RESUMEN
Chronic progressive external ophthalmoplegia (CPEO) plus syndrome due to pathogenic biallelic variants in TOP3A gene has been described in only one single patient. We report two adult siblings with c.614A>G (p.Asp205Gly) homozygous missense variant in the TOP3A gene who had CPEO plus syndrome.
Asunto(s)
Oftalmoplejía Externa Progresiva Crónica , Oftalmoplejía , Adulto , Humanos , Oftalmoplejía Externa Progresiva Crónica/genética , Oftalmoplejía Externa Progresiva Crónica/patología , Mutación Missense , Homocigoto , Oftalmoplejía/genética , ADN Mitocondrial/genéticaRESUMEN
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder that often presents with gastrointestinal and neurological symptoms. Here we report a 33-year-old male who presented with a 16-year history of diarrhea with black stool and progressive weight loss. He complained of progressive bilateral blurred vision, upper eyelids heaviness, ocular motility impairment, and color blindness. Peripheral neuropathy, bilateral sensorineural deafness, hyperlactatemia, diabetes mellitus, hepatic steatosis, blood coagulation dysfunction, and diffuse leukoencephalopathy were detected in the systemic evaluation. Based on the novel homozygous pathogenic variant in the TYMP gene (c.1159+1G>A), he was diagnosed with MNGIE. On ophthalmic examinations, the thickness of the inner retina and ganglion cell complex significantly decreased. ERG showed diffusely decreased amplitudes. The electronegative electroretinogram, which was first reported in MNGIE, indicated a more severe inner retina impairment. The bilateral papillomacular bundle defect and central vision loss in MNGIE are consistent with classical mitochondrial optic neuropathies' features. According to the literature, pigmentary retinopathy, optic neuropathy, and abnormal pupillary reflexes are uncommon ocular features of MNGIE. This study contributes to a better understanding of ocular manifestations in MNGIE and demonstrates that MNGIE may have dyschromatopsia and an electronegative electroretinogram.
Asunto(s)
Encefalomiopatías Mitocondriales , Oftalmoplejía , Enfermedades del Sistema Nervioso Periférico , Masculino , Humanos , Adulto , Mutación , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/genética , Ojo/patología , Oftalmoplejía/diagnóstico , Oftalmoplejía/genéticaRESUMEN
Large single mitochondrial DNA (mtDNA) deletion syndrome is a rare inborn error of metabolism with variable heteroplasmy levels and clinical phenotype among affected individuals. Chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial disease [J Intern Med. 2020;287(6):592-608 and Biomed Rep. 2016;4(3):259-62]. The common CPEO clinical manifestations are ptosis and ophthalmoplegia. More variable phenotypic manifestations of CPEO (CPEO plus) include involvement of the peripheral nervous system and myopathy. Here, we describe a 62-year-old female with CPEO and the major mtDNA deletion present at 40% heteroplasmy, who had a coexistent previously undescribed CPEO phenotypic feature of persistent unexplained macrocytosis without anemia. Building on this case, we reviewed other major mtDNA deletion cases seen in our Adult Metabolic Diseases Clinic (AMDC) at the University of British Columbia, Vancouver, Canada, from 2016 to 2022. The major mtDNA deletion cases (n = 26) were compared with mtDNA missense variants identified in the clinic over the same period who acted as the comparison group (n = 16). Of these, the most frequent diagnosis was maternally inherited diabetes and deafness and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Ten out of 26 (38%) of mtDNA deletion patients had macrocytosis with elevated mean corpuscular volume (MCV), median (interquartile range) of 108 fL (102-114 fL). Seven of the patients with macrocytosis had no pertinent etiology. None of the comparison group had macrocytosis. There was a significant difference (p = 0.000) between the MCV and MCH in the mtDNA deletion group compared to the comparison group. This communication sheds light on the association of macrocytosis with the mtDNA deletion syndrome. It would be of great interest to determine if the association is found in other mitochondrial disease clinic populations.
