Erratum: Neurofilament light chain and vaccination status associate with clinical outcomes in severe COVID-19.

[This corrects the article DOI: 10.1016/j.isci.2022.105272.].

First families with spinocerebellar ataxia type 7 in Poland.

INTRODUCTION: We present the first two Polish families diagnosed with spinocerebellar ataxia type 7 (SCA7) and draw attention to cardiac involvement as a new potential manifestation of this disease. MATERIAL AND METHODS: Two well-documented kindreds are presented. RESULTS: The proband from Family 1 presented aged 54 years with vision worsening followed by progressive imbalance. Brain MRI demonstrated cerebellar atrophy. Genetic testing confirmed CAG repeat expansion (42/10) in ATXN7 gene. The proband from Family 2 developed imbalance at age 20, followed by progressive deterioration of vision. Brain MRI revealed cerebellar atrophy. Additionally, she developed chronic congestive heart failure and, at age 38, had cardiomyopathy with an ejection fraction of 20% and significant mitral and tricuspid regurgitation. Genetic analysis found abnormal CAG expansion in the ATXN7 (46/10). CONCLUSIONS AND CLINICAL IMPLICATIONS: Vision loss due to pigmentary retinal degeneration is the distinguishing feature of SCA7 and often the initial manifestation. Although SCA7 is one of the most common SCAs in Sweden, it has never been reported in neighbouring Poland. Until now, cardiac abnormalities have only been described in infantile-onset SCA7 with large CAG repeats. The observed cardiac involvement in Family 2 may be coincidental, albeit a new possible manifestation of SCA7 cannot be excluded.

Management of Poor-Grade Aneurysmal Subarachnoid Hemorrhage and Key Pearls for Achieving Favorable Outcomes: An Illustrative Case.

Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with high patient mortality. Despite recent advances in management strategies, the prognosis for poor-grade aSAH remains dismal. We present a challenging case of a patient presenting with poor-grade aSAH. A 46-year-old female presented to the emergency department after losing consciousness following a sudden headache. The examination showed a dilated left pupil and a Glasgow Coma Scale of 4. Imaging revealed a ruptured anterior communicating artery (ACoM) aneurysm, after which the patient was subsequently taken to the neuro-interventional radiology suite. We showed that carefully managing blood pressure and intracranial pressure (ICP) makes it possible to achieve a favorable outcome and reduce the risk of secondary brain injury in aSAH, regardless of patient presentation. We propose maintaining blood pressure at <160 mmHg prior to intervention, after which it can be permitted to increase to 160-240 mmHg for the purpose of preventing vasospasm. Additionally, transcranial doppler (TCD) is essential to detect vasospasm due to the subtility of symptoms in patients with aSAH. Once identified, vasospasm can be successfully treated with balloon angioplasty. Finally, targeted temperature management (TTM), mannitol, hypertonic saline, and neuromuscular paralysis are essential for the postoperative management of ICP levels.

Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome.

OBJECTIVES: This paper presents the first report of amyotrophic lateral sclerosis (ALS) kindred due to the KIF5A p.Arg1007Lys, a splice-altering variant. METHODS: An index case was a 54-year-old male who developed progressive gait difficulty and imbalance followed by mild parkinsonism, spasticity, neuropathy, ataxia, and cognitive impairment with predominant subcortical frontal involvement. Brain MRI showed marked bilateral parietal lobes atrophy. Electromyography demonstrated chronic diffuse neurogenic changes. Due to the positive history of similar symptoms in his father and the diagnosis of ALS in 10 other family members, extensive genetic testing was pursued. RESULTS: Genetic screening for GRN, C9orf72, TARDBP, SOD1, FUS, MAPT mutations, and hereditary ataxia panel, was unremarkable. Whole-exome sequencing revealed c.3020G > A (p.Arg1007Lys) mutation in the KIF5A gene, later confirmed in two affected relatives. DISCUSSION: Similar to previous reports on KIF5A-related ALS, our index case, had a mild disease course with prolonged survival. However, as the rate of progression and survival time differed even among the same family members, other factors were probably at play. Additionally, our index case and his father displayed features overlapping ALS, spastic paraplegia, Charcot-Marie-Tooth disease type 2, and frontotemporal dementia. Therefore, we suggest considering KIF5A mutations in the differential diagnosis, particularly in the presence of overlapping features of spasticity, neuropathy, cerebellar ataxia, and dementia.

First report on spinocerebellar ataxia type 3 (Machado-Joseph disease) in Poland.

Spinocerebellar ataxia type 3 (SCA3; Machado-Joseph disease, MJD) is the most common autosomal-dominant form of genetic ataxia worldwide. However, it has never been reported in Eastern Europe. This letter presents the first three families with SCA3 from Poland and discusses the practical implications of the disease for clinicians.

