Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert / Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease

Antecedentes y objetivos: La enfermedad de Steinert o distrofia miotónica tipo 1 (DM1), (OMIM 160900) es la miopatía más prevalente en el adulto. Es una enfermedad multisistémica con alteración de prácticamente todos los órganos y tejidos y una variabilidad fenotípica muy amplia, lo que implica que deba ser atendida por diferentes especialistas que dominen las alteraciones más importantes. En los últimos años se ha avanzado de manera exponencial en el conocimiento de la enfermedad y en su manejo. El objetivo de la guía es establecer recomendaciones para el diagnóstico, el pronóstico, el seguimiento y el tratamiento de las diferentes alteraciones de la DM1. Material y métodos: Esta guía de consenso se ha realizado de manera multidisciplinar. Se ha contado con neurólogos, neumólogos, cardiólogos, endocrinólogos, neuropediatras y genetistas que han realizado una revisión sistemática de la literatura. Recomendaciones: Se recomienda realizar un diagnóstico genético con cuantificación precisa de tripletes CTG. Los pacientes con DM1 deben seguir control cardiológico y neumológico de por vida. Antes de cualquier cirugía con anestesia general debe realizarse una evaluación respiratoria. Debe monitorizarse la presencia de síntomas de disfagia periódicamente. Debe ofrecerse consejo genético a los pacientes con DM1 y a sus familiares. Conclusión: La DM1 es una enfermedad multisistémica que requiere un seguimiento en unidades especializadas multidisciplinares

Background and objectives: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. Material and methods: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. Recommendations: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. Conclusion: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up

Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations.

OBJECTIVE: To clinically and pathologically characterize a cohort of patients presenting with a novel form of distal myopathy and to identify the genetic cause of this new muscular dystrophy. METHODS: We studied 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy. Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles. RESULTS: In all 3 Spanish families, we identified a unique missense variant in the ACTN2 gene cosegregating with the disease. The affected members of the Swedish family carry a different ACTN2 missense variant. INTERPRETATION: ACTN2 encodes for alpha actinin2, which is highly expressed in the sarcomeric Z-disk with a major structural and functional role. Actininopathy is thus a new genetically determined distal myopathy. ANN NEUROL 2019;85:899-906.

Expanding the importance of HMERF titinopathy: new mutations and clinical aspects.

OBJECTIVE: Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied. METHODS: Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated. RESULTS: Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF. CONCLUSIONS: Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.

Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

Copy number variation analysis increases the diagnostic yield in muscle diseases.

OBJECTIVE: Copy number variants (CNVs) were analyzed from next-generation sequencing data, with the aim of improving diagnostic yield in skeletal muscle disorder cases. METHODS: Four publicly available bioinformatic analytic tools were used to analyze CNVs from sequencing data from patients with muscle diseases. The patients were previously analyzed with a targeted gene panel for single nucleotide variants and small insertions and deletions, without achieving final diagnosis. Variants detected by multiple CNV analysis tools were verified with either array comparative genomic hybridization or PCR. The clinical significance of the verified CNVs was interpreted, considering previously identified variants, segregation studies, and clinical information of the patient cases. RESULTS: Combining analysis of all different mutation types enabled integration of results and identified the final cause of the disease in 9 myopathy cases. Complex effects like compound heterozygosity of different mutation types and compound disease arising from variants of different genes were unraveled. We identified the first large intragenic deletion of the titin (TTN) gene implicated in the pathogenesis of a severe form of myopathy. Our work also revealed a "double-trouble" effect in a patient carrying a single heterozygous insertion/deletion mutation in the TTN gene and a Becker muscular dystrophy causing deletion in the dystrophin gene. CONCLUSIONS: Causative CNVs were identified proving that analysis of CNVs is essential for increasing the diagnostic yield in muscle diseases. Complex severe muscular dystrophy phenotypes can be the result of different mutation types but also of the compound effect of 2 different genetic diseases.

Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation.

