ABSTRACT
Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.
Subject(s)
Spinocerebellar Degenerations , Spinocerebellar Degenerations/diagnostic imaging , Spinocerebellar Degenerations/genetics , Spinocerebellar Degenerations/therapy , Fibroblast Growth Factors , Introns , Humans , Male , Female , Adult , Middle Aged , Aged , Brain/diagnostic imaging , Magnetic Resonance ImagingABSTRACT
We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.
Subject(s)
Amyotrophic Lateral Sclerosis , Muscular Atrophy, Spinal , Muscular Dystrophies, Limb-Girdle , Muscular Dystrophy, Duchenne , Myotonic Dystrophy , Registries , Adolescent , Adult , Aged , Aged, 80 and over , Canada , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Young AdultABSTRACT
Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index-4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index-4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.
Subject(s)
Leukoencephalopathies/psychology , Parents/psychology , Stress, Psychological/psychology , Adult , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Infant , Male , Pilot Projects , Surveys and QuestionnairesABSTRACT
AIMS: Previously, detection of ANO5 protein has been complicated by unspecific antibodies, most of which have not identified the correct protein. The aims of the study were to specify ANO5 protein expression in human skeletal muscle, and to investigate if the ANO5 protein levels are affected by different ANO5 mutations in anoctaminopathy patients. METHODS: Four different antibodies were tested for ANO5 specificity. A sample preparation method compatible with membrane proteins, combined with tissue fractionation was used to determine ANO5 expression in cell cultures expressing ANO5, in normal muscles and eight patient biopsies with six different ANO5 mutations in homozygous or compound heterozygous states, and in other dystrophies. RESULTS: Only one specific monoclonal N-terminal ANO5 antibody was efficient in detecting the protein, showing that ANO5 is expressed as a single 107 kD polypeptide in human skeletal muscle. The truncating mutations c.191dupA and c.1261C>T were found to abolish ANO5 expression, whereas the studied point mutations had variable effects; however, all the ANO5 mutations resulted in clearly reduced ANO5 expression in the patient muscle membrane fraction. Attempts to detect ANO5 using immunohistochemistry were not yet successful. CONCLUSIONS: The data presented here indicate that the ANO5 protein expression is decreased in ANO5-mutated muscular dystrophy and that most of the non-truncating pathogenic ANO5 mutations likely destabilize the protein and cause its degradation. The method described here allows direct analysis of human ANO5 protein, which can be used in diagnostics, for evaluating the pathogenicity of the potentially harmful ANO5 variants of uncertain significance.
Subject(s)
Anoctamins/analysis , Anoctamins/genetics , Anoctamins/metabolism , Muscular Dystrophies, Limb-Girdle/diagnosis , Muscular Dystrophies, Limb-Girdle/genetics , Antibodies, Monoclonal , Antibody Specificity , Blotting, Western/methods , Female , Humans , Male , MutationABSTRACT
An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
Subject(s)
Exome , Genes , Genetic Diseases, Inborn/diagnosis , Mutation , Sequence Analysis, DNA , Canada , Child , Genetic Diseases, Inborn/genetics , High-Throughput Nucleotide Sequencing , HumansABSTRACT
Expansion of polyalanine tracts causes at least nine inherited human diseases. Among these, a polyalanine tract expansion in the poly (A)-binding protein nuclear 1 (expPABPN1) causes oculopharyngeal muscular dystrophy (OPMD). So far, there is no treatment for OPMD patients. Developing drugs that efficiently sustain muscle protection by activating key cell survival mechanisms is a major challenge in OPMD research. Proteins that belong to the Wnt family are known for their role in both human development and adult tissue homeostasis. A hallmark of the Wnt signaling pathway is the increased expression of its central effector, beta-catenin (ß-catenin) by inhibiting one of its upstream effector, glycogen synthase kinase (GSK)3ß. Here, we explored a pharmacological manipulation of a Wnt signaling pathway using lithium chloride (LiCl), a GSK-3ß inhibitor, and observed the enhanced expression of ß-catenin protein as well as the decreased cell death normally observed in an OPMD cell model of murine myoblast (C2C12) expressing the expanded and pathogenic form of the expPABPN1. Furthermore, this effect was also observed in primary cultures of mouse myoblasts expressing expPABPN1. A similar effect on ß-catenin was also observed when lymphoblastoid cells lines (LCLs) derived from OPMD patients were treated with LiCl. We believe manipulation of the Wnt/ß-catenin signaling pathway may represent an effective route for the development of future therapy for patients with OPMD.
