Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary form of cerebral small vessel disease leading to early cerebrovascular changes. These changes result from mutations in the NOTCH3 gene that cause progressive accumulations of granular osmiophilic material (GOM) deposits, thickening arterial walls and reducing or restricting blood flow in the brain. The clinical presentation of CADASIL is characterized by migraines with aura, early and recurrent strokes, progressive cognitive impairment, and psychiatric disturbances. CADASIL is rare but frequently underrecognized or misdiagnosed. A genetic condition with a 50% risk of inheritance from an affected parent, the gold standard for diagnosis is genetic testing to determine the presence of mutations in the NOTCH3 gene. This presentation aims to familiarize neuropsychologists with the condition of CADASIL through a unique case study highlighting important psychological, social, and ethical considerations raised by genetic testing.

This case study presents a 67-year-old, right-handed, married female diagnosed with CADASIL who was referred for neuropsychological evaluation of cognitive function and low mood concerns following multiple ischemic events.

Results revealed severe cognitive deficits in domains of attention, learning, and memory. Her superior verbal abilities and executive function remained largely intact. Assessment of mood revealed elevations in symptoms of depression and anxiety. The patient was aware of CADASIL in her father, paternal aunt, and younger brother, but elected to forego any genetic testing to confirm whether she had the condition until she experienced a stroke at age 61. She has two adult children who have also elected to forego testing and currently remain asymptomatic. Cognitive profile, mood disturbances, and patient perspectives on refraining from pre-symptomatic genetic testing for CADASIL diagnosis will be discussed.

Aspects of this case are consistent with a small body of literature evidencing distinct psychological, emotional, and social challenges among families carrying genetic risk of CADASIL. While providing an example of an often underrecognized neurological disorder with which neuropsychologists should be familiar, this case uniquely raises ethical questions relevant to care providers and current treatment guidelines regarding genetic testing among families carrying highly heritable neurological conditions. In particular, personal ethical challenges around deciding to pursue or forego pre-symptomatic testing, and implications for family planning, highlight the importance of genetic counseling for affected families.

Prion disease is a rare, invariably fatal neurodegenerative disease characterized by rapid neuronal degeneration; Mutations to PRNP gene cause genetic prion disease (GPD). In animal models, microglial activation, astrocytosis, and release of neurofilament precede the onset of frank symptoms (Sorce & Nuvolone 2020, Minikel 2020). In humans at risk for GPD, prodromal pathology appears to occur in only a brief window prior to symptom onset (Vallabh et al. 2020, Thompson et al. 2021), but some data suggest that known PRNP mutation carriers may exhibit cognitive abnormalities prior to meeting clinical diagnostic criteria (Mole et al., 2021). We aim to examine pre-symptomatic differences in cognitive processing speed (CPS) and executive function (EF) in PRNP mutation carriers and controls.

Our sample includes two groups from an ongoing observational study on GPD (Vallabh et al., 2020): known PRNP mutation carriers (N = 32, Age M = 45.77, SD = 14.75) and control group of non-carriers with a family history of GPD and healthy controls with no known history (N = 11, Age M = 42.01, SD = 12.43). All participants completed a full cognitive battery at baseline and on an annual basis. We compared first visit cognitive testing measuring CPS and EF using: National Institute of Health (NIH) Toolbox [Pattern Comparison (NIH-PC), Flanker, Dimensional Card Sorting Task (NIH-DCCS)], Trail Making Test (TMT) A and B, and Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference Test (CWIT).

Independent t-tests and Mann-Whitney U tests compared cognitive test performance between groups. Across all cognitive test measures assessed, none exhibited significant differences between groups after Bonferroni correction for N=10 tests (corrected P > 0.05). Mean scores for mutation carriers were non-significantly lower than controls on TMT-B (Z-score Mdn = .29, SD = 1.33 vs. Z-score Mdn = .96, SD = .97), NIH-PC (Age-corrected Standard Score [ACSS] M = 100.13, SD = 20.76 vs. ACSS score M = 114.82, SD = 14.61) and NIH-Flanker (ACSS score M = 83.58, SD = 9.72 vs. ACSS score M = 90.64, SD = 10.94), and NIH-DCCS (ACSS M = 101.29, SD = 16.37 vs. ACSS score M = 112.00, SD = 16.28) but not for TMT-A or all four conditions of CWIT.

