Gordon Holmes Syndrome is a rare inherited disease characterized by both neurological and reproductive signs and symptoms. Most patients develop neurologic challenges in early adulthood and cerebellar ataxia occurs as...Gordon Holmes Syndrome is a rare inherited disease characterized by both neurological and reproductive signs and symptoms. Most patients develop neurologic challenges in early adulthood and cerebellar ataxia occurs as the disease progresses. In the majority of patients, hypogonadism is hypogonadotropic but rarely hypergonadotropic. We report a case of a 26-year-old female in Nigeria, with hypergonadotropic hypogonadism and cerebellar atrophy from a non-consanguineous marriage and no family history.展开更多
Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progres...Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich's ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore,an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of wholeexome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.展开更多
Background:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been perform...Background:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.Methods:Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing(WES)and copy number variation(CNV)calling with ExomeDepth.Likely causal CNV predictions were validated by CNVseq.Results:Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients,providing a 46.3%positive molecular diagnostic rate.Ten different genes were involved,of which four most common genes were SACS,SYNE1,ADCK3 and SETX,which accounted for 76.0%(19/25)of the positive cases.The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide.Clinical features of the patients carrying SACS,SYNE1 and ADCK3 mutations were summarized.Conclusions:Our results expand the genetic spectrum and clinical profiles of ARCA patients,demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA,and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.展开更多
“Something is rotten in the state of Denmark”. These words of Shakespeare remember us that any small case can be connected with wider situation in the Globe. We would like to understand how changes electrical system...“Something is rotten in the state of Denmark”. These words of Shakespeare remember us that any small case can be connected with wider situation in the Globe. We would like to understand how changes electrical systems in time and what we will get in future. But what we know today about our home? Prominent scientists - physicists connect the past and future of our world with the formation and changes of black holes. “A black hole is a region of space-time whose gravitational attraction is so strong that even objects moving at the speed of light cannot leave it.” “A super massive black hole is a black hole with a mass of 105 - 1011 solar masses. Super massive black holes have been found at the center of many galaxies, including the Milky Way. Our galaxy revolves around a super massive black hole. This position of stellar bodies should be preserved for hundreds of millions of years.”展开更多
We report a patient with severe ataxia due to Dandy-Walker malformation, who showed functional recovery over 10 months corresponding to a change in a cerebellar peduncle lesion. A 20-month-old female patient who was d...We report a patient with severe ataxia due to Dandy-Walker malformation, who showed functional recovery over 10 months corresponding to a change in a cerebellar peduncle lesion. A 20-month-old female patient who was diagnosed with Dandy-Walker syndrome and six age- and sex-matched healthy control subjects were enrolled. The superior cerebellar peduncle, the middle cerebellar peduncle, and the inferior cerebellar peduncle were evaluated using fractional anisotropy and the apparent diffusion coefficient. The patients＇ functional ambulation category was 0 at the initial visit, but improved to 2 at the follow-up evaluation, and Berg＇s balance scale score also improved from 0 to 7. Initial diffusion tensor tractography revealed that the inferior cerebellar peduncle was not detected, that the fractional anisotropy of the superior cerebellar peduncle and middle cerebellar peduncle decreased by two standard deviations below, and that the apparent diffusion coefficient increased by two standard deviations over normal control values. However, on follow-up diffusion tensor tractography, both inferior cerebellar peduncles could be detected, and the fractional anisotropy of superior cerebellar peduncle increased to within two standard deviations of normal controls. The functional improvement in this patient appeared to correspond to changes in these cerebellar peduncles. We believe that evaluating cerebellar peduncles using diffusion tensor imaging is useful in cases when a cerebellar peduncle lesion is suspected.展开更多
