Heterozygous de novo variants in HSPD1 cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation.

INTRODUCTION: Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. HSPD1 encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in HSPD1 have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous HSPD1 variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for HSPD1 variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val). METHODS: Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis. RESULTS: Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly. DISCUSSION: We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants.

OBJECTIVE: Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. METHODS: Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. RESULTS: The patients presented at 9 to 14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds, and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32, and 33 were found. INTERPRETATION: This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Free sialic acid storage disease without sialuria.

We performed high-resolution in vitro proton nuclear magnetic resonance spectroscopy on cerebrospinal fluid and urine samples of 44 patients with leukodystrophies of unknown cause. Free sialic acid concentration was increased in cerebrospinal fluid of two siblings with mental retardation and mild hypomyelination. By contrast, urinary excretion of free sialic acid in urine was normal on repeated testing by two independent methods. Both patients were homozygous for the K136E mutation in SLC17A5, the gene responsible for the free sialic acid storage diseases. Our findings demonstrate that mutations in the SLC17A5 gene have to be considered in patients with hypomyelination, even in the absence of sialuria.

Hospital Utilization Among Rural Children Served by Pediatric Neurology Telemedicine Clinics.

Importance: Telemedicine is increasingly used to provide outpatient pediatric neurology consultations in underserved communities. Although telemedicine clinics have been shown to improve access, little is known about how they alter patients' utilization of hospital services. Objective: To evaluate the association between access to telemedicine clinics and hospital utilization among underserved children with neurologic conditions. Design, Setting, and Participants: This retrospective cross-sectional study included 4169 patients who received outpatient care from pediatric neurologists affiliated with an academic children's hospital in California between January 1, 2009, and July 31, 2017, either in person or using telemedicine. Exposures: Consultation modality (telemedicine or in person) in the outpatient neurology clinics. Main Outcomes and Measures: Demographic and clinical variables were abstracted from the hospital's electronic medical records. The association between the modality of outpatient neurology care and patients' utilization of the emergency department and hospitalizations was evaluated. Both all-cause and neurologic condition-related hospital utilization were analyzed using multivariable negative binomial regression in overall and matched samples. Results: The telemedicine cohort comprised 378 patients (211 [55.8%] male), and the in-person cohort comprised 3791 patients (2090 [55.1%] male). The mean (SD) age at the first encounter was 7.4 (5.4) years for the telemedicine cohort and 7.8 (5.1) years for the in-person cohort. The telemedicine cohort was more likely than the in-person cohort to have nonprivate insurance (public insurance, self-pay, or uninsured), lower education, and lower household income. The rates of all-cause and neurologic hospital encounters were lower among children who received pediatric neurology consultations over telemedicine compared with children who received care in the in-person clinics (5.7 [95% CI, 3.5-8.0] vs 20.1 [95% CI, 18.1-22.1] per 100 patient-years and 3.7 [95% CI, 2.0-5.3] vs 8.9 [95% CI, 7.8-10.0] per 100 patient-years, respectively; P < .001). Even after adjusting for demographic and clinical factors, the telemedicine cohort had a lower risk of hospital encounters (emergency department visits and admissions) with an adjusted incidence rate ratio of 0.57 (95% CI, 0.38-0.88) for all-cause encounters and an adjusted incidence rate ratio of 0.60 (95% CI, 0.36-0.99) for neurologic encounters. After matching on travel time to the neurology clinic, the adjusted incidence rate ratio was 0.19 (95% CI, 0.04-0.83) for all-cause admissions and 0.14 (95% CI, 0.02-0.82) for neurologic admissions. Conclusions and Relevance: Pediatric neurology care through real-time, audiovisual telemedicine consultations was associated with lower hospital utilization compared with in-person consultations, suggesting that high-cost hospital encounters can be prevented by improving subspecialty access.

Appointment completion in pediatric neurology telemedicine clinics serving underserved patients.

BACKGROUND: To determine whether telemedicine improves access to outpatient neurology care for underserved patients, we compared appointment completion between urban, in-person clinics and telemedicine clinics held in rural and underserved communities where neurology consultations are provided remotely. METHODS: In this retrospective study, we identified patients scheduled for outpatient care from UCDH pediatric neurologists between January 1, 2009, and July 31, 2017, in person and by telemedicine. Demographic and clinical variables were abstracted from electronic medical records. We evaluated the association between consultation modality and visit completion in overall and matched samples using hierarchical multivariable logistic regression. RESULTS: We analyzed 13,311 in-person appointments by 3,831 patients and 1,158 telemedicine appointments by 381 patients. The average travel time to the site of care was 45.8 ± 52.1 minutes for the in-person cohort and 22.3 ± 22.7 minutes for the telemedicine cohort. Telemedicine sites were located at an average travel time of 217.1 ± 114.8 minutes from UCDH. Telemedicine patients were more likely to have nonprivate insurance, lower education, and lower household income. They had different diagnoses and fewer complex chronic conditions. Telemedicine visits were more likely to be completed than either "cancelled" or missed ("no show") compared with in-person visits (OR 1.57, 95% CI: 1.34-1.83; OR 1.66, 95% CI: 1.31-2.10 matched on travel time to the site of care; OR 2.22, 95% CI: 1.66-2.98 matched on travel time to UCDH). CONCLUSIONS: The use of telemedicine for outpatient pediatric neurology visits has high odds of completion and can serve as an equal adjunct to in-person clinic visits.

CSF and Blood Levels of GFAP in Alexander Disease

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.