OBJECTIVE: Describe the incidence of cancer in a large cohort of patients with myotonic dystrophy type 1 (DM1) and to unravel the underlying molecular mechanisms. METHODS: Standardized incidence ratios (SIRs) were calculated in the Gipuzkoa DM1 cohort (1985-2013), dividing observed numbers by expected numbers for all cancers combined and stratified by sex. An estimation of the expected incidence was achieved by multiplying the age- and sex-specific incidence rates from the Basque population cancer registry by the person-years observed in the study cohort. Large-scale gene expression of peripheral blood mononuclear cell samples derived from 10 individuals with DM1 (5 men, 5 women) and 10 healthy matched controls was analyzed by the Human Gene 1.0 ST Affymetrix microarray. RESULTS: During 18,796 person-years of follow-up, corresponding to 424 patients with DM1, we observed 70 cancers in 62 patients giving a 1.81-fold risk (95% confidence interval [CI] 1.37-2.36), which was stronger in women than in men. Ovary (SIR 8.33, 95% CI 1.72-24.31) and endometrium (SIR 6.86, 95% CI 2.23-16.02) in women and thyroid (SIR 23.33, 95% CI 9.38-48.08) and brain (SIR 9.80, 95% CI 3.18-22.88) in both sexes were tumor sites with significantly higher risks in DM1. There were differences in gene expression between healthy controls and patients with DM1 and between men and women with DM1; all patients with DM1 combined and female patients with DM1 displayed significant downregulation of the microRNA (miRNA)-200c/141 tumor suppressor family. CONCLUSIONS: Oncologic risk is increased in DM1, especially in women and for gynecologic, brain, and thyroid cancer. Expression of the miRNA-200/miRNA-141 tumor suppressor family is decreased in women with DM1.

Factores de riesgos fetales en la restricción del crecimiento intrauterino en gestantes / Maternal and fetal risk factors for intrauterine growth restriction in pregnant women

Introducción: la restricción del crecimiento intrauterino es una afección caracterizada por una limitación del potencial del crecimiento fetal y constituyen una de las situaciones clínicas más frecuentes en Obstetricia.Objetivo: determinar los factores de riesgos fetales en la restricción del crecimiento intrauterino en gestantes.Métodos: se realizó un estudio transversal desde enero del 2010 hasta enero del 2012. Se seleccionó una muestra de 111 gestantes y se les aplicó protocolos de trabajo.Resultados: las pacientes que tuvieron niños con restricción del crecimiento intrauterino (63,5 por ciento) estuvieron entre los 19 y 34 años de edad y 63,5 por ciento fueron nulíparas. Predominó el bajo peso materno pre gestacional con un 47,6 por ciento y la escasa ganancia de peso en el embarazo con un 81 por ciento, el 100 por ciento de los casos presentó alteración de la circunferencia abdominal y del peso fetal por ultrasonido.Conclusiones: el ultrasonido fue el método más significativo para el diagnóstico de la restricción del crecimiento intrauterino(AU)

Introduction: Intrauterine growth restriction is characterized by limited potential of fetal growth and is one of the most common clinical situations in obstetrics.Objective: To determine risk factors for intrauterine growth restriction in outpatients referred to the municipal service of second opinion about this entity in Playa municipality.Methods: From January 2010 up to January 2012, a cross-sectional study was carried out in 111 pregnant women to whom working protocols were applied.Results: Nineteen to thirty four years old mothers had babies with intrauterine growth restriction (63.5percent) all of them were nulliparas. Low pre gestational mothers weight (47,6percent) was predominant with low weight gain during pregnancy (81percent). According to the ultrasound testing, all the studied cases presented with altered abdominal circumference and fetal weight.Conclusions: Ultrasonographic study was the most significant method for diagnosis of intrauterine growth restriction(AU)

New mutation of the desmin gene identified in an extended Indian pedigree presenting with distal myopathy and cardiac disease.

In this report, we describe a new mutation located in the coiled 1B domain of desmin and associated with a predominant cardiac involvement and a high degree of cardiac sudden death in a large Indian pedigree with 12 affected members. The index cases was 38-year-old man who presented with progressive difficulty in gripping footwear of 5 years duration with the onset in the left lower limb followed by right lower limb in 6 months. 3 years from onset, he developed lower limb proximal and truncal muscle weakness. There was mild atrophy of the shoulder girdle muscles with grade 3 weakness, moderate wasting of thigh and anterior leg muscles with proximal muscle weakness and foot drop. At 40 years, he had a pacemaker implanted. The 9 exons and intronic boundaries of the desmin gene were sequenced and a heterozygous nucleotide change c. 734A > G in exon 3 was identified.

