Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.

PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.

End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy.

OBJECTIVE: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes. METHODS: We performed a gene-based collapsing test of rare protein-truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large-scale databases, gnomAD and TOPMed. Western blotting was used to investigate the functional consequences of variants. Clinical and magnetic resonance imaging features of mutated patients were characterized. RESULTS: We showed that LAMB1 truncating variants escaping nonsense-mediated messenger RNA decay are strongly overrepresented in CSVD patients, reaching genome-wide significance (p < 5 × 10-8 ). Using 2 antibodies recognizing the N- and C-terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in the endogenous fibroblasts of patients and trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy. INTERPRETATION: These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. ANN NEUROL 2021;90:962-975.

Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P = 3.12 × 10-17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P = 7.6 × 10-18, OR = 27.1) and 1000 Genomes (P = 1.5 × 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.

Focal cortical subarachnoid hemorrhage revealed by recurrent paresthesias: a clinico-radiological syndrome strongly associated with cerebral amyloid angiopathy.

BACKGROUND: Focal subarachnoid hemorrhage (SAH) is often revealed by transient and recurrent focal neurological episodes. This cause is important to identify because it carries a high risk of intracerebral hemorrhage (ICH). We report the clinical, imaging and prognostic data of 17 patients with focal SAH revealed by short episodes of paresthesias mimicking transient ischemic attacks. METHODS: The medical records and imaging data of patients with focal acute SAH at the cerebral convexity and at least one episode of focal paresthesia having attended the Neurology Department of Caen University Hospital in the last 10 years were retrospectively reviewed. Hemorrhagic lesions, ischemic lesions, cerebral microbleeds (CMBs), superficial siderosis, white matter changes (leukoaraiosis) and modified Boston criteria for cerebral amyloid angiopathy (CAA) were assessed. All patients or relatives were contacted after a median delay of 16 months in order to seek for new events (death, stroke, recurrent focal symptoms, ICH and dementia) that occurred since hospital discharge. RESULTS: Seventeen patients (12 men) aged 69-96 years were identified. All but 1 had multiple, repeated, stereotyped and brief attacks of paresthesias, associated in some of them with motor and/or speech difficulties, but only 1 had a headache. SAHs were seen on CT scans in 15/17 patients and on T2* gradient-echo magnetic resonance imaging (MRI) in all patients. They were multiple SAHs in 14/17 patients, including at least 1 SAH in the central or pre- or postcentral sulcus contralateral to the symptoms in all patients. Five patients had punctate cortical hyperintensities on diffusion-weighted MRI. Eleven patients had CMBs, and 4 of them had more than 5 CMBs. Seven patients met the modified Boston criteria for probable and 10 for possible CAA. At follow-up, 5 patients had a subsequent ICH, 4 of whom had received antithrombotic treatments. Five patients died (1 from ICH). Six patients developed dementia. CONCLUSION: The combination of transient, repeated and stereotyped attacks of unilateral paresthesias with a contralateral sulcal SAH seems to preferentially occur in elderly people and is often indicative of CAA.

Stroke in hereditary hemorrhagic telangiectasia patients. New evidence for repeated screening and early treatment of pulmonary vascular malformations: two case reports.

BACKGROUND: Paradoxical embolism due to pulmonary arteriovenous malformations is the main mechanism of brain infarction in patients with hereditary hemorrhagic telangiectasia. International Guidelines have recently been published to clarify the performance of screening tests and the effectiveness of treatment for pulmonary arteriovenous malformations. CASE PRESENTATION: We present two cases of hereditary hemorrhagic telangiectasia patients of our hospital who experienced an acute stroke secondary to paradoxical embolism. CONCLUSIONS: These two cases show that the guidelines must be followed to prevent the occurrence of ischemic stroke in patients with hereditary hemorrhagic telangiectasia, and that although they may be adequate in most cases, there are some patients who need a more personalized approach.

Episodic Autobiographical Memory Impairment and Differences in Pronoun Use: Study of Self-Awareness in Functional Amnesia and Transient Global Amnesia.

The subjective experience associated to memory processing is the core of the definition of episodic autobiographical memory (EAM). However, while it is widely known that amnesia affects the content of memories, few studies focused on the consequences of an impairment of EAM on the subjective self, also called the I-self. In the present study, we explored the I-self in two puzzling disorders that affect EAM: functional amnesia, which has an impact on autobiographical memory, and transient global amnesia (TGA), which only affects episodic memory. I-self was assessed through an original measure of self-integration in autobiographical narratives, namely the use of general or personal pronouns. Results showed that patients with functional amnesia tended to use general pronouns, whereas patients with TGA preferentially used the first person. The link between I-self and depersonalization-derealisation tendencies was also explored, showing dissociative tendencies in patients with functional amnesia but not in patients with TGA. We discuss these results from a combined neuropsychological and psychopathological perspective, with a view to proposing an explanatory model of the links between self-awareness and the episodic component of autobiographical memory.

Cutaneous and Mixed Nerve Silent Period Recordings in Symptomatic Paroxysmal Kinesigenic Dyskinesia.

OBJECTIVE: The underlying neurophysiologic mechanism responsible for secondary paroxysmal kinesigenic dyskinesia (PKD) is still unclear. Here, we study the pathogenesis of PKD in two patients with a demyelinating lesion in the spinal cord. METHODS: Electromyogram recordings from affected arms of two patients with spinal cord lesions presenting PKD were compared with our laboratory standards. The cutaneous silent period (CuSP), mixed nerve silent period (MnSP) and coincidence period (CiP), defined as the common period between the CuSP and MnSP, were recorded. RESULTS: A large decrease in the MnSP and disappearance of the CiP were observed in our patients, which was secondary to simultaneous extinction of the third portion of the MnSP, while the CuSP was normal. The MnSP and CiP were normal after recovery. CONCLUSIONS: Our results demonstrate that the third portion of the MnSP and the CuSP do not correspond to the same physiologic process. These findings suggest that PKD patients have abnormal spinal interneuron integration.