Ataxia Telangiectasia (AT) is a rare autosomal recessive multisystem disease. The diagnosis is often made on a clinical triad that combines neurological signs dominated by a progressive cerebellar ataxia, oculocutaneo...Ataxia Telangiectasia (AT) is a rare autosomal recessive multisystem disease. The diagnosis is often made on a clinical triad that combines neurological signs dominated by a progressive cerebellar ataxia, oculocutaneous signs (telangiectasia, coffee stain milk), immunodeficiency (humoral and cellular) with sinopulmonary infections and elevated alphaphetoprotein. The diagnosis of AT is usually early, however, some forms may be revealed late. We reported a case of a 19-year-old patient, admitted for severe pneumonia with Klebsiella Pneumonia. In its history, it was found a notion of recurrent respiratory infections and bronchiectasis. In its clinical examination, it had been discovered cerebellar ataxia and occulocutaneous telangiectasia. The determination of plasmatic alphafoetoprotein was elevated, and the search of immunodeficiency showed a mixed deficit (humoral and cellular) suggesting the diagnosis of AT.展开更多
Introduction: Ataxia telangiectasia (AT) is a rare disease characterized by immunodeficiency and neurological manifestations. Ataxia, resulting from cerebella atrophy, runs a progressive incapacitating course. Clinica...Introduction: Ataxia telangiectasia (AT) is a rare disease characterized by immunodeficiency and neurological manifestations. Ataxia, resulting from cerebella atrophy, runs a progressive incapacitating course. Clinical monitoring of the disease course is mandatory for early treatment. Aim: To study clinical severity of AT and correlate it with the degree of cerebellar atrophy. Patients and Methods: We retrospectively studied all children (less than 14 years) with AT seen at Hamad General Hospital Clinics between 1998-2013. We collected basic demographic data, parental consan-guinity, family history, AT clinical severity scores, and reviewed CBC with differential counts;alpha-fetoprotein, serum immunoglobulins and lymphocyte subsets. Cranial MRI scans of each subject were reviewed by a neuroradiologist. Cerebellar atrophy was visually and semi-quantitatively scored. Results: We analyzed data on 18 AT children (10 males and 8 females), mean age of 76.9 months. 77.8% had a positive family history of AT and 41.7% parental consanguinity. Lymphopenia was observed in 77.8% and high serum alpha-fetoprotein in 87.5% of children. Clinical severity of ataxia was 17.1 ± 8.4 (mean ± SD);86.7% of patients were moderate-severe. MRI cerebellar atrophy score was 1.9 ± 1.3 (mean ± SD), and moderate in 51% of patients. AT clinical severity score correlated (coefficient r = 0.566) but not statistically significant p = 0.088) with MRI cerebellar atrophy scores. Conclusions: Moderate to severe ataxia and marked cerebellar atrophy are quite common in AT children. There is a correlation between AT clinical severity and cerebellar atrophy. Larger prospective studies might further determine the significance of our observations and help practicing practitioners monitor the progression of the disease.展开更多
文摘Gordon Holmes Syndrome is a rare inherited disease characterized by both neurological and reproductive signs and symptoms. Most patients develop neurologic challenges in early adulthood and cerebellar ataxia occurs as the disease progresses. In the majority of patients, hypogonadism is hypogonadotropic but rarely hypergonadotropic. We report a case of a 26-year-old female in Nigeria, with hypergonadotropic hypogonadism and cerebellar atrophy from a non-consanguineous marriage and no family history.
文摘Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich's ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore,an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of wholeexome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.
基金supported by grants from the National Natural Science Foundation of China(82071260 to Z.-Y.W.)the Research Foundation for Distinguished Scholar of Zhejiang University(188020-193810101/089 to Z.-Y.W.).
文摘Background:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.Methods:Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing(WES)and copy number variation(CNV)calling with ExomeDepth.Likely causal CNV predictions were validated by CNVseq.Results:Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients,providing a 46.3%positive molecular diagnostic rate.Ten different genes were involved,of which four most common genes were SACS,SYNE1,ADCK3 and SETX,which accounted for 76.0%(19/25)of the positive cases.The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide.Clinical features of the patients carrying SACS,SYNE1 and ADCK3 mutations were summarized.Conclusions:Our results expand the genetic spectrum and clinical profiles of ARCA patients,demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA,and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.
文摘“Something is rotten in the state of Denmark”. These words of Shakespeare remember us that any small case can be connected with wider situation in the Globe. We would like to understand how changes electrical systems in time and what we will get in future. But what we know today about our home? Prominent scientists - physicists connect the past and future of our world with the formation and changes of black holes. “A black hole is a region of space-time whose gravitational attraction is so strong that even objects moving at the speed of light cannot leave it.” “A super massive black hole is a black hole with a mass of 105 - 1011 solar masses. Super massive black holes have been found at the center of many galaxies, including the Milky Way. Our galaxy revolves around a super massive black hole. This position of stellar bodies should be preserved for hundreds of millions of years.”