Tratamiento de la endometriosis con 5 mg o 25 mg diarios de mifepristona durante 6 meses. Ensayo clínico aleatorizado, doble ciego / Treatment with 5mg or 25mg of mifepristone daily for six months. A randomized double-blind study

Objetivos. Evaluar la eficacia y seguridad de 5 y 25 mg de mifepristona en el tratamiento de la endometriosis. Diseño. Ensayo clínico aleatorizado, doble ciego. Lugar. Hospital Eusebio Hernández, La Habana, Cuba. Sujetos. Veintiséis mujeres con diagnóstico laparoscópico de endometriosis. Tratamientos. Grupo I: una tableta oral diaria de 25mg de mifepristona, o grupo II: una tableta oral diaria de 5mg de mifepristona, durante 6 meses. Se realizó laparoscopia y biopsia endometrial pre y postratamiento. Variable para evaluar eficacia. Reducción de la intensidad de la dismenorrea medida por una escala visual análoga. Resultados. En ambos grupos las disminuciones de la intensidad de la dismenorrea y la dispareunia fueron muy significativas comparadas con los valores iniciales. Todas las mujeres estaban en amenorrea a los 45 días de tratamiento. Conclusiones. La mifepristona, en dosis de 25 o 5mg, podría ser una alternativa para el tratamiento de la endometriosis (AU)

Objectives. To evaluate the safety and efficacy of 5 mg and 25 mg doses of mifepristone for the treatment of endometriosis. Design. Randomized double-blind study. Setting. Eusebio Hernández Hospital, Havana, Cuba. Subjects. Twenty-six women laparoscopically diagnosed with endometriosis were included. Treatment. Group I received one tablet of 25mg mifepristone daily and group II received one tablet of 5mg mifepristone daily for 6 months. Laparoscopy and endometrial biopsy were performed before and after treatment. Variable to evaluate efficacy. Reduction in the intensity of dysmenorrhea measured by a visual analogue scale. Results. In both groups reductions in the intensity of dysmenorrhea and dyspareunia were highly significant compared with initial values (P<.001). All the women were amenorrheic after 45 days of treatment. Conclusions. At doses of 5mg or 25mg, mifepristone could be an alternative for the treatment of endometriosis (AU)

A novel CRYAB mutation resulting in multisystemic disease.

Mutations in the CRYAB gene, encoding alpha-B crystallin, cause distinct clinical phenotypes including isolated posterior polar cataract, myofibrillar myopathy, cardiomyopathy, or a multisystemic disorder combining all these features. Genotype/phenotype correlations are still unclear. To date, multisystemic involvement has been reported only in kindred harboring the R120G substitution. We report a novel CRYAB mutation, D109H, associated with posterior polar cataract, myofibrillar myopathy and cardiomyopathy in a two-generation family with five affected individuals. Age of onset, clinical presentation, and muscle abnormalities were very similar to those described in the R120G family. Alpha-B crystallin may form dimers and acts as a chaperone for a number of proteins. It has been suggested that the phenotypic diversity could be related to the various interactions between target proteins of individual mutant residues. Molecular modeling indicates that residues D109 and R120 interact with each other during dimerization of alpha-B crystallin; interestingly, the two substitutions affecting these residues (D109H and R120G) are associated with the same clinical phenotype, thus suggesting a similar pathogenic mechanism. We propose that impairment of alpha-B crystallin dimerization may also be relevant to the pathogenesis of these disorders.

Myopathy with hexagonally cross-linked crystalloid inclusions: delineation of a clinico-pathological entity.

