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Journal of the Peripheral Nervous... Jun 2022Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were... (Review)
Review
BACKGROUND AND AIMS
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were described in populations with Caucasian ancestry, genetic research on CMT in Africa is scant. Only a few cases of CMT have been reported, mainly from North Africa. The current study aimed to summarise available data on CMT in Africa, with emphasis on the epidemiological, clinical, and genetic features.
METHODS
We searched PubMed, Scopus, Web of Sciences, and the African Journal Online for articles published from the database inception until April 2021 using specific keywords. A total of 398 articles were screened, and 28 fulfilled our selection criteria.
RESULTS
A total of 107 families totalling 185 patients were reported. Most studies were reported from North Africa (n = 22). The demyelinating form of CMT was the commonest subtype, and the phenotype varied greatly between families, and one family (1%) of CMT associated with hearing impairment was reported. The inheritance pattern was autosomal recessive in 91.2% (n = 97/107) of families. CMT-associated variants were reported in 11 genes: LMNA, GDAP1, GJB1, MPZ, MTMR13, MTMR2, PRX, FGD4/FRABIN, PMP22, SH3TC2, and GARS. The most common genes reported are LMNA, GDAP1, and SH3TC2 and have been found mostly in Northern African populations.
INTERPRETATION
This study reveals that CMT is not rare in Africa, and describes the current clinical and genetic profile. The review emphasised the urgent need to invest in genetic research to inform counselling, prevention, and care for CMT in numerous settings on the continent.
Topics: Africa; Charcot-Marie-Tooth Disease; Genes, Recessive; Humans; Microfilament Proteins; Mutation; Phenotype; Proteins
PubMed: 35383421
DOI: 10.1111/jns.12489 -
Neurology. Clinical Practice Dec 2020Migraine is a common and often refractory feature for individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy... (Review)
Review
BACKGROUND
Migraine is a common and often refractory feature for individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) without consensus guidelines for treatment. Migraine treatment poses a theoretical risk within this unique population with precarious cerebrovascular autoregulation, given the vasomodulatory influence of many antimigraine medications. In this systematic review and meta-analysis, we evaluate the frequency and efficacy of treatments for migraine in individuals with CADASIL.
METHODS
A search protocol was designed to include all available publications reporting antimigraine therapies for CADASIL. Individual responses to medications were categorized as unfavorable, neutral, or favorable. Responses across medication classes were compared using the Mann-Whitney test.
RESULTS
Thirteen studies were included, yielding a cohort of 123 individuals with a median age of 53 years (range: 23-83 years), with 61% (75/123) being women. No controlled trials were identified. Simple analgesics (35.8%, 44/123) and beta-blockers (22.0%, 27/123) were the most common abortive and prophylactic strategies, respectively. Over half (54.4%) of all patients had used more than 1 medication sequentially or concomitantly. Beta-blockers were significantly associated with a neutral or unfavorable response (13.5%, 22/163, = 0.004). We found no significant associations among other medication categories.
CONCLUSIONS
Migraine in CADASIL remains a formidable therapeutic challenge, with patients often tried on several medications. Antimigraine prophylaxis with beta-blockers may be contraindicated relative to other common therapies in CADASIL. Controlled studies are needed to rigorously evaluate the safety and efficacy of antimigraine therapies in this population.
PubMed: 33520412
DOI: 10.1212/CPJ.0000000000000769 -
The Cochrane Database of Systematic... Apr 2021Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one...
BACKGROUND
Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one of the globin chains that make up haemoglobin. In β-thalassaemia there is an underproduction of β-globin chains combined with excess of free α-globin chains. The excess free α-globin chains precipitate in red blood cells, leading to their increased destruction (haemolysis) and ineffective erythropoiesis. The conventional treatment is based on the correction of haemoglobin through regular red blood cell transfusions and treating the iron overload that develops subsequently with iron chelation therapy. Although, early detection and initiations of such supportive treatment has improved the quality of life for people with transfusion-dependent thalassaemia, allogeneic hematopoietic stem cell transplantation is the only widely available therapy with a curative potential. Gene therapy for β-thalassaemia has recently received conditional authorisation for marketing in Europe, and may soon become widely available as another alternative therapy with curative potential for people with transfusion-dependent thalassaemia. This is an update of a previously published Cochrane Review.
