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Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade-off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models.
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Epilepsias Mioclónicas , Humanos , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/patología , Linaje , InvestigaciónRESUMEN
OBJECTIVE: The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype-phenotype correlations may suggest prognostic factors associated with severe phenotypes. BACKGROUND: Hemiplegic migraine is a rare disease and data concerning the pediatric population are even more rare as they are often extrapolated from mixed cohorts. METHODS: We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first attack occurred under the age of 18 years. RESULTS: We enrolled nine patients (seven males and two females) first referred to our three centers. Three of the nine (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both genetic mutations. The patients experienced at least one aura feature other than hemiplegia during the first attack. The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h; 3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range) duration of follow-up was 7.4 (2.2, 3-10) years. During the first year from the disorder's onset, only four patients had additional attacks. Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2). CONCLUSION: The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time. Furthermore, the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning.
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Migraña con Aura , Masculino , Femenino , Humanos , Niño , Migraña con Aura/diagnóstico , Migraña con Aura/epidemiología , Migraña con Aura/genética , Estudios de Seguimiento , ATPasa Intercambiadora de Sodio-Potasio/genética , Mutación/genética , Fenotipo , LinajeRESUMEN
Benign hereditary chorea (BHC) is a rare genetically heterogeneous movement disorder, in which conventional neuroimaging has been reported as normal in most cases. Cystic pituitary abnormalities and features of empty sella have been described in only 7 patients with BHC to date. We present 4 patients from 2 families with a BHC phenotype, 3 of whom underwent targeted pituitary MR imaging and genetic testing. All four patients in the two families displayed a classic BHC phenotype. The targeted pituitary MR imaging demonstrated abnormal pituitary sella morphology. Genetic testing was performed in three patients, and showed mutations causing BHC in three of the patients, as well as identifying a novel nonsense mutation of the TITF1/NKX2-1 gene in one of the patients. The presence of the abnormal pituitary sella in two affected members of the same family supports the hypothesis that this sign is a distinct feature of the BHC phenotype spectrum due to mutations in the TITF1 gene. Interestingly, these abnormalities seem to develop in adult life and are progressive. They occur in at least 26% of patients affected with Brain-lung-thyroid syndrome. As a part of the management of these patients we recommend to perform follow-up MRI brain with dedicated pituitary imaging also in adult life as the abnormality can occur years after the onset of chorea.
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Corea , Hipotiroidismo Congénito , Corea/genética , Hipotiroidismo Congénito/genética , Humanos , Mutación , Proteínas Nucleares/genética , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genéticaRESUMEN
The identification of biomarkers for neurodegenerative disorders such as Huntington's disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39-51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.
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Enfermedad de Huntington , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Estudios de Seguimiento , Telómero/genética , Leucocitos Mononucleares , Leucocitos , BiomarcadoresRESUMEN
Plasma small RNAs have been recently explored as biomarkers in Huntington's disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the results in an independent population of 23 HD, 15 pre-HD, 24 PP, 28 Alzheimer's disease (AD) patients (to control the disease-specificity) and 22 HS through real-time PCR. The microarray results showed higher levels of U13 small nucleolar RNA (SNORD13) in HD patients than controls (fold change 1.54, p = 0.003 HD vs. HS, and 1.44, p = 0.0026 HD vs. PP). In the validation population, a significant increase emerged with respect to both pre-HD and the control groups (p < 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p < 0.001) and the disease duration (r = 0.59; p = 0.003). The receiver operating characteristic (ROC) curve analysis showed the high accuracy of SNORD13 in discriminating HD patients from other groups (AUC = 0.963). An interactome and pathway analysis on SNORD13 revealed enrichments for factors relevant to HD pathogenesis. We report the unprecedented finding of a potential disease-specific role of SNORD13 in HD. It seems to peripherally report a 'tipping point' in the pathogenic cascade at the neuronal level.
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Enfermedad de Huntington , MicroARNs , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , ARN Nucleolar Pequeño/genética , Proyectos Piloto , Proteína Huntingtina/genética , BiomarcadoresRESUMEN
Human frataxin is an iron-binding protein involved in the mitochondrial iron-sulfur (Fe-S) clusters assembly, a process fundamental for the functional activity of mitochondrial proteins. Decreased level of frataxin expression is associated with the neurodegenerative disease Friedreich ataxia. Defective function of frataxin may cause defects in mitochondria, leading to increased tumorigenesis. Tumor-initiating cells show higher iron uptake, a decrease in iron storage and a reduced Fe-S clusters synthesis and utilization. In this study, we selected, from COSMIC database, the somatic human frataxin missense variants found in cancer tissues p.D104G, p.A107V, p.F109L, p.Y123S, p.S161I, p.W173C, p.S181F, and p.S202F to analyze the effect of the single amino acid substitutions on frataxin structure, function, and stability. The spectral properties, the thermodynamic and the kinetic stability, as well as the molecular dynamics of the frataxin missense variants found in cancer tissues point to local changes confined to the environment of the mutated residues. The global fold of the variants is not altered by the amino acid substitutions; however, some of the variants show a decreased stability and a decreased functional activity in comparison with that of the wild-type protein.
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Proteínas de Unión a Hierro/química , Proteínas de Unión a Hierro/genética , Mutación Missense , Neoplasias/genética , Sustitución de Aminoácidos , Bases de Datos Genéticas , Humanos , Modelos Moleculares , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Conformación Proteica , Estabilidad Proteica , FrataxinaRESUMEN
Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.
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Corea/genética , Cuerpo Estriado/patología , Mutación , Hidrolasas Diéster Fosfóricas/genética , Secuencia de Aminoácidos , Animales , Niño , Corea/diagnóstico , Cuerpo Estriado/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Conformación Proteica , Alineación de Secuencia , Transducción de Señal , Adulto JovenRESUMEN
To clarify the population history of dentatorubropallidoluysian atrophy (DRPLA) in Italy and to date back the introduction of the mutation, we reconstructed extended haplotypes flanking the CAG repeat in 10 patients of Italian ancestry, analyzing their similarity/dissimilarity as a function of distance from the CAG repeat. Our aim was to compare the hypothesis of a single, recent genealogy connecting all the observed haplotypes with the alternative hypothesis of multiple introductions by more distantly related haplotypes from outer sources. Polymorphic DNA markers were chosen to cover a region of 153 kb flanking the CAG repeat, that is, informative for dating the age of the DNA segment unaffected by recombination. In all patients, an expansion of the ATN1 CAG segment was confirmed residing onto the same narrow haplotype described to be associated with the CAG expansion in the Japanese and Portuguese populations. We also observed the disruption of the DRPLA haplotype at longer distances, on both sides of the CAG. Our results are compatible with a single founder in the last 600 years, most likely before the last 270 years. These estimates for the Sicilian population largely overlap a period in which the Japanese haplotype with the DRPLA mutation could have been introduced by the Portuguese maritime travelers.
