RESUMEN
We report a case of monozygotic twin sisters with hereditary spastic paraplegia type 4 (SPG4) and epilepsy, only one of whom had a diagnosis of narcolepsy type 1 (NT1). The older sister with NT1 exhibited excessive daytime sleepiness, cataplexy, sleep-onset rapid eye movement period in the multiple sleep latency test, and decreased orexin levels in cerebrospinal fluid. Both sisters had HLA-DRB1*15:01-DQB1*06:02 and were further identified to have a novel missense mutation (c.1156A > C, p.Asn386His) in the coding exon of the spastin (SPAST) gene. The novel missense mutation might be involved in the development of epilepsy. This case is characterised by a combined diagnosis of SPG4 and epilepsy, and it is the first report of NT1 combined with epilepsy and genetically confirmed SPG4. The fact that only one of the twins has NT1 suggests that acquired and environmental factors are important in the pathogenesis of NT1.
RESUMEN
SPG31 is an autosomal dominant hereditary spastic paraplegia caused by pathogenic variants in the receptor expression-enhancing protein 1 (REEP1) gene. We analyzed 488 DNA samples from unrelated HSP patients collected by Japan Spastic Paraplegia Research Consortium and found 15 Japanese SPG31 families. We investigated each family and found a total of 25 individuals with REEP1 variants (comprising 22 patients and three asymptomatic carriers). Fourteen REEP1 variants (five missense, three nonsense, four frameshift, one splice site, and one large deletion) including 11 novel ones were detected. Seventy percent of the patients (14 of 20) showed a pure form and the others (6 of 20) showed a complicated form with peripheral neuropathy. Fifty percent of the patients had neurological symptoms before the age of 10 and 20% of them at age 41-50. The mean age of onset was 19.6 ± 18.7 (from 5 to 67, n = 15) years for males and 32.8 ± 24.7 (from 4 to 60, n = 5) years for females. Although the difference was not statistically significant (p = 0.38, Mann-Whitney U test), males tended to have an earlier age of onset. Moreover, all three asymptomatic carriers were female. We investigated additional factors as to phenotypic appearance in one family with apparent intrafamilial variability in age at onset and clinical severity, but no additional factors including gene variants could be found. This is the first report of clinical and genetic findings of SPG31 in Japan, which may lead to further studies of the genotype-phenotype correlation of SPG31.
Asunto(s)
Paraplejía Espástica Hereditaria , Femenino , Humanos , Japón/epidemiología , Masculino , Proteínas de Transporte de Membrana/genética , Mutación , Fenotipo , Paraplejía Espástica Hereditaria/genéticaRESUMEN
Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by weakness and leg spasticity. LYST is responsible for Chédiak-Higashi syndrome (CHS), which exhibits partial oculocutaneous albinism, primary immunodeficiency, and bleeding tendency in childhood. Although neurological symptoms of CHS also appear in adulthood, a phenotype of spastic paraplegia has rarely been reported in CHS. In this study, we investigated LYST mutations in 387 HSP patients through the Japan Spastic Paraplegia Research Consortium to clarify the frequency of LYST mutations in HSP, finding six adult patients with LYST mutations in four HSP families. They exhibited intellectual disability, cerebellar ataxia, neuropathy, and pyramidal signs. Meanwhile, only 15 patients with CHS in childhood have been revealed in a decade by a nationwide survey in Japan. Thus, LYST mutations might indicate a HSP phenotype in a considerable number of adult patients with CHS.
Asunto(s)
Síndrome de Chediak-Higashi/genética , Mutación , Paraplejía Espástica Hereditaria/genética , Proteínas de Transporte Vesicular/genética , Adulto , Síndrome de Chediak-Higashi/diagnóstico , Diagnóstico Diferencial , Salud de la Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/diagnóstico , Secuenciación del Exoma/métodosRESUMEN
Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs due to pyramidal tract dysfunction. REEP2 mutations have been identified as a cause of "pure" HSP, SPG72, with both autosomal dominant and autosomal recessive inheritance. We describe a rare Nepalese family with early-onset pure-type HSP harboring a heterozygous REEP2 missense mutation (c.119T>G, p.Met40Arg). This is only the second SPG72 family with autosomal dominant inheritance. The proband presented slow and spastic gait at age 2 years and the symptoms progressed slowly. The proband's father and uncle presented even milder symptoms of pure spastic paraplegia. Our study may provide an opportunity to further study the genotype-phenotype correlation of SPG72.
