RESUMEN
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.
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Calambre Muscular , Linaje , Proteína de Replicación C , Humanos , Calambre Muscular/genética , Masculino , Femenino , Proteína de Replicación C/genética , Adulto , Persona de Mediana Edad , Japón , Enfermedad de la Neurona Motora/genética , Vestibulopatía Bilateral/genética , Ataxias Espinocerebelosas/genética , Expansión de las Repeticiones de ADN/genética , Pueblos del Este de AsiaRESUMEN
PURPOSE: Mutations of the COL4A1 gene, a major structural protein of vessels, may cause hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome. The vascular structure and function of patients with HANAC is poorly known. Here, we report a family with HANAC syndrome associated to a previously unreported mutation in COL4A1. The structure and function of retinal vessels were detailed by adaptive optics ophthalmoscopy (AOO) and optical coherence tomography (OCT) angiography. METHODS: Clinical data from six affected individuals (43 to 72 years old) from a single family comprising two generations were collected. Imaging charts including conventional fundus imaging, OCT-angiography and AOO in static and dynamic (flicker) mode were reviewed. DNA sequencing was done in the proband. RESULTS: DNA sequencing of the proband revealed a heterozygous deletion of COL4A1 (NM_001845) at position 1120 in the intron 20 resulting in the loss of splicing donor site for exon 20 (c.1120 + 2_1120 + 8del heterozygote). Four patients had arterial hypertension, and three had kidney dysfunction, one of which under dialysis. By fundus examination, five had typical retinal arteriolar tortuosity with arteriolar loops. Wall-to-lumen ratio of arteries was within normal limits, that is, lower than expected for hypertensive patients. Several foci of arteriolar irregularities were noted in the two oldest patients. In three affected subjects, evaluation of the neurovascular coupling showed a higher flicker-induced vasodilation than a control population (6 % to 11 %; n < 5 %). CONCLUSIONS: Structural and dynamic analysis of retinal vessels in a HANAC family bearing a previously unreported intronic COL4 mutation was done. In addition to arteriolar tortuosity, we found reduced wall-to-lumen ratio, arteriolar irregularity and increased vasodilatory response to flicker light. These abnormalities were more marked in the oldest subjects. This abnormal flicker response affected also non-tortuous arteries, suggesting that microvascular dysfunction extends beyond tortuosity. Such explorations may help to better vascular dysfunction related to HANAC and hence better understand the mechanisms of end-organ damage.
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Aneurisma , Calambre Muscular , Humanos , Adulto , Persona de Mediana Edad , Anciano , Calambre Muscular/complicaciones , Calambre Muscular/genética , Colágeno Tipo IV/genética , Intrones , Aneurisma/complicaciones , Aneurisma/genética , Vasos Retinianos , Mutación , Tomografía de Coherencia ÓpticaRESUMEN
Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome is an autosomal dominant genetic disease caused by COL4A1 gene mutation, with major clinical manifestations of white matter lesion, aneurysm, retinal artery tortuosity, polycystic kidney, microscopic hematuria and muscle cramps. This article reports the clinical features and genotype of one toddler with HANAC syndrome caused by COL4A1 gene mutation. The boy, aged 1 year and 8 months, had an insidious onset, with the clinical manifestations of pyrexia and convulsion, white matter lesions in the periventricular region and the centrum semiovale on both sides, softening lesions beside the left basal ganglia, retinal arteriosclerosis, microscopic hematuria and muscle cramps. Whole exome sequencing revealed a pathogenic de novo heterozygous mutation in the COL4A1 gene, (NM_001845) c.4150+1(IVS46)G>T, and therefore, the boy was diagnosed with HANAC syndrome. COL4A1 gene mutation detection should be performed for children with unexplained white matter lesion, stroke, hematuria, polycystic kidney, cataract and retinal artery tortuosity or families with related history.
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Aneurisma , Colágeno Tipo IV/genética , Calambre Muscular , Genotipo , Humanos , Lactante , Masculino , Calambre Muscular/genética , Mutación , SíndromeRESUMEN
Collagen IV is a major component of basement membranes (BMs). The α1(IV) chain, encoded by the COL4A1 gene, is expressed ubiquitously and associates with the α2(IV) chain to form the α1α1α2(IV) heterotrimer. Several COL4A1 mutations affecting a conformational domain containing integrin-binding sites are responsible for the systemic syndrome of hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC). To analyze the pathophysiology of HANAC, Col4a1 mutant mice bearing the p.Gly498Val mutation were generated. Analysis of the skeletal muscles of Col4a1G498V mutant animals showed morphologic characteristics of a muscular dystrophy phenotype with myofiber atrophy, centronucleation, focal inflammatory infiltrates, and fibrosis. Abnormal ultrastructural aspects of muscle BMs was associated with reduced extracellular secretion of the mutant α1α1α2(IV) trimer. In addition to muscular dystrophic features, endothelial cell defects of the muscle capillaries were observed, with intracytoplasmic accumulation of the mutant α1α1α2(IV) molecules, endoplasmic reticulum cisternae dilation, and up-regulation of endoplasmic reticulum stress markers. Induction of the unfolded protein response in Col4a1 mutant muscle tissue resulted in an excess of apoptosis in endothelial cells. HANAC mutant animals also presented with a muscular functional impairment and increased serum creatine kinase levels reflecting altered muscle fiber sarcolemma. This extensive description of the muscular phenotype of the Col4a1 HANAC murine model suggests a potential contribution of primary endothelial cell defects, together with muscle BM alterations, to the development of COL4A1-related myopathy.
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Vasos Sanguíneos/anomalías , Colágeno Tipo IV/genética , Calambre Muscular/genética , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/patología , Mutación/genética , Enfermedad de Raynaud/genética , Animales , Apoptosis , Vasos Sanguíneos/patología , Peso Corporal , Creatina Quinasa/sangre , Distrofina/metabolismo , Estrés del Retículo Endoplásmico , Células Endoteliales/patología , Células Endoteliales/ultraestructura , Matriz Extracelular/metabolismo , Integrina beta1/metabolismo , Ratones , Ratones Mutantes , Músculo Esquelético/ultraestructura , Tamaño de los Órganos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismoRESUMEN
The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling. SUMMARY STATEMENT: This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition.
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Colágeno Tipo IV/genética , Calambre Muscular/genética , Mutación/genética , Neuronas/patología , Enfermedad de Raynaud/genética , Vasos Retinianos/anomalías , Animales , Modelos Animales de Enfermedad , Ratones Transgénicos , Neuroglía/metabolismo , Neuronas/metabolismo , Retina/metabolismo , Vasos Retinianos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.
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Colágeno Tipo IV/genética , Enfermedades Renales Quísticas/etiología , Calambre Muscular/complicaciones , Calambre Muscular/genética , Mutación , Enfermedad de Raynaud/complicaciones , Enfermedad de Raynaud/genética , Factores de Edad , Animales , Animales Recién Nacidos , Enfermedades Renales Quísticas/metabolismo , Glomérulos Renales/metabolismo , Ratones , Calambre Muscular/metabolismo , Calambre Muscular/fisiopatología , Permeabilidad , Enfermedad de Raynaud/metabolismo , Enfermedad de Raynaud/fisiopatologíaRESUMEN
COL4A1-associated disorders encompass a wide range of hereditary vasculopathy, including porencephaly and HANAC (adult-onset hemorrhagic stroke with cerebral aneurysm and retinal arterial tortuosity, renal cysts, and thenar muscle cramp). It remains elusive whether or not porencephaly and HANAC are molecularly distinctive disorders due to different classes of mutations. We report on a girl with porencephaly and an episode of microangiopathic hemolysis in infancy and her father with HANAC, both of whom had a heterozygous missense mutation of COL4A1 (c.3715G>A, p.G1239R). The current observation implies phenotypic diversities of COL4A1 mutations.
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Colágeno Tipo IV/genética , Padre , Feto/anomalías , Calambre Muscular/genética , Mutación/genética , Porencefalia/genética , Enfermedad de Raynaud/genética , Adulto , Secuencia de Bases , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Linaje , Embarazo , Adulto JovenRESUMEN
INTRODUCTION: Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation. METHODS: Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied. RESULTS: A G1306A mutation in the Nav1.4 voltage-gated sodium channel of skeletal muscle was identified. This mutation is known to cause myotonia fluctuans. No giant myotonic discharges or painful muscle cramps were found in the other G1306A families. CONCLUSIONS: Ephaptic transmission between neighboring muscle fibers may not only cause the unusual size of the myotonic discharges in this family, but also a more severe type of potassium-aggravated myotonia than myotonia fluctuans.
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Potenciales Evocados Motores/genética , Salud de la Familia , Calambre Muscular/complicaciones , Calambre Muscular/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Adulto , Electromiografía , Femenino , Humanos , Persona de Mediana EdadAsunto(s)
Calambre Muscular/diagnóstico , Enfermedad de Raynaud/diagnóstico , Trastornos de la Visión/diagnóstico , Colágeno Tipo IV/genética , Femenino , Humanos , Persona de Mediana Edad , Calambre Muscular/genética , Enfermedad de Raynaud/genética , Hemorragia Retiniana/diagnóstico , Vasos Retinianos/patología , Tomografía de Coherencia ÓpticaAsunto(s)
Pruebas Genéticas , Enfermedades Renales Quísticas/genética , Anciano , Diagnóstico Diferencial , Pruebas Genéticas/métodos , Humanos , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Calambre Muscular/diagnóstico , Calambre Muscular/diagnóstico por imagen , Calambre Muscular/genética , Riñón Poliquístico Autosómico Dominante/diagnóstico , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Riñón Poliquístico Autosómico Dominante/genética , Enfermedad de Raynaud/diagnóstico , Enfermedad de Raynaud/diagnóstico por imagen , Enfermedad de Raynaud/genéticaRESUMEN
INTRODUCTION: Phosphoglycerate mutase deficiency (PGAM) is a rare metabolic myopathy that results in terminal block in glycogenolysis. Clinically, patients with PGAM deficiency are asymptomatic, except when they engage in brief, strenuous efforts, which may trigger myalgias, cramps, muscle necrosis, and myoglobinuria. An unusual pathologic feature of PGAM deficiency is the association with tubular aggregates. METHODS: We report an African-American patient from Panama with partial deficiency of PGAM who presented with asymptomatic elevation of creatine kinase levels and tubular aggregates on muscle biopsy. RESULTS: Muscle biopsies showed subsarcolemmal and sarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM enzymatic activity was decreased and gene sequencing revealed a heterozygous mutation in codon 78 of exon 1 of the PGAM2 gene, which is located on the short arm of chromosome 7. CONCLUSIONS: PGAM deficiency has been reported in 14 patients, 9 of whom were of African-American ethnicity, and in 5 (36%) tubular aggregates were seen on muscle biopsy. Contrary to previously reported cases, our patient was initially asymptomatic. This further expands the PGAM deficiency phenotype.
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Calambre Muscular/patología , Debilidad Muscular/patología , Músculo Esquelético/patología , Fosfoglicerato Mutasa/deficiencia , Adulto , Humanos , Masculino , Calambre Muscular/enzimología , Calambre Muscular/genética , Debilidad Muscular/enzimología , Debilidad Muscular/genética , Músculo Esquelético/enzimología , Fosfoglicerato Mutasa/genética , Fosfoglicerato Mutasa/metabolismoRESUMEN
OBJECTIVE: The authors hypothesized that variants within genes, such as COL5A1, COL3A1, COL6A1, and COL12A1, that code for connective tissue components of the musculoskeletal system may modulate susceptibility to exercise-associated muscle cramping (EAMC). Specifically, the aim of this study was to investigate if the COL5A1 rs12722 (C/T), COL3A1 rs1800255 (G/A), COL6A1 rs35796750 (T/C), and COL12A1 rs970547 (A/G) polymorphisms are associated with a history of EAMC. DESIGN: Retrospective genetic case-control association study. SETTING: Participants were recruited at triathlon and ultra-marathon events and were asked to report physical activity, medical history, and cramping history. PARTICIPANTS: One hundred sixteen participants with self-reported history of EAMC within the past 12 months before an ultra-endurance event were included as cases in this study (EAMC group). One hundred fifty participants with no self-reported history of previous (lifelong) EAMC were included as controls (NON group). INTERVENTIONS: All participants were genotyped for the selected variants. MAIN OUTCOME MEASURES: Differences in genotype frequency distributions, for COL5A1 rs12722, COL3A1 rs1800255, COL6A1 rs35796750, and COL12A1 rs970547, among the cases and controls. RESULTS: The COL5A1 CC genotype was significantly overrepresented (P = 0.031) among the NON group (21.8%) when compared with the EAMC group (11.1%). No significant genotype differences were found for the COL3A1 (P = 0.828), COL6A1 (P = 0.300), or COL12A1 (P = 0.120) genotypes between the EAMC and NON groups. CONCLUSIONS: This study identified, for the first time, the COL5A1 gene as a potential marker for a history of EAMC.
