Primary dystonias and genetic disorders with dystonia as clinical feature of the disease

Dystonia is probably the most common form of movement disorder encountered in the clinical practice. It is characterized by sustained muscle contractions, usually producing twisting and repetitive movements or abnormal postures or positions. Dystonias can be classified in several ways, including primarily by the clinical phenomenology or by the underlining etiology, in particular to understand if the presentation is genetically determined. By advances of genetics, including contemporary genomic technologies, there is a growing understanding of the molecular underpinnings of genetically determined dystonias. The intricacy of information requires a user friendly, novel database that may efficiently serve clinicians to inform of advances of the field and to diagnose and manage these often complex cases.Here we present an up to date, comprehensive review – in tabulated formats – of genetically determined primary dystonias and complex Mendelian disorders with dystonia as central feature. The detailed search up to December 24, 2012, identified 24 hereditary primary dystonias (DYT1 to DYT 25) that are mostly monogenic disorders, and a larger group (>70) of genetic syndromes in which dystonia is one of the characteristic clinical features. We organized the findings not only by individual information (name of the conditions, pattern of inheritance, chromosome and gene abnormality, clinical features, relevant ancillary tests and key references), but also provide symptom-oriented organization of the clinical entities for efficient inquiries.     

Myoclonus in fraternal twin toddlers: A French family with a novel mutation in the SGCE gene

Myoclonus dystonia is a rare movement disorder caused by mutations in the SGCE gene on chromosome 7q21 (DYT11) encoding the epsilon-sarcoglycan. Myoclonus is present in almost all patients and affects most often neck, trunk and upper limbs. Dystonia is present in about half of the patients. The mode of inheritance is autosomal dominant with variable clinical expression and maternal imprinting. Onset is usually in childhood or adolescence. Alcohol might relieve symptoms.We present a 33 month old girl and her twin brother with disabling involuntary jerky movements during intentional tasks. Family history of this French family was positive for the paternal uncle, his two daughters and the paternal great grandfather. Sequencing of the SGCE gene revealed a novel nonsense mutation c.942C > A (p.Tyr314X) in exon 7, confirming the diagnosis of myoclonus dystonia. Treatment with valproic acid significantly reduced myoclonic episodes and ameliorated life quality.     

Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B

In 2016, two research groups independently identified microdeletions and pathogenic variants in the lysine-specific histone methyltransferase 2B gene, KMT2B in patients with early-onset progressive dystonia. KMT2B-dystonia (DYT28) is emerging as an important and frequent cause of childhood-onset progressive generalised dystonia and is estimated to potentially account for up to 10% of early-onset generalised dystonia. Herein, we review variants in KMT2B associated with dystonia, as well as the clinical phenotype, treatment and underlying disease mechanisms. Furthermore, in context of this newly identified condition, we summarise our approach to the genetic investigation of paediatric dystonia.     

DYT2 screening in early-onset isolated dystonia

Background

Mutations in HPCA, a gene implicated in calcium signaling in the striatum, have been recently described in recessive dystonia cases previously grouped under the term “DYT2 dystonia”. Positive patients reported so far show focal onset during childhood with subsequent generalization and a slowly progressive course to adulthood.

Chromosome changes connect immunodeficiency and cancer in ataxia-telangiectasia

Ataxia-telangiectasia (AT) is a primary genetic immunodeficiency disease predisposing to cancer. Approximately 40% of patients with AT develop malignancy, usually of the lymphoid system. Increased chromosome breakage in AT leads to rearrangements such as translocations and inversions. The preferred chromosome breakpoints in AT involve genes in the immune system: the immunoglobulin (Ig) gene loci in chromosome bands 2p12, 14q32, and 22q11 and the T cell receptor (TCR) gene loci in chromosome bands 7p13, 7q35, and 14q11. Identical chromosome breakpoints are observed in chromosome rearrangements in normal T cells, Burkitt's lymphoma, and adult T cell leukemia. Molecular analysis of these chromosome rearrangements reveals recombination between an oncogene and Ig or between Ig and TCR. In AT, chromosome rearrangements connect the immune system to lymphoid cancer.     

