectively enrolled 14 patients aged 1-17 years in collaboration with PKS Kids Italia ONLUS. The Sleep Disturbance Scale for Children (SDSC) questionnaire was administered to caregivers. Then, video polysomnography (VPSG) of at least 24 h was performed and results were compared with a same-aged control group. Results: A total of 92% of patients had abnormal SDSC scores, extremely high in the "disorder of initiating and maintaining sleep" (DIMS) and "sleep breathing disorders" (SBD) subscales. VPSG showed a significantly impaired macrostructure in PKS patients, with a higher Arousal Index (p < 0.00001) and percentage of time spent in N3 (p < 0.00001), and reduced Sleep Efficiency (p = 0.0006). After dividing both PKS and controls into two groups based on median age, some peculiarities emerged: the younger group had higher Awakenings Index (p = 0.0207) and percentage of time spent in N1 (p = 0.015) while the older group showed higher time in bed (TIB) (p = 0.0485), compared with controls. Due to poor compliance, the Apnea-Hypopnea Index (AHI) was evaluated only for 10 PKS children, being significantly increased (p = 0.0427) compared with controls. SBD subscale scores in SDSC were significantly related to AHI values in VPSG (p = 0.0099). Conclusions: This study constitutes the first attempt to describe the sleep pattern in PKS. Despite small numbers due to the rarity of the syndrome, our VPSG results confirm the high prevalence of sleep disorders (SDs) in these patients. It is therefore essential to investigate and treat them. The SDSC scale is a good screening tool for early detection also in these patients, with particular sensitivity in detecting breathing disorders.

Neuropsychological and behavioral disorders as presentation symptoms in two brothers with early-infantile Niemann-Pick type C.

BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal storage disease caused by mutations in NPC1 or NPC2 genes. CASE PRESENTATION: We present two brothers with the same compound heterozygous variants in exon 13 of the NPC1 gene (18q11.2), the first one (c.1955C> G, p. Ser652Trp), inherited from the mother, the second (c.2107T>A p.Phe703Ile) inherited from the father, associated to the classical biochemical phenotype of NPC. The two brothers presented unspecific neurologic symptoms with difference in age of onset: one presented dyspraxia and motor clumsiness at age 7 years, the other showed a systemic presentation with hepatosplenomegaly noted at the age of two months and neurological symptoms onset at age 4 with speech disturbance. Clinical evolution and neuroimaging data led to the final diagnosis. Systemic signs did not correlate with the onset of neurological symptoms. Miglustat therapy was started in both patients. CONCLUSIONS: We highlight the extreme phenotypic heterogeneity of NP-C in the presence of the same genetic variant and the unspecificity of neurologic signs at onset as previously reported. We report some positive effects of miglustat on disease progression assessed also with neuropsychological follow-up, with an age-dependent response.

Long-term follow-up in infantile-onset SCAR18: A case report.

Autosomal recessive spinocerebellar ataxia type 18 (SCAR18) is caused by pathogenic variants in the Glutamate Receptor, Ionotropic, Delta-2 (GRID2) gene. We describe the long-term follow-up from 1 to 31 years of an Italian patient with congenital SCAR18 who is compound heterozygous for a maternally-inherited nonsense variant and a de novo microdeletion. To date, this is the longest follow-up in congenital SCAR18.