Asunto(s)
Predisposición Genética a la Enfermedad , Proteínas de Transporte de Membrana/genética , Paraplejía Espástica Hereditaria/genética , Adulto , Edad de Inicio , Preescolar , Estudios de Asociación Genética , Genotipo , Heterocigoto , Humanos , Masculino , Mutación Missense/genética , Nepal/epidemiología , Linaje , Paraplejía Espástica Hereditaria/epidemiología , Paraplejía Espástica Hereditaria/patologíaRESUMEN
BACKGROUND: ALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A. CASE PRESENTATION: A Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine. CONCLUSIONS: Since the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.
Asunto(s)
Aldehído Deshidrogenasa/genética , Huesos/anomalías , Catarata/complicaciones , Catarata/genética , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/genética , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/genética , Paraplejía Espástica Hereditaria/complicaciones , Paraplejía Espástica Hereditaria/genética , Adulto , Pueblo Asiatico/genética , Femenino , Heterocigoto , Humanos , Masculino , Mutación , Proteínas de la Mielina/genética , Linaje , FenotipoRESUMEN
Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Saposinas/genética , Anciano , Animales , Estudios de Casos y Controles , Neuronas Dopaminérgicas/patología , Femenino , Humanos , Masculino , Ratones , Ratones Mutantes , Persona de Mediana Edad , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Enfermedad de Parkinson/patologíaRESUMEN
Recently, the expansion of an intronic AAGGG repeat in the replication factor C subunit 1 (RFC1) gene was reported to cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In Europeans, the expansion accounted for 22% of sporadic patients with late-onset ataxia. We genotyped 37 Japanese patients comprising 25 familial (autosomal recessive or undecided transmission) and 12 sporadic ones with late-onset ataxia. We found intronic repeat expansions in RFC1 in three (12%) of the familial patients and one (8.5%) of the sporadic ones. Although our cohort study was small, the disease frequency in Japanese patients with CANVAS might be lower than that in European ones. In addition, we found biallelic ACAGG repeat expansion in one patient, indicating ACAGG repeat expansion might cause CANVAS. Clinically, we found one patient with sleep apnea syndrome, which has not been reported previously. Thus, this study might expand the clinical and genetic spectrum of CANVAS.
Asunto(s)
Expansión de las Repeticiones de ADN/genética , Predisposición Genética a la Enfermedad , Proteína de Replicación C/genética , Degeneraciones Espinocerebelosas/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Intrones/genética , Japón/epidemiología , Masculino , Persona de Mediana Edad , Degeneraciones Espinocerebelosas/epidemiología , Degeneraciones Espinocerebelosas/patologíaRESUMEN
BACKGROUND: To find out the physiological method for evaluating the severity of central autonomic dysfunction, we performed detailed evaluation of cutaneous vasomotor neural function in a comparatively large sample of multiple system atrophy (MSA). METHODS: We evaluated cutaneous vasomotor neural function in 24 MSA patients. Skin sympathetic nerve activity (SSNA) and sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex [SVR]) were recorded at rest, as well as reflex changes after electrical stimulation. The parameters investigated were SSNA frequency at rest, reflex latency and amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and spontaneous SVR and SSR frequency. RESULTS: There were negative correlations between resting SSNA and disease duration or the SCOPA-AUT score, but these were not significant. SSNA reflex latency displayed significant positive correlations with disease duration and SCOPA-AUT score (p < 0.001 and p < 0.01, respectively). In all five patients who underwent the same examination twice, SSNA reflex latency was significantly longer at the second examination than at the first examination (p < 0.005). A significant positive correlation was identified between recovery time of skin blood flow and SCOPA-AUT score or reflex latency (p < 0.05). Significant correlations were not observed between SCOPA-AUT score or disease duration and other parameters. CONCLUSIONS: These results suggest that some MSA patients with a comparatively short duration of disease potentially have impaired thermoregulatory function. Measurement of sympathetic outflow to the skin is potentially a useful tool for predicting the severity of central autonomic dysfunction in MSA.
Asunto(s)
Atrofia de Múltiples Sistemas , Estimulación Eléctrica , Humanos , Atrofia de Múltiples Sistemas/complicaciones , Reflejo , Piel , Sistema Nervioso SimpáticoRESUMEN
We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC). Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene. A mouse homolog of one UBAP1 frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80). All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes. Our study demonstrated that mutations in the UBAP1 gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.
Asunto(s)
Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad , Enfermedades Neurodegenerativas/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Animales , Pueblo Asiatico , Niño , Modelos Animales de Enfermedad , Endosomas/genética , Femenino , Mutación del Sistema de Lectura/genética , Humanos , Japón , Masculino , Ratones , Persona de Mediana Edad , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/metabolismo , Neuronas/patología , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/fisiopatología , Secuenciación del ExomaRESUMEN
The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.
