There are few reports on pregnancies in sporadic and familial amyotrophic lateral sclerosis (ALS). We report on a young woman with sporadic ALS who gave birth twice during the course of her disease. The first pregnancy occurred 13 months after the onset of symptoms, and one month after diagnosis. The pregnancy was uncomplicated and resulted in vaginal delivery of a healthy boy. Fifteen months later, when she was already bed-ridden, she became pregnant again. She received a percutaneous endoscopic gastrostomy in the 21st gestational week and underwent early Caesarean section in the 34th week of gestation. The child was ventilated for 72 h in a neonatological unit. The patient was tracheotomized and ventilated two months later, i.e. 47 months after symptom onset, and died nine months later from gastrointestinal haemorrhage. Her two children have developed without abnormalities to date. This case confirms that pregnancies in early-stage ALS can develop normally and may result in uncomplicated vaginal delivery. Pregnancies in late stages may be critical for mother and child, and early delivery by Caesarean section may become necessary although neonatal outcome can be good.
We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
The hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant genetic disease characterized by amyloid formation in different tissues due to pathogenic variants in the TTR gene. Great heterogeneity in the penetrance and manifestation of ATTRv amyloidosis is observed. In Bulgaria, the most common TTR pathogenic variant is Glu89Gln. Other TTR pathogenic variants are also found - Val30Met, Ser77Phe, Gly47Glu and Ser52Pro. There is a proven founder effect for the Glu89Gln variant, thus the aim of the present study is to investigate the founder effect for the other TTR pathogenic variants in Bulgaria. Haplotype analysis was performed by using microsatellite markers close to the TTR gene. DNA samples from ATTRv amyloidosis patients and their healthy relatives were analyzed. Theoretical haplotype reconstruction was done with Arlequin v.3.01 software. The age of the most recent common ancestor (hypothetical founder) for the studied variants was calculated with the DMLE 2.2 software. In addition, DBS screening among 100 Roma newborns was done for the Gly47Glu TTR variant via direct Sanger sequencing. The reconstructed haplotypes of the patients were compared to their healthy relatives and to a control group of 40 healthy individuals. The results showed a possible founder effect for each of the studied variants. The Val30Met haplotype was compared to published haplotype data for this variant and no similarity was found. The result from the DBS screening showed no pathogenic TTR variants in exon 2 of the gene, so we considered the presence of the Gly47Glu variant in our population a sporadic event. With this study, we succeeded to gain a more complete picture of the population genetics of ATTRv amyloidosis in Bulgaria and made another step towards a more detailed understanding of the disease epidemiology.
Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy ((ATTR-CM), caused by an extracellular deposition of insoluble amyloid fibrils in the myocardium. It is a life threatening disease with life expectancy of 2 to 6 years after diagnosis. There are two types – hereditary and wild type. Recent data reveal that the wild type ATTR-CM is a common cause of heart failure with preserved ejection fraction, especially in elderly men. Hereditary ATTR amyloidosis is not so rare in Bulgaria. Five different mutations have been diagnosed, the most common being p.Glu89Gln, identified in 62 unrelated families with 117 patients and 72 mutation carriers. ATTR-CM diagnosis is often delayed or even missed, however its early recognition has become very important as a new drug, which is a transthyretin stabilizer is now available and other drugs are under development. Updated knowledge about the clinical presentation, diagnostic algorithm, available and future therapeutic options for ATTR-CM are a prerequisite for an early identification, timely treatment and better prognosis of the affected patients. The diagnosis requires a multidisciplinary approach with the participation of experienced specialists, multimodality imaging, well equipped histopathological and genetic laboratories. Establishing centres of expertise could improve the management of the patients with ATTR-CM.
Transthyretin amyloid (ATTR) amyloidosis is an adult-onset, rare systemic disorder characterized by the accumulation of misfolded fibrils in the body, including the peripheral nerves, the heart and the gastrointestinal tract. Gastrointestinal manifestations are common in hereditary (ATTRv) amyloidosis and are present even before the onset of the polyneuropathy in some cases. Delays in diagnosis of ATTRv amyloidosis with gastrointestinal manifestations commonly occur because of fragmented knowledge among gastroenterologists and general practitioners, as well as a shortage of centers of excellence and specialists dedicated to disease management. Although the disease is becoming well-recognized in the societies of Neurology and Cardiology, it is still unknown for most gastroenterologists. This review presents the recommendations for ATTRv amyloidosis with gastrointestinal manifestations elaborated by a working group of European gastroenterologists and neurologists, and aims to provide digestive health specialists with an overview of crucial aspects of ATTRv amyloidosis diagnosis to help facilitate rapid and accurate identification of the disease by focusing on disease presentation, misdiagnosis and management of gastrointestinal symptoms.
Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24–3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
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