We did not detect any significant cognitive deficits in known PRNP mutation carriers. This is consistent with the lack of prodromal pathological biomarker changes or cognitive changes as reported in Vallabh et al 2020, and with the finding of Mole et al. 2021 that most tests reveal impairment only at a stage where carriers report subjective symptoms. Our results suggest an opportunity for primary prevention to preserve full cognitive health in at-risk individuals. However, small sample size and limited test sensitivity may leave us underpowered to detect subtle deficits. Future research is warranted to further investigate the neuropsychological profile of pre-symptomatic GPD.

Norrie disease is a rare, x-linked recessive genetic disorder associated with an NDP gene mutation. Males are predominantly affected. Typical symptoms include vision loss around the time of birth and progressive hearing loss. Cognitive and behavioral abnormalities also occur in 30-50% of individuals, including developmental delays, intellectual disability, cognitive regression, psychosis, and aggression. There is limited research, however, examining the neuropsychological deficits in adulthood resulting from Norrie disease, especially with neuropsychological data and in individuals without other neurological manifestations of the disease, such as seizures. Here, we present the neurocognitive profile of a patient with Norrie disease who presented for a cognitive evaluation in adulthood due to report of more recent memory decline.

Mr. Smith is a Caucasian male in his mid-40's who previously underwent genetic testing and was subsequently diagnosed with Norrie disease. As a result of his diagnosis, he experienced complete vision loss since birth and bilateral hearing loss that began in childhood and gradually worsened in adolescence. Medical history was otherwise unremarkable. Developmental milestones were met on time. Historical intelligence testing conducted in elementary school revealed borderline on one intelligence test to high average performance on other intelligence tests. However, he was retained grades several times due to factors such as behavioral disruptions and academic difficulties. He had been employed as an assembly line worker for many years, but had not worked for 10 years prior to the neuropsychological evaluation. Emotionally, he had a longstanding history of anxiety and endorsed mild anxiety and depression at the time of the evaluation. The patient first noticed memory difficulties in adolescence then noticed further decline four years prior to the neuropsychological evaluation (around when he received a left-ear cochlear implant), which had remained stable since onset.

In the context of low average premorbid intellectual functioning, Mr. Smith's neurocognitive profile was notable for difficulties with alphanumeric set-shifting and abstract thinking, with otherwise preserved cognitive functioning. Weaknesses observed on testing may have represented longstanding weaknesses and did not rise to the level of a cognitive disorder. Affective distress was also suspected to have accounted for some of the cognitive lapses the patient reported experiencing with day-to-day functioning.

The current poster aims to contribute to the limited body of literature examining neuropsychological deficits in adulthood resulting from Norrie disease. This is especially critical given that the long-term cognitive dysfunction of this disorder is relatively unknown and could negatively impact patients' quality of life over time.

The purpose of the present study is to characterize the trajectory of internalizing and externalizing behaviors in children with NF1 longitudinally from the early childhood period to the school age period on a broad psychosocial norm-referenced measure using linear mixed model growth curves.

Children with NF1 (n=28) were seen at least once between the ages of 3-8 years old and then again between the ages of 9-13 years old. Parents completed the Behavior Assessment System for Children (BASC) Second Edition; the version of the BASC administered depended on age (i.e., preschool form or child form). Linear mixed model growth curve analyses were used to examine the developmental trajectories of children with NF1 on the following scales, which were selected due to findings in the literature: Externalizing Problems, Internalizing Problems, Hyperactivity, Anxiety, Depression, Attention, and Executive Function. T-scores (M=50, SD=10) were used. Higher scores indicate more challenges.

By using loess lines to qualitatively describe the patterns of ratings across time, it is evident that most scales (Externalizing Problems, Internalizing Problems, Hyperactivity, Attention Problems, Executive Function) demonstrated curvilinear trajectory patterns, with scores peaking in the 8-10-year-old range, then decreasing again. However, there was no statistically significant effect of age on any of the scales. Notably, trajectories largely included standard scores within the normative range (T-scores between 45-55).

Overall, the models also suggest that most children with NF1 are within the average range of functioning on all scales examined across the childhood period. Furthermore, with the exception of the Depression and Anxiety scales, ratings tend to peak around the 8-10-year period, and then decrease into early adolescence. Thus, when working with patients with NF1, it may be the case that clinicians note relative increases in challenges across these domains in late childhood, though these challenges may decrease over time during this age range. Linear growth curve modeling identified that the developmental trajectories of internalizing and externalizing behaviors of children with NF1, as rated by parents, remain stable across the childhood period. Importantly, low power may have contributed to the lack of observed age effects. Longitudinal research would be beneficial to capture patterns that may emerge in adolescence or adulthood.

Fahr’s disease is a rare genetic neurological disorder characterized by abnormal idiopathic calcification of the basal ganglia, typically with extrapyramidal symptoms, speech difficulty, behavioral disturbances, and progressive neurologic dysfunction. A small number of case reports have explored the neuropsychological profile of Fahr’s disease patients, and even fewer have followed the course of neuropsychological functioning over time.

A 53-year-old Asian woman presented for a neuropsychological reevaluation (2021) after experiencing a recurrence of memory difficulties and mood changes. Relevant medical history was significant for systemic lupus erythematosus (SLE) and Fahr’s disease. Following an episode of acute confusion, the patient underwent a head CT (2019) which revealed extensive calcification throughout the cerebellum, central pons, and periventricular and subcortical white matter, suggestive of Fahr’s disease. Two months later, she underwent an initial neuropsychological evaluation (2019), which demonstrated prominent attention and processing speed deficits contributing to variably impaired new learning and memory along with spatial planning and problem-solving difficulties. The etiology of her cognitive deficits was determined to likely reflect metabolic and immune instability, consistent with her history of SLE and Fahr’s disease. An updated CT (2021) revealed increased calcification throughout the bilateral corona radiata, basal ganglia, cerebellar hemispheres, and midbrain, which was determined to be compatible with progressive Fahr’s disease.

The patient’s neurocognitive profile from current neuropsychological testing (2021) was marked by notable deficits in attention and processing speed, delayed memory, problem solving, visuospatial reasoning, and motor dexterity. Compared to her initial evaluation, her cognitive profile remained stable save for a slight decline in processing speed. The largest change was seen within the psychiatric domain. Self-reported depressive symptoms involving anhedonia, concentration difficulties, and anxiety symptoms involving nervousness and tension were more pronounced in her current evaluation. In addition, she endorsed an increase in apathy compared to her initial evaluation.

The cognitive profile seen in this patient is consistent with the current literature relating to the clinical sequelae of Fahr’s disease in patients that eventually went on to develop dementia. Despite an increase in brain calcification seen on CT imaging over an 18-month interval, the patient’s neurocognitive profile remained relatively stable. An increase in psychiatric symptoms appeared to be the most prominent change over repeated neuropsychological assessment, which elucidates the heterogenous course of Fahr’s disease from a neuropsychological perspective. Further exploration of this disorder is warranted to better understand the clinical progression of symptoms over time.

The SIN3A gene mutation is a rare genetic mutation with few reported cases (< 1 in 1,000,000) associated with autosomal dominant Witteveen-Kolk Syndrome, a rare neurodevelopmental syndrome only discussed in the past decade (Witteveen et al., 2016). This syndrome can be characterized by short stature, distinctive facial features, developmental delay, mild intellectual disability, autism spectrum disorder, hypotonia, and seizures (Balasubramanian et al., 2021), however a paucity of information regarding comprehensive neuropsychological functioning in these individuals is present in the literature, and even this recent review study noted that intellectual ability was rarely assessed through formal testing (6 of 28 cases). We present a case, “M”, to help describe a potential pattern of neurocognitive strengths and weaknesses in this population.

The participant, “M”, was diagnosed with a de novo mutation in the SIN3A gene at the age of 11 years with previous diagnoses of global developmental delay, hypotonia, autism spectrum disorder, specific learning disability in mathematics, developmental coordination disorder, and attention deficit hyperactivity disorder. M was seen for a comprehensive neuropsychological evaluation at 11 years of age at an academic medical center, which consisted of comprehensive review of medical and school records, parent and child interview, questionnaires, and performance-based testing.

M’s verbal and language skills emerged as a particular strength. Her verbal memory, verbal fluency, and verbal comprehension skills were all in the average range or above, as were reading, reading comprehension, and spelling skills. M demonstrated a pattern of notable weaknesses in visuospatial skills, including impaired visuospatial reasoning, visuomotor integration, visual scanning, visual perception, and visual memory. Additionally, M demonstrated a slight weakness in Low Average mathematics skills. M also demonstrated fine motor impairment with impaired speed, coordination, and accuracy. Although immediate auditory attention was noted to be average, performance on a test of sustained attention indicated a moderate persistence of attention concerns. Likewise, M’s mother reported her to be very elevated on symptoms of both attention and hyperactivity/impulsivity. Finally, M’s mother reported elevated concerns related to M’s peer relations and atypical behaviors and below average adaptive skills.

