Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).

OBJECTIVES: Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions. METHODS: We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B. RESULTS: In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine. INTERPRETATION: Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024.

[Disorder-related case groups for needs-based hospital care]. / Störungsbezogene Fallgruppen für eine bedarfsgerechte Krankenhausversorgung.

BACKGROUND: The individual needs of patients are central to hospital care. Due to the resulting complexity grouping of patients with similar therapeutic needs seems to facilitate an efficient organization of processes and the required treatment resources in hospital care. OBJECTIVE: The aim of this study was to develop a system of disorder-related, treatment-oriented case groups as a possible tool for the efficient and needs-based organization of hospital care. MATERIAL AND METHODS: The disorder-related groups were developed in a multistage, mixed-methods design. The technical content and quantitative description of the case groups and the extent of treatment included all consecutive inpatient treatment cases discharged between 1 January 2017 and 31 December 2017 from 9 psychiatric hospitals in Hesse, Germany. RESULTS: All diagnoses in chapter F of the German modification of the International Statistical Classification of Diseases 10 (ICD-10-GM) were grouped into a total of 10 disorder-related groups. Analyses included 20,252 inpatient hospital treatment cases. Substantial management-relevant differences between the case groups could be identified and the various case group-specific configurations of clinically relevant comorbidities could be demonstrated. DISCUSSION: The presented disorder-related grouping system and configuration of comorbidities suggest a modular organization of therapeutic measures and constitute a promising basis for needs-based management of patient care. Future work will show to what degree the disorder-related groups can facilitate a needs-specific treatment and align economic and therapeutic interests of psychiatric care.

Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome.

BACKGROUND AND OBJECTIVE: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult-onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG)n repeat expansions in the second intron of the replication factor complex subunit 1 (RFC1). However, a small number of cases with typical CANVAS do not carry the common biallelic repeat expansion. The objective of this study was to expand the genotypic spectrum of CANVAS by identifying sequence variants in RFC1-coding region associated with this condition. METHODS: Fifteen individuals diagnosed with CANVAS and carrying only 1 heterozygous (AAGGG)n expansion in RFC1 underwent whole-genome sequencing or whole-exome sequencing to test for the presence of a second variant in RFC1 or other unrelated gene. To assess the effect of truncating variants on RFC1 expression, we tested the level of RFC1 transcript and protein on patients' derived cell lines. RESULTS: We identified 7 patients from 5 unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)n expansion together with a second truncating variant in trans in RFC1, which included the following: c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6), and c.2876del (p.Pro959GlnfsTer24). Patient fibroblasts containing the c.1267C>T (p.Arg423Ter) or c.2876del (p.Pro959GlnfsTer24) variants demonstrated nonsense-mediated mRNA decay and reduced RFC1 transcript and protein. DISCUSSION: Our report expands the genotype spectrum of RFC1 disease. Full RFC1 sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)n expansions. In addition, it sheds further light on the pathogenesis of RFC1 CANVAS because it supports the existence of a loss-of-function mechanism underlying this complex neurodegenerative condition.

Parametrically enhanced interactions and nonreciprocal bath dynamics in a photon-pressure Kerr amplifier.

Photon-pressure coupling between two superconducting circuits is a promising platform for investigating radiation-pressure coupling in distinct parameter regimes and for the development of radio-frequency (RF) quantum photonics and quantum-limited RF sensing. Here, we implement photon-pressure coupling between two superconducting circuits, one of which can be operated as a parametric amplifier. We demonstrate a Kerr-based enhancement of the photon-pressure single-photon coupling rate and an increase of the cooperativity by one order of magnitude in the amplifier regime. In addition, we observe that the intracavity amplification reduces the measurement imprecision of RF signal detection. Last, we demonstrate that RF mode sideband cooling is unexpectedly not limited to the effective amplifier mode temperature arising from quantum noise amplification, which we interpret in the context of nonreciprocal heat transfer between the two circuits. Our results demonstrate how Kerr amplification can be used as resource for enhanced photon-pressure systems and Kerr cavity optomechanics.

Cooling photon-pressure circuits into the quantum regime.

Quantum control of electromagnetic fields was initially established in the optical domain and has been advanced to lower frequencies in the gigahertz range during the past decades extending quantum photonics to broader frequency regimes. In standard cryogenic systems, however, thermal decoherence prevents access to the quantum regime for photon frequencies below the gigahertz domain. Here, we engineer two superconducting LC circuits coupled by a photon-pressure interaction and demonstrate sideband cooling of a hot radio frequency (RF) circuit using a microwave cavity. Because of a substantially increased coupling strength, we obtain a large single-photon quantum cooperativity 𝒞q0 ∼ 1 and reduce the thermal RF occupancy by 75% with less than one pump photon. For larger pump powers, the coupling rate exceeds the RF thermal decoherence rate by a factor of 3, and the RF circuit is cooled into the quantum ground state. Our results lay the foundation for RF quantum photonics.