Asunto(s)
Mutación , Paraplejía/genética , Polineuropatías/genética , Proteínas/genética , Corteza Sensoriomotora/patología , Adulto , Edad de Inicio , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Masculino , Paraplejía/patología , Linaje , Polineuropatías/patología , Corteza Sensoriomotora/metabolismoRESUMEN
PLA2G6-associated neurodegeneration (PLAN) comprises heterogeneous neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation 2B, and Parkinson disease 14 (PARK14). In addition, very recently, PLA2G6 mutations have been reported to represent a phenotype of hereditary spastic paraplegia (HSP). In this study, we screened 383 HSP families to clarify the frequency of PLA2G6 mutations in the Japan Spastic Paraplegia Research Consortium, and revealed the clinical characteristics of HSP with PLA2G6 mutations. We found three families with compound heterozygous mutations of the PLA2G6 gene, c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, and c.1187-2 A > G/c.1933C > T, and one family with a homozygous mutation of the PLA2G6 gene, c.1904G > A/c.1904G > A. All three families with compound heterozygous mutations presented a uniform phenotype of a complicated form of HSP with infantile/child-onset spastic paraplegia, cerebellar ataxia, and mental retardation. On the other hand, the family with a homozygous mutation presented a late-onset complicated form of HSP with parkinsonism. This study may extend the clinical and genetic findings for PLAN.
Asunto(s)
Fosfolipasas A2 Grupo VI/genética , Mutación , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Paraplejía Espástica Hereditaria/complicaciones , Edad de Inicio , Anciano , Niño , Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Enfermedades Neurodegenerativas/etiología , Trastornos Parkinsonianos/etiología , FenotipoRESUMEN
The originally published version of this article contained an error in Fig. 1 and Table 2. The correct figure and table of this article should have read as below. This has now been corrected in the PDF and HTML versions of the article. The authors apologize for any inconvenience caused.
RESUMEN
BACKGROUND: Non-dystrophic myotonias (NDMs) are skeletal muscle disorders involving myotonia distinct from myotonic dystrophy. It has been reported that the muscle pathology is usually normal or comprises mild myopathic changes in NDMs. We describe various pathological findings mimicking those of myotonic dystrophy (DM) in biopsied muscle specimens from a patient with NDMs with a long disease duration. CASE PRESENTATION: A 66-year-old Japanease man presented eye closure myotonia, percussion myotonia and grip myotonia together with the warm-up phenomenon and cold aggravation from early childhood. On genetic analysis, a heterozygous mutation of the SCN4A gene (c.2065 C > T, p.L689F), with no mutation of the CLCN1, DMPK, or ZNF9/CNBP gene, was detected. He was diagnosed as having NDMs. A biopsy of the biceps brachii muscle showed increasing fiber size variation, internal nuclei, chained nuclei, necrotic fibers, fiber splitting, endomysial fibrosis, pyknotic nuclear clumps and disorganized intermyofibrillar networks. Sarcoplasmic masses, tubular aggregates and ragged-red fibers were absent. CONCLUSION: It is noteworthy that the present study revealed various pathological findings resembling those seen in DM, although the pathology is usually normal or mild in NDMs. The pathological similarities may be due to muscular modification with long-standing myotonia or excessive muscle contraction based on abnormal channel activity.
Asunto(s)
Músculo Esquelético/patología , Miotonía/genética , Miotonía/patología , Canal de Sodio Activado por Voltaje NAV1.4/genética , Anciano , Heterocigoto , Humanos , Masculino , MutaciónRESUMEN
We report the first family with a glycyl-tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot-Marie-Tooth disease (DI-CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI-CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Glicina-ARNt Ligasa/genética , Adulto , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Conducción Nerviosa/fisiología , Linaje , Nervio Sural/patología , Adulto JovenRESUMEN
Hereditary spastic paraplegias (HSPs) are characterized by various inherited disorders in which weakness and spasticity of the lower extremities are the predominant symptoms. Recently, HSP caused by ALDH18A1 mutations has been reported as SPG9 with autosomal dominant (SPG9A) and autosomal recessive (SPG9B) transmission. In this study, we obtained clinical and genetic findings in two Japanese families with SPG9B. One family had a novel compound heterozygous mutation (c.1321 C > T/c.1994G > A) in the ALDH18A1 gene. The other family had a homozygous mutation (c.383 G > A/c.383 G > A) in the ALDH18A1 gene. To date, only two SPG9B families with ALDH18A1 mutations have been reported. This is the first report of SPG9 in non-Caucasians. Furthermore, we found cerebellar ataxia in one family, although cerebellar ataxia has not been reported in SPG9B so far. SPG9B might involve a complicated HSP including cerebellar ataxia and cognitive impairment. This study expands the clinical and genetic spectrum of ALDH18A1-related disorders.
Asunto(s)
Aldehído Deshidrogenasa/genética , Ataxia Cerebelosa/genética , Disfunción Cognitiva/genética , Mutación Missense , Paraplejía Espástica Hereditaria/genética , Sustitución de Aminoácidos , Ataxia Cerebelosa/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Femenino , Humanos , Masculino , Paraplejía Espástica Hereditaria/diagnóstico por imagenRESUMEN
To investigate the vasomotor regulation in multiple system atrophy (MSA), we simultaneously recorded muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure in 14 MSA patients without syncope and 18 healthy subjects. Resting MSNA bursts were significantly less frequent in MSA patients than healthy subjects (p < 0.001), while the increase of MSNA bursts with head-up tilt was significantly greater in MSA patients (p < 0.01). In patients with MSA, orthostatic hypotension may be prevented by an augmented MSNA response.
Asunto(s)
Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Atrofia de Múltiples Sistemas/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Determinación de la Presión Sanguínea , Electrocardiografía , Femenino , Humanos , Hipotensión Ortostática/fisiopatología , Masculino , Persona de Mediana Edad , Músculos/fisiopatología , DescansoRESUMEN
On whole-exome sequencing, a novel compound heterozygous mutation (c.2923A>G/c.3523_3524insTGTCCG, p.T975A/p.1175_1176insVS) and a novel homozygous one (c.3534G>C, p.W1178C) in the PNPLA6 gene were identified in sporadic and familial Japanese patients with Boucher-Neuhäuser syndrome (BNS), respectively. However, we did not find any mutations in the PNPLA6 gene in 88 patients with autosomal recessive hereditary spastic paraplegia (ARHSP). Our study confirmed the earlier report that a PNPLA6 mutation causes BNS. This is the first report on PNPLA6 mutations in non-Caucasian patients. Meanwhile, PNPLA6 mutations might be extremely rare in Japanese ARHSP patients. Moreover, we first found hypersegmented neutrophils in two BNS patients with PNPLA6 mutations.
Asunto(s)
Hipogonadismo/genética , Mutación , Fosfolipasas/genética , Distrofias Retinianas/genética , Ataxias Espinocerebelosas/genética , Secuencia de Bases , Exoma , Femenino , Estudios de Asociación Genética , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Hipogonadismo/diagnóstico , Masculino , Neutrófilos/patología , Distrofias Retinianas/diagnóstico , Ataxias Espinocerebelosas/diagnósticoAsunto(s)
Ataxia , Trastornos Neurológicos de la Marcha , Inmunoglobulinas Intravenosas/farmacología , Factores Inmunológicos/farmacología , Neoplasias del Mediastino/diagnóstico , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Polineuropatía Paraneoplásica , Trastornos de la Sensación , Adulto , Ataxia/diagnóstico , Ataxia/tratamiento farmacológico , Ataxia/etiología , Trastornos Neurológicos de la Marcha/diagnóstico , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/etiología , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Masculino , Neoplasias del Mediastino/complicaciones , Neoplasias de Células Germinales y Embrionarias/complicaciones , Polineuropatía Paraneoplásica/diagnóstico , Polineuropatía Paraneoplásica/tratamiento farmacológico , Polineuropatía Paraneoplásica/etiología , Trastornos de la Sensación/diagnóstico , Trastornos de la Sensación/tratamiento farmacológico , Trastornos de la Sensación/etiologíaRESUMEN
To date, four families with spinocerebellar ataxia type 5 (SCA5) with four distinct mutations in the spectrin, beta, nonerythrocytic 2 gene (SPTBN2) have been reported worldwide. In the present study, we identified the first Japanese family with SCA5, and analyzed this family clinically and genetically. The clinical features of the five patients in this family revealed late-onset autosomal-dominant pure cerebellar ataxia. We collected DNA samples from the majority of the family members across two generations, and exome sequencing combined with Sanger sequencing revealed a novel heterozygous three-nucleotide in-frame deletion mutation (c.2608_2610delGAG) in exon 14 of the SPTBN2 gene. This mutation cosegregated with the disease in the family and resulted in a glutamic acid deletion (p.E870del) in the sixth spectrin repeat, which is highly conserved in the SPTBN2 gene. This is the first three-nucleotide in-frame deletion mutation in this region of the beta-3 spectrin protein highly likely to be pathogenic based on exome and bioinformatic data.