Due to the rarity of M’s de novo mutation in the SIN3A gene, M’s pattern of weaknesses in visuospatial skills, fine motor skills, attention/executive functioning, and social skills, as well as her strengths in verbal skills can aid in further understanding the pattern of cognitive strengths and weaknesses in children with a mutation in the SIN3A gene. Additionally, given her mild weaknesses in math skills, it is possible that M’s performance on mathematics assessments may be impacted by her visuospatial weakness and thus better conceptualized as a visuospatial issue rather than a learning disability. Overall, this case can aid in identifying specific cognitive risk factors, such as visuospatial skills, in this population and lead to more targeted assessment and intervention, and highlights the importance of more nuanced cognitive evaluation as reporting of a general cognitive ability score alone may obscure underlying patterns of cognitive strength and weakness.

Wiedemann-Steiner syndrome (WSS) is a rare Mendelian disorder of the epigenetic machinery caused by heterozygous pathogenic variants in KMT2A. Currently, the specific neurocognitive profile of this syndrome remains unknown. This case series provides insight into the cognitive phenotype of WSS.

This study involves a retrospective medical chart review of 10 pediatric patients, each with a molecularly confirmed diagnosis of WSS who underwent clinical neuropsychological evaluation at an academic medical center.

The majority of patients performed in the below average to very low ranges in Nonverbal Reasoning, Visual/Spatial Perception, Visuoconstruction, Visual Memory, Attention, Working Memory and Math Computation skills. In contrast, over half the sample performed within normal limits on Receptive Vocabulary, Verbal Memory, and Word Reading. Wilcoxon signed rank test showed weaker Nonverbal versus Verbal Reasoning skills (p = .005). Most caregivers reported deficits in executive functioning, most notably in emotion regulation.

Nonverbal reasoning/memory, visuospatial/construction, attention, working memory, executive functioning, and math computation skills are areas of weakness among those with WSS. These findings overlap with research on Kabuki syndrome, which is caused by variants in KMT2D, and suggest disruption in the neurogenesis of the hippocampal formation may drive shared pathogenesis of the two syndromes.

Noonan syndrome is a genetic disorder with high prevalence of congenital heart defects, such as pulmonary stenosis, atrial septal defect and hypertrophic cardiomyopathy. Scarce data exists regarding the safety of pregnancy in patients with Noonan syndrome, particularly in the context of maternal cardiac disease.

We performed a retrospective chart review of patients at Yale-New Haven Hospital from 2012 to 2020 with diagnoses of Noonan syndrome and pregnancy. We analysed medical records for pregnancy details and cardiac health, including echocardiograms to quantify maternal cardiac dysfunction through measurements of pulmonary valve peak gradient, structural heart defects and interventricular septal thickness.

We identified five women with Noonan syndrome (10 pregnancies). Three of five patients had pulmonary valve stenosis at the time of pregnancy, two of which had undergone cardiac procedures. 50% of pregnancies (5/10) resulted in pre-term birth. 80% (8/10) of all deliveries were converted to caesarean section after a trial of labour. One pregnancy resulted in intra-uterine fetal demise while nine pregnancies resulted in the birth of a living infant. 60% (6/10) of livebirths required care in the neonatal intensive care unit. One infant passed away at 5 weeks of age.

The majority of mothers had pre-existing, though mild, heart disease. We found high rates of prematurity, conversion to caesarean section, and elevated level of care. No maternal complications resulted in long-term morbidity. Our study suggests that women with Noonan syndrome and low-risk cardiac lesions can become pregnant and deliver a healthy infant with counselling and risk evaluation.

Mitral valvar prolapse is the most common anomaly of the mitral valve apparatus throughout childhood. Fibrillin is one of the structural components of the elastin-associated microfibrils found in the mitral valve. A case-controlled study has performed to investigate the relationship between fibrillin 1 gene intron 56 polymorphism and risk of mitral valvar prolapse in Turkish children.

A total of 77 patients with mitral valvar prolapse diagnosed by clinical evaluation and echocardiography and 89 normal children of same age and sex were studied. The fibrillin-1 gene intron 56 polymorphism was identified by the polymerase chain reaction-based restriction analysis.

There was a significant difference in the distribution of fibrillin-1 gene intron 56 genotypes (p = 0.0001) and allelic frequency (p = 0.0001) between the cases and the controls.

Patients with mitral valvar prolapse have higher frequencies of fibrillin-1 gene intron 56 GC genotypes. Healthy children have higher frequencies of fibrillin-1 gene intron 56 CC genotypes. We speculate that the higher frequency of fibrillin-1 gene intron 56 G-allele increases the risk of mitral valvar prolapse.