Subject(s)
Lithium Chloride/pharmacology , Lithium Chloride/therapeutic use , Muscular Dystrophy, Oculopharyngeal/drug therapy , Muscular Dystrophy, Oculopharyngeal/pathology , Wnt Signaling Pathway/drug effects , Animals , Cell Death/drug effects , Cell Differentiation/drug effects , Cell Line , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Green Fluorescent Proteins/metabolism , Humans , Lymphocytes/drug effects , Lymphocytes/metabolism , Mice , Muscular Dystrophy, Oculopharyngeal/metabolism , Mutant Proteins/metabolism , Myoblasts/drug effects , Myoblasts/metabolism , Myoblasts/pathology , Poly(A)-Binding Protein I/genetics , Poly(A)-Binding Protein I/metabolism , Protein Transport/drug effects , Trinucleotide Repeat Expansion/genetics , beta Catenin/metabolismABSTRACT
BACKGROUND: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. METHODS: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. RESULTS: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. CONCLUSIONS: The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.
Subject(s)
Genetic Predisposition to Disease/genetics , Heat-Shock Proteins/genetics , Muscle Spasticity/genetics , Mutation/genetics , Spinocerebellar Ataxias/congenital , Cohort Studies , DNA Mutational Analysis , Electromyography , Female , Heterozygote , Humans , Male , Muscle Spasticity/ethnology , Phenotype , Quebec , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spinocerebellar Ataxias/ethnology , Spinocerebellar Ataxias/geneticsABSTRACT
BACKGROUND: We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence. METHODS: Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region. RESULTS: All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c. 229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22. CONCLUSION: The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XIXth century, largely by Acadian immigrants.
Subject(s)
Muscular Dystrophies, Limb-Girdle/ethnology , Muscular Dystrophies, Limb-Girdle/genetics , Polymorphism, Single Nucleotide/genetics , Sarcoglycans/genetics , Adolescent , Adult , Aged , Canada/epidemiology , Canada/ethnology , Cohort Studies , Creatine Kinase/metabolism , DNA Mutational Analysis , Disease Progression , Female , France/ethnology , Gene Frequency , Genomics/methods , Genotype , Humans , Lordosis/etiology , Lung Diseases/etiology , Male , Middle Aged , Muscle, Skeletal/pathology , Muscular Dystrophies, Limb-Girdle/complications , Spain/ethnologyABSTRACT
OBJECTIVE: To assess the evolution and life expectancy in patients with oculopharyngeal muscular dystrophy (OPMD) who are homozygotes for two (GCN)13 expansions in the PABPN1 encoding gene. BACKGROUND: OPMD is particularly frequent among French Canadians (FCs) and Uzbek Jews (UJs), who carry a same size, (GCN)13, PABPN1 mutation. The high rate of consanguinity among UJs together with late disease onset and normal fertility results in homozygous cases. METHODS: For 15 to 20 years, we followed 4 FC and 6 UJ homozygotes with OPMD and compared them with their heterozygous parents and siblings. In addition to clinical evaluation, electrodiagnostic tests, psychological tests, and brain imaging studies were performed. RESULTS: In all (GCN)13-(GCN)13 patients, OPMD started before age 35 years, with bilateral ptosis and dysphagia; external ophthalmoparesis and dysphonia followed within a few years, as well as weakness in proximal limb muscles. All patients had recurrent aspirations and lost weight; 4 patients required surgical interventions to alleviate dysphagia, and 5 required feeding gastrostomies. Most patients were followed by psychiatrists due to cognitive decline, recurrent depression, or psychotic episodes. Six patients died at ages 50, 51, 53, 56, 56, and 57 years. The eldest patient is now 51 years old; she is cachectic and requires special diet and psychiatric care for paranoid psychosis and uninhibited behavior. CONCLUSIONS: Oculopharyngeal muscular dystrophy progresses faster in homozygote compared with heterozygote patients. It is not restricted to the muscles, but also involves the CNS with cognitive decline and psychotic manifestations and leads to a reduced life expectancy.