基金supported by the Basic Scientific Research Program of National Research Foundation of Korea Funded by Ministry of Education, Science and Technology, No.2011-0003426
文摘We report a patient with severe ataxia due to Dandy-Walker malformation, who showed functional recovery over 10 months corresponding to a change in a cerebellar peduncle lesion. A 20-month-old female patient who was diagnosed with Dandy-Walker syndrome and six age- and sex-matched healthy control subjects were enrolled. The superior cerebellar peduncle, the middle cerebellar peduncle, and the inferior cerebellar peduncle were evaluated using fractional anisotropy and the apparent diffusion coefficient. The patients＇ functional ambulation category was 0 at the initial visit, but improved to 2 at the follow-up evaluation, and Berg＇s balance scale score also improved from 0 to 7. Initial diffusion tensor tractography revealed that the inferior cerebellar peduncle was not detected, that the fractional anisotropy of the superior cerebellar peduncle and middle cerebellar peduncle decreased by two standard deviations below, and that the apparent diffusion coefficient increased by two standard deviations over normal control values. However, on follow-up diffusion tensor tractography, both inferior cerebellar peduncles could be detected, and the fractional anisotropy of superior cerebellar peduncle increased to within two standard deviations of normal controls. The functional improvement in this patient appeared to correspond to changes in these cerebellar peduncles. We believe that evaluating cerebellar peduncles using diffusion tensor imaging is useful in cases when a cerebellar peduncle lesion is suspected.
文摘Ataxia Telangiectasia (AT) is a rare autosomal recessive multisystem disease. The diagnosis is often made on a clinical triad that combines neurological signs dominated by a progressive cerebellar ataxia, oculocutaneous signs (telangiectasia, coffee stain milk), immunodeficiency (humoral and cellular) with sinopulmonary infections and elevated alphaphetoprotein. The diagnosis of AT is usually early, however, some forms may be revealed late. We reported a case of a 19-year-old patient, admitted for severe pneumonia with Klebsiella Pneumonia. In its history, it was found a notion of recurrent respiratory infections and bronchiectasis. In its clinical examination, it had been discovered cerebellar ataxia and occulocutaneous telangiectasia. The determination of plasmatic alphafoetoprotein was elevated, and the search of immunodeficiency showed a mixed deficit (humoral and cellular) suggesting the diagnosis of AT.
文摘Introduction: Ataxia telangiectasia (AT) is a rare disease characterized by immunodeficiency and neurological manifestations. Ataxia, resulting from cerebella atrophy, runs a progressive incapacitating course. Clinical monitoring of the disease course is mandatory for early treatment. Aim: To study clinical severity of AT and correlate it with the degree of cerebellar atrophy. Patients and Methods: We retrospectively studied all children (less than 14 years) with AT seen at Hamad General Hospital Clinics between 1998-2013. We collected basic demographic data, parental consan-guinity, family history, AT clinical severity scores, and reviewed CBC with differential counts;alpha-fetoprotein, serum immunoglobulins and lymphocyte subsets. Cranial MRI scans of each subject were reviewed by a neuroradiologist. Cerebellar atrophy was visually and semi-quantitatively scored. Results: We analyzed data on 18 AT children (10 males and 8 females), mean age of 76.9 months. 77.8% had a positive family history of AT and 41.7% parental consanguinity. Lymphopenia was observed in 77.8% and high serum alpha-fetoprotein in 87.5% of children. Clinical severity of ataxia was 17.1 ± 8.4 (mean ± SD);86.7% of patients were moderate-severe. MRI cerebellar atrophy score was 1.9 ± 1.3 (mean ± SD), and moderate in 51% of patients. AT clinical severity score correlated (coefficient r = 0.566) but not statistically significant p = 0.088) with MRI cerebellar atrophy scores. Conclusions: Moderate to severe ataxia and marked cerebellar atrophy are quite common in AT children. There is a correlation between AT clinical severity and cerebellar atrophy. Larger prospective studies might further determine the significance of our observations and help practicing practitioners monitor the progression of the disease.