A novel myopathy characterized by hexagonally cross-linked tubular arrays has been reported in five patients. We studied the clinical and histopathological features of five additional unrelated patients with this myopathy. Patients experienced exercise intolerance with exercise-induced myalgia and weakness, without rhabdomyolysis. One patient additionally presented mild permanent pelvic girdle muscle weakness. Age at onset varied between 13 and 56 years. The inclusions were eosinophilic on H and E, bright red with modified Gomori's trichrome stains, present in type 2 fibers, and revealed immunoreactivity selectively for a caveolin-3-antibody. Ultrastructurally, the inclusions showed a highly organized, hexagonally cross-linked crystalloid structure. Mutations in the caveolin-3 encoding gene were excluded. Biochemical assessment of glycogenolysis in muscle was normal. Inherited or sporadic myopathy with hexagonally cross-linked tubular arrays is associated with a homogeneous clinical and histopathological phenotype. This myopathy should be included in the differential diagnosis of patients with exercise intolerance and myalgia.

Características clínicas y moleculares de una familia con síndrome de neoplasia endocrina múltiple tipo 1 / Clinical and molecular features in a family with multiple endocrine neoplasia type-1 syndrome

INTRODUCCIÓN: Los rasgos clínicos del síndrome de neoplasia endocrina múltiple tipo 1 (NEM-1) son: hiperplasia o adenoma de las glándulas paratiroides, adenoma hipofisario y tumores endocrinos gastroenteropancreáticos. Se debe a mutaciones del gen MEN1, localizado en la región q13 del cromosoma 11. El pronóstico de los pacientes depende del crecimiento tumoral y de su potencial metastático.PACIENTES Y MÉTODO: Se revisan las historias clínicas de los miembros de esta familia (6 varones y 2 mujeres) con NEM-1 diagnosticados entre 1995 y 2007 en el Hospital Donostia de San Sebastián. El estudio familiar de todos los pacientes y familiares (19 casos de 2 generaciones) se hizo en dos fases. La primera, mediante técnica de cribado de mutaciones y la segunda, por multiplex ligation-dependent probe amplification (MLPA)para detectar deleciones del gen.RESULTADOS: El cribado de mutaciones no permitió identificar ninguna variante patogénica en el probando de esta familia. El estudio mediante MLPA reveló una deleción que afectaba al exón 1 y 2 del gen MEN1. De los 10 familiares con esta alteración molecular, 8 presentaron algún rasgo fenotipico del síndrome (8 con hiperparatiroidismo, 2 con prolactinomas y 3 con gastrinomas) tras 12 años de seguimiento.CONCLUSIÓN: Se comentan las formas clínicas del síndromeNEM-1 en esta familia y la alteración molecular encontrada. El estudio de deleciones del gen MEN1 debería incorporarse al cribado molecular sistemático

BACKGROUND: The clinical features of multiple endocrineneoplasia type-1 (MEN-1) syndrome are hyperplasia or adenoma of the parathyroid glands, pituitary adenoma and gastroenteropancreatic endocrine tumors. This syndrome isdue to mutations in the MEN1 gene, located on the q13 region of chromosome 11. Prognosis depends on tumoralgrowth and metastatic potential.PATIENTS AND METHOD: We reviewed the medical records ofthe members of a family (6 men and 2 women) with MEN-1syndrome diagnosed between 1995 and 2007 in Hospital Donostia, San Sebastian (Spain). Familial study of all patients and family members (19 cases from 2 generations) was performed in 2 phases. The first phase consisted of mutation screening and the second of multiplex ligation-dependent probe amplification (MLPA) to detect deletions.RESULTS: Screening of mutations identified no pathogenicvariants in the proband of this family. MLPA revealed a deletion affecting exons 1 and 2 of the MEN1 gene. Of the 10 family members with this molecular alteration, 8 had at least one phenotypic feature of this syndrome (hyperparathyroidism in 8, prolactinomas in 2, and gastrinomas in 3) after 12 years of follow-up.CONCLUSION: We discuss the clinical forms of MEN-1 syndrome in this family and the molecular alteration found. Study of MEN1 gene deletions should be incorporated into routine molecular screening

CTG expansion & haplotype analysis in DM1 gene in healthy Iranian population.