Subject(s)
Cognition Disorders/mortality , Life Expectancy , Muscular Dystrophy, Oculopharyngeal/mortality , Cognition Disorders/complications , Cognition Disorders/genetics , Female , Follow-Up Studies , Humans , Longevity/genetics , Male , Middle Aged , Muscular Dystrophy, Oculopharyngeal/complications , Muscular Dystrophy, Oculopharyngeal/geneticsABSTRACT
It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal. The population of Eastern Canada, we are convinced, will still allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies as well as contribute to the uncovering of their mutated genes. We have summarized our current knowledge of the various hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada. The study of the more common and homogenous features of these diseases has been largely completed.
Subject(s)
Hereditary Sensory and Motor Neuropathy/epidemiology , Paraparesis, Spastic/epidemiology , Spinocerebellar Degenerations/epidemiology , Canada/epidemiology , Hereditary Sensory and Motor Neuropathy/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Humans , Paraparesis, Spastic/genetics , Paraparesis, Spastic/physiopathology , Spinocerebellar Degenerations/genetics , Spinocerebellar Degenerations/physiopathologyABSTRACT
BACKGROUND: Myotonia is observed in classic congenital myotonia caused by CLCN1 mutations and in sodium-channel myotonia (SCM) due to SCN4A mutations. METHODS: We assessed 66 electrically proven cases of myotonia belonging to 17 French-Canadian families living in the Saguenay Lac St-Jean area of Quebec, a region well known for its genetic founder effects. The CLCN1 gene was sequenced in one affected member of each family. SCN4A exons with known SCM mutations were subsequently sequenced in families where no CLCN1 mutations were found. RESULTS: Six families, 33% of cases (22/66), presenting classic congenital myotonia phenotypes were found to carry two previously identified CLCN1 mutations. In the other 11 families comprising 66% of cases (44/66), a new dominant SCN4A mutation in exon 24 (M1476I) was uncovered and segregated with a variable SCM phenotype. Although all carriers of this novel mutation had electrical myotonia, some were asymptomatic (25%) and age at onset was variable in the others (5 to 67, mean 21). Cold aggravated myotonia was observed in 41% of cases and painful myotonia in 18%. Additional features observed include aggravation of symptoms with pregnancies (7%), localized muscle swelling (2%), myotonic reactions to anesthesia (2%), and food-induced paralysis (2%). CONCLUSIONS: This cohort is the largest described with a variable sodium-channel myotonia phenotype caused by a single SCN4A mutation. The clinical variability observed in this cohort underlines the phenotypic heterogeneity of SCN4A mutations and suggests that variants in other genes likely modulate clinical expression.
Subject(s)
Cold Temperature/adverse effects , Founder Effect , Myotonia/genetics , Pain/genetics , Sodium Channels/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , France/ethnology , Humans , Male , Middle Aged , Mutation , Myotonia/complications , Myotonia/diagnosis , NAV1.4 Voltage-Gated Sodium Channel , Pain/complications , Pain/diagnosis , Quebec , White People/geneticsABSTRACT
Mutations in senataxin have been described recently in 24 cases of French-Canadian descent with ataxia-oculomotor apraxia 2. This recessive ataxia is associated with an elevation in alpha-fetoprotein as in ataxia-telangiectasia. Because ataxia-telangiectasia cells are highly radiosensitive, we used a colony survival assay to measure the radiosensitivity of lymphoblastoid cell lines derived from five French-Canadian patients with ataxia-oculomotor apraxia 2. Two were homozygous for the common French-Canadian L1976R SETX missense mutation; the three others were compound heterozygotes for the common mutation and three different missense mutations. Overall, lymphoblastoid cell lines derived from these cases did not show significant variation from a normal response to 1 Gray of ionizing radiation but the two patients who were homozygous for the common L1976R mutation fell in the intermediate or non-diagnostic range.
Subject(s)
Apraxias/diagnosis , Ataxia/diagnosis , Ocular Motility Disorders/diagnosis , Adolescent , Apraxias/genetics , Apraxias/immunology , Ataxia/genetics , Ataxia/immunology , Cell Line , Child , Colony-Forming Units Assay/methods , DNA Helicases , DNA Mutational Analysis , Genetic Predisposition to Disease/genetics , Humans , Lymphocytes/physiology , Lymphocytes/radiation effects , Multifunctional Enzymes , Mutation/genetics , Neoplasms/diagnosis , Neoplasms/genetics , Ocular Motility Disorders/genetics , Ocular Motility Disorders/immunology , Prognosis , Quebec/ethnology , RNA Helicases/genetics , Radiation, Ionizing , alpha-Fetoproteins/geneticsABSTRACT
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of pathologies. We have identified a cohort of 14 French-Canadian patients from eight different families displaying a novel form of LGMD with an autosomal recessive inheritance. These patients share some features with previously described cases of 'quadriceps myopathy' that evolved into an LGMD. All demonstrate quadriceps femoris asymmetrical atrophy. Creatine kinase values were variable from normal to 6000 U/l. Clinical evaluations and MRI studies demonstrate a variable intrafamilial and interfamilial phenotype. Asymmetrical muscle involvement was clinically observed and confirmed by imaging. MRI studies suggest that the hamstrings and the adductor magnus are the first limb muscles to demonstrate fatty infiltration. Muscle pathology shows no sign of active inflammation but increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization. A genome-wide scan using the two largest families uncovered linkage to marker D11S1360 on chromosome 11p12 [multipoint logarithm of the odds (LOD) score of 2.78]. Further genotyping for the eight families confirmed linkage to this new LGMD locus (multipoint LOD score of 4.56). Fine mapping subsequently defined a less than 3.3 cM candidate interval on 11p13-p12. Haplotype analysis of carrier chromosomes suggests that the most frequent mutation may account for up to 81.3% of French-Canadian mutations. In this study, we describe the chromosomal locus of a new form of recessive LGMD with prominent quadriceps femoris atrophy.
Subject(s)
Chromosomes, Human, Pair 11/genetics , Muscular Atrophy/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Adult , Aged , Chromosome Mapping/methods , Female , Genes, Recessive , Haplotypes , Humans , Lod Score , Magnetic Resonance Imaging , Male , Middle Aged , Muscle, Skeletal/ultrastructure , Muscular Atrophy/etiology , Muscular Atrophy/pathology , Muscular Dystrophies, Limb-Girdle/complications , Muscular Dystrophies, Limb-Girdle/pathology , Mutation , Pedigree , PhenotypeABSTRACT
Congenital muscular dystrophies (CMDS) are a heterogeneous group of disorders. A growing number of CMDS have been found to be associated with joint hyperlaxity. We recruited 14 French-Canadian cases belonging to 11 families affected by a novel autosomal recessive congenital muscular dystrophy with hyperlaxity (CMDH). All cases come from the southwestern part of Quebec, suggesting a new French-Canadian founder effect. All patients present muscle weakness, proximal contractures coexisting with distal joint hyperlaxity. Pathological and genetic studies have excluded that mutations in the three genes coding for collagen VI subunits are responsible for this disease. A genome-wide scan established linkage of two CMDH families to a region on chromosome 3p23-21. Further linkage analysis confirmed that all families are linked to the same region (log of the odds score of 5.3). Haplotype analysis defines a 1.6-cM candidate interval and suggests that two common mutations may account for 78% of carrier chromosomes. This study describes and maps a new form of recessive CMD with joint hyperlaxity distinct from Ullrich and Bethlem myopathies with a founder effect in the French-Canadian population.