OBJECTIVES
To evaluate the effectiveness and safety of different types of hematopoietic stem cell transplantation, in people with transfusion-dependent β-thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of the most recent search: 07 April 2021.
SELECTION CRITERIA
Randomised controlled trials and quasi-randomised controlled trials comparing hematopoietic stem cell transplantation with each other or with standard therapy (regular transfusion and chelation regimen).
DATA COLLECTION AND ANALYSIS
Two review authors independently screened trials and had planned to extract data and assess risk of bias using standard Cochrane methodologies and assess the quality using GRADE approach, but no trials were identified for inclusion in the current review.
MAIN RESULTS
No relevant trials were retrieved after a comprehensive search of the literature.
AUTHORS' CONCLUSIONS
We were unable to identify any randomised controlled trials or quasi-randomised controlled trials on the effectiveness and safety of different types of hematopoietic stem cell transplantation in people with transfusion-dependent β-thalassaemia. The absence of high-level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately-powered, randomised controlled clinical trials.
Topics: Hematopoietic Stem Cell Transplantation; Humans; beta-Thalassemia
PubMed: 33880750
DOI: 10.1002/14651858.CD008708.pub5 -
Movement Disorders Clinical Practice Nov 2022Cerebellar ataxias comprise a large group of heterogeneous disorders with both motor and non-motor symptoms (NMS). (Review)
Review
BACKGROUND
Cerebellar ataxias comprise a large group of heterogeneous disorders with both motor and non-motor symptoms (NMS).
OBJECTIVE
We wanted to ascertain the reported prevalence of NMS in different subtypes of hereditary cerebellar ataxias.
METHODS
Systematic review of studies of hereditary cerebellar ataxias (involving >5 patients) who were assessed for NMS, published in the English literature in PUBMED and EMBASE databases from 1947 to 2021.
RESULTS
A total of 35 papers, with data from 1311 autosomal dominant spinocerebellar ataxia (SCA), 893 autosomal recessive cerebellar ataxia (ARCA), and 53 X-linked ataxia cases were included with a total of 450 controls. Mean age for SCA cases at diagnosis was 47.6 (SD, 14.9) years, for ARCA cases was 34.6 (SD, 14.7) years and for X-linked ataxia cases was 68.6 (9.1) years. The prevalence of cognitive problems in SCAs was between 23% and 75% (ranging from mild to severe), being least prevalent in SCA6. The prevalence of depression in SCAs was between 13% and 69% and sleep disorders were between 7% and 80%. Pain was reported by 18% to 60% of patients, especially in SCA3, and fatigue by 53% to 70%. The prevalence of reported cognitive dysfunction in ARCA was 12.5% to 100% and depression between 14% and 51%. The prevalence of anxiety in X-linked ataxias (FXTAS) was 17 % and depression 55%.
CONCLUSIONS
The presence of NMS in hereditary cerebellar ataxias is common. The prevalence and spectrum of NMS in SCAs, ARCAs, and X-linked ataxias vary. In routine clinical practice, NMS in cerebellar ataxias are under-recognized and certainly under-reported. Therefore, they are unlikely to be addressed adequately. Improved ascertainment of NMS in cerebellar ataxias in clinical practice will enable holistic treatment of these patients.
PubMed: 36339305
DOI: 10.1002/mdc3.13532 -
PharmacoEconomics Apr 2022Spinal muscular atrophy (SMA) is a severe neuromuscular disease that is inherited in an autosomal recessive manner with an estimated incidence of 1 in 10,000 live...
BACKGROUND
Spinal muscular atrophy (SMA) is a severe neuromuscular disease that is inherited in an autosomal recessive manner with an estimated incidence of 1 in 10,000 live births. The traditional classification of SMA includes five types (Types 0-4 SMA) based on patient age at disease onset and the highest motor milestone achieved. Spinal muscular atrophy leads to progressive muscle denervation, skeletal muscle atrophy and loss of motor function and ambulation, though phenotypes vary along a disease continuum. Regardless of disease severity, or access to treatment, a multidisciplinary approach to care is required to ease the burden of disease. To date, limited global data exist regarding the cost and resource use associated with SMA management.
OBJECTIVE
We planned to perform a systematic literature review to identify studies on cost and healthcare resource use associated with SMA.
