Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex.

BACKGROUND AND PURPOSE: Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA-binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. METHODS: Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of EGR2 were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two-hybrid assay. RESULTS: A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the EGR2 gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB-EGR2 protein interactions can result in dramatic neuropathy. CONCLUSION: Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission.

Clinical spectrum of BICD2 mutations.

BACKGROUND AND PURPOSE: Mutations in the BICD2 gene cause autosomal dominant lower extremity-predominant spinal muscular atrophy 2A (SMALED2A), a condition that is associated with a specific pattern of thigh and calf muscle involvement when studied by magnetic resonance imaging (MRI). Patients may present minor clinical sensory impairment, but objective sensory involvement has yet to be demonstrated. METHODS: We collected clinical data from 11 patients from five different families carrying mutations in BICD2. Genetic diagnosis was achieved using gene panel testing and skin biopsies were taken from two patients to study the epidermal nerve fiber density. RESULTS: In the studied patients, three new pathogenic mutations were detected as well as the already defined pathogenic p.Ser107Leu mutation. The most frequent clinical picture was characterized by lower-limb weakness in combination with foot deformities. One patient manifested clinical and electrophysiological sensory impairment, and the epidermal nerve fiber density study of another patient revealed the existence of a small-fiber neuropathy. Muscle MRI showed a common pattern of fat deposition including selective involvement of gluteus medius and minimus at the pelvic level, the anterior compartment of the thigh and the posterior compartment of the calf, with only mild or no involvement of the intrinsic foot muscles. CONCLUSIONS: We report three new pathogenic mutations in the BICD2 gene. Muscle MRI confirms the existence of a selective pattern of thigh and leg muscle involvement in SMALED2A, providing additional information regarding pelvic and foot muscles. Moreover, our results raise the possibility of sensory involvement in the disease.

On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next-generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.

The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.

BACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype. METHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays. RESULTS: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression. CONCLUSIONS: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.

Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.

Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range.

Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients.

Laing myopathy is a distal myopathy caused by mutations in the tail of the slow beta-myosin heavy chain gene MYH7. A large cluster of patients belonging to different families, with Laing myopathy due to p.K1729del mutation, was found in the Safor region, Spain. The same mutation was previously reported in an American family with Italian ancestry. The possibility that p.K1729del in MYH7 might be a founder mutation in the Safor patients and the chance of a common origin with the Italian-American family mutation was investigated by haplotype analyses, mutation data origin estimation and historical inquiry. Our results show that the p.K1729del in MYH7 harboured by patients from the Safor indeed is a founder mutation. A common ancestral origin of this mutation in the Spanish and Italian families is also suggested because they all share a core SNP haplotype at locus MYH7. Data estimation yields the origin of the mutation in the Safor at the beginning of the XVII century, when the Moorish were spelt and the region was resettled with Italian families.

Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria.

Hereditary cystathioninuria is due to mutations in the CTH gene that encodes for cystathionase, a pyridoxal-5'-phosphate (PLP) dependent enzyme. To date, mutations in this gene have been described in 10 unrelated cystathioninuric patients. Enzyme assays have showed that mutated cystathionase exhibits lower activity than controls. As cystathioninuria is usually accompanied by a wide variety of symptoms, it has been questioned whether it is a disease or just a biochemical finding not associated with the clinical picture of these patients. This is the first report of Spanish patients with cystathioninuria and mild to severe neurological symptoms in childhood. After oral pyridoxine therapy biochemical parameters have normalized but clinical amelioration was not evident. All patients were homozygotes for the c.200C>T (p.T67I) variant which is the most prevalent inactivating mutation in the CTH gene. To further investigate the history of the alleles carrying the c.200C>T transition in Europe, we also constructed the haplotypes on the CTH locus in our Spanish patients as well as in a clinical series of cystathioninuric patients from the Czech Republic harboring the same nucleotide change. We suggest that the CTH p.T67I substitution could have an ancient common origin, which probably occurred in the Neolithic Era and spread throughout Europe.

Mutations in the urocanase gene UROC1 are associated with urocanic aciduria.