UNLABELLED: Myotonic dystrophy type 1 (DM1) is due to an unstable expansion of CTG repeat in the DMPK gene (19q13.3). The CTG repeat is highly polymorphic (5 to 37) in healthy individuals. According to the hypothesis that expanded (CTG)n alleles originated from larger normal alleles, there may exist a correlation between the prevalence of DM1 and the frequency of large size normal alleles. Strong linkage disequilibrium between different length alleles and the three biallelic markers, Alu, Hinf1 and Taq1, has been reported. OBJECTIVE: To determine the distribution of normal alleles, the frequency of larger normal alleles and analysis of the three biallelic markers, in healthy Iranian controls. MATERIAL AND METHODS: Polymerase chain reaction (PCR) was conducted on two hundred unrelated healthy individuals from different ethnic groups living in Iran to determine the size of the alleles. Markers were analyzed by PCR/RFLP on 174 chromosomes from other control healthy individuals. RESULTS: Our data reveals that 23.7% of alleles had 5 CTG repeats and 7.2% of alleles had > 18 CTG repeats. The analysis of haplotypes revealed that 75% of CTG5 and 80% of CTG > 18 had the (+++) haplotype. CONCLUSION: The frequency of alleles with CTG > 18 in Iran is similar to that of Western Europe and Japan.

[Molecular and clinical characteristics of a family with Alagille syndrome]. / Características clínicas y moleculares de una familia con síndrome de Alagille.

BACKGROUND AND OBJECTIVE: The Alagille syndrome (AS) is characterized by biliary ductopenia and abnormalities of heart, eyes, face, bones, kidneys and brain with a dominant inheritability. Mutations of Jagged 1 gene are observed in individuals with the full syndrome and/or relatives with little or no phenotypic features. Prognosis of patients depends on the hepatic and cardiovascular involvement. PATIENTS AND METHOD: We present the cases of a woman and her 2 male nephews with AS. We performed a molecular study of the Jagged 1 gene in family members with and without the syndrome. RESULTS: The molecular study detected mutations in the position 2785+2 of TAAG (intron 19) of the Jagged 1 gene in 3 relatives with the full syndrome and in 2 other members with a partial syndrome. Other relatives, without mutation, have some of the phenotypic features of it. CONCLUSIONS: We comment on the clinical forms of AS in this family and the detected mutation. Molecular diagnosis allows to make a genetic counsel.

Características clínicas y moleculares de una familia con síndrome de Alagille / Molecular and clinical characteristics of a family with Alagille syndrome

Fundamento y objetivo: El síndrome de Alagille (SA) se caracteriza por ductopenia biliar y anomalías del corazón, ojos, cara, huesos, riñón y cerebro, junto a una herencia dominante. Las mutaciones del gen Jagged 1 se observan en sujetos con el síndrome completo y/o familiares que tienen pocos o ningún rasgo fenotípico del síndrome. El pronóstico de los pacientes depende de la afectación hepática y cardiovascular. Pacientes y método: Se presentan los casos de una mujer y sus 2 sobrinos (varones) con SA. Se realizó estudio molecular del gen Jagged 1 en los miembros de la familia con síndrome y sin él. Resultados: El estudio molecular detectó mutaciones en la posición 2785+2 del TAAG (intrón 19) del gen Jagged 1 en 3 familiares que tienen el síndrome completo y en otros 2 casos con síndrome parcial. Otros familiares, sin mutación, presentan alguno de los rasgos fenotípicos del síndrome. Conclusiones: Se comentan las formas clínicas del SA en esta familia y la mutación encontrada. El diagnóstico molecular permite realizar un consejo genético

Background and objective: The Alagille syndrome (AS) is characterized by biliary ductopenia and abnormalities of heart, eyes, face, bones, kidneys and brain with a dominant inheritability. Mutations of Jagged 1 gene are observed in individuals with the full syndrome and/or relatives with little or no phenotypic features. Prognosis of patients depends on the hepatic and cardiovascular involvement. Patients and method: We present the cases of a woman and her 2 male nephews with AS. We performed a molecular study of the Jagged 1 gene in family members with and without the syndrome. Results: The molecular study detected mutations in the position 2785+2 of TAAG (intron 19) of the Jagged 1 gene in 3 relatives with the full syndrome and in 2 other members with a partial syndrome. Other relatives, without mutation, have some of the phenotypic features of it. Conclusions: We comment on the clinical forms of AS in this family and the detected mutation. Molecular diagnosis allows to make a genetic counsel

[Clinical and molecular features in a family with multiple endocrine neoplasia type-1 syndrome]. / Características clínicas y moleculares de una familia con síndrome de neoