Challenges in Genetic Diagnosis of Mitochondrial Diseases: What Can Functional Genomics' Studies Do?

Introduction: Mitochondrial oxidative phosphorylation (OXPHOS) diseases are challenging both from clinical and therapeutic perspectives. The advent of next-generation sequencing (NGS) boosted the discovery of new genetic defects affecting OXPHOS, with pathogenic variants identified in >350 genes to date [1]. However, in many patients, novel variants of unknown clinical significance are found.

Posterior semicircular canal cupulolithiasis during acute pontomedullary demyelination.

Positional vertigo poses a diagnostic challenge in people with multiple sclerosis (MS). The characteristics of positional nystagmus and its response to repositioning manoeuvres are usually sufficient to diagnose benign paroxysmal positional vertigo (BPPV). However, certain BPPV variants respond poorly to repositioning manoeuvres and their nystagmus pattern can resemble that of central positional vertigo caused by infratentorial demyelination.

Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

Background: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare.

Methods: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019.

GenEye24: Novel rapid screening test for the top-3 Leber's Hereditary Optic Neuropathy pathogenic sequence variants.

Leber's Hereditary Optic Neuropathy (LHON) has been mainly (90-95 %) associated to one of three variants: m.3460G>A, m.11778G>A, m.

TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey.

Generation and Characterization of Novel iPSC Lines from a Portuguese Family Bearing Heterozygous and Homozygous Mutations.

Mutations in granulin () have been associated with neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). In Portugal, mutations account for around half of all FTLD cases with known genetic origin. Here, we describe the generation and characterization of three human-induced pluripotent stem cell (hiPSC) lines from a Portuguese family harboring heterozygous and homozygous mutation.

Posttranslational modifications of proteins are key features in the identification of CSF biomarkers of multiple sclerosis.

Background: Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system (CNS) characterized by demyelination and concomitant axonal loss. The lack of a single specific test, and the similarity to other inflammatory diseases of the central nervous system, makes it difficult to have a clear diagnosis of multiple sclerosis. Therefore, laboratory tests that allows a clear and definite diagnosis, as well as to predict the different clinical courses of the disease are of utmost importance.

PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency.

Identification of a novel deletion in SURF1 gene: Heterogeneity in Leigh syndrome with COX deficiency.

Leigh syndrome (LS) is a rare, progressive neurodegenerative mitochondrial disorder of infancy. It is a genetically heterogeneous disease. The mutations in SURF1 gene are the most frequently known cause.

Neuromyelitis optica in Portugal (NEMIPORT) - A multicentre study.

Background: Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease of the CNS. There have been few epidemiologic studies on NMO, none in Portugal.

Objective: To analyze the clinical, biological and MRI characteristics from a cohort of Portuguese patients who fulfilled the Wingerchuk 2006 NMO/NMOSD criteria.