His108Arg Transthyretin Amyloidosis-Shedding Light on a Distinctively Malignant Variant.

Variant transthyretin amyloidosis cardiomyopathy (ATTRv-CM) is a rare form of cardiac amyloidosis associated with many possible mutations in the transthyretin gene, presenting as various distinct clinical phenotypes. Among these, the His108Arg mutation is the most prevalent TTR variant in Austria. However, data describing its clinical phenotype are lacking.

Reduction in Tc-DPD myocardial uptake with therapy of ATTR cardiomyopathy.

Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). We aimed to determine the impact of RNAi therapeutics on myocardial amyloid load using quantitative single photon emission computed tomography/computed tomography (SPECT/CT) imaging in patients with ATTRv-related cardiomyopathy (ATTRv-CM). We furthermore compared them with wild-type ATTR-CM (ATTRwt-CM) patients treated with tafamidis.

Genetic pain loss disorders.

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks.

Convolutional Neural Networks for Fully Automated Diagnosis of Cardiac Amyloidosis by Cardiac Magnetic Resonance Imaging.

Aims: We tested the hypothesis that artificial intelligence (AI)-powered algorithms applied to cardiac magnetic resonance (CMR) images could be able to detect the potential patterns of cardiac amyloidosis (CA). Readers in CMR centers with a low volume of referrals for the detection of myocardial storage diseases or a low volume of CMRs, in general, may overlook CA. In light of the growing prevalence of the disease and emerging therapeutic options, there is an urgent need to avoid misdiagnoses.

Diagnosis and treatment of cardiac amyloidosis: an interdisciplinary consensus statement.

The prevalence and significance of cardiac amyloidosis have been considerably underestimated in the past; however, the number of patients diagnosed with cardiac amyloidosis has increased significantly recently due to growing awareness of the disease, improved diagnostic capabilities and demographic trends. Specific therapies that improve patient prognosis have become available for certain types of cardiac amyloidosis. Thus, the earliest possible referral of patients with suspicion of cardiac amyloidosis to an experienced center is crucial to ensure rapid diagnosis, early initiation of treatment, and structured patient care.

The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on .

Objective: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.

Methods: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and single-gene sequencing (n = 104). We further queried WES repositories for variants and measured blood levels of the -encoded protein neprilysin.

Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots.

Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin () gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory.

Chance or challenge, spoilt for choice? New recommendations on diagnostic and therapeutic considerations in hereditary transthyretin amyloidosis with polyneuropathy: the German/Austrian position and review of the literature.

Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTR) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America.

Author Correction: Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum.

Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family.

Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8 T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8 T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses.

Neuropathy-causing mutations in HSPB1 impair autophagy by disturbing the formation of SQSTM1/p62 bodies.

HSPB1 (heat shock protein family B [small] member 1) is a ubiquitously expressed molecular chaperone. Most mutations in HSPB1 cause axonal Charcot-Marie-Tooth neuropathy and/or distal hereditary motor neuropathy. In this study we show that mutations in HSPB1 lead to impairment of macroautophagic/autophagic flux.

Development and validation of a TTR-specific copy number screening tool, and application to potentially relevant patient cohorts.

TTR amyloidosis (ATTR) is a fatal condition caused by extracellular deposits of misfolded transthyretin. Patients often present with cardiac disease, but manifestations may also involve other organs including the peripheral nervous system. ATTR is considered familial when heterozygous mutations in the TTR gene are present (ATTRmutant or ATTRm), or acquired when no TTR aberrations are detected (ATTRwildtype or ATTRwt).

Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease.

The small heat shock protein HSPB1 (Hsp27) is an ubiquitously expressed molecular chaperone able to regulate various cellular functions like actin dynamics, oxidative stress regulation and anti-apoptosis. So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Most mutations in HSPB1 target its highly conserved α-crystallin domain, while other mutations affect the C- or N-terminal regions or its promotor.

Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy.

Tibial muscular dystrophy (TMD) is the first described human titinopathy. It is a mild adult-onset slowly progressive myopathy causing weakness and atrophy in the anterior lower leg muscles. TMD is caused by mutations in the last two exons, Mex5 and Mex6, of the titin gene (TTN).

Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies.

Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained.

Whole exome sequencing in congenital pain insensitivity identifies a novel causative intronic NTRK1-mutation due to uniparental disomy.

Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents. No mutations in known HSAN genes were identified.