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Rapidly Resolving and Recurrent Contralateral Subdural Hematoma From Disseminated Intravascular Coagulation.

BACKGROUND: Acute, recurrent subdural hematoma (SDH) is a rare entity in the absence of trauma. Atraumatic SDH may be due to vascular disorders, coagulopathies, or intracranial hypotension. It is a rare complication of disseminated intravascular coagulation (DIC), with no prior reports in patients with intracranial metastatic colon cancer (MCC). Rapid resolution of the initial acute SDH with contralateral recurrence has not yet been reported in the literature. We present a case of rapidly resolving and recurrent, contralateral acute SDH from DIC secondary to MCC. CASE DESCRIPTION: A 77-year-old woman with MCC presented with severe, acute onset headache. She progressed to unresponsiveness, dilated right pupil, and Glasgow Coma Scale (GCS) score of 4T. Initial computed tomography (CT) of the head demonstrated a right, 17-mm SDH with a right-to-left midline shift. Repeat CT head 8 hours later revealed resolution of the right SDH. She was extubated with notable clinical improvement. Laboratory examination showed international normalized ratio of 3.4, leukocytosis, and thrombocytopenia. The next morning, she became lethargic, GCS score of 3, with bilateral fixed pupils and dilated to 5-mm, and she was then reintubated. Repeat CT head demonstrated a new left SDH with bilateral uncal herniation. A small hyperdense focus in the left parietal region was suspicious for intraparenchymal hematoma versus a hemorrhagic metastatic focus. Shortly after, she was extubated due to do not resuscitate status, and she then passed away. CONCLUSIONS: To our knowledge, this is the first case illustrating rapidly resolving and recurrent, contralateral acute SDH from DIC in a patient with MCC. Clinical recognition of this phenotypic pattern should raise the question of an underlying coagulopathy.

Progressive supranuclear palsy is not associated with neurogenic orthostatic hypotension.

OBJECTIVE: To evaluate the pattern and severity of autonomic dysfunction in autopsy-confirmed progressive supranuclear palsy (PSP) compared to α-synuclein pathology. METHODS: Autopsy-confirmed cases of 14 patients with PSP, 18 with multiple system atrophy (MSA), and 24 with Lewy body disease (LBD) with antemortem autonomic testing were reviewed retrospectively. All patients underwent comprehensive clinical evaluations by a movement disorder specialist, formal autonomic testing, and postmortem examinations at Mayo Clinic. RESULTS: The absence of orthostatic hypotension (OH) was the strongest autonomic parameter that distinguished PSP from α-synucleinopathies (0% vs 69%, p < 0.0001). Tests of adrenergic failure, which distinguish neurogenic OH, also differentiated PSP from other groups. These included the pressure recovery time (p = 0.0008), adrenergic impairment score (p = 0.001), and magnitude of change of systolic (p = 0.0002) and diastolic (p = 0.0001) blood pressures (BPs) during upright tilt. In addition, REM sleep behavior disorder was seen less frequently (p = 0.006) in PSP (33%) compared to MSA (87%) and LBD (90%). Antemortem clinical diagnostic accuracy for these phenotypically variable disorders was 57% for PSP and 83% for α-synucleinopathies. CONCLUSION: Our results suggest that the cardiovascular adrenergic system, which sustains BP during standing, is relatively unaffected, if not spared, in PSP. These findings increase our understanding of the clinical signature of PSP and have the potential to improve diagnostic accuracy in atypical parkinsonisms by distinguishing PSP from the α-synucleinopathies.

Biomarkers of Nonmotor Symptoms in Parkinson's Disease.

Biomarkers are helpful for early diagnosis, assessment of disorder severity, prognosis, and prediction of response to therapy. Given that early therapeutic intervention may be useful in forestalling or slowing neurodegenerative conditions, employing reliable biomarkers to identify asymptomatic individuals who are destined to develop clinical Parkinson's disease (PD) is critical. Two important observations have been repeatedly found in persons who eventually develop clinical PD: (1) significant neuronal loss occurs in the substantia nigra and (2) the presence of nonmotor symptoms (NMS). Each of these findings occurs prior to the development of motor signs and symptoms, often preceding the clinical diagnosis of PD by a decade or more. As such, NMS themselves, and factors associated with their development may be useful clinical biomarkers for predicting future development of motor PD. Recently, research criteria for prodromal PD, defined as presence of motor and/or NMS, but not yet fulfilling the classic PD diagnosis, have been proposed by the International Parkinson and Movement Disorder Society Task Force. Although there are a small number of biomarkers associated with NMS of PD, in this chapter, discussion follows concerning the expanding literature associated with clinical, biochemical, imaging, and genetic biomarkers of NMS in patients with PD.