Subject(s)
Chromosomes, Human, Pair 3/genetics , Joint Instability/genetics , Muscular Dystrophies/genetics , Adolescent , Adult , Child , Chromosome Mapping/methods , Collagen Type VI/deficiency , Collagen Type VI/genetics , Female , Genetic Linkage , Haplotypes , Humans , Joint Instability/complications , Male , Muscle Fibers, Skeletal/pathology , Muscular Dystrophies/complications , Muscular Dystrophies/congenital , Muscular Dystrophies/pathology , Mutation , Pedigree , PhenotypeABSTRACT
Recessive ataxias are a heterogeneous group of diseases. We identified a group of 23 French-Canadian cases belonging to 17 families affected by an autosomal recessive spastic ataxia associated with frequent white matter changes. The fact that 59% of these families have a genealogical relationship to the Portneuf County of Quebec suggests that this is a new form of ataxia with a regional founder effect. All cases present with cerebellar ataxia and spasticity. There is great intrafamilial and interfamilial variability, as illustrated by the spectrum of age of diagnosis (range: 2-59 years, mean: 15.0) and the presence of white matter changes on MRI in 52.4% of cases. The more severe cases have spasticity from birth, scoliosis, dystonia and cognitive impairment and were considered cases of cerebral palsy. Brain MRI constantly shows cerebellar atrophy, which in some cases may be associated with cortical atrophy, leucoencephalopathy and corpus callosum thinning. A genome wide scan uncovered linkage of three families to marker D2S2321 localized on chromosome 2q33-34. Linkage analysis confirmed that all families are linked to the same region [multipoint log of the odds (LOD) score of 5.95]. Haplotype analysis and allele sharing suggest that one common mutation may account for 97% of carrier chromosomes in Quebec. The uncovering of the mutated gene may point to a common pathway for pyramidal and cerebellar degeneration as both are often observed in recessive ataxias and complicated paraplegias.
Subject(s)
Cerebellar Ataxia/genetics , Chromosomes, Human, Pair 2/genetics , Paraplegia/genetics , Spastic Paraplegia, Hereditary/genetics , Adolescent , Adult , Atrophy/genetics , Brain/pathology , Cerebellar Ataxia/pathology , Child , Child, Preschool , Cohort Studies , Corpus Callosum/pathology , Family Health , Female , Genes, Recessive/genetics , Genetic Linkage/genetics , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Mutation/genetics , Pedigree , Phenotype , QuebecABSTRACT
Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).
Subject(s)
Genetic Diseases, Inborn/epidemiology , Genetics, Medical , Genetics, Population , Ethnicity/genetics , Founder Effect , France/ethnology , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/history , Genetics, Medical/history , Genetics, Population/history , History, 17th Century , History, 18th Century , History, 19th Century , Humans , Indians, North American/genetics , Quebec/epidemiologyABSTRACT
BACKGROUND: Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2. OBJECTIVES: To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype. METHODS: Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations. RESULTS: A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudière region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype. CONCLUSIONS: Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.
Subject(s)
Genetic Predisposition to Disease/genetics , Hereditary Sensory and Autonomic Neuropathies/epidemiology , Hereditary Sensory and Autonomic Neuropathies/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Adult , Aged , Base Sequence/genetics , Child , Child, Preschool , Chromosome Mapping , Chromosomes, Human, Pair 12/genetics , Cohort Studies , DNA Mutational Analysis , Female , Genetic Testing , Genotype , Humans , Infant , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Minor Histocompatibility Antigens , Pedigree , Peripheral Nerves/pathology , Peripheral Nerves/physiopathology , Phenotype , Prevalence , Protein Serine-Threonine Kinases , Quebec/epidemiology , WNK Lysine-Deficient Protein Kinase 1ABSTRACT
The dominant oculo-pharyngeal muscular dystrophy mutation consists of an expanded (GCN)(12-17) in the coding region of the PolyA Binding Protein Nuclear 1 gene. A founder effect has been demonstrated in Canadian and Bukhara Jewish populations with relatively high prevalence of this disease. Since the oculo-pharyngeal muscular dystrophy prevalence was remarkably high in Southern Uruguay, a founder effect was hypothesized. To identify the ancestral haplotype we determined the (GCN) repeat number and the variants of four intragenic SNPs in Uruguayan OPMD families and a control sample. All families carrying the mutation (GCG)(11)(GCA)(3)(GCG) shared a common ancestral haplotype and the age of the mutation was estimated in 37-53 generations by a composite likelihood method. One family carrying the (GCG)(9)(GCA)(3)(GCG) allele had a different haplotype. The genealogical and molecular data suggested that the common ancestors were Canary Islands' settlers that arrived in Uruguay in the XIX century.
Subject(s)
Founder Effect , Muscular Dystrophy, Oculopharyngeal/genetics , Mutation/genetics , Poly(A)-Binding Protein II/genetics , Trinucleotide Repeat Expansion/genetics , DNA Mutational Analysis , Family Health , Female , Genealogy and Heraldry , Genetic Testing , Haplotypes , Heterozygote , Humans , Male , Muscular Dystrophy, Oculopharyngeal/metabolism , Muscular Dystrophy, Oculopharyngeal/physiopathology , Pedigree , Phenotype , Polymorphism, Single Nucleotide/genetics , UruguayABSTRACT
INTRODUCTION: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD), with late onset due to ptosis and/or dysphagia, is caused by short (GCG)8-13 triplet-repeat expansions in the polyadenylation binding protein 2 (PABP2) gene, which is localized in chromosome 14q11. The severity of the dominant OPMD as well as the number of expansions that cause the disease are variable. (GCG)9 is mentioned as the most frequent and the genotype/phenotype has still not been well-determined. OBJECTIVE: To describe the type of expansions (GCG)n found in Spanish families with OPMD, establishing if there is variability of them and the possible geno-phenotypical correlations. METHODS: Clinicopathological and molecular studies have been performed in 15 consecutive patients, belonging to seven Spanish families with OPMD. The muscular biopsy study under electronmicroscopy shows intranuclear inclusions (INIs) in all the examined patients (one patient per family). The genetic findings confirm the cause of the disease in all the affected members and in one clinically asymptomatic member of one recently examined family: three families (six, one and one studied members, respectively) present the (GCG)9 expansion, two families (one studied member each one) present the (GCG)10 expansion and two families (one and four studied members respectively) present the (GCG)11 expansion. In these 15 patients with a short GCG expansion causing OPMD, clinical tests for OPMD and a follow-up study of their clinical course have been carefully assessed: in patients with the (GCG)9 expansion major abnormalities appeared in extrinsic ocular mobility and more precocious presentation of limb girld (lumbopelvic preferentially) weakness leading to a great disability before the seventh decade of life under the seventies in some patients and sometimes leading to death. In patients with (GCG)10 and (GCG)11 expansions, eye movements are always preserved and the limb girld muscles weakness did not appear before the seventh decade. No correlation seems to exist between age of onset of the ptosis or dysphagia and the different (GCG)n expansions and the surgical treatment of ptosis, performed in eight patients, showed good results independently of the (GCG)n mutation. CONCLUSIONS: Although further clinical and genetic studies are necessary to establish a strict genotype/phenotype correlation in OPMD, we concluded that the (GCG)9 expansion involve more severe phenotypes than those related to the (GCG)10 or (GCG)11 expansions. Therefore, genetic testing could benefit prognosis in asymptomatic individuals.
Subject(s)
Muscular Dystrophy, Oculopharyngeal/genetics , Poly(A)-Binding Protein II/genetics , Trinucleotide Repeat Expansion , Adult , Aged , Female , Genotype , Humans , Male , Middle Aged , Muscular Dystrophy, Oculopharyngeal/pathology , Phenotype , SpainABSTRACT
Oculopharyngeal muscular dystrophy (OPMD) is a muscle disease of late onset associated with progressive ptosis of the eyelids, dysphagia, and unique tubulofilamentous intranuclear inclusions (INIs). OPMD is usually transmitted as an autosomal dominant trait (OMIM 164300). A rarer allelic autosomal recessive form has also been observed (OMIM 257950). Both forms are caused by short (GCG)8-13 expansions in the polyadenylate-binding protein nuclear 1 gene (PABPN1) located on chromosome 14q11.1. The mutations cause the lengthening of an N-terminal polyalanine domain. Both slippage and unequal recombination have been proposed as the mutation mechanisms. The size of the mutation has not yet been conclusively shown to inversely correlate with the severity of the phenotype. Mutated PABPN1 proteins have been shown to be constituents of the INIs. The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70, SKIP, and abundant poly(A)-mRNA. The exact mechanism responsible for polyalanine toxicity in OPMD is unknown. Various intranuclear inclusion dependent and independent mechanisms have been proposed based on the major known function of PABPN1 in polyadenylation of mRNA and its shuttling from the nucleus to the cytoplasm. OPMD is one of the few triplet-repeat diseases for which the function of the mutated gene is known. Because of the increasing number of diseases caused by polyalanine expansions and the pathological overlap with CAG/polyglutamine diseases, what pathological insight is gained by the study of OPMD could lead to a better understanding of a much larger group of developmental and degenerative diseases.