Diagnosis and treatment of pediatric onset isolated dystonia

Isolated dystonia refers to a genetic heterogeneous group of progressive conditions with onset of symptoms during childhood or adolescence, progressive course with frequent generalization and marked functional impairment. There are well-known monogenic forms of isolated dystonia with pediatric onset such as DYT1 and DYT6 transmitted with autosomal dominant inheritance and low penetrance. Genetic findings of the past years have widened the etiological spectrum and the phenotype. The recently discovered genes (GNAL, ANO-3, KTM2B) or variant of already known diseases, such as Ataxia-Teleangectasia, are emerging as another causes of pediatric onset dystonia, sometimes with a more complex phenotype, but their incidence is unknown and still a considerable number of cases remains genetically undetermined.Due to the severe disability of pediatric onset dystonia treatment remains unsatisfactory and still mainly based upon oral pharmacological agents. However, deep brain stimulation is now extensively applied with good to excellent results especially when patients are treated early during the course of the disease.     

Mutations in SOX9 cause both autosomal sex reversal and campomelic dysplasia

The human testis determining factor (SRY) has been cloned from the Y chromosome. This gene is a dominant inducer of male differentiation. Mutations in the SRY gene result in an XY individual developing as a sex reversed phenotypic female. Sex reversal in humans can also be caused by mutations located in autosomal or X-linked loci. One such sex-reversing locus (SRAI) is associated with the developmental disorder campomelic dysplasia (CD). Both these syndromes were mapped to human chromosome 17q by the identification of balanced reciprocal translocations in five unrelated patients. The translocation breakpoint of one such XY-female CD patient was mapped and the region surrounding it cloned. The closest distal marker used to map the translocation breakpoint was the SOX9 gene. Because of the close proximity of this gene to the breakpoint, it was subjected to mutation analysis in patients without overt chromosome rearrangements. Analysis of DNA from these patients and their parents identified de novo mutations in the SOX9 gene in patients with both autosomal sex reversal and CD. This showed that mutations in the SOX9 gene are responsible for both syndromes.     

Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma

BACKGROUND: Neuroblastoma tumorigenesis may involve the differential inactivation of multiple tumor suppressor genes. Recent data have suggested that a neuroblastoma suppressor gene may be located on the long arm of chromosome 11 (11q). PROCEDURE: We therefore analyzed 295 primary neuroblastomas from a representative group of patients for loss of heterozygosity (LOH) at 25 polymorphic markers spanning 11q. RESULTS: LOH was observed in 129 primary neuroblastomas (44%), and a common region of LOH mapped to 11q14-23. No correlation was found between 11q LOH and adverse prognostic variables, but a strong inverse relationship between 11q LOH and MYCN amplification (P < 0.001) was observed. There was no difference in overall survival when patients were stratified by 11q LOH status. However, 11q LOH was associated with a decreased overall survival probability when patients whose tumors had a single copy of MYCN were analyzed separately (P = 0.008). CONCLUSION: These data support the hypothesis that a tumor suppressor gene mapping within 11q14-23 is frequently inactivated during the malignant evolution of neuroblastoma.     

