Faculty Bibliography

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic/likely pathogenic, significance of one C-terminal truncating variant, one splice-site variant and the missense variants remained unclear. Three missense variants in the CTD-interacting domain of SCAF4 were predicted to destabilize the domain. Twenty-three variants occurred de novo, and variants were inherited in 13 cases. Frequent clinical findings were mild developmental delay with speech impairment, seizures, and skeletal abnormalities such as clubfoot, scoliosis or hip dysplasia. Cognitive abilities ranged from normal IQ to severe intellectual disability (ID), with borderline to mild ID in the majority of individuals. Our study confirms the role of SCAF4 variants in neurodevelopmental disorders and further delineates the associated clinical phenotype.

PURPOSE/OBJECTIVE:Defects in the gene encoding selenocysteine insertion sequence binding protein 2, SECISBP2, result in global impaired selenoprotein synthesis manifesting a complex syndrome with characteristic serum thyroid function tests due to impaired thyroid hormone metabolism. Knowledge about this multisystemic defect remains limited. METHODS:Genetic and laboratory investigations were performed in affected members from 6 families presenting with short stature and failure to thrive. RESULTS:Four probands presented a complex neurodevelopmental profile, including absent speech, autistic features, and seizures. Pediatric neurological evaluation prompted genetic investigations leading to the identification of SECISBP2 variants before knowing the characteristic thyroid tests in 2 cases. Thyroid hormone treatment improved motor development, whereas speech and intellectual impairments persisted. This defect poses great diagnostic and treatment challenges for clinicians, as illustrated by a case that escaped detection for 20 years because SECISBP2 was not included in the neurodevelopmental genetic panel, and his complex thyroid status prompted antithyroid treatment instead. CONCLUSION/CONCLUSIONS:This syndrome uncovers the role of selenoproteins in humans. The severe neurodevelopmental disabilities manifested in 4 patients with SECISBP2 deficiency highlight an additional phenotype in this multisystem disorder. Early diagnosis and treatment are required, and long-term evaluation will determine the full spectrum of manifestations and the impact of therapy.

Adult polyglucosan body disease (APBD) is a rare autosomal recessive glycogen storage disorder that leads to slowly progressive multi-organ dysfunction in adulthood. A novel disease-specific patient-reported outcome measure was created and administered to assess symptom burden and health-related quality of life (HR-QOL) in APBD. Thirty-six participants between 30 and 79 years of age (83% ≥60 years, 56% male) completed the anonymous questionnaire independently or with a caregiver proxy (75% self-report). Unemployment predicted an 18.3 (95% CI: 2.8, 33.8; p = 0.028) higher composite disease severity score and a 28.8 (95% CI: 8.2, 49.4; p = 0.010) higher composite HR-QOL score. Use of one or more assistive devices also predicted a 29.3 (95% CI: 8.3, 50.4; p = 0.011) higher composite disease severity score and a 41.8 (95% CI: 10.9, 72.8; p = 0.013) higher composite HR-QOL score. Proxy survey completion predicted a 19.4 (95% CI: 4.1, 34.7; p = 0.020) higher composite disease severity score compared to self-report. Older age at survey completion predicted a 27.4 higher composite HR-QOL score (95% CI: 2.5, 52.4; p = 0.039) for participants in their sixties compared to those between 30 and 59 years old. The development of the Adult Polyglucosan Body Disease questionnaire on Symptom burden and health-related Quality of life (APBD-SQ) marks an important stride forward in capturing the patient experience as a tool for disease monitoring and future research.

BACKGROUND:Adult polyglucosan body disease (APBD) is caused by a deficiency in glycogen branching enzyme that leads to polyglucosan accumulation in multiple organs. It has a progressive clinical course with prominent neurologic manifestations. We aim to describe the neuro-ophthalmic manifestations of APBD. METHODS:This is a case series of 3 individuals with genetically proven APBD. Written informed consent was provided by the brothers. We also performed a literature review on the current state of knowledge on APBD through PubMed. RESULTS:Brother 1 developed gait imbalance and length-dependent polyneuropathy in his 40s followed by progressive urinary symptoms in his 50s. He reported diplopia and blurry vision in his 60s. Neuro-ophthalmic assessment revealed bilateral optic neuropathy, convergence insufficiency, and a right fourth nerve palsy. Genetic testing showed a homozygous pathogenic variant in GBE1 c.986A>C p.Tyr329Ser. Brother 2 developed progressive urinary symptoms in his 40s that were followed by cognitive deficits, length-dependent polyneuropathy, and lower extremity weakness in his 50s and 60s. He reported blurred vision, and neuro-ophthalmic evaluation revealed bilateral optic neuropathy. Genetic testing revealed the same variant as Brother 1, GBE1 c.986A>C p.Tyr329Ser. Brother 3 developed progressive urinary urgency and lower extremity weakness in his 50s followed by a length-dependent polyneuropathy in his 60s. He reported diplopia and blurry vision in his 70s. Neuro-ophthalmic assessment revealed bilateral optic neuropathy and convergence insufficiency. Genetic testing revealed the same variant as Brothers 1 and 2, GBE1 c.986A>C p.Tyr329Ser. CONCLUSIONS:There is an array of afferent and efferent neuro-ophthalmic manifestations in APBD. Neuro-ophthalmic evaluation is crucial in evaluating and treating patients with APBD, particularly in those with visual dysfunction.

FEZF2 encodes a transcription factor critical to neurodevelopment that regulates other neurodevelopment genes. Rare variants in FEZF2 have previously been suggested to play a role in autism, and cases of 3p14 microdeletions that include FEZF2 share a neurodevelopmental phenotype including mild dysmorphic features and intellectual disability. We identified seven heterozygous predicted deleterious variants in FEZF2 (three frameshifts, one recurrent missense in two independent cases, one nonsense, and one complete gene deletion) in unrelated individuals with neurodevelopmental disorders including developmental delay/intellectual disability, autism, and/or attention-deficit/hyperactivity. Variants were confirmed to be de novo in five of seven cases and paternally inherited from an affected father in one. Predicted deleterious variants in FEZF2 may affect the expression of genes that are involved in fate choice pathways in developing neurons, and thus contribute to the neurodevelopmental phenotype. Future studies are needed to clarify the mechanism by which FEZF2 leads to this neurodevelopmental disorder.

BACKGROUND:Mutations in the CLN6 gene cause late infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease of childhood onset. Clinically, individuals present with progressive motor and cognitive regression, ataxia, and early death. The aim of this study is to establish natural history data of individuals with classic, late-infantile-onset (age less than five years) CLN6 disease. METHODS:We analyzed the natural history of 25 patients with late-infantile-onset CLN6, utilizing the Hamburg motor-language scale to measure disease progression. The key outcomes were CLN6 disease progression, assessed by rate of decline in motor and language clinical domain summary scores (0 to 6 total points); onset and type of first symptom; onset of first seizure; and time from first symptom to complete loss of function. RESULTS:Median age of total motor and language onset of decline was 42 months (interquartile range 36 to 48). The estimated rate of decline in total score was at a slope of -1.20 (S.D. 0.30) per year, after the start of decline. Complete loss of both motor and language function was found to be, on average, 88.1 months (S.D. 13.5). CONCLUSIONS:To our knowledge, this is the largest international study that monitors the longitudinal natural history and progression of CLN6 disease. These data may serve as a template for future interventional trials targeted to slow the progression of this devastating disease.

A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.

BACKGROUND:We sought to identify patient and provider factors associated with low completion of genetic testing, specifically chromosomal microarray (CMA), for autism spectrum disorder (ASD). METHODS:Medical record review was conducted of children newly diagnosed with ASD without prior genetic testing at a single academic medical center from February 2015 through January 2016. RESULTS:Only 41.9% of individuals with ASD completed CMA testing over at least 18 months from diagnosis (n = 140 of 334). Time to CMA completion varied, with a median of 86.5 days (interquartile range 2 to 214.5 days). Provider recommendation of genetic testing at the diagnostic visit and greater number of follow-up visits were associated with CMA completion. On multivariate regression, CMA completion was inversely associated with age (odds ratio [OR] = 0.8 for each year older, 95% confidence interval [CI] 0.7, 0.9; P = 0.001) and directly associated with intellectual disability or global developmental delay (OR = 2.2, 95% CI 1.3, 3.8; P = 0.004), first-degree relative with ASD (OR = 2.5, 95% CI 1.0, 6.0; P = 0.044), and public insurance (OR = 1.7, 95% CI 1.0, 2.9; P = 0.037). Parental concern and cost/insurance coverage were the most frequently documented barriers. CONCLUSIONS:Workflows to support early genetic testing recommendation and ordering soon after diagnosis may increase utilization, incorporating both family and provider perspectives. Genetic counseling highlighting the utility of genetic testing across the life span, phenotypic variability of genetic disorders, and possibility of de novo variants in ASD may also improve utilization.

Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disorder with enzyme replacement therapy available. We present two siblings with a clinical diagnosis of CLN2 disease, but no identifiable TPP1 variants after standard clinical testing. Long-read sequencing identified a homozygous deep intronic variant predicted to affect splicing, confirmed by clinical DNA and RNA sequencing. This case demonstrates how traditional laboratory assays can complement emerging molecular technologies to provide a precise molecular diagnosis.

CSF1R-related leukoencephalopathy is an autosomal dominant neurological disorder causing microglial dysfunction with a wide range of neurologic complications, including motor dysfunction, dementia and seizures. This case report highlights an unusual presentation of CSF1R-related leukoencephalopathy with radiographic spinal cord involvement initially diagnosed as multiple sclerosis. The case highlights the importance of considering adult-onset neurogenetic disorders in the setting of white matter disease. Genetic testing provides a confirmatory diagnosis for an expanding number of adult-onset leukoencephalopathies and informs therapeutic decision-making.