Faculty Bibliography

Wolfram syndrome is a neurodegenerative disorder caused by pathogenic variants in the genes WFS1 or CISD2. Clinically, the classic phenotype is composed of optic atrophy, diabetes mellitus type 1, diabetes insipidus, and deafness. Wolfram syndrome, however, is phenotypically heterogenous with variable clinical manifestations and age of onset. We describe four cases of genetically confirmed Wolfram syndrome with variable presentations, including acute-on-chronic vision loss, dyschromatopsia, and tonic pupils. All patients had optic atrophy, only three had diabetes, and none exhibited the classic Wolfram phenotype. MRI revealed a varying degree of the classical features associated with the syndrome, including optic nerve, cerebellar, and brainstem atrophy. The cohort's genotype and presentation supported the reported phenotype-genotype correlations for Wolfram, where missense variants lead to milder, later-onset presentation of the Wolfram syndrome spectrum. When early onset optic atrophy and/or diabetes mellitus are present in a patient, a diagnosis of Wolfram syndrome should be considered, as early diagnosis is crucial for the appropriate referrals and management of the associated conditions. Nevertheless, the condition should also be considered in otherwise unexplained, later-onset optic atrophy, given the phenotypic spectrum.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease primarily affecting the optic nerves and spinal cord, which is usually associated with anti-aquaporin-4 antibodies. Here, we present two individuals who were negative for anti-aquaporin-4 antibodies and were initially diagnosed with seronegative NMOSD. Each patient's clinical course and radiographic features raised suspicion for an alternative disease process. Both individuals were found to have pathogenic variants of MT-ND5, encoding subunit 5 of mitochondrial complex I, ultimately leading to a revised diagnosis of a primary mitochondrial disorder. These cases illustrate the importance of biochemical and genetic testing in atypical cases of NMOSD.

The AIFM1 gene encodes a mitochondrial protein that acts as a flavin adenine dinucleotide-dependent nicotinamide adenine dinucleotide oxidase and apoptosis regulator. Monoallelic pathogenic AIFM1 variants result in a spectrum of X-linked neurological disorders, including Cowchock syndrome. Common features in Cowchock syndrome include a slowly progressive movement disorder, cerebellar ataxia, progressive sensorineural hearing loss, and sensory neuropathy. We identified a novel maternally inherited hemizygous missense AIFM1 variant, c.1369C>T p.(His457Tyr), in two brothers with clinical features consistent with Cowchock syndrome using next-generation sequencing. Both individuals had a progressive complex movement disorder phenotype, including disabling tremor poorly responsive to medications. Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus ameliorated contralateral tremor and improved their quality of life; this suggests the beneficial role for DBS in treatment-resistant tremor within AIFM1-related disorders.

Heterozygosity for missense variants and small in-frame deletions in GARS1 has been reported in patients with a range of genetic neuropathies including Charcot-Marie-Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and infantile spinal muscular atrophy (iSMA). We identified two unrelated patients who are each heterozygous for a previously unreported missense variant modifying amino-acid position 336 in the catalytic domain of GARS1. One patient was a 20-year-old woman with iSMA, and the second was a 41-year-old man with CMT2D. Functional studies using yeast complementation assays support a loss-of-function effect for both variants; however, this did not reveal variable effects that might explain the phenotypic differences. These cases expand the mutational spectrum of GARS1-related disorders and demonstrate phenotypic variability based on the specific substitution at a single residue.

We examined the use of a 50-m timed test (50MTT) in an effort to develop objective and easily administered outcome measures for clinical trials in CLN3 disease. Individuals with genetically confirmed CLN3 disease were enrolled from a single institution over a two-year period beginning in August 2019 for baseline assessment. The time to complete independent travel over 50 m was recorded as the outcome of the 50MTT. Performance was measured in a distraction-free hallway with a single turn after 25 m. Data on healthy children were gathered from previous studies by the investigators. A total of 19 children with CLN3 disease (12 males) ranging in age from 66 to 193 months (median 94 months) participated in the study. All children had evidence of vision loss at the time of assessment, and 21.1% had a history of seizures. The 50MTT demonstrated a robust correlation with clinician ratings of gait and overall physical disability based on the Unified Batten Disease Rating Scale (Spearman's rho, Gait r = 0.705, p = 0.001; Physical Symptoms r = 0.876, p < 0.001). When compared to typically developing children, the diagnosis of CLN3 disease was predictive of a 34.98 s increase in the 50MTT (SE = 1.29, p < 0.001) with age as an independent predictor. This study demonstrates preliminary evidence that the 50MTT may be an efficient instrument to capture gross motor functioning in ambulatory individuals with CLN3 disease, and may be a lens for overall physical disability in the condition. As this test may be accomplished with minimal cost and in a shorter amount of time with less reliance on attention or vision as the 6-min walk test, it may be an appealing adjunctive outcome measure in CLN3 clinical trials.
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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.