原发性肠淋巴瘤p53基因与13q14染色体变异与预后的关系

目的：临床发现尽管原发性肠淋巴瘤的免疫表型相同,但预后也可以截然不同,提示其预后不是单一因素所决定的,可能还与其基因或染色体的变异有关。p53基因是一种重要的抑癌基因,13q14缺失是多种淋巴细胞增殖性疾病常见的染色体异常,该研究拟探讨p53基因与13q14染色体变异在原发性肠淋巴瘤的预后判断、指导治疗中的作用,为临床治疗方案的制定提供依据。方法：采用改良的FISH技术检测了30例原发性肠淋巴瘤及10例淋巴结反应性增生患者的石蜡切片中p53基因及13q14染色体变异情况,分析其与原发性肠淋巴瘤预后的关系。结果：①Ⅰ~Ⅱ期患者中22.7%有p53基因缺失,Ⅲ~Ⅳ期患者中75.0%有p53基因缺失（χ2=6.903, P<0.01）;②MALT淋巴瘤中14.3%有p53基因缺失,非MALT淋巴瘤中56.3%有p53基因缺失（χ2=5.662, P<0.05）;③p53基因缺失者平均生存期为13.4月,明显短于p53基因正常者36.1月（t=2.637,P<0.05）;④13q14缺失在原发性肠淋巴瘤中发生率为40%,但在10例淋巴结反应性增生患者的石蜡切片中未检测到。13q14缺失与原发性肠淋巴瘤病理类型、临床分期以及平均生存期的关系不大;⑤p53基因缺失与13q14缺失无明显相关性。结论：p53基因缺失在非MALT淋巴瘤及Ⅲ~Ⅳ期患者中发生率较高。p53基因缺失的原发性肠淋巴瘤病例恶性程度高、预后差,宜早期联合化疗。13q14缺失与患者预后无明显相关性。［中国当代儿科杂志,2009,11（7）：555-558］     

良性家族性婴儿惊厥一家系基因定位及钾离子通道基因测序研究

目的：对一良性家族性婴儿惊厥家系进行基因定位，并对候选基因钾离子通道基因KCNQ2进行测序分析。方法：共抽取14例血样，包括全部9例患者。同时对家系全部成员行脑电图、全身及神经系统检查。在19qD19S245至D19S250间选择6对微卫星标记进行连锁分析。KCNQ2基因外显子测序引物序列采用Biervert等所报道的序列。结果：该家系两点间连锁结果排除了与19q及8q24连锁的可能。在20q13.3(D20S480)最大LOD值为0.60（外显率90%）。染色体单体型分析提示可能与20q13.3连锁。KCNQ2基因测序发现外显子6有一C/T杂合突变多态性，外显子17有1个A/C错义多态性，内含子14人一4个碱基插入多态性。结论：该家系的连锁结果排除了与19q的连锁可能，提示BFIC的遗传多态性。该家系所发现的多态性变化对其他癫痫家系的连锁分析及其他癫综合征分子遗传学机制的研究，均有重要意义。     

Site Specific Mapping of Chromosome 21 Gene Probes and the Study of Down Syndrome

Eleven site-specific gene probes derived from human chromosome 21 were assigned to each region on the original chromosome by in situ hybridization. These probes were isolated from a lambda library, which contains inserts from chromosome 21 in the human-mouse hybrid cell WA17. This cell contains chromosome 21 as its only human chromosome. These single copy inserts had unique DNA sequence and had been screened for restriction fragment length polymorphism (RFLP) in the DNA of unrelated humans. Among the eleven probes, five were assigned to 21q22.3, two to 21 ql 1, and the four remaining genes were respectively assigned to 21 ql 1 - 21q21, 21q21, 21q21 - 21q22.1, and a centromeric region. The gene locus of superoxide dismutase-1 (SOD-1) was determined to be at 21q22.1. Since region q22 is suggested to be the gene loci of the main features of Down syndrome, probes in the region may yield information about this disorder. A pericentric probe is useful in determining predisposition to non-disjunction in 21 trisomy. We determined gene loci for these site-specific gene probes in order to make a complete gene map of the chromosome.     

Molecular genetics of Wilms' tumour

Wilms' tumour, or nephroblastoma, is an embryonal malignancy of the kidney with an incidence of approximately 1 in 10000 live births. It occurs in both sporadic and familial forms, but only 1% of Wilms' tumour patients have a positive family history. The molecular genetics of Wilms' tumour have been the subject of extensive research and at least three genes ( WT 1, WT 2, WT 3) have been implicated. WT 1 has been mapped to 11p13, and it has been suggested that loss or inactivation of a tumour-suppressor gene at 11p13 might be a primary event in the development of Wilms' tumour. The WT 2 gene maps to 11p15 in the region of the Beckwith-Wiedemann locus. The WT 3 locus is likely to be located to chromosome 16q. The understanding of the molecular genetics of Wilms' tumour is reviewed briefly.     

Novel homozygous sequence variants in the GDF5 gene underlie acromesomelic dysplasia type‐grebe in consanguineous families

Acromesomelic dysplasia Grebe type (AMDG) is characterized by severe knob like non‐functional fingers and short acromesomelic limbs, and is inherited in an autosomal recessive manner. Disease causing sequence variants in the GDF5 (Growth Differentiation Factor 5) gene located on chromosome 20q11.22 are responsible for causing AMDG. In the study, presented here, two consanguineous families with AMDG were clinically and genetically characterized. After establishing linkage in the two families (A and B) to GDF5 gene on chromosome 20q11.22, Sanger DNA sequencing was performed in all available affected and unaffected members. Sequence analysis of the GDF5 gene revealed two novel variants including a duplication (c.157_158dupC, p.Leu53Profs*41) in family A, and a nonsense (p.Trp291*) in family B. Our findings extend the body of evidence that supports the importance of GDF5 in the development of limbs.     

Clinical and Molecular Genetics of Inherited Hydrocephalus*

ABSTRACT Congenital hydrocephalus has a broad spectrum of etiology and has not been elucidated in terms of pathogenesis or mechanism of hydrocephalus. Recent advance of molecular genetics disclosed the genetic defects of X-linked hydrocephalus (HSAS), MASA syndrome and X-linked spastic paraplegia (SPGI), characterized by mutations in LICAM, a gene coding for a neural cell adhension molecule. Meanwhile, genetic heterogeneity in X-linked hydrocephalus has been pointed out; linkage to markers within Xq27.3. We reviewed inherited hydrocephalus and chromosomal aberrations with hydrocephalus because fibroblasts from patients with these disorders may be useful for a molecular genetic approach to inherited hydrocephalus. Animal models of congenital hydrocephalus are also very important for a comparative mapping analysis between mice and human. We have tried to clone a candidate gene of hydrocephalus using fibroblasts which show a de nove chromosomal aberration [t(4;16)(q35;q22.1)], because the synteny conservation locus for mouse hydrocephalus-3 (hy-3) gene is suggested to be located in the long arm of human chromosome 16. A rearranged band of 1.2 Mb was detected by Pulse-Field Gel Electrophoresis (PFGE) with Not I digestion using the calretinin probe. It may exist within 1.2 Mb distal apart from calretinin gene. Further analysis is carried out in order to clone this candidate gene of congenital hydrocephalus.     

Cohen's syndrome: non-causal association with vascular rings

Cohen syndrome is an autosomal recessive disorder characterized by hypotonia, mental retardation, microcephalia, typical craniofacial features, myopia and chorioretinal dystrophy. The responsible gene has been mapped to chromosome 8q 22 (COH 1). Since it was described more than 100 patients have been reported. However, none of them has been associated with vascular rings. Our hospital has studied eight pediatric cases and 25% of them were related with vascular rings.     

Molecular analysis of medulloblastomas occurring simultaneously in monozygotic twins

We report male monocygotic twins with concordant desmoplastic medulloblastoma diagnosed at the age of 20 months. Both tumours were completely removed. As chromosomal loci 17p13 and 9q31 are frequently altered in medulloblastoma these regions were analysed in both tumours in detail using restriction fragment length polymorphism and microsatellite analysis. No common aberration was found. The c-myc gene on chromosome 8q21 was not amplified. Conclusion Although a common genetic defect has not been found in our patients’ tumours the clinical presentation supports the assumption of an inherited genetic predisposition to develop medulloblastoma in at least some cases. Received: 23 November 1995 Accepted: 22 February 1996     

ACTH resistance syndromes

Inherited adrenocorticotropin (ACTH) insensitivity syndromes comprise a group of rare diseases in which resistance to ACTH is either the sole feature or associated with other symptoms. This review focuses on two autosomal recessive disorders, familial glucocorticoid deficiency (FGD) (MIM*202200) and the triple A syndrome (MIM*231550), which have at least three different molecular aetiologies. In FGD, several missense mutations within the coding region of the ACTH receptor (MC2-R) have been identified in some, but not all patients, and segregation analyses and functional studies in a Y6 cell expression system confirmed that these mutations cause the disease. Some cases of FGD are not linked to the MC2-R locus on chromosome 18p11.2 suggesting genetic heterogeneity. The triple A syndrome is clinically characterized by the triad of adrenal insufficiency, achalasia and alacrima and a variety of neurological symptoms. After excluding several candidate genes we mapped this syndrome to a 6 cM interval on chromosome 12q13 with no indication for genetic heterogeneity. The identification of the gene(s) causing FGD without mutations in the MC2-R and causing the triple A syndrome may reveal novel aspects in cell signalling and neuroendocrinology.     

DELETION MAPPING OF CRITICAL REGION FOR HYPOSPADIAS, PENOSCROTAL TRANSPOSITION AND IMPERFORATE ANUS ON HUMAN CHROMOSOME 13

BACKGROUND: The 13q-deletion syndrome causes human congenital birth defects due to the loss of regions of one long arm of human chromosome 13. A distal critical region for severe genitourinary and anorectal birth defects in the region of 13q32.2-34 has been suggested; we sought to narrow this critical region. METHODS: From patients with karyotypes revealing haploinsufficiency for distal chromosome 13q and their parents, peripheral blood was obtained and lymphocytes were immortalized for DNA isolation. Genetic and molecular cytogenetic methods were used to map deletions. Patient and parental samples were genotyped with a panel of 20 microsatellite markers spanning 13q31.3 qter and deletions identified by loss of heterozygosity. Deletions were also mapped using a panel of 35 BAC clones from the same region as probes for fluorescence in-situ hybridization on patient lymphoblastoid metaphase preparations. The data were synthesized and a deletion map defining the critical region was generated. RESULTS: Eight patients with known deletions around 13q32qter and their parents were analyzed, and categorized into three groups: three patients with anorectal and genitourinary anomalies (hypospadias, penoscrotal transposition), four male patients without anorectal and genitourinary anomalies, and one XY patient with ambiguous genitalia without anorectal anomalies. We mapped the critical region for anorectal and genitourinary anomalies to a approximately 9.5-Mb interval of 13q33.3-q34 delineated by markers D13S280-D13S285; this spans approximately 8% of the chromosome and contains 20 annotated genes CONCLUSION: The critical region of chromosome 13q mediating genitourinary/anorectal anomalies has been mapped, and will be narrowed by additional patients and further mapping. Identification of the gene(s) mediating these syndromic genitourinary defects should further our knowledge of molecular mediators of non-syndromic hypospadias, penoscrotal transposition and anorectal malformations.     

Tuberous sclerosis complex: a review.

Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder characterized by the potential for hamartoma formation in almost every organ. The inheritance is autosomal dominant with almost complete penetrance but variable expressivity. The two gene loci that code for TSC are TSC1, located on chromosome 9q34, and TSC2 on 16p13.3. TSC complex may affect the skin, central nervous system, kidneys, heart, eyes, blood vessels, lungs, bone, and gastrointestinal tract. The diagnosis of TSC is based on the identification of hamartomas in more than one organ system. Treatment should be symptomatic and organ specific. A multidisciplinary management approach is necessary.