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Haplotipos/genética , Mutación/genética , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Atrofia , Emparejamiento Base/genética , Femenino , Humanos , Italia , Masculino , Linaje , Recombinación Genética/genéticaRESUMEN
Benign hereditary chorea (BHC) is a rare autosomal dominant condition characterized by early onset, non-progressive chorea, usually caused by mutations in the thyroid transcription factor-1 gene (TITF1). We describe a novel mutation arising de novo in a proband presenting in infancy with delayed walking and ataxia. She later developed chorea, then hypothyroidism and a large cystic pituitary mass. Her daughter presented in infancy with delayed walking and ataxia and went on to develop non-progressive chorea and a hormonally inactive cystic pituitary mass. Mutational analysis of the whole coding region of the TITF1 gene was undertaken and compared with a population study of 160 control subjects. This showed that both affected subjects have a heterozygous A > T substitution at nucleotide 727 of the TITF1 gene changing lysine to a stop codon at residue 211. Genetic analysis of parents and siblings of the proband confirmed that the mutation arose de novo in the proband. The mutated lysine is an evolutionarily highly conserved amino acid in the protein homoeodomain (HD) where most point mutations associated with BHC are located. The range of mutations in BHC is reviewed with particular emphasis on pituitary abnormalities. Cystic pituitary masses and abnormalities of the sella turcica are reported in just 6.4 % of published cases. This is a new nonsense mutation associated with ataxia, benign chorea and pituitary abnormalities which further extends the phenotype of this condition. Mutational screening of TITF1 is important in cases of sporadic or dominant juvenile-onset ataxia, with mild chorea where no other cause is found, particularly if pituitary abnormalities are seen on imaging.
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Corea/genética , Hipotiroidismo/genética , Mutación , Proteínas Nucleares/genética , Enfermedades de la Hipófisis/genética , Factores de Transcripción/genética , Adulto , Corea/complicaciones , Corea/patología , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Hipotiroidismo/complicaciones , Hipotiroidismo/patología , Persona de Mediana Edad , Linaje , Enfermedades de la Hipófisis/complicaciones , Enfermedades de la Hipófisis/patología , Hipófisis/patología , Factor Nuclear Tiroideo 1 , Tomografía Computarizada por Rayos X , Reino UnidoRESUMEN
SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.
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The precursor of Nerve Growth Factor (proNGF) is the predominant form of NGF in the brain, where its tissue levels are increased in neurodegenerative diseases. proNGF exists in two main splicing variants, the long proNGF-A and the short proNGF-B. We demonstrated that proNGF-B is selectively increased in the hippocampus of rats affected by early diabetic encephalopathy and that native, purified proNGFs elicit different responses when used to stimulate PC12 cells. Therefore, the evaluation of the proNGF-B/proNGF-A ratio may be of important diagnostic and prognostic value in pathologies characterized by dysfunctions of NGF system. To date there is not clear pharmacological characterization of the different proNGFs variants, due to the lack of a proper recombinant proNGF-A. Using a bioinformatics approach, we predicted aminoacid sites involved in proNGF-A intracellular cleavage/conversion into proNGF-B, we cloned and expressed non-cleavable proNGF-A in HeLa cells and pursued a first characterization of their secretion modalities. Finally, we studied the biological effects of different proNGF-A mutants, stimulating PC12 cells with conditioned media from transfected HeLa cells. Based on our results, we propose the A73Y mutation as essential to obtaining an intact proNGF-A, limiting its conversion to proNGF-B. proNGF-A A73Y is probably released in an activity dependent manner and, when supplied to PC12 cells, shows a moderate differentiative capacity opposed to high neuroprotective potential. This preliminary study lays the foundation for future research aimed at uncovering the selective biological activities of proNGF-A and proNGF-B, and at developing pharmacological treatments that target the unbalance of proNGF system, induced by neurodegeneration.
