4 '-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4 '-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4 '-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4 '-phosphopantetheine as a candidate therapeutic for PKAN

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Neurodegeneration with Brain Iron Accumulation: Diagnosis and Management

Neurodegeneration with brain iron accumulation (NBIA) encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders

Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation

Background: Neurodegeneration with brain iron accumulation (NBIA) disorders comprise a group of rare but devastating inherited neurological diseases with unifying features of progressive cognitive and motor decline, and increased iron deposition in the basal ganglia. Although at present there are no proven disease-modifying treatments, the severe nature of these monogenic disorders lends to consideration of personalized medicine strategies, including targeted gene therapy. In this review we summarize the progress and future direction towards precision therapies for NBIA disorders. / Methods: This review considered all relevant publications up to April 2021 using a systematic search strategy of PubMed and clinical trials databases. / Results: We review what is currently known about the underlying pathophysiology of NBIA disorders, common NBIA disease pathways, and how this knowledge has influenced current management strategies and clinical trial design. The safety profile, efficacy and clinical outcome of clinical studies are reviewed. Furthermore, the potential for future therapeutic approaches is also discussed. / Discussion: Therapeutic options in NBIAs remain very limited, with no proven disease-modifying treatments at present. However, a number of different approaches are currently under development with increasing focus on targeted precision therapies. Recent advances in the field give hope that novel strategies, such as gene therapy, gene editing and substrate replacement therapies are both scientifically and financially feasible for these conditions

A Dissociation between Symbolic Number Knowledge and Analogue Magnitude Information

Semantic understanding of numbers and related concepts can be dissociated from rote knowledge of arithmetic facts. However, distinctions among different kinds of semantic representations related to numbers have not been fully explored. Working with numbers and arithmetic requires representing semantic information that is both analogue (e.g., the approximate magnitude of a number) and symbolic (e.g., what ÷ means). In this article, the authors describe a patient (MC) who exhibits a dissociation between tasks that require symbolic number knowledge (e.g., knowledge of arithmetic symbols including numbers, knowledge of concepts related to numbers such as rounding) and tasks that require an analogue magnitude representation (e.g., comparing size or frequency). MC is impaired on a variety of tasks that require symbolic number knowledge, but her ability to represent and process analogue magnitude information is intact. Her deficit in symbolic number knowledge extends to a variety of concepts related to numbers (e.g., decimal points, Roman numerals, what a quartet is) but not to any other semantic categories that we have tested. These findings suggest that symbolic number knowledge is a functionally independent component of the number processing system, that it is category specific, and that it is anatomically and functionally distinct from magnitude representations

Objective Measurement of Gait Abnormalities in Huntington Disease using a Shoe-Worn Inertial Sensor (P5.291)

OBJECTIVE: To evaluate the feasibility and utility of a shoe-worn inertial sensor to measure gait abnormalities in Huntington disease (HD) in the home setting. BACKGROUND: Clinical rating scales provide only point assessments of disease-related impairments in HD, lack sensitivity, and require that a clinician experienced in the scale’s use evaluate the patient. A tool that would allow longitudinal, objective, quantitative measurement of impairments may offer advantages over standard clinical rating scales. DESIGN/METHODS: This was a pilot, single-blind, controlled observational study. Five ambulatory HD subjects and 5 age/gender-matched healthy controls wore inertial sensors manufactured by APDM, Inc. attached to each shoe during waking hours for 7 days. Gait parameters calculated from the sensors included stride length([percnt]height); stride velocity([percnt]height/sec); step duration(sec); double support time([percnt]); pitch at toe off (degrees) and heel strike (degrees); cadence(steps/min); and variability in each of these measures. Following blinded descriptive data analysis by APDM, independent samples t-tests were used to compare means for selected gait metrics between HD and control subjects, and Pearson correlation coefficients were used to interrogate the relationships between gait metrics, chorea score, and Total Functional Capacity (TFC, a measure of disease severity). RESULTS: Subjects were able to successfully apply, wear and charge the sensors. Blinded gait analysis correctly identified the HD and control subjects for 4/5 pairs. Significant differences were found between HD/control groups in mean(SD) stride length [53.96(9.25), 67.68(7.25), p=0.03]; mean(SD) variability per week (as measured by coefficient of variation) in stride length [28.57(5.54), 20.27(3.78), p=0.02] and pitch at toe off [25.57(4.00), 17.56(4.07), p=0.01]. Lower TFC scores correlated with greater variability in stride length[R=-0.82]; pitch at toe off[R=-0.80]; and increased double support time[R=-0.75]. Higher chorea scores correlated with shorter stride length[R=-0.76]. CONCLUSIONS: Inertial sensors may offer a feasible mechanism to objectively measure clinically-relevant gait abnormalities in HD

Femur Fractures in 5 Individuals With Pantothenate Kinase-associated Neurodegeneration: The Role of Dystonia and Suggested Management

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, neurodegenerative disorder that manifests with progressive loss of ambulation and refractory dystonia, especially in the early-onset classic form. This leads to osteopenia and stress on long bones, which pose an increased risk of atraumatic femur fractures. The purpose of this study is to describe the unique challenges in managing femur fractures in PKAN and the effect of disease manifestations on surgical outcomes. METHODS: A retrospective case review was conducted on 5 patients (ages 10 to 20 y) with PKAN with a femur fracture requiring surgical intervention. Data regarding initial presentation, surgical treatment, complications, and outcomes were obtained. RESULTS: All patients were non-ambulatory, with 4 of 5 patients sustaining an atraumatic femur fracture in the setting of dystonia episode. One patient had an additional contralateral acetabular fracture. Postoperatively, 4 of the 5 patients sustained orthopaedic complications requiring surgical revision, with 3 of these secondary to dystonia. Overall, 4 required prolonged hospitalization in the setting of refractory dystonia. CONCLUSION: Femur fractures in PKAN present distinct challenges for successful outcomes. A rigid intramedullary rod with proximal and distal interlocking screws is most protective against surgical complications associated with refractory dystonia occurring during the postoperative period. Multidisciplinary planning for postoperative care is essential and may include aggressive sedation and pain management to decrease the risk of subsequent injuries or complications. LEVEL OF EVIDENCE: Level IV