Evolution of Movement Disorders in Patients With CLN2-Batten Disease Treated With Enzyme Replacement Therapy.

OBJECTIVES: Neuronal ceroid lipofuscinosis type 2 (CLN2-disease) is an inherited childhood-onset neurodegenerative condition, with classical early features of speech delay, epilepsy, myoclonus, ataxia, and motor regression. This study aimed to better characterize the spectrum of movement disorders in CLN2-disease in a cohort of children receiving enzyme replacement therapy (ERT). METHODS: A cohort of 18 children attending a single center for treatment with cerliponase alfa ERT was systematically assessed using a standardized structured history and a double-scored, video-recorded examination using the Unified Batten Disease Rating Scale (UBDRS) and Abnormal Involuntary Movement Scale. RESULTS: Noncanonical movement disorders are common: while ataxia (89%) and myoclonus (83%) were near-universal, spasticity and dystonia were experienced by over half (61% each), with children having a median of 4 distinct movement disorder phenotypes. This progression was stereotyped with initial ataxia/myoclonus, then hyperkinesia/spasticity, and later hypokinesia. ERT slows progression of movement disorders, as measured by the UBDRS physical subscale, with 1.45 points-per-month progression before diagnosis and 0.44 points-per-month while on treatment (p = 0.019). DISCUSSION: Movement disorders are a core feature of CLN2-disease and follow a typical pattern of progression which is slowed by ERT. Identifying and treating movement disorders should become standard, especially given increased patient survival.

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. Highlights: This article provides an up-to-date review of the current literature about Neurodegeneration with Brain Iron Accumulation (NBIA), with a focus on disease pathophysiology, current and previously trialed therapies, and future treatments in development, including consideration of potential genetic therapy approaches.

The role of manganese dysregulation in neurological disease: emerging evidence.

Manganese is an essential trace metal. The dysregulation of manganese seen in a broad spectrum of neurological disorders reflects its importance in brain development and key neurophysiological processes. Historically, the observation of acquired manganism in miners and people who misuse drugs provided early evidence of brain toxicity related to manganese exposure. The identification of inherited manganese transportopathies, which cause neurodevelopmental and neurodegenerative syndromes, further corroborates the neurotoxic potential of this element. Moreover, manganese dyshomoeostasis is also implicated in Parkinson's disease and other neurodegenerative conditions, such as Alzheimer's disease and Huntington's disease. Ongoing and future research will facilitate the development of better targeted therapeutical strategies than are currently available for manganese-associated neurological disorders.

Precision medicine for genetic childhood movement disorders.

Increasingly effective targeted precision medicine is either already available or in development for a number of genetic childhood movement disorders. Patient-centred, personalized approaches include the repurposing of existing treatments for specific conditions and the development of novel therapies that target the underlying genetic defect or disease mechanism. In tandem with these scientific advances, close collaboration between clinicians, researchers, affected families, and stakeholders in the wider community will be key to successfully delivering such precision therapies to children with movement disorders. What this paper adds Precision medicine for genetic childhood movement disorders is developing rapidly. Accurate diagnosis, disease-specific outcome measures, and collaborative multidisciplinary work will accelerate the progress of such strategies.

Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia.

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

Pulmonary hemorrhage as a complication of Respiratory Syncyntial Virus (RSV) bronchiolitis.

Respiratory Syncytial Virus (RSV) is a common cause of bronchiolitis. Although there are a number of recognized complications, pulmonary hemorrhage has not been reported previously. A retrospective case notes review was performed through an electronic search of a Pediatric Intensive Care Unit's medical records. Seven patients with RSV infection and pulmonary hemorrhage were identified and included in this case series. Six of the seven patients were born prematurely (30-36 weeks gestation). All patients required blood transfusion. The pulmonary hemorrhage events all occurred after a period of mechanical ventilation and following extubation. All of the patients required reintubation with a mean of 5 further days of mechanical ventilation. Pulmonary hemorrhage is an uncommon complication of RSV infection, which has not been reported previously in the literature. Further studies are required to determine incidence, pathogenesis, and outcome. Pediatr Pulmonol. 2017;52:E32-E36. © 2016 Wiley Periodicals, Inc.

Predictive value of developmental testing in the second year for cognitive development at five years of age.

There is mixed evidence about the predictive validity of the Griffiths mental developmental scales. This study aimed to assess the predictive value of developmental assessments of children in their second year using the Griffiths mental development scales for neuro-developmental status at five years using the Wechsler preschool and primary scale of intelligence, revised (WPPSI-R). In a longitudinal study 253 children were assessed in their second year of life using the Griffiths scales and again at five years using the WPPSI-R. The scores were compared and the predictability of the WPPSI-R outcome on the basis of Griffiths scores was assessed. The WPPSI-R full scale IQ and the performance IQ at age five could be predicted moderately by the Griffiths general quotient (GQ) and by the personal/social scale. The Griffiths GQ was not a significant predictor of verbal IQ at age 5. The Griffiths performance scale predicted subsequent WPPSI-R performance IQ, and marginally the Full Scale IQ. For the early identification of children at risk for language delay, the Griffiths scales may not be suitable. However, a shortened form would be useful to predict overall cognitive development from the second year to school entry, focussing on the personal-social and performance scales.

Health outcomes of children born to mothers with chronic kidney disease: a pilot study.

This study aimed to study the health of children born to mothers with chronic kidney disease. Twenty-four children born to mothers with chronic kidney disease were compared with 39 matched control children born to healthy mothers without kidney disease. The well-being of each child was individually assessed in terms of physical health, neurodevelopment and psychological health. Families participating with renal disease were more likely to be from lower socio-economic backgrounds. Significantly fewer vaginal deliveries were reported for mothers with renal disease and their infants were more likely to experience neonatal morbidity. Study and control children were comparable for growth parameters and neurodevelopment as assessed by the Griffiths scales. There was no evidence of more stress amongst mothers with renal disease or of impaired bonding between mother and child when compared to controls. However, there was evidence of greater externalizing behavioral problems in the group of children born to mothers with renal disease. Engaging families in such studies is challenging. Nonetheless, families who participated appreciated being asked. The children were apparently healthy but there was evidence in this small study of significant antenatal and perinatal morbidity compared to controls. Future larger multi-center studies are required to confirm these early findings.