Faculty Bibliography

Neuronal ceroid lipofuscinosis type 8 (CLN8) disease is an ultra-rare autosomal recessive lysosomal disorder that results in epilepsy, vision loss, and developmental regression. Due to limited information on the natural history of CLN8 disease, we analyzed disease features and progression as part of gene therapy clinical trial readiness. We performed an international cross-sectional study using semi-structured interviews, as well as measures of adaptive functioning and a motor-language scale adapted from CLN2 disease. The interviews were conducted with parents of children with CLN8 disease from January to May 2020. The cohort included 6 individuals with CLN8 disease (4 males, 2 females) of which the median age was 9.9 years (IQR 6.0-12.9) among the 5 living children. The median age of onset of symptoms was 4.1 years (IQR 3.8-5.4), onset of seizures was 4.5 years (IQR 4.3-5.4), onset of vision loss was 6.5 years (IQR 6.0-7.6), and age at diagnosis was 6.6 years (IQR 4.8-8.3). Initial symptoms were seizures (n = 2), language decline (n = 2), motor decline (n = 1), and dementia (n = 1). The most common seizure types were tonic-clonic and myoclonic (n = 4 each). Of those with three or more timepoints of decline in motor and language summary scores, there was a rapid median annual rate of decline of 1.4 score units (IQR 1.1-2.0) from initial decline, where 6 represents normal function and 0 represents no verbal or motor skills. The cohort demonstrated impaired adaptive functioning on the Vineland-III with a median composite score of 65 (IQR 39-65). CLN8 disease is often, but not always, a late infantile form of neuronal ceroid lipofuscinosis in which seizures typically occur earlier than vision loss. Measurable and rapid progression of motor and language functioning was demonstrated in the majority of the cohort, informing clinical trial design.
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Objectives: While national medical guidelines recommend genetic testing for all individuals with non-syndromic autism spectrum disorder (ASD), there is underutilization of genetic testing. This study aims to define the perspectives and approaches to initial genetic testing of ASD diagnosticians in order to improve utilization. Methods: A prospective cross-sectional study was conducted using an anonymous online survey distributed to 59 staff neurologists, developmental-behavioral pediatricians, psychologists, post-graduate physician fellows, and nurse practitioners from a single academic medical center. Questions explored knowledge, attitudes, and practices of initial genetic testing for ASD among diagnosticians. Results: Among the 30 respondents (51% response rate), a lack of comprehensive pre-test genetic counseling was identified and forgetfulness was the most prevalent reason for not recommending genetic testing (n = 7/23, 30%). Insurance prior authorization (PA) for genetic testing was a major barrier for clinicians. More than half of respondents (n = 13/25, 52%) reported being uncomfortable with the PA process. Conclusions: Variability in knowledge and practices among ASD diagnosticians regarding genetic testing was identified. Therefore, potential interventions like clinician and administrative staff education, as well as genetic counselor integration into ASD clinics, may be useful to improve genetic testing utilization.

Batten disease, also known as neuronal ceroid lipofuscinosis, refers to a diverse group of 13 hereditary inborn errors of metabolism resulting in the abnormal accumulation of autofluorescent storage material in lysosomes leading to neurodegeneration, typically with associated intractable epilepsy, behavioral dysregulation, cognitive, motor, language and visual decline, as well as a shortened life expectancy [1]. Assessment of disease progression within this population is fraught with difficulty because individuals may have limited attention or cooperation affecting compliance with requested tasks, or have visual impairment reducing options for methods of assessment. Further, language and cognitive assessments have been designed to assess typically developing individuals based on specific age limits, which then fail to capture low developmental functioning once the mental age of the individual drops below the basal age of the assessment tool. Yet, metrics to measure disease progression are essential to inform therapeutic decision-making, prognostication, and clinical trial outcomes.

OBJECTIVE:To quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB). METHODS:In order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer. RESULTS:/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen. CONCLUSIONS:Loss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.

Both 5q-linked spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are fatal monogenic neuromuscular disorders caused by loss-of-function mutations. SMA is an autosomal recessive disorder affecting motor neurons that is typically caused by homozygous whole-gene deletions of SMN1. DMD is an X-linked recessive muscle disease most often due to exon deletions, but also duplications and smaller sized variants within the DMD gene. Gene replacement therapy offers the opportunity to correct the underlying genetic defect by the introduction of a functional gene. We review the transformative work from clinical trials to United States Food and Drug Administration approval of onasemnogene abeparvovec-xioi in SMA and its application in clinical practice and the early results of microdystrophin delivery in DMD. We also review the introduction of antisense oligonucleotides to alter pre-messenger RNA splicing to promote exon inclusion (as in nusinersen in SMA) or exclusion (as in eteplirsen in DMD) into neuromuscular therapeutics. There are multiple promising novel genetically mediated therapies on the horizon, which in aggregate point towards a hopeful future for individuals with SMA and DMD.

Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the AMPD2 gene. We evaluated the son of a consanguineous couple who presented with profound hypotonia and global developmental delay. Other features included sensorineural hearing loss, asymmetric astigmatism, and high myopia. Clinical whole-exome sequence analysis identified a homozygous missense variant in AMPD2 (NM_001257360.1:c.2201C > T, p.[Pro734Leu]) that has not been previously reported. Given the strong phenotypic overlap with PCH9, including the identification of the typical "Figure 8" appearance of the brainstem on neuroimaging, we suspect this variant was causative of the neurodevelopmental disability in this individual. An additional homozygous nonsense variant in COL11A1 (NM_001854.4:c.1168G > T, p.[Glu390Ter]) was identified. Variants in this alternatively spliced region of COL11A1 have been identified to cause an autosomal recessive form of Stickler syndrome type 2 characterized by sensorineural hearing loss and eye abnormalities, but without musculoskeletal abnormalities. The COL11A1 variant likely also contributed to the individual's phenotype, suggesting two potentially relevant genetic findings. This challenging case highlights the importance of detailed phenotypic characterization when interpreting whole exome data.