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Colágeno Tipo III/genética , Colágeno Tipo VI/genética , Colágeno Tipo V/genética , Colágeno Tipo XII/genética , Ejercicio Físico/fisiología , Calambre Muscular/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Estudios de Asociación Genética , Marcadores Genéticos , Genotipo , Técnicas de Genotipaje , Humanos , Modelos Logísticos , Persona de Mediana Edad , Calambre Muscular/etiología , Estudios Retrospectivos , Factores de Riesgo , AutoinformeRESUMEN
BACKGROUND: Muscle cramps are a common problem characterized by a sudden, painful, and involuntary contraction of a muscle or muscle group. Most muscle cramps develop in the calf muscles, particularly in situations of prolonged exercise; however, some may be related to underlying systemic conditions such as the hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome. Muscle cramps appear to be the initial symptom of the HANAC syndrome; however, the clinical characteristics of these muscle cramps have rarely been described in detail. CASE PRESENTATION: We report a familial case of autosomal-dominant muscle cramps in four members of a Japanese family spanning across three generations. The muscle cramps were recognized as systemic symptoms of the HANAC syndrome associated with a novel COL4A1 pathogenic variant, NM_001845:c.1538Gâ¯>â¯A, p.(Gly513Asp). The four affected individuals indicated that the first episodes of the muscle cramps occurred in early childhood. In addition, they reported that the muscle cramps are characterized by an abrupt onset of severe pain without muscle contraction. The painful recurrent attacks occurred spontaneously in various muscles throughout the body, but rarely in the calf muscle. The muscle pain lasts for several minutes, cannot be ameliorated by stretching the affected muscle, and leaves a feeling of discomfort that lasts for 24-48â¯h. The serum creatine kinase levels of the patients were persistently elevated; however, their electromyography results did not reveal any specific abnormalities. CONCLUSIONS: Recognition of the clinical characteristics of the muscle cramps in the HANAC syndrome may facilitate early diagnosis of the syndrome and enable proper treatment of the patients, improve their long-term outcomes, and facilitate the design and adaption of appropriate genetic counseling.
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Aneurisma , Enfermedades Renales , Preescolar , Humanos , Calambre Muscular/genética , Colágeno Tipo IV/genética , Mutación/genética , Aneurisma/complicaciones , SíndromeRESUMEN
We review the muscular dystrophies and metabolic myopathies associated with myalgia and rhabdomyolysis together with some less well-recognized associations based upon the personal practice of the authors. A careful history and clinical examination will direct investigation towards an accurate molecular diagnosis. Non-specific exercise-induced myalgia in the presence of muscle hypertrophy and a high creatine kinase will point towards a muscular dystrophy. Symptoms occurring within minutes of exercise and with isometric contraction, especially with a history of a 'second wind' phenomenon, suggest a disorder of glycogen metabolism. In those patients in whom symptoms occur after prolonged exercise, infections, fasting, stress, and cold, a disorder of fatty acid oxidation should be considered. Heat-induced rhabdomyolysis caused by exercising in hot and humid climates should lead the clinician to suspect a mutation in RYR1. Serum creatine kinase level should be a checked in all children presenting with leg pains. A careful history and examination and laboratory confirmation of myoglobinuria will target investigations leading to a correct molecular diagnosis.
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Tolerancia al Ejercicio , Errores Innatos del Metabolismo/diagnóstico , Calambre Muscular/diagnóstico , Distrofias Musculares/diagnóstico , Rabdomiólisis/diagnóstico , Algoritmos , Niño , Diagnóstico Diferencial , Prueba de Esfuerzo , Humanos , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapia , Técnicas de Diagnóstico Molecular , Calambre Muscular/genética , Calambre Muscular/terapia , Distrofias Musculares/genética , Distrofias Musculares/terapia , Rabdomiólisis/genética , Rabdomiólisis/terapiaRESUMEN
McArdle's disease is an autosomal recessive glycogenosis due to mutation in the myophosphorylase gene (PYGM) resulting in a pure myopathy. The clinical onset typically occurs in childhood with cramps, myalgia, and intolerance to physical exercise, although late onset forms are also reported. We describe a case of a 17-year-old male complaining of cramps and myalgia following brief and intense exercise. The patient reported marked improvement in muscle fatigability few minutes after starting aerobic exercise. When he was a child, he had experienced few episodes of vomiting, nausea, and black colored urine following physical activity. Laboratory testings revealed high creatine kinase serum levels. Genetic testings for metabolic myopathies demonstrated a compound heterozygous for two PYGM mutations (p.R570Q and p.K754Nfs*49) allowing the diagnosis of McArdle's disease. To date, 183 mutations in the PYGM gene are listed in Human Gene Mutation Database Professional 2021.2, but this novel compound heterozygosis has never been reported before.
