Autosomal dominant hypocalcemia, caused by activating mutations of the calcium-sensing receptor (CASR) gene, is characterized by hypocalcemia with an inappropriately low concentration of parathyroid hormone (PTH). In this report, we describe the identification of a novel missense mutation in the CASR gene, in a boy with autosomal dominant hypocalcemia. Polymerase chain reaction (PCR)-single strand and DNA sequencing revealed a heterozygous mutation in CASR gene that causes a leucine substitution for serine at codon 123 (p.Leu123Ser). This mutation was absent in DNA from 50 control patients. In silico studies suggest that the identified variant was likely pathogenic. Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected. Clinical manifestations of the index case started with seizures at 14 months of age; cognitive impairment and several neuropsychological disabilities were noted during childhood. Extrapyramidal signs and basal ganglia calcification developed later, namely, hand tremor and rigidity at the age of 7 and 18 years, respectively. Laboratory analysis revealed hypocalcemia, hyperphosphatemia, and low-serum PTH with hypomagnesemia and mild hypercalciuria. After 2 years of treatment with calcium supplements and calcitriol, some brief periods of clinical improvement were reported; as well as an absence of nephrocalcinosis.
Late-life psychosis presents a challenge, wherein a wide range of differential diagnoses should be considered. Very late-onset schizophrenia-like psychosis (VLOSLP) is a nosological entity that remains a conundrum. We provide a comprehensive literature review on the neurobiological underpinnings of VLOSLP. We describe a case that typifies the clinical presentation of VLOSLP. Although not pathognomonic, certain features, namely the two-stage progression of psychotic episode, partition delusions, multimodal hallucinations, and absent formal thought disorder or negative symptoms, are quite suggestive of VLOSLP. Several medical causes that might cause late-life psychosis, including neuroinflammatory/immunology diseases, were ruled out. Neuroimaging revealed basal ganglia lacunar infarctions along with chronic white matter small-vessel ischemic disease. The diagnosis of VLOSLP is based on clinical evidence, and the aforementioned clinical features support this diagnostic hypothesis. This case adds to the growing body of evidence pertaining to the relevance of cerebrovascular risk factors in the pathophysiology of VLOSLP, alongside age-specific neurobiological processes. We hypothesized that microvascular brain lesions disrupt the frontal-subcortical circuitry and uncover other core neuropathological processes. Future research should focus on identifying a specific biomarker that would allow clinicians to more accurately diagnose VLOSLP, differentiate it from other overlapping clinical entities such as dementia or post-stroke psychosis, and provide a tailored treatment for the patient.
Visual Hallucinations (VH) are a common psychiatric symptom of Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). According to the Perception-Attention Deficits Model, VH stem from impaired perceptual (bottom-up), including dorsal (DVS) and ventral visual streams (VVS), and attentional (top-down) processes, with a persistent Default Mode Network (DMN) activity and a dysfunctional imbalance of Dorsal (DAN) and Ventral Attentional Networks (VAN).We review the literature on the neurobiological underpinnings of VH in DLB and PD, concerning overlapping and different mechanisms.In DLB hallucinators, PET-scan findings of disconnection between higher and primary visual areas and dysfunctional recruitment of the VVS, corroborate other imaging and neuropathologic studies which document inferior longitudinal fasciculus damage and increased temporal lobe Lewy body (LB) pathology. The alteration of network topography is more pronounced in the DAN and DMN. The involvement of anterior cortical regions, clustering around attentional networks, is demonstrated in neuropathologic, volumetric and perfusion studies. VH severity closely correlates with anterior cingulate cortex and inferior temporal cortex hypoperfusion, structural changes in the DVS (superior parietal gyrus and precuneus) and increased diffusivity of the right thalamic projections to parieto-occipital cortices. Thalamocortical dysfunction alongside decreased cholinergic activity in reticular nucleus, which receive projections from the nucleus basalis of Meynert, seems to play a crucial role.Both DLB and demented PD hallucinators have more frontal cortical atrophy, yet greater in DLB, supporting top-down mechanisms.Regarding PD hallucinators, findings of cortical atrophy in inferior parietal lobule, cuneus, lingual lobule, and precentral gyrus correlated with hallucination scores. However, some studies did not evidence volumetric cortical differences between hallucinators and non-hallucinators. Moreover, LB are not necessarily present in hallucinators, suggesting other neuropathologic mechanisms in the genesis of VH, namely altered neurochemical circuitry. Volume loss in pedunculopontine nucleus and right-thalamus support the hypothesis of a dysfunctional cholinergic brainstem control of the cortex. PET-scan studies discovered higher 5-HT2A receptor levels in the inferolateral temporal and prefrontal cortices. A greater nigrostriatal impairment is documented in the right-caudate of hallucinators. Therefore, VH may arise from an inability to activate DAN (in which caudate is involved) and consequent faulty visuo-perceptual processing by DMN and VAN.
IntroductionAssessment of neuropsychiatric sequelae of traumatic brain injury (TBI) brings about challenges in the forensic setting, comprising analysis of neurobiological variables, preinjury variables (personality/psychiatric disturbances), postinjury psychosocial, allowing the expert witness to provide clear and appropriate explanations, so the court can decide with justice, particularly in civil law cases.ObjectivesDiscuss the main clinical and neuroimagiologic aspects to consider in civil litigation of TBI cases.MethodsComprehensive literature review.ResultsAlthough accurate predictions are difficult, some generalizations can be made. Recovery from hypoxic and diffuse axonal injury (DAI) takes longer and is less complete than focal contusions. Posttraumatic amnesia is the main predictor of long-term cognitive outcome. In moderate/severe TBI (m/sTBI) occurs chronic lesion expansion (axonal degeneration) and brain atrophy. DAI topography determinates the cognitive disfunction pattern yet underestimated in conventional neuroimaging. Diffusion-Tension-Imaging (DTI) may be valuable to outcome predictions in m/sTBI: structural disconnection within the Default Mode and the Salience Networks are linked to attention and executive impairments; hippocampus and fornix damage correlates with memory/learning impairments. Conversely, DTI findings can be misleading in mild TBI (mTBI), and case-by-case analysis seldomly prove its scientific validity.ConclusionsTo elaborate formulations within reasonable medical certainty, outcome predictions should not be made until at least six months following the TBI, considering that most mTBI symptoms resolve in few months, and up to 1-½ years, when m/sTBI neuropathologic changes stabilize. The neurobiological underpinnings are fundamental for causality formulations, however atypical outcomes in mTBI are frequently predicated upon non–brain-injury psychiatric conditions and psychosocial factors.DisclosureNo significant relationships.
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