Urocanase is an enzyme in the histidine pathway encoded by the UROC1 gene. This report describes the first putative mutations, p.L70P and p.R450C, in the coding region of the UROC1 gene in a girl with urocanic aciduria presenting with mental retardation and intermittent ataxia. Computed (in silico) predictions, protein expression studies and enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme. The p.L70P substitution, which probably implies the disruption of an alpha-helix in the N-terminus, would alter its properties and therefore, its function. The p.R450C change would render impossible any interaction between urocanase and its substrate and would loss its enzyme activity. Consequently, these studies suggest that both mutations could alter the correct activity of urocanase, which would explain the clinical and biochemical findings described in this patient.

Identification of three novel mutations in the MYO7A gene.

Three new mutations in the myosin VIIA gene involved in the pathogenesis of Usher syndrome type Ib are reported. These mutations are K1080X in exon 25, E1170K in exon 28, and Y1719C in exon 37. It is presumed that these mutations are involved in the Usher syndrome Ib phenotype.

Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2).

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

[Characterization of major ambulatory surgery in a basic general hospital]. / Caracterización de la cirugia mayor ambulatoria en un hospital general básico.

BACKGROUND: Outpatient surgery initially came into being and further developed as a result of the progressive increase in the demand and in hospital expenses. Although it has afforded the possibility of lowering the cost per procedure and of improving the efficiency of the hospitals by maintaining the degrees of patient satisfaction and safety, it has also made it necessary to question the customary activity indicators. This had led us to assess the outpatient surgery units of the recently-opened Algeciras Hospital based on the customary system of payment in other countries, the Related Diagnostic Groups (RDG's). METHODS: Descriptive study regarding 3,051 surgical procedures performed on a scheduled basis in 1997 (not including the minor surgery using a local anesthetic), using as a source of information the minimum basic set of data for hospital discharge, obtaining and analyzing the RDG's. The hospital stays avoided based on the average stay of those patients admitted for the same RDG within the time period under study have been calculated. RESULTS: Major surgery performed on an outpatient basis afforded the possibility of an overall replacement percentage of 50.4% (33.3% of all of the patients who underwent surgery on a scheduled basis, that is, 4.1% of all of this Hospital's admissions), which meant an savings of 2,112 hospital stays. The most frequent RDG's having the greatest impact on stays avoided were the surgical procedures performed on the crystalline lens and the scraping or conization procedures performed for reasons other than malignant neoplasia. The readmission rate was 1.5%. CONCLUSIONS: The overall replacement rate obtained by this major outpatient surgery unit is considered to be acceptable, although it must increase within the next few years. We found differences in the spread of the processes dealt with as compared to other units in our environment, this being explainable due to the difficulties involved in starting up surgery of these characteristics.

[The Medical Telegraph (1847-1850) and the introduction of anesthesiology in Spain]. / El Telégrafo Médico (1847-1850) y la introducción de la anestesiología en España.

The object of our study is to amplify the knowledge of Spanish anesthesiology in the 19th century analyzing the role filled by El Telégrafo Médico (1847-1850) at the introduction of anesthesiology in Spain. We have obtained 32 articles on anaesthesiology. Ten of them (31,25%) were written by Spanish authors and 22 (68,75%) by foreign authors. Eleven articles refer to ether, 17 to chloroform and 4 to other anesthetics. Spanish medical professionals received relevant information about this subject from this medical journal edited in Barcelona.

[Analysis of the anesthesiology doctoral theses in Cadiz during the Six-Year Revolution]. / Análisis de las tesis doctorales anestésicas gaditanas del Sexenio Revolucionario.

Manuel Ruiz Zorrilla, after the 1868 Revolution, made possible in Spain the decentralization of doctorate's studies, which traditionally were done in Madrid. It was because of that fact that the Doctor degree could be obtained at the Faculty of Medicine in Cadiz during the Sexenio Revolucionario. The intention of this work is to analyse the anaesthesiologist doctorate thesis defended at the Faculty of Medicine in Cadiz during that period. We give unpublished news about the evolution of the obstetrics anaesthesia in Spain and different opinions about the use of anaesthetics in labours at that time.

