Manuel Melo-Pires

Clinico-Pathological Correlations of the Most Common Neurodegenerative Dementias

Neurodegenerative dementias are a group of neurological disorders characterized by deterioration in several cognitive domains in which there is selective and progressive loss of specific populations of neurons. The precise neurobiological basis for the different neurodegenerative dementias remains unknown. It is expected that different pathologies reflect different mechanisms, at least early in the neurodegeneration process. The next decades promise treatments directed to causes and mechanisms, bringing an outstanding challenge to clinicians due to heterogeneous clinical presentations with the same molecular pathology. The purpose of this brief review is to describe the key neuropathological features of the most common neurodegenerative dementias (Alzheimer disease, dementia with Lewy bodies and Parkinson’s disease dementia, and frontotemporal lobar degeneration) and the relationship with the clinical syndromes described in clinico-pathological studies. We expect this overview contributes for the understanding of this broad topic integrating the two ends of the spectrum: clinical and pathological.

New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing

Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis.

Acute hemorrhagic leukoencephalitis with severe brainstem and spinal cord involvement: MRI features with neuropathological confirmation.

Acute hemorrhagic leukoencephalitis (AHLE) is a rare and fulminant demyelinating disease considered to be the most severe form of acute disseminated encephalomyelitis (ADEM). A 70‐year‐old man was admitted to our emergency department (ED) after 1 week of unspecific abdominal symptoms and moderate fever in the first 3 days. Within the ED he developed a rapid onset coma and flaccid tetraparesis. Cerebrospinal fluid (CSF) analysis showed mild polymorphonuclear pleocytosis and magnetic resonance imaging (MRI) revealed supratentorial focal white matter lesions and diffuse involvement of the medulla and spinal cord. A presumptive diagnosis of ADEM was made and the patient was treated with corticosteroids followed by intravenous immunoglobulin. His neurological state did not improve and the MRI on day 8 after admission showed an increased number of lesions, mainly in the brainstem, with hemorrhagic foci. The patient died the following day and pathological features confirmed the diagnosis of AHLE. This is a unique presentation of a rare disease with detailed MRI characteristics and pathological confirmation. Although this condition is usually fatal, early recognition and aggressive therapeutic management can facilitate survival. J. Magn. Reson. Imaging 2011;33:957–961.

Acute ischemic stroke secondary to glioblastoma. A case report.

Glioblastoma is a malignant infiltrative glial tumor occurring most often over 50 years of age, with diverse clinical presentations. We describe a case of temporal lobe glioblastoma with a rare presentation as an acute ischemic stroke, discussing the imaging and histopathological findings, and reviewing the literature. A 77-year-old woman had sudden onset of left hemiparesis and hemihypoesthesia. The neuroradiological studies revealed an acute ischemic lesion in the right lenticulostriate arteries territory and a right anterior temporal lobe tumor, enhancing heterogeneously after contrast with enhancement of the right middle cerebral artery wall. Histopathological analysis of the resected temporal lesion revealed a glioblastoma multiforme with tumoral infiltration of the vascular wall. Glioblastoma should be considered in the etiology of acute ischemic stroke, where neuroimaging plays an important diagnostic role, enabling a more immediate therapeutic approach, with a consequent impact on survival.

DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology

Mutations in DJ-1 (encoded by PARK7) are a very rare cause of early-onset recessive Parkinsons disease. We describe a patient with early-onset parkinsonism, starting at the age of 22, with poor response to levodopa and additional features in progression (dystonia, pyramidal signs and dementia), who died when he was 49 years old. The neuropathological study showed severe substantia nigra and locus coeruleus neuronal loss, with diffuse Lewy body pathology (Lewy bodies, aberrant neurites, grain-like structures, spheroids and scattered glial pathology). Genetic analysis revealed a novel c.515T > A; p.L172Q mutation in the PARK7 gene. To evaluate the pathogenicity of this new mutation we explored DJ-1 expression levels in vitro showing a massive reduction in DJ-1 protein levels due to a highly unstable and rapidly degraded L172Q mutant. DJ-1 immunohistochemistry of brain tissue revealed no staining in our case. This is the first neuropathological report of a brain from DJ-1-linked parkinsonism that, although based on a single case study, suggests that DJ-1 mutations are causative of α-synucleinopathy. These results can help in the understanding of Parkinsons disease pathophysiology, promote research studies to increase the knowledge on the pathways involved in the neurodegeneration process, and pave the way for new therapeutic interventions.