Asunto(s)
Anemia , Oftalmoplejía Externa Progresiva Crónica , Oftalmoplejía , Femenino , Humanos , Oftalmoplejía Externa Progresiva Crónica/genética , Oftalmoplejía/diagnóstico , Oftalmoplejía/genética , ADN Mitocondrial/genéticaRESUMEN
PURPOSE: Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. METHODS: The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. RESULTS: Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. CONCLUSION: Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.
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Blefaroptosis , Oftalmoplejía , Humanos , Músculos Oculomotores/inervación , Pueblos del Este de Asia , Genotipo , Oftalmoplejía/diagnóstico , Oftalmoplejía/genética , Oftalmoplejía/congénito , Fibrosis , Fenotipo , Blefaroptosis/diagnóstico , Blefaroptosis/genética , Blefaroptosis/cirugía , Cinesinas/genéticaRESUMEN
Here we characterized a mouse model knocked-in for a frameshift mutation in RYR1 exon 36 (p.Gln1970fsX16) that is isogenic to that identified in one parent of a severely affected patient with recessively inherited multiminicore disease. This individual carrying the RYR1 frameshifting mutation complained of mild muscle weakness and fatigability. Analysis of the RyR1 protein content in a muscle biopsy from this individual showed a content of only 20% of that present in a control individual. The biochemical and physiological characteristics of skeletal muscles from RyR1Q1970fsX16 heterozygous mice recapitulates that of the heterozygous parent. RyR1 protein content in the muscles of mutant mice reached 38% and 58% of that present in total muscle homogenates of fast and slow muscles from wild-type (WT) littermates. The decrease of RyR1 protein content in total homogenates is not accompanied by a decrease of Cav1.1 content, whereby the Cav1.1/RyR1 stoichiometry ratio in skeletal muscles from RyR1Q1970fsX16 heterozygous mice is lower compared to that from WT mice. Electron microscopy (EM) revealed a 36% reduction in the number/area of calcium release units accompanied by a 2.5-fold increase of dyads (triads that have lost one junctional sarcoplasmic reticulum element); both results suggest a reduction of the RyR1 arrays. Compared to WT, muscle strength and depolarization-induced calcium transients in RyR1Q1970fsX16 heterozygous mice muscles were decreased by 20% and 15%, respectively. The RyR1Q1970fsX16 mouse model provides mechanistic insight concerning the phenotype of the parent carrying the RYR1 ex36 mutation and suggests that in skeletal muscle fibres there is a functional reserve of RyR1.
Asunto(s)
Canales de Calcio Tipo L/genética , Debilidad Muscular/genética , Miopatías Estructurales Congénitas/genética , Oftalmoplejía/genética , Canal Liberador de Calcio Receptor de Rianodina/deficiencia , Adulto , Alelos , Animales , Modelos Animales de Enfermedad , Mutación del Sistema de Lectura/genética , Heterocigoto , Humanos , Ratones , Microscopía Electrónica , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/ultraestructura , Debilidad Muscular/patología , Miopatías Estructurales Congénitas/fisiopatología , Oftalmoplejía/fisiopatología , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/ultraestructuraRESUMEN
Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.
Asunto(s)
Parálisis Facial/genética , Fibrosis/genética , Mutación , Oftalmoplejía/genética , Enfermedades del Sistema Nervioso Periférico/genética , Tubulina (Proteína)/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Sustitución de Aminoácidos , Arginina , Niño , Preescolar , Parálisis Facial/diagnóstico , Parálisis Facial/fisiopatología , Femenino , Fibrosis/diagnóstico , Fibrosis/fisiopatología , Histidina , Humanos , Lactante , Masculino , Oftalmoplejía/diagnóstico , Oftalmoplejía/fisiopatología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Síndrome , Adulto JovenRESUMEN
MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models. Affected members of two families share a haploidentical region that contains a homozygous 10 bp frameshift mutation in exon 1 of MYF5 (c.23_32delAGTTCTCACC [p.Gln8Leufs∗86]) predicted to undergo nonsense-mediated decay. Affected members of the third family harbor a homozygous missense change in exon 1 of MYF5 (c.283C>T [p.Arg95Cys]). Using in vitro assays, we show that this missense mutation acts as a loss-of-function allele by impairing MYF5 DNA binding and nuclear localization. We performed whole-genome sequencing in one affected individual with the frameshift mutation and did not identify additional rare variants in the haploidentical region that might account for differences in severity among the families. These data support the direct role of MYF5 in rib, spine, and extraocular muscle formation in humans.
Asunto(s)
Mutación/genética , Factor 5 Regulador Miogénico/genética , Oftalmoplejía/genética , Costillas/anomalías , Columna Vertebral/anomalías , Alelos , Secuencia de Aminoácidos , Canal Anal/anomalías , Animales , Proteínas de Unión al ADN/genética , Esófago/anomalías , Exones/genética , Femenino , Cardiopatías Congénitas , Humanos , Riñón/anomalías , Deformidades Congénitas de las Extremidades , Masculino , Ratones Noqueados , Proteína MioD/genética , Fenotipo , Alineación de Secuencia , Tráquea/anomalías , Secuenciación Completa del Genoma/métodosRESUMEN
Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c.1507-9G>A), which was predicted to affect mRNA splicing by activating a cryptic acceptor site. The frequency of the variant is very low in the general human population, and its presence in our families can be attributed to a founder effect. This study provides an updated review of the known causative mutations of the ECEL1 gene, enriching the allelic spectrum to include the noncoding sequence.
Asunto(s)
Artrogriposis/genética , Variación Genética , Intrones/genética , Metaloendopeptidasas/genética , Oftalmoplejía/genética , Enfermedades de la Retina/genética , Adolescente , Cromosomas Humanos/genética , Simulación por Computador , Exoma/genética , Femenino , Humanos , Recién Nacido , Masculino , LinajeRESUMEN
Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.
Asunto(s)
Fibrosis/patología , Músculos Oculomotores/patología , Oftalmoplejía/patología , Nervio Óptico/patología , Retina/patología , Adulto , Nervios Craneales/patología , Femenino , Fibrosis/genética , Humanos , Masculino , Mutación Missense/genética , Oftalmoplejía/genética , Disco Óptico/patología , Fenotipo , Células Ganglionares de la Retina/patología , Tomografía de Coherencia Óptica/métodos , Adulto JovenRESUMEN
Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening to search for therapeutic drugs to be used for treating mitochondrial diseases associated with dominant mutations in the nuclear ANT1 gene, which encodes for the mitochondrial ADP/ATP carrier. Dominant ANT1 mutations are involved in several degenerative mitochondrial pathologies characterized by the presence of multiple deletions or depletion of mitochondrial DNA in tissues of affected patients. Thanks to the presence in yeast of the AAC2 gene, orthologue of human ANT1, a yeast mutant strain carrying the M114P substitution equivalent to adPEO-associated L98P mutation was created. Five molecules were identified for their ability to suppress the defective respiratory growth phenotype of the haploid aac2M114P. Furthermore, these molecules rescued the mtDNA mutability in the heteroallelic AAC2/aac2M114P strain, which mimics the human heterozygous condition of adPEO patients. The drugs were effective in reducing mtDNA instability also in the heteroallelic strain carrying the R96H mutation equivalent to the more severe de novo dominant missense mutation R80H, suggesting a general therapeutic effect on diseases associated with dominant ANT1 mutations.
Asunto(s)
Translocador 1 del Nucleótido Adenina/genética , Ensayos Analíticos de Alto Rendimiento/métodos , Translocasas Mitocondriales de ADP y ATP/genética , Enfermedades Mitocondriales/tratamiento farmacológico , Mutación , Preparaciones Farmacéuticas/administración & dosificación , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , ADN Mitocondrial/genética , Genes Dominantes , Humanos , Enfermedades Mitocondriales/genética , Oftalmoplejía/tratamiento farmacológico , Oftalmoplejía/genética , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genéticaRESUMEN
Biallelic mutations in the C1QBP gene have been associated with mitochondrial cardiomyopathy and combined respiratory-chain deficiencies, with variable onset (including intrauterine or neonatal forms), phenotypes, and severity. We studied two unrelated adult patients from consanguineous families, presenting with progressive external ophthalmoplegia (PEO), mitochondrial myopathy, and without any heart involvement. Muscle biopsies from both patients showed typical mitochondrial alterations and the presence of multiple mitochondrial DNA deletions, whereas biochemical defects of the respiratory chain were present only in one subject. Using next-generation sequencing approaches, we identified homozygous mutations in C1QBP. Immunoblot analyses in patients' muscle samples revealed a strong reduction in the amount of the C1QBP protein and varied impairment of respiratory chain complexes, correlating with disease severity. Despite the original study indicated C1QBP mutations as causative for mitochondrial cardiomyopathy, our data indicate that mutations in C1QBP have to be considered in subjects with PEO phenotype or primary mitochondrial myopathy and without cardiomyopathy.
Asunto(s)
Proteínas Portadoras , Miopatías Mitocondriales , Proteínas Mitocondriales , Oftalmoplejía Externa Progresiva Crónica , Oftalmoplejía , Proteínas Portadoras/genética , ADN Mitocondrial/genética , Homocigoto , Humanos , Miopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Mutación , Oftalmoplejía/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Oftalmoplejía Externa Progresiva Crónica/patologíaRESUMEN
Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis, and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Although dominantly inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase-deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G>C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G>C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells, and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the 19th locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes.
Asunto(s)
ADN Mitocondrial/genética , GMP-Reductasa/genética , Enfermedades de Inicio Tardío/genética , Músculo Esquelético/enzimología , Oftalmoplejía/genética , Adenina/metabolismo , Anciano , Células Cultivadas , Deficiencia de Citocromo-c Oxidasa/metabolismo , Replicación del ADN , ADN Mitocondrial/metabolismo , Femenino , Fibroblastos/enzimología , GMP-Reductasa/deficiencia , GMP-Reductasa/metabolismo , Guanina/metabolismo , Células HEK293 , Células HeLa , Heterocigoto , Humanos , Enfermedades de Inicio Tardío/metabolismo , Enfermedades de Inicio Tardío/patología , Músculo Esquelético/patología , Oftalmoplejía/enzimología , Oftalmoplejía/fisiopatología , Fosforilación Oxidativa , Empalme del ARN , Eliminación de Secuencia , Secuenciación del ExomaRESUMEN
Missense variants in TUBB3 have historically been associated with either congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or malformations of cortical development (MCD). Until a recent report identified two amino acid substitutions in four patients that had clinical features of both disorders, pathogenic variants of TUBB3 were thought distinct to either respective disorder. Three recurrent de novo Gly71Arg TUBB3 substitutions and a single patient with a de novo Gly98Ser substitution blurred the MCD and CFEOM3 phenotypic distinctions. Here we report a second patient with a missense c.292G>A (p.Gly98Ser) substitution, but without CFEOM3, the first reported evidence that even the same TUBB3 substitution can produce a spectrum of TUBB3 syndrome phenotypes. Our patient presented with amblyopia, exotropia, optic disc pallor, and developmental delay. Neuroimaging identified hypoplasia of the corpus callosum, interdigitation of the frontal lobe gyri, and dysplasia or hypoplasia of the optic nerves, basal ganglia, brainstem, and cerebellum. This report identifies the TUBB3 Gly98Ser substitution to be recurrent but inconsistently including CFEOM3, and identifies the absence of joint contractures and the presence of optic disc abnormalities that may be genotype-specific to the TUBB3 Gly98Ser substitution.
Asunto(s)
Enfermedades Hereditarias del Ojo/genética , Fibrosis/genética , Malformaciones del Desarrollo Cortical/genética , Oftalmoplejía/genética , Tubulina (Proteína)/genética , Adulto , Sustitución de Aminoácidos/genética , Niño , Enfermedades Hereditarias del Ojo/diagnóstico por imagen , Enfermedades Hereditarias del Ojo/patología , Femenino , Fibrosis/diagnóstico por imagen , Fibrosis/patología , Genotipo , Humanos , Lactante , Masculino , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/patología , Mutación Missense/genética , Neuroimagen , Oftalmoplejía/diagnóstico por imagen , Oftalmoplejía/patología , LinajeRESUMEN
The tubulinopathies refer to a wide range of brain malformations caused by mutations in one of the seven genes encoding different tubulin's isotypes. The ß-tubulin isotype III (TUBB3) gene has a primary function in nervous system development and axon generation and maintenance, due to its neuron-specific expression pattern. A recurrent heterozygous mutation, c.1228G > A; p.E410K, in TUBB3 gene is responsible of a rare disorder clinically characterized by congenital fibrosis of the extraocular muscle type 3 (CFEOM3), intellectual disability and a wide range of neurological and endocrine abnormalities. Other mutations have been described spanning the entire gene and genotype-phenotype correlations have been proposed. We report on a 3-year-old boy in whom clinical exome sequencing allowed to identify a de novo TUBB3 E410K mutation as the molecular cause underlying a complex phenotype characterized by a severe bilateral palpebral ptosis refractory to eye surgery, psychomotor delay, absent speech, hypogonadism, celiac disease, and cyclic vomiting. Brain MRI revealed thinning of the corpus callosum with no evidence of malformation cortical dysplasia. We reviewed available records of patients with TUBB3 E410K mutation and compared their phenotype with the clinical outcome of patients with other mutations in TUBB3 gene. The present study confirms that TUBB3 E410K results in a clinically recognizable phenotype, unassociated to the distinct cortical dysplasia caused by other mutations in the same gene. Early molecular characterization of TUBB3 E410K syndrome is critical for targeted genetic counseling and prompt prospective care in term of neurological, ophthalmological, endocrine, and gastrointestinal follow-up.
Asunto(s)
Fibrosis/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Malformaciones del Desarrollo Cortical/genética , Oftalmoplejía/genética , Tubulina (Proteína)/genética , Encéfalo/anomalías , Preescolar , Fibrosis/complicaciones , Fibrosis/diagnóstico , Fibrosis/patología , Regulación del Desarrollo de la Expresión Génica/genética , Estudios de Asociación Genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/patología , Neuronas/metabolismo , Neuronas/patología , Oftalmoplejía/complicaciones , Oftalmoplejía/diagnóstico , Oftalmoplejía/patología , Secuenciación del ExomaRESUMEN
Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.
Asunto(s)
Trastorno del Espectro Autista/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Discapacidad Intelectual/diagnóstico por imagen , Tractos Piramidales/diagnóstico por imagen , Tubulina (Proteína)/genética , Sustancia Blanca/diagnóstico por imagen , Adulto , Factores de Edad , Anisotropía , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Trastorno del Espectro Autista/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Estudios de Casos y Controles , Corteza Cerebral/patología , Niño , Cuerpo Calloso/patología , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Endofenotipos , Femenino , Fibrosis/diagnóstico por imagen , Fibrosis/genética , Fibrosis/patología , Fibrosis/fisiopatología , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Síndrome de Kallmann/diagnóstico por imagen , Síndrome de Kallmann/genética , Síndrome de Kallmann/patología , Síndrome de Kallmann/fisiopatología , Masculino , Mutación , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/patología , Pruebas Neuropsicológicas , Oftalmoplejía/diagnóstico por imagen , Oftalmoplejía/genética , Oftalmoplejía/patología , Oftalmoplejía/fisiopatología , Tamaño de los Órganos , Tractos Piramidales/patología , Síndrome , Sustancia Blanca/patología , Adulto JovenRESUMEN
Unraveling the genetics of the paralytic strabismus syndromes known as congenital cranial dysinnervation disorders (CCDDs) is both informing physicians and their patients and broadening our understanding of development of the ocular motor system. Genetic mutations underlying ocular CCDDs alter either motor neuron specification or motor nerve development, and highlight the importance of modulations of cell signaling, cytoskeletal transport, and microtubule dynamics for axon growth and guidance. Here we review recent advances in our understanding of two CCDDs, congenital fibrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome (DRS), and discuss what they have taught us about mechanisms of axon guidance and selective vulnerability. CFEOM presents with congenital ptosis and restricted eye movements, and can be caused by heterozygous missense mutations in the kinesin motor protein KIF21A or in the ß-tubulin isotypes TUBB3 or TUBB2B. CFEOM-causing mutations in these genes alter protein function and result in axon growth and guidance defects. DRS presents with inability to abduct one or both eyes. It can be caused by decreased function of several transcription factors critical for abducens motor neuron identity, including MAFB, or by heterozygous missense mutations in CHN1, which encodes α2-chimaerin, a Rac-GAP GTPase that affects cytoskeletal dynamics. Examination of the orbital innervation in mice lacking Mafb has established that the stereotypical misinnervation of the lateral rectus by fibers of the oculomotor nerve in DRS is secondary to absence of the abducens nerve. Studies of a CHN1 mouse model have begun to elucidate mechanisms of selective vulnerability in the nervous system.
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Axones/fisiología , Síndrome de Retracción de Duane/genética , Fibrosis/genética , Oftalmoplejía/genética , Animales , Axones/metabolismo , Anomalías Congénitas , Síndrome de Retracción de Duane/metabolismo , Síndrome de Retracción de Duane/patología , Enfermedades Hereditarias del Ojo/genética , Fibrosis/metabolismo , Fibrosis/patología , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Ratones , Mutación , Mutación Missense , Trastornos de la Motilidad Ocular/genética , Músculos Oculomotores/anomalías , Músculos Oculomotores/patología , Oftalmoplejía/metabolismo , Oftalmoplejía/patología , Cráneo/fisiopatología , Tubulina (Proteína)/genéticaRESUMEN
We report ten individuals of four independent consanguineous families from Turkey, India, Libya, and Pakistan with a variable clinical phenotype that comprises arthrogryposis, spontaneously resolving respiratory insufficiency at birth, muscular atrophy predominantly of the distal lower limbs, scoliosis, and mild distal sensory involvement. Using whole-exome sequencing, SNPchip-based linkage analysis, DNA microarray, and Sanger sequencing, we identified three independent homozygous frameshift mutations and a homozygous deletion of two exons in PIEZO2 that segregated in all affected individuals of the respective family. The mutations are localized in the N-terminal and central region of the gene, leading to nonsense-mediated transcript decay and consequently to lack of PIEZO2 protein. In contrast, heterozygous gain-of-function missense mutations, mainly localized at the C terminus, cause dominant distal arthrogryposis 3 (DA3), distal arthrogryposis 5 (DA5), or Marden-Walker syndrome (MWKS), which encompass contractures of hands and feet, scoliosis, ophthalmoplegia, and ptosis. PIEZO2 encodes a mechanosensitive ion channel that plays a major role in light-touch mechanosensation and has recently been identified as the principal mechanotransduction channel for proprioception. Mice ubiquitously depleted of PIEZO2 are postnatally lethal. However, individuals lacking PIEZO2 develop a not life-threatening, slowly progressive disorder, which is likely due to loss of PIEZO2 protein in afferent neurons leading to disturbed proprioception causing aberrant muscle development and function. Here we report a recessively inherited PIEZO2-related disease and demonstrate that depending on the type of mutation and the mode of inheritance, PIEZO2 causes clinically distinguishable phenotypes.
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Artrogriposis/genética , Canales Iónicos/genética , Atrofia Muscular/genética , Propiocepción , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Escoliosis/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Alelos , Aracnodactilia/diagnóstico , Aracnodactilia/genética , Artrogriposis/diagnóstico , Blefarofimosis/diagnóstico , Blefarofimosis/genética , Niño , Preescolar , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/genética , Contractura/diagnóstico , Contractura/genética , Femenino , Estudio de Asociación del Genoma Completo , Homocigoto , Humanos , India , Canales Iónicos/metabolismo , Libia , Masculino , Mecanotransducción Celular , Atrofia Muscular/diagnóstico , Mutación Missense , Oftalmoplejía/diagnóstico , Oftalmoplejía/genética , Pakistán , Linaje , Polimorfismo de Nucleótido Simple , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Escoliosis/diagnóstico , Turquía , Adulto JovenRESUMEN
Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient. The oxygen consumption rate (OCR) and complex activity I and IV was measured. Patients 1 and 2 had exhibited global developmental delay and seizure since early infancy. Blood lactate, the lactate-to-pyruvate ratio, and urinary excretion of Krebs cycle intermediates were markedly elevated. Patient 1 also was noted for ophthalmoplegia. Patient 2 had left ventricular hypertrophy and ataxia. Patient 3 developed dysarthria, gait disturbance, and right-side weakness at age 29. Brain magnetic resonance imaging demonstrated abnormal signal intensity involving the bilateral thalami, midbrain, or pons. Based on WES, patient 1 had p.Glu415Gly and p.Arg484Trp variants in MTO1. In patient 2, p.Gln111ThrfsTer5 and RNA mis-splicing were identified in TSFM. Patient 3 carried p.Met151Thr and p.Met246Lys variants in AARS2. Skin fibroblasts of three patients exhibited decreased OCRs and complex 1 activity, and mitochondrial DNA was normal. These results demonstrate the utility of WES for identifying the genetic cause of extremely rare mitochondrial disorders, which has implications for genetic counseling.