[Postoperative complications in a case of iatrogenic hypothyroidism induced by diet drugs]. / Complicaciones postoperatorias de un hipotiroidismo iatrógeno no detectado inducido por fármacos adelgazantes.

Oral thyroid preparations, which were first administered in 1892 to treat myxedema, are the oldest effective endocrine medications. Since thyroxin became available, such drugs have been dispensed without a physician's prescription and have come to be mistakenly referred to as "diet pills". Self-prescription of such products can cause changes in thyroid function, with systemic repercussions. We report the case of a woman who took thyroid extracts, among other diet drugs to enhance weight loss without medical supervision. The patient failed to report taking such drugs during the preanesthetic visit. Interrupting therapy several days before surgery produced a state of hypothyroidism that led to marked postoperative hemodynamic changes necessitating transfer to the intensive care unit.

[Controversies surrounding pain and inhalation anesthesia in nineteenth century Spain]. / Controversias en torno al dolor y la anestesia inhalatoria en la España del siglo XIX.

The introduction of inhaled anesthetics to Spain in 1847 brought appearances by enthusiastic promotors, prudent and reserved admirers and stubborn adversaries - sparking controversy over the use of the new gases. In some cases debate involved the discussion of various concepts of pain, as is shown by heated exchanges among Eusebio Castelo Serra, Manuel Santos Guerra and Zacarías Benito González in the pages of the journal Boletín de Medicina, Cirugía y Farmacia, in three articles appearing between 1850 and 1851 on the concept of pain: Sobre el dolor de las enfermedades y principalmente en las operaciones quirúrgicas, Modificación de dos instrumentos and Estudios sobre el dolor. Investigation into the authors' biographies and an analysis of the content of the articles has permitted us to reconstruct some aspects of the concept of pain in Spain in the middle of the nineteenth century.

[Latex allergy. Reaction to intraoperative anaphylaxis]. / Alergia al látex. Reacción de anafilaxia intraoperatoria.

We report a case of anaphylaxis during surgery as a result of reaction to latex. The patient was a 26-year old woman undergoing emergency exploratory laparotomy. Sixty minutes after the start of the procedure, rash, confluent cutaneous wheals and severe bronchospasm appeared. An allergic reaction was suspected and treatment with corticoids, H1 and H2 antihistamines, theophylline and adrenalin was begun, after which the symptoms disappeared. We wish to emphasize that in the presurgical taking of the patient's case history, no relevant diseases or known allergies were mentioned, and that all complementary analytical data obtained before surgery were within the normal limits. The woman had had a cesarean section seven months before, with no anesthetic complications. Later, the patient mentioned suffering sinusitis and food allergies, describing a clear history of atopy.

[Syndromic hereditary deafness. Usher's syndrome. Oto-neurologic and genetic factors]. / Sordera hereditaria sindrómica: síndrome de Usher. Aspectos otoneurológicos y genéticos.

Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by congenital bilateral sensorineural hearing loss and progressive loss of vision due to retinitis pigmentosa (RP). The prevalence of Usher syndrome is estimated to be 3-4.4 cases per 100.000 people. Several clinical types have been distinguished by age at onset, rate of progression, and severity of symptoms. Type I (USH1) is characterized by a congenital, severe-to-profound deafness and absent vestibular function. Type II (USH2) shows a congenital and moderate-to-severe hearing loss and normal vestibular response. It is also suggested a third type (USH3), clinically similar to USH2, but with progressive hearing loss. Genetic heterogeneity of USH is quite extensive. Up to now, seven different loci responsible for the defect are known: 14q, 11q, 11p, 10q and 21q for USH1; 1q for USH2 and 3q for USH3. Moreover, there are USH1 and USH2 families that fail to show linkage to these candidate regions demonstrating that should exist other loci causing USH, although their ubications are unknown. To date, only two genes involved in the USH pathology are known, although together they are responsibles of about the 80% of total USH cases: myosin VIIA, an unconventional myosin, involved in the USH1b phenotype and a protein similar to the laminina, responsible for the USH2a phenotype.