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Biología Computacional/métodos , Variación Genética/genética , Factor de Crecimiento Nervioso/genética , Precursores de Proteínas/genética , Proteínas Recombinantes/genética , Animales , Secuencia de Bases , Células HeLa , Humanos , Factor de Crecimiento Nervioso/química , Células PC12 , Precursores de Proteínas/química , Ratas , Proteínas Recombinantes/químicaRESUMEN
The CACNA1A gene codes for the alpha(1A) pore-forming subunit of Ca(2+) voltage-gated Cav2.1 channels. CACNA1A mutations are responsible for Familial Hemiplegic Migraine (FHM) type 1, Episodic Ataxia (EA) type 2 and Spinocerebellar Ataxia type 6. The structure of the human gene includes, at present, 49 exons; however almost nothing is known about the 5' regulatory region, and there is now evidence suggesting the presence of additional exons at the 3' of the gene. The 892 bp fragment upstream of exon 1 and its deletion mutants were characterised for their transcriptional activity by using luciferase as a reporter gene. The 3' region was analysed by Rapid Amplification of the cDNA 3' End. Both regions were screened for mutations in a series of FHM and EA patients by SSCP and sequencing. At the 5' end of the gene a minimal promoter region was identified within the first 497 bp from ATG. By screening a larger fragment for mutations, the 5 bp deletion (g.-757_-753delCTTTC) was identified in a FHM patient. The deletion significantly increased the transcriptional activity, most likely due to the removal of half a turn of the DNA helix, changing the orientation of downstream binding sites for transcriptional factors. At the 3' end of the gene a new exon 48, followed by a strong poly-A signal, was identified as well as a new splice variant. The 5 bp insertion (g.38429_38430insCTTTT) in this exon was found in an EA patient. The two new regions can open the way for the study of human CACNA1A gene expression regulation and can be sites of mutations associated with FHM or EA phenotypes.
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Ataxia/genética , Canales de Calcio/genética , Exones/genética , Migraña con Aura/genética , Eliminación de Secuencia/genética , Análisis de Varianza , Ataxia/sangre , Línea Celular Tumoral , Biología Computacional/métodos , Análisis Mutacional de ADN , Humanos , Italia , Migraña con Aura/sangre , Datos de Secuencia Molecular , Neuroblastoma/metabolismo , FenotipoRESUMEN
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, nâ¯=â¯62), pre-manifest HD patients (pre-HD, nâ¯=â¯38), and age-matched controls (nâ¯=â¯76). Significant LTL differences were observed between the three groups (pâ¯<â¯.0001), with LTL values in the order: HDâ¯<â¯pre-HDâ¯<â¯controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (pâ¯=â¯.03). The overall data seem to indicate that after age 30â¯years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed.
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Enfermedad de Huntington/patología , Leucocitos/fisiología , Acortamiento del Telómero/fisiología , Telómero/genética , Expansión de Repetición de Trinucleótido/genética , Adulto , Factores de Edad , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Proteína Huntingtina/genética , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Análisis de Regresión , Adulto JovenRESUMEN
Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
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Proteínas Portadoras/genética , Cromosomas Humanos Par 2/genética , Expansión de las Repeticiones de ADN , Epilepsias Mioclónicas/genética , Intrones , Adolescente , Adulto , Niño , Preescolar , Mapeo Cromosómico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Adulto JovenRESUMEN
Benign hereditary chorea (BHC) is an autosomal dominant disorder of early onset characterised by non progressive choreic movements with normal cognitive function occasionally associated with hypothyroidism and respiratory problems. Numerous pieces of evidence link BHC with TITF-1/NKX2.1 gene mutations. We studied a patient with a familial benign hereditary chorea and normal thyroid and respiratory function. Sequence analysis of TITF-1 revealed the presence of a heterozygous C>T substitution at nucleotide 532, predicted to change an arginine (CGA) with a stop codon (TGA) at position 178 (R178X). A functional analysis shows that the mutated TTF-1 is not binding DNA, nor activating the canonical thyroid target gene promoter or interfering with the ability of wild type TTF-1 to activate transcription. In addition, the mutated protein is predominantly cytoplasmic, rather than nuclear as in the case of the wild type TTF-1. Thus, we have identified a new mutation in the TTF-1 coding gene in a patient with benign hereditary chorea. The results show that the mutation leads to a haploinsufficiency of TITF-1 and opens the question of genotype/phenotype correlation.
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Corea/genética , Corea/metabolismo , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Química Encefálica/genética , Núcleo Celular/genética , Corea/fisiopatología , Codón sin Sentido/genética , Citoplasma/genética , Análisis Mutacional de ADN , Inglaterra , Femenino , Marcadores Genéticos/genética , Genotipo , Haplotipos/genética , Heterocigoto , Humanos , Lactante , Fenotipo , Mutación Puntual/genética , Ratas , Factor Nuclear Tiroideo 1RESUMEN
Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington's disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their TBP genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder.
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Channelopathy mutations prove informative on disease causing mechanisms and channel gating dynamics. We have identified a novel heterozygous mutation in the KCNA1 gene of a young proband displaying typical signs and symptoms of Episodic Ataxia type 1 (EA1). This mutation is in the S4 helix of the voltage-sensing domain and results in the substitution of the highly conserved phenylalanine 303 by valine (p.F303V). The contributions of F303 towards K+ channel voltage gating are unclear and here have been assessed biophysically and by performing structural analysis using rat Kv1.2 coordinates. We observed significant positive shifts of voltage-dependence, changes in the activation, deactivation and slow inactivation kinetics, reduced window currents, and decreased current amplitudes of both Kv1.1 and Kv1.1/1.2 channels. Structural analysis revealed altered interactions between F303V and L339 and I335 of the S5 helix of a neighboring subunit. The substitution of an aromatic phenylalanine with an aliphatic valine within the voltage-sensor destabilizes the open state of the channel. Thus, F303 fine-tunes the Kv1.1 gating properties and contributes to the interactions between the S4 segment and neighboring alpha helices. The resulting channel's loss of function validates the clinical relevance of the mutation for EA1 pathogenesis.
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Ataxia/genética , Ataxia/metabolismo , Canalopatías/genética , Canalopatías/metabolismo , Activación del Canal Iónico/genética , Canal de Potasio Kv.1.1/genética , Canal de Potasio Kv.1.1/metabolismo , Mutación , Alelos , Secuencia de Aminoácidos , Ataxia/diagnóstico , Canalopatías/diagnóstico , Secuencia Conservada , Femenino , Genotipo , Humanos , Canal de Potasio Kv.1.1/química , Masculino , Modelos Moleculares , Linaje , Fenilalanina/genética , Conformación Proteica , Evaluación de SíntomasRESUMEN
INTRODUCTION: ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated. METHODS: We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders. RESULTS: We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence. CONCLUSION: Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations.
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Adenilil Ciclasas/genética , Discapacidades del Desarrollo/etiología , Trastornos del Movimiento , Mutación/genética , Adolescente , Adulto , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/complicaciones , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/epidemiología , Trastornos del Movimiento/genéticaRESUMEN
The thyroid transcription factor 1 (TTF-1) is encoded, on chromosome 14q13, by the gene termed TITF-1/NKX2.1. Mutations in this gene have been associated with chorea, hypothyroidism, and lung disease, all included in the "brain-thyroid-lung syndrome." We here describe two cases of novel missense mutations [NM_003317.3:c.516G>T and c.623G>C resulting in p.(Gln172His) and p.(Trp208Ser), respectively] in TITF-1/NKX2-1 in non-consanguineous patients. We provide a functional study of the role of the two mutations on the TTF-1 ability to bind DNA and to trans-activate both thyroid and lung specific gene promoters. Our results confirm the difficulty to correlate the TTF-1 activity with the clinical phenotype of affected patients and highlight the need to increase the limited knowledge we have on the activity of TTF-1 in neuronal cells.
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Corea/genética , Mutación Missense , Proteínas Nucleares/genética , Factores de Transcripción/genética , Adulto , Niño , Femenino , Humanos , Masculino , Fenotipo , Regiones Promotoras Genéticas , Factor Nuclear Tiroideo 1RESUMEN
Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, particularly in the cerebellum. The other two disorders are Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). These disorders show distinct phenotypes that often overlap but have different pathogenic mechanisms. EA2 and FHM1 are due to mutations causing, respectively, a loss and a gain of channel function. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein. This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; thus the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity. We will provide a short review for an update on the SCA6 molecular mechanism.