New massive parallel sequencing approach improves the genetic characterization of congenital myopathies

Congenital myopathies (CMs) are a heterogeneous group of muscle diseases characterized by hypotonia, delayed motor skills and muscle weakness with onset during the first years of life. The diagnostic workup of CM is highly dependent on the interpretation of the muscle histology, where typical pathognomonic findings are suggestive of a CM but are not necessarily gene specific. Over 20 loci have been linked to these myopathies, including three exceptionally large genes (TTN, NEB and RYR1), which are a challenge for molecular diagnosis. We developed a new approach using massive parallel sequencing (MPS) technology to simultaneously analyze 20 genes linked to CMs. Assay design was based on the Ion AmpliSeq strategy and sequencing runs were performed on an Ion PGM system. A total of 12 patients were analyzed in this study. Among the 2534 variants detected, 14 pathogenic mutations were successfully identified in the DNM2, NEB, RYR1, SEPN1 and TTN genes. Most of these had not been documented and/or fully characterized, hereby contributing to expand the CM mutational spectrum. The utility of this approach was demonstrated by the identification of mutations in 70% of the patients included in this study, which is relevant for CMs especially considering its wide phenotypic and genetic heterogeneity.

Clinical, biochemical, molecular, and histological features of 65 Portuguese patients with mitochondrial disorders.

Mitochondrial disorders display remarkable genetic and phenotypic heterogeneity.

Freezing of gait--first motor manifestation in late infantile variant neuronal ceroid lipofuscinosis.

Freezing of gait is generally seen in adults with degenerative or vascular parkinsonism [1], being very uncommon in infants or children. Neuronal ceroid lipofuscinoses (NCL) comprise a large group of neurodegenerative lysosomal disorders clinically characterized by progressive loss of vision, psychomotor deterioration, epilepsy and early death [2]. Historically, classification has been based on age of onset, ultrastructural morphology of the storage material showed by electron microscopy and genetic defect [3]. In CLN6 disease, late infantile variant, the onset is between18 months to 8 years [2]. The most important clinical features are seizures andmotor deterioration, followed by myoclonus, speech impairment, ataxia and mental regression [2]. Here we present a boy with CLN6 disease and freezing as first motor symptom. The 8 year-old boy of Portuguese descent was born of nonconsanguineous parents, after unremarkable gestation and delivery. He had normal developmental milestones apart from a moderate delay in expressive language acquisition. By the age of 3 years he presented multiple generalized tonic clonic, myoclonic and atypical absences seizures. His epilepsy was refractory to treatment, despite adequate trials of multiple antiepileptic drugs. At 4 years he developed freezing of gait, in the absence of other parkinsonian signs. Freezing would appear when starting to walk, going through narrow passages or walking in open spaces (video segment one). All by himself he learned strategies to overcome freezing, like flexing his thigh when starting to walk (video segment one). He presented rapid motor deterioration and, a month later, was unable to walk without help. By that time he had a complex gait disorder, characterized by a mixture of freezing, apraxia, ataxia and postural instability (video segment two). Simultaneously visual impairment was detected. His condition declined over the years with language regression, blindness and appearance of pyramidal signs (spasticity, extensor plantar response) (video segment three). For a year he has his seizures controlled. He is currently bedridden, has almost no communication skills, and is being fed through a percutaneous gastrostomy.

Clinical, Neuropathological, and Genetic Characteristics of the Novel IVS9+1delG GRN Mutation in a Patient with Frontotemporal Dementia

Frontotemporal lobar degeneration (FTLD) refers to a clinically, pathologically, and genetically heterogeneous group of dementias that arises from the degeneration of the frontal and temporal lobes. Mutations in the progranulin gene (GRN) are a major cause of FTLD with TDP-43 inclusions. Herein, we describe the clinical, neuropathological, and genetic findings in a case of autosomal dominant behavioral variant of frontotemporal dementia (bvFTD) with asymmetrical parkinsonism and prominent visuospatial deficits that carries a novel GRN mutation. This case highlights important clinical characteristics that seem to be common in FTLD GRN-associated patients, such as asymmetrical parkinsonism and parietal symptoms, and that are correlated to the pathological involvement of striatum (rather than substantia nigra in our case) and parietal lobe. We also emphasize that plasma progranulin level can be useful to infer about the pathogenicity of new GRN mutations.

LAMA2 gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early‐onset muscle disease, caused by disease‐associated variants in the laminin‐α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2‐related muscular dystrophies (LAMA2‐MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease‐associated variants were identified in 86 patients, representing the largest number of patients and new disease‐causing variants in a single report. The collaborative variant collection was supported by the LOVD‐powered LAMA2 gene variant database (https://www.LOVD.nl/LAMA2), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease‐associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2‐MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late‐onset LAMA2‐MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases.