Clinical features and mutational analysis in 114 young children with Wilson disease from South China

Wilson disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene. Clinical features and mutational analysis of Chinese children with WD at early age were rarely described. Herein, we retrospectively examined 114 children with WD at the mean of 5.9 years old age at diagnosis. Eight patients developed acute liver failure at mean age of 9.7 years old, 4 of whom died. Among the 114 patients, 86.0% were presymptomatic with isolated elevation of transaminases at diagnosis, 99.1% had decreased ceruloplasmin, and 68.4% had urinary copper excretion over 100 μg/24 hr. Bi‐allele pathogenic ATP7B mutations were identified in all patients. Among the 60 mutations detected, 10 were novel, including 7 missense mutations (p.I566N, p.T704I, p.C980F, p.G1030 V, p.A1096Q, p.L1327P, and p.L1373F), 1 nonsense mutation (p.K866X), 1 small insertion (p.Y44LfsX2), and 1 small deletion (p.R1118PfsX10). The most frequent mutations were p.R778L, p.P992L, and p.I1148T, which affected 27.2, 25.4, and 20.2% of the 114 WD children, respectively. The patients carrying p.R778L presented a higher rate of acute liver failure than the patients without p.R778L (9.7% vs. 4.8%). These results will be helpful in establishing early diagnosis of WD at the gene level, offering beneficial information for genetic counseling and providing clues to genotype/phenotype correlation of ATP7B mutations.     

鸟氨酸氨甲酰基转移酶缺陷症三例临床和基因突变分析

目的 分析鸟氨酸氨甲酰基转移酶缺陷症(ornithine carbamoyltransferase deficiency,OTCD)的临床表现、遗传学特点,从基因水平了解OTCD的致病因素,达到基因诊断和遗传咨询的目的.方法 应用聚合酶链反应扩增3例OTCD患者的鸟氨酸氨甲酰转移酶(ornithine carbamoyltransferase,OTC)基因各个外显子所在片段,并进行直接测序,以检测突变.结果 例1在生后6月以呕吐起病,为错义突变T262I,其母亲表型正常,为T262I杂合突变;例2在2岁时以烦躁不安起病,为错义突变R277W,例2父母未行基因检测;例3以嗜睡在新生儿期起病,为错义突变I172M,其母表型正常,为I172M杂合突变.结论 基因分析是诊断OTCD有效可行的方法.T262I突变及R277W突变是症状较轻的温和突变,I172M突变是起病年龄早及症状重的突变.对致病基因进行突变检测不仅可以诊断OTCD,而且可以发现无症状的基因携带者,为遗传咨询及产前诊断提供依据.

Abstract：

Objective To analyze the clinical and genetic characteristics of three children with ornithine carbamoyltransferase deficiency(OTCD), and to provide a practical method for gene diagnosis and genetic counseling of the disease. Methods All exons of the ornithine carbamoyltransferase (OTC) gene were screened by polymerase chain reaction-DNA direct sequencing in the three OTCD patients. Results One patient firstly presented as vomiting at 6 month of age. A missense mutation of T262I was detected. His mother had the same mutation without any clinical symptoms. The second patient presented as restlessness, and had a missense mutation of R277W. Gene analysis of his parents was not available. The third patient presented as neonatal lethargy, harbored a missense mutation of I172M. His mother had the same mutation without any clinical symptoms. Conclusion Gene mutation analysis is a feasible way for diagnosing OTCD. Patients with I172M mutation present symptom early, while those with T262I and R277W mutations manifest symptoms later. Gene mutation analysis will be important for asymptomatic and prenatal diagnosis and genetic counseling.     

Clinical features of patients with coronavirus disease 2019 from a designated hospital in Beijing,China

Clinical and laboratory data on patients with coronavirus disease 2019 (COVID-19) in Beijing, China, remain extremely limited. In this study, we summarized the clinical characteristics of patients with COVID-19 from a designated hospital in Beijing. In total, 55 patients with laboratory-confirmed SARS-CoV-2 infection in Beijing 302 Hospital were enrolled in this study. Demographic data, symptoms, comorbidities, laboratory values, treatments, and clinical outcomes were all collected and retrospectively analyzed. A total of 15 (27.3%) patients had severe symptoms, the mean age was 44.0 years (interquartile range [IQR], 34.0-56.0), and the median incubation period was 7.5 days (IQR, 5.0-11.8). A total of 26 (47.3%) patients had exposure history in Wuhan of less than 2 weeks, whereas 20 (36.4%) patients were associated with familial clusters. Also, eighteen (32.7%) patients had underlying comorbidities including hypertension. The most common symptom of illness was fever (45; 81.8%); 51 (92.7%) patients had abnormal findings on chest computed tomography. Laboratory findings showed that neutrophil count, percentage of lymphocyte, percentage of eosinophil, eosinophil count, erythrocyte sedimentation rate, albumin, and serum ferritin are potential risk factors for patients with a poor prognosis. A total of 26 patients (47.3%) were still hospitalized, whereas 29 (52.7%) patients had been discharged. Compared with patients in Wuhan, China, the symptoms of patients in Beijing are relatively mild. Older age, more comorbidities, and more abnormal prominent laboratory markers were associated with a severe condition. On the basis of antiviral drugs, it is observed that antibiotics treatment, appropriate dosage of corticosteroid, and gamma globulin therapy significantly improve patients' outcomes. Early identification and timely medical treatment are important to reduce the severity of patients with COVID-19.     

Molecular defects of the C7 gene in two patients with complement C7 deficiency

Different genetic mutations have been described in complement components resulting in total or subtotal deficiency states. In this work we report the genetic basis of C7 deficiency in a previously reported Spanish patient exhibiting a combined total deficiency of C7 and C4B associated with systemic lupus erythematosus. Exon-specific polymerase chain reaction and sequencing revealed a not previously described single base mutation in exon 10 (T1458A) leading to a stop codon that causes the premature truncation of the C7 protein (C464X). Additionally, a C to A transversion at position 1561 (exon 11) was found in the patient resulting in an amino acid change (R499S). This latter mutation has been previously reported in individuals with subtotal C7 deficiency or with combined subtotal C6/C7 deficiency from widely spaced geographical areas. Another novel mutation was found in a second patient with meningococcal meningitis of Bolivian and Czech origin; a 11-base pair deletion of nucleotides 631-641 in exon 6 leading to the generation of a downstream stop codon causing the premature truncation of the C7 protein product (T189 x 193). This patient was found to be a heterozygous compound for another mutation in C7; a two-base pair deletion of nucleotides 1922 and 1923, 1923 and 1924 or 1924 and 1925 in exon 14 (1922delAG/1923delGA/1924delAG), leading again to the generation of a downstream stop codon that provokes the truncation of the C7 protein (S620x630). This latter mutation has been recently reported by our group in another Spanish family. Our results provide more evidences for the heterogeneous molecular basis of C7 deficiency.     

Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait

Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait. Am. J. Med. Genet. 71:336–340, 1997. © 1997 Wiley-Liss, Inc.     

Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes

Eighteen unrelated pyruvate kinase (PK)-deficient Indian patients were identified in the past 4 years with varied clinical phenotypes ranging from a mild chronic haemolytic anaemia to a severe transfusion-dependent disorder. We identified 17 different mutations in the PKLR gene among the 36 mutated alleles. Ten novel mutations were identified: 427G>A, 499C>A, 1072G>A, 1180G>T, 1216G>A, 1220A>G, 644delG, IVS5 (+20) C>A, IVS9 (+44) C>T, and IVS9 (+93) A>C. A severe syndrome was commonly associated with some mutations, 992A>G, 1436G>A, 1220A>G, 644delG and IVS9 (+93) A>C, in the PKLR gene. Molecular graphics analysis of human red blood cell PK (RPK), based on the crystal structure of human PK, shows that mutations located near the substrate or fructose 1,6-diphosphate binding site may change the conformation of the active site, resulting in very low PK activity and severe clinical symptoms. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. In particular, the 1216G>A and 1219G>A mutations significantly affect the interdomain interaction because they are located near the catalytic site in the A/B interface domains. The most frequent mutations in the Indian population appear to be 1436G>A (19.44%), followed by 1456C>T (16.66%) and 992A>G (16.66%). This is the first study to correlate the clinical profile with the molecular defects causing PK deficiency from India where 10 novel mutations that produce non-spherocytic haemolytic anaemia were identified.     

Clinical and mutation analysis of 24 Chinese patients with ornithine transcarbamylase deficiency

The principal aim of this study was to examine the clinical manifestations, biochemical features, and molecular genetic characteristics of Chinese patients with ornithine transcarbamylase deficiency (OTCD) at a single medical center. We retrospectively analyzed 24 patients (17 males and 7 females) diagnosed with OTCD between 2006 and 2015. Five male patients had a neonatal presentation; 12 male patients had late onset disease and 7 female patients presented as symptomatic. Patients with a neonatal presentation had the highest peak plasma ammonia and glutamine levels at diagnosis with a high mortality (80% vs 16% in late onset disease). Most of the male late onset disease cases displayed neurologic damage with a mild elevation in plasma ammonia, and a significant increase in serum glutamine, which was commonly misdiagnosed as intracranial infection. In the symptomatic female group, mortality was abnormally high in China with some patients dying at the time of presentation during the first episode of hyperammonemia. Refractory hyperammonemia, serious hepatic function damage, recurrent infection and lethal mutation are the main reasons for poor clinical outcomes of the symptomatic females. Molecular analyses identified 19 different mutations, including 3 novel mutations (c.103insA, c.591C>A and c.805G>A).     

Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE,PTT, and southern analysis

Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant predisposition to colorectal cancer. We screened the entire coding region of the APC gene for mutations in an unselected series of 105 Dutch FAP kindreds. For the analysis of exons 1–14, we employed the GC-clamped denaturing gradient gel electrophoresis (DGGE), while the large exon 15 was examined using the protein truncation test. Using this approach, we identified 65 pathogenic mutations in the above 105 apparently unrelated FAP families. The mutations were predominantly either frameshifts (39/65) or single base substitutions (18/65), resulting in premature stop codons. Mutations that would predict abnormal RNA splicing were identified in seven cases. In one of the families, a nonconservative amino acid change was found to segregate with the disease. In spite of the large number of APC mutations reported to date, we identified 27 novel germline mutations in our patients, which reiterates the great heterogeneity of the mutation spectrum in FAP. In addition to the point mutations identified in our patients, structural rearrangements of APC were found in two pedigrees, by Southern blot analysis. The present study indicates that the combined use of DGGE, protein truncation test, and Southern blot analysis offers an efficient strategy for the presymptomatic diagnosis of FAP by direct mutation detection. We found that the combined use of the currently available molecular approaches still fails to identify the underlying genetic defect in a significant subset of the FAP families. The possible causes for this limitation are discussed. © 1997 Wiley-Liss, Inc.     

Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype--phenotype correlation

Patients with Usher syndrome type II (USH2) show moderate-to-severe hearing loss (HL), retinitis pigmentosa and normal vestibular function. The progression of HL remains controversial. To evaluate whether a phenotype-genotype correlation exists regarding the issue of progression of HL, only USH2 patients with a defined genotype were selected. Ophthalmologic, vestibular and audiometric examination along with a mutation analysis of the USH2A gene (exons 1--21) was performed in twenty-eight Spanish USH2 patients. Ten different pathogenic mutations and 17 sequence variants not associated with the disease were found. Six of the 10 mutations are novel. Disease alleles were identified in 13 of the 28 families tested. Eight of these 13 families had a mutation found in both alleles. In the other five families, only one mutation was identified. The phenotypic data provide evidence for the existence of phenotypic differences between patients with the same genotype. These differences were observed at both the interfamilial and intrafamilial levels.     

Wiskott-Aldrich综合征10例临床特点与实验室诊断分析

目的探讨10例Wiskott-Aldrich综合征(WAS)患儿的临床及分子特点。方法总结10例拟诊WAS患儿临床资料,包括血常规、免疫功能、骨髓常规和扫描电镜检查及临床表型评分。流式细胞术(FCM)检测10例患儿外周血单个核细胞(PBMC)中WAS蛋白(WASP)表达。PCR扩增WASP基因序列并直接双向测序分析9例患儿及其亲属突变情况。结果本组均男性,多以自幼大便带血丝及皮肤瘀点瘀斑起病。均有血小板减少伴小血小板,湿疹和免疫缺陷表现。临床表型评分3例评5分,3例评4分,4例评3分。具有阳性家族史患儿临床诊断年龄明显早于无家族史者。多数患儿IgA(8/9)、IgE(8/9)和IgG(7/9)升高,除6例CD4~+T比例下降(6/9),其余患儿淋巴细胞亚群分类正常。1例淋巴细胞增殖功能降低(1/3)。骨髓常规缺乏特征性改变。5例患儿淋巴细胞扫描电镜(SEM)均可见典型微绒毛异常。10例患儿WASP均为阴性,9例行WASP基因分析发现7种不同突变,3例为新型突变(168 C>A,T45 K;747-748 del T,I 238 Fs X260;253 Ins A,C73X)。8例位于编码区,1例位于内含子。4...     

三阴性乳腺癌患者BRCA1和BRCA2基因突变的临床特征及预后因素

目的:探究三阴性乳腺癌患者BRCA1和BRCA2基因突变检测的临床意义及预后因素分析.方法:研究对象选取为2003年1月至2015年12月之间的三阴性乳腺癌156例,所有患者均通过PCR法和DNA序列测定检验BRCA1和BRCA2基因突变情况,分析乳腺癌患者BRCA1和BRCA2基因突变特点.应用Log-Rank检验对BRCA1和/或BRCA2基因突变的三阴性乳腺癌患者的各项指标如年龄、ECOG状态、临床分期、淋巴结阳性数、月经状态和给药方式进行单因素分析.应用Cox风险比例回归模型分析患者年龄、ECOG状态、临床分期、淋巴结阳性数、肿瘤大小、月经状态和给药方式等多因素分析.结果:三阴乳腺癌患者发生基因突变21例,总体发生率13.46％,BRCA1突变15例,BRCA2突变6例.Log-Rank检验结果显示,发病年龄越大,ECOG评分越高,临床分期越晚,淋巴结阳性数越多,预后越差(P＜0.05),而发病时月经状态和给药方式与预后无关.COX风险比例回归模型显示,肿瘤大小(相对危险度,3.163;95％CI:1.455～9.287;P＜0.05)和淋巴结转移数(相对危险度,1.859;95％CI:1.254～6.875;P＜0.05)是BRCA基因突变三阴性乳腺癌独立的预后因素.结论:BRCA1和BRCA2基因突变可能与乳腺癌尤其是三阴乳腺癌可能有着密切的相关性,发病年龄、ECOG评分,临床分期和淋巴结阳性数及肿瘤大小与BRCA基因突变的三阴乳腺癌预后有关.     

Clinical,immunological and genetic characterization of patients with X-linked agammaglobulinemia in Costa Rica

X-linked agammaglobulinemia is caused by mutations in the gene encoding Bruton tyrosine kinase. It produces an arrest in the maturation and differentiation of B cells with very low levels of all immunoglobulins isotypes. The aim of the study was to characterize the clinical, immunological and genetic defects in patients with XLA in Costa Rica. Sixteen cases were identified over a period of 30 years, a case every 2 years, approximately. Three patients were asymptomatic and diagnosis was made on family history. The average age of onset of symptoms was 1.46 years-old (0.08–6.1). Six patients (44%) had onset of symptoms before 1 year of age and 12 (81%) patients before 5 years of age. The average age of diagnosis was 3.63 years-old (0.17–13, SD 3.51 years-old the average time between the onset of symptoms and the diagnosis was 2.5 years (2.5 months to 12 years, SD 3 years). The initial reason to study the patients was a recurrent infection, family history of XLA, arthritis and neutropenia. Four patients had pneumonia and two had suppurative lung disease. Nine patients had recurrent infections: acute otitis media, sinusitis, mastoiditis and recurrent diarrhoea. Three patients presented with arthritis. Neutropenia as an isolated event was not identified in any case. All patients receive monthly IVIG and no deaths were reported. Three new likely pathogenic/pathogenic variants in BTK gene have been described in our population. This is the first report of XLA Costa Rican patients and their BTK mutations.     

Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5-oxoprolinase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT-PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141-bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491 --> A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847 --> T [ARG283 --> CYS] mutation in exon 9.     

Molecular analysis of the hepatitis B virus presurface and surface gene in patients from eastern China with occult hepatitis B

This study was designed to detect and analyze mutations that occur within the presurface and surface (pre‐S/S) gene of HBV in patients with occult hepatitis B, and determine their relationship to that disorder. Among 254 HBsAg negative samples of blood collected in eastern China, 183 were positive for anti‐HBc alone, 61 were positive for anti‐HBe alone, and 10 samples were positive for HBeAg. Within this group, 15 samples were found to be HBV DNA positive by real‐time PCR and were designated Group I. A control group of 28 HBsAg positive samples were chosen at random from patients with chronic hepatitis B and designated Group II. The HBV pre‐S/S gene was amplified by PCR and subjected to sequencing analysis. Occult hepatitis B was found in 1.6% of the patients with anti‐HBc alone and in 3.3% of those with anti‐HBe alone. Occult hepatitis B also was found in all HBsAg negative but HBeAg positive samples. Sequencing analysis showed a significant correlation between point mutations within the “a” determinant and occult hepatitis B (P < 0.0001), and a close relationship between pre‐S deletion mutations and occult hepatitis B (P = 0.06). There were unique amino acid mutations at the G145 position other than G145R. The HBV DNA levels in patients with occult hepatitis B were significantly lower than those found in the control group. The “a” determinant mutations and pre‐S deletions may play important roles in occult hepatitis B by affecting the expression, synthesis and secretion of the S protein and by impeding viral release and replication. J. Med. Virol. 85: 979–986, 2013. © 2013 Wiley Periodicals, Inc.     

Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome‐like phenotype

We have previously shown that mutations in the genes encoding DNA Ligase IV (LIGIV) and RAD50, involved in DNA repair by nonhomologous‐end joining (NHEJ) and homologous recombination, respectively, lead to clinical and cellular features similar to those of Nijmegen Breakage Syndrome (NBS). Very recently, a new member of the NHEJ repair pathway, NHEJ1, was discovered, and mutations in patients with features resembling NBS were described. Here we report on five patients from four families of different ethnic origin with the NBS‐like phenotype. Sequence analysis of the NHEJ1 gene in a patient of Spanish and in a patient of Turkish origin identified homozygous, previously reported mutations, c.168C>G (p.Arg57Gly) and c.532C>T (p.Arg178Ter), respectively. Two novel, paternally inherited truncating mutations, c.495dupA (p.Asp166ArgfsTer20) and c.526C>T (p.Arg176Ter) and two novel, maternal genomic deletions of 1.9 and 6.9 kb of the NHEJ1 gene, were found in a compound heterozygous state in two siblings of German origin and in one Malaysian patient, respectively. Our findings confirm that patients with NBS‐like phenotypes may have mutations in the NHEJ1 gene including multiexon deletions, and show that considerable clinical variability could be observed even within the same family. Hum Mutat 31:1059–1068, 2010. © 2010 Wiley‐Liss, Inc.     

Clinical characteristics of COVID-19 in patients with preexisting ILD: A retrospective study in a single center in Wuhan,China

Since the outbreak of 2019 novel coronavirus (SARS-CoV-2) pneumonia, many patients with underlying disease, such as interstitial lung disease (ILD), were admitted to Tongji hospital in Wuhan, China. To date, no data have ever been reported to reflect the clinical features of Corona Virus Disease 2019 (COVID-19) among these patients with preexisting ILD. We analyzed the incidence and severity of COVID-19 patients with ILD among 3201 COVID-19 inpatients, and compared two independent cohorts of COVID-19 patients with pre-existing ILD (n = 28) and non-ILD COVID-19 patients (n = 130). Among those 3201 COVID-19 inpatients, 28 of whom were COVID-19 with ILD (0.88%). Fever was the predominant symptom both in COVID-19 with ILD (81.54%) and non-ILD COVID-19 patients (72.22%). However, COVID-19 patients with ILD were more likely to have cough, sputum, fatigue, dyspnea, and diarrhea. A very significantly higher number of neutrophils, monocytes, interleukin (IL)-8, IL-10, IL-1β, and D-Dimer was characterized in COVID-19 with ILD as compared to those of non-ILD COVID-19 patients. Furthermore, logistic regression models showed neutrophils counts, proinflammatory cytokines (tumor necrosis factor-alpha, IL6, IL1β, IL2R), and coagulation dysfunction biomarkers (D-Dimer, PT, Fbg) were significantly associated with the poor clinical outcomes of COVID-19. ILD patients could be less vulnerable to SARS-CoV-2. However, ILD patients tend to severity condition after being infected with SARS-CoV-2. The prognosis of COVID-19 patients with per-existing ILD is significantly worse than that of non-ILD patients. And more, aggravated inflammatory responses and coagulation dysfunction appear to be the critical mechanisms in the COVID-19 patients with ILD.     

Clinical and molecular characterization of Indian patients with fructose‐1, 6‐bisphosphatase deficiency: Identification of a frequent variant (E281K)

Fructose‐1, 6‐bisphosphatase deficiency is an autosomal recessive disorder of gluconeogenesis caused by genetic defect in the FBP1 gene. It is characterized by episodic, often life‐threatening metabolic acidosis, liver dysfunction, and hyperlactatemia. Without a high index of suspicion, it may remain undiagnosed with devastating consequences. Accurate diagnosis can be achieved either by enzyme assay or gene studies. Enzyme assay requires a liver biopsy and is tedious, invasive, expensive, and not easily available. Therefore, genetic testing is the most appropriate method to confirm the diagnosis. Molecular studies were performed on 18 suspected cases presenting with episodic symptoms. Seven different pathogenic variants were identified. Two common variants were noted in two subpopulations from the Indian subcontinent; p.Glu281Lys (E281K) occurred most frequently (in 10 patients) followed by p.Arg158Trp (R158W, in 4 patients). Molecular analysis confirmed the diagnosis and helped in managing these patients by providing appropriate genetic counseling. In conclusion, genetic studies identified two common variants in the Indian subcontinent, thus simplifying the diagnostic algorithm in this treatable disorder.     

Identification of 14 novel GLB1 mutations, including five deletions, in 19 patients with GM1 gangliosidosis from South America

GM1 gangliosidosis is a lysosomal storage disorder caused by the absence or reduction of lysosomal beta-galactosidase activity because of mutations in the GLB1 gene. Three major clinical forms have been established: type I (infantile), type II (late infantile/juvenile) and type III (adult). A mutational analysis was performed in 19 patients with GM1 gangliosidosis from South America, mainly from Argentina. Two of them were of Gypsy origin. Main clinical findings of the patients are presented. All 38 mutant alleles were identified: of the 22 different mutations found, 14 mutations are described here for the first time. Among the novel mutations, five deletions were found. Four of them are relatively small (c.435_440delTCT, c.845_846delC, c.1131_1145del15 and c.1706_1707delC), while the other one is a deletion of 1529 nucleotides that includes exon 5 and is caused by an unequal crossover between intronic Alu sequences. All the described patients with GM1 gangliosidosis were affected by the infantile form, except for four unrelated patients classified as type II, III, and II/III (two cases). The two type II/III patients bore the previously described p.R201H mutation, while the adult patient bore the new p.L155R. The juvenile patient bore two novel mutations: p.S434L and p.G554E. The two Gypsy patients are homozygous for the p.R59H mutation as are all Gypsy patients previously genotyped.