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Glucógeno Fosforilasa de Forma Muscular , Enfermedad del Almacenamiento de Glucógeno Tipo V , Adolescente , Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Humanos , Masculino , Calambre Muscular/genética , Mutación , MialgiaRESUMEN
BACKGROUND: COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies in humans. However, the causative genes for a number of hereditary multicystic kidney diseases, myopathies with cramps, and heritable intracranial aneurysms remain unknown. METHODS: We characterized the renal and extrarenal phenotypes of subjects from three families who had an autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), which we propose is a syndrome. Linkage studies involving microsatellite markers flanking the COL4A1-COL4A2 locus were performed, followed by sequence analysis of COL4A1 complementary DNA extracted from skin-fibroblast specimens from the subjects. RESULTS: We identified three closely located glycine mutations in exons 24 and 25 of the gene COL4A1, which encodes procollagen type IV alpha1. The clinical renal manifestations of the HANAC syndrome in these families include hematuria and bilateral, large cysts. Histologic analysis revealed complex basement-membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appears to affect both small vessels and large arteries. CONCLUSIONS: COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.
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Anomalías Múltiples/genética , Colágeno Tipo IV/genética , Aneurisma Intracraneal/genética , Enfermedades Renales Quísticas/genética , Calambre Muscular/genética , Enfermedades Vasculares/genética , Membrana Basal/patología , Femenino , Enfermedades Genéticas Congénitas/genética , Hematuria/genética , Humanos , Enfermedades Renales Quísticas/patología , Masculino , Mutación , Linaje , Fenotipo , SíndromeAsunto(s)
Fumarato Hidratasa/genética , Mutación de Línea Germinal/genética , Leiomiomatosis/genética , Enfermedades Musculares/genética , Mutación Missense/genética , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genética , Adulto , Femenino , Fumarato Hidratasa/deficiencia , Humanos , Hallazgos Incidentales , Neoplasias Renales/genética , Masculino , Enfermedades Mitocondriales/genética , Calambre Muscular/genética , Fatiga Muscular/genética , Mialgia/genética , Síndromes Neoplásicos Hereditarios , LinajeAsunto(s)
Perros/genética , Perros/fisiología , Calambre Muscular/veterinaria , Carrera/fisiología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Animales , Perros/clasificación , Calambre Muscular/genética , Calambre Muscular/fisiopatología , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Mutación/genética , Miostatina , Tamaño de los ÓrganosRESUMEN
Since 2005, several neurological diseases, including porencephaly, leukoencephalopathy and intracerebral hemorrhage without hypertension, and retinal arteriolar tortuosity have been linked to mutations in the COL4A1 gene, which encodes the alpha1 chain of type IV collagen, the main constituent of basement membranes. In three families, we observed a new syndrome that we called HANAC, for hereditary angiopathy with nephropathy, aneurysms and muscle cramps, which is associated with morphological alterations of cutaneous and renal basement membranes. This novel "basalopathy" is caused by glycine mutations in COL4A1 exons 24 and 25. We discuss phenotype-genotype correlations and the implications of the HANAC syndrome for the diagnosis of autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.
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Colágeno Tipo IV/genética , Aneurisma Intracraneal/genética , Enfermedades Renales Quísticas/genética , Calambre Muscular/genética , Enfermedades Vasculares/genética , Anomalías Múltiples/genética , Membrana Basal , Humanos , Mutación , SíndromeRESUMEN
Mutations in the KCNA1 gene encoding the voltage-gated potassium (K+) channel Kv1.1 have been linked to rare neurological syndromes, episodic ataxia type 1 (EA1) and myokymia. In 2009, a KCNA1 mutation was identified in a large family with autosomal dominant hypomagnesemia. Despite efforts in establishing a genotype-phenotype correlation for the wide variety of symptoms in EA1, little is known on the serum magnesium (Mg2+) levels in these patients. In the present study, we describe a new de novo KCNA1 mutation in a Polish patient with tetany and hypomagnesemia. Electrophysiological and biochemical analyses were performed to determine the pathogenicity of the mutation. A female patient presented with low serum Mg2+ levels, renal Mg2+ wasting, muscle cramps, and tetanic episodes. Whole exome sequencing identified a p.Leu328Val mutation in KCNA1 encoding the Kv1.1 K+ channel. Electrophysiological examinations demonstrated that the p.Leu328Val mutation caused a dominant-negative loss of function of the encoded Kv1.1 channel. Cell surface biotinylation showed normal plasma membrane expression. Taken together, this is the second report linking KCNA1 with hypomagnesemia, thereby emphasizing the need for further evaluation of the clinical phenotypes observed in patients carrying KCNA1 mutations.