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Alanina-ARNt Ligasa/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Factores de Elongación de Péptidos/genética , Proteínas de Unión al ARN/genética , Enfermedades Raras/genética , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , ADN Mitocondrial/genética , Disartria/genética , Disartria/fisiopatología , Exoma/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/fisiopatología , Imagen por Resonancia Magnética , Masculino , Mitocondrias/genética , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/fisiopatología , Mutación , Oftalmoplejía/genética , Oftalmoplejía/fisiopatología , Linaje , Enfermedades Raras/diagnóstico por imagen , Enfermedades Raras/fisiopatología , Secuenciación del ExomaRESUMEN
INTRODUCTION: The objective of this study was to obtain a 6-month natural history of motor function performance in individuals with RYR1- related myopathy (RYR1-RM) by using the Motor Function Measure-32 (MFM-32) and graded functional tests (GFT) while facilitating preparation for interventional trials. METHODS: In total, 34 participants completed the MFM-32 and GFTs at baseline and 6-month visits. RESULTS: Motor deficits according to MFM-32 were primarily observed in the standing and transfers domain (D1; mean 71%). Among the GFTs, participants required the most time to ascend/descend stairs (>7.5 s). Functional movement, determined by GFT grades, was strongly correlated with MFM-32 (D1; r ≥ 0.770, P < 0.001). Motor Function Measure-32 and GFT scores did not reflect any change in performance between baseline and 6-month visits. DISCUSSION: The MFM-32 and GFTs detected motor impairment in RYR1-RM, which remained stable over 6 months. Thus, these measures may be suitable for assessing change in motor function in response to therapeutic intervention. Muscle Nerve 60: 80-87, 2019.
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Movimiento/fisiología , Miopatías Estructurales Congénitas/fisiopatología , Canal Liberador de Calcio Receptor de Rianodina/genética , Adolescente , Adulto , Niño , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miopatías Estructurales Congénitas/genética , Miopatía del Núcleo Central/genética , Miopatía del Núcleo Central/fisiopatología , Oftalmoplejía/genética , Oftalmoplejía/fisiopatología , Canal Liberador de Calcio Receptor de Rianodina/deficiencia , Adulto JovenRESUMEN
INTRODUCTION: Valosin-containing protein (VCP) variants that affect muscle, bone, and the nervous system are termed multisystem proteinopathy. VCP myopathy is manifested as limb-girdle weakness, distal weakness and scapuloperoneal weakness. METHODS: We reviewed clinical, genetic, and muscle biopsy data from 6 members of a family with VCP myopathy. RESULTS: Clinical features of family members were complex and included dementia, myopathy, and hearing impairment. Ophthalmoplegia, ptosis, and dysphagia were present in 3 siblings. Rimmed vacuoles were observed in muscle biopsies, consistent with the pathological changes of VCP myopathy. A heterozygous VCP c.463C>A (p.R155S) that segregated in an autosomal-dominant pattern was identified by genetic analysis. CONCLUSIONS: VCP myopathy can cause unusual manifestations that include ophthalmoplegia, ptosis, and dysphagia. This study increased our understanding of the clinical manifestations of VCP myopathy. Muscle Nerve 59:365-369, 2019.