METHODS
A comprehensive search was conducted in 2019 using several electronic databases in addition to supplementary sources and updated in 2021 in order to capture recently published studies. Electronic searches performed in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform were supplemented by searches of the grey literature (reference lists, conference proceedings, global Health Technology Assessment body websites and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full-text publications was evaluated with reference to a published checklist. To accommodate heterogeneity across studies including countries, currencies, populations, time units and methods of reporting used, costs were reported in Euros in 2019.
RESULTS
A total of 51 publications, comprising 49 unique studies of patients with SMA that met all eligibility criteria were included in the final selection. The publications comprised data from 14 countries and seven additional studies that reported multi-national data. Because of the heterogeneity between the different types of SMA, data were frequently reported separately for individuals with Type 1 or early-onset SMA and for Types 2, 3, and 4 SMA or later-onset SMA. Generally, direct medical costs and resource use were reported to be highest for patients with Type 1 SMA, decreasing incrementally for patients with Type 2 and Type 3 disease. Where cost categories were similar, direct costs were much lower in Europe than in the USA. Indirect costs were primarily associated with informal care, which was a substantial burden on patients and families in terms of both cost and time. Cost drivers were generally found to be dependent on SMA type.
CONCLUSIONS
Long-term robust studies are required to fully elucidate the economic burden of SMA. Considering that motor function can vary broadly, especially in Type 2 SMA, it would be beneficial to understand how costs and resource use are affected by different degrees of ambulation. Reporting data in terms of achieved motor function could also mitigate the challenges of comparing global data studies of small populations. Global, regional, and/or local data collection platforms and disease registry networks could play an important role in helping to address current data gaps.
Topics: Costs and Cost Analysis; Europe; Humans; Muscular Atrophy, Spinal; Spinal Muscular Atrophies of Childhood; Technology Assessment, Biomedical
PubMed: 34761360
DOI: 10.1007/s40273-021-01105-7 -
Genetics in Medicine : Official Journal... Nov 2021Mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma are rare autosomal recessive lysosomal storage disorders. Data on the natural course of the diseases are scarce....
PURPOSE
Mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma are rare autosomal recessive lysosomal storage disorders. Data on the natural course of the diseases are scarce. These data are important for counseling, therapies development, and improvement of outcome. The aim of this study is to gain knowledge on the natural history of ML by obtaining data on survival, symptom onset, presenting symptoms, diagnosis, and pathogenic variants associated with the MLII or MLIII phenotype.
METHODS
A systematic review on all published MLII and MLIII cases between 1968 and August 2019 was performed.
RESULTS
Three hundred one articles provided data on 843 patients. Median age at diagnosis: 0.7 for MLII and 9.0 years for MLIII. Median survival: 5.0 for MLII and 62.0 years for MLIIIII. Median age of death: 1.8 for MLII and 33.0 years for MLIII. Most frequent causes of death in all ML were pulmonary and/or cardiac complications. Pathogenic variants were described in 388 patients (GNPTAB: 571, GNPTG 179).
CONCLUSION
This review provides unique insights into the natural history of MLII and MLIII, with a clear genotype-phenotype correlation with the most frequent pathogenic variant c.3503_3504del in MLII and in MLIII alpha/beta c.22A>G for GNPTAB. All pathogenic GNPTG variants resulted in MLIII gamma.
Topics: Genetic Association Studies; Humans; Mucolipidoses; Phenotype; Transferases (Other Substituted Phosphate Groups)
PubMed: 34172897
DOI: 10.1038/s41436-021-01244-4 -
Frontiers in Genetics 2021Mutations in the STRC (MIM 606440) gene, inducing DFNB16, are considered a major cause of mild-moderate autosomal recessive non-syndromic hearing loss (ARNSHL). We...
Mutations in the STRC (MIM 606440) gene, inducing DFNB16, are considered a major cause of mild-moderate autosomal recessive non-syndromic hearing loss (ARNSHL). We conducted a systematic review and meta-analysis to determine the global prevalence and characteristics of STRC variations, important information required for genetic counseling. PubMed, Google Scholar, Medline, Embase, and Web of Science were searched for relevant articles published before January 2021. The pooled prevalence of DFNB16 in GJB2-negative patients with hearing loss was 4.08% (95% CI: 0.0289-0.0573), and the proportion of STRC variants in the mild-moderate hearing loss group was 14.36%. Monoallelic mutations of STRC were 4.84% (95% CI: 0.0343-0.0680) in patients with deafness (non-GJB2) and 1.36% (95% CI: 0.0025-0.0696) in people with normal hearing. The DFNB16 prevalence in genetically confirmed patients (non-GJB2) was 11.10% (95% CI: 0.0716-0.1682). Overall pooled prevalence of deafness-infertility syndrome (DIS) was 36.75% (95% CI: 0.2122-0.5563) in DFNB16. The prevalence of biallelic deletions in STRC gene mutations was 70.85% (95% CI: 0.5824-0.8213). Variants in the STRC gene significantly contribute to mild-moderate hearing impairment. Moreover, biallelic deletions are a main feature of STRC mutations. Copy number variations associated with infertility should be seriously considered when investigating DFNB16.
PubMed: 34621290
DOI: 10.3389/fgene.2021.707845 -
International Journal of Molecular... Feb 2023Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and... (Review)
Review
Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.
Topics: Animals; Adult; Humans; Myotonic Dystrophy; Phosphorylation; Alternative Splicing; RNA, Messenger; Muscular Atrophy; Muscle, Skeletal
PubMed: 36834509
DOI: 10.3390/ijms24043091 -
Genes Jul 2023(1) Background: encodes a nuclear receptor transcription factor that is considered to promote cell differentiation, affect retinal development, and regulate...
(1) Background: encodes a nuclear receptor transcription factor that is considered to promote cell differentiation, affect retinal development, and regulate phototransduction in rods and cones. This study aimed to analyze the clinical characteristics and observe the prognosis of autosomal dominant retinopathy (ADRP) and autosomal recessive retinopathy (ARRP) associated with ; (2) Methods: variants were collected from our exome sequencing data and identified per the American College of Medical Genetics and Genomics criteria. Data from our cohort and a systemic literature review were conducted to explore the variants spectrum and potential genotype-phenotype correlations; (3) Results: Nine pathogenic variants/likely pathogenic variants in , including five novel variants, were detected in eight families (four each with ADRP and ARRP). Follow-up data showed schisis/atrophy in the macula and retinal degeneration initiation around the vascular arcades with differences in ADRP and ARRP. A systemic literature review indicated patients with ADRP presented better visual acuity ( < 0.01) and later onset age ( < 0.0001) than did those with ARRP; (4) Conclusions: Macular schisis and retinal degeneration around vascular arcades may present as the prognosis of -retinopathy, dominant, or recessive. Our data might further enrich our understanding of variants and associated inherited retinopathy.
Topics: Humans; Atrophy; Longitudinal Studies; Orphan Nuclear Receptors; Retinal Degeneration
PubMed: 37628579
DOI: 10.3390/genes14081525 -
Brain and Behavior Jun 2023Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically... (Review)
Review
BACKGROUND
Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically proven, isolated dystonia syndrome. However, its pathophysiology remains unclear.
OBJECTIVES
This study was aimed at profiling the functional neuroimaging findings in DYT1 dystonia and harmonizing the pathophysiological implications for DYT1 dystonia from the standpoint of different neuroimaging techniques.
METHODS
A systematic review was conducted using identified studies published in English from Medline, PsycINFO, Embase, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR), between 1985 and December 2019 (PROSPERO protocol CRD42018111211).
RESULTS
All DYT1 gene carriers irrespective of clinical penetrance have reduced striatal GABA, dopamine receptors and increased metabolic activity in the lentiform nucleus, supplementary motor area, and cerebellum in addition to an abnormal cerebellothalamocortical pathway. Nonmanifesting carriers on the other hand have a disruption of the distal (thalamocortical) segment and have larger putaminal volumes than manifesting carriers and healthy controls. Activation of the midbrain, thalamus, and sensorimotor cortex was only found in the manifesting carriers.
CONCLUSIONS
Therefore, we propose that DYT1 dystonia is a cerebellostriatothalamocortical network disorder affecting either the structure or function of the different structures or nodes in the network.
Topics: Humans; Dystonia; Dystonic Disorders; Molecular Chaperones; Neuroimaging
PubMed: 37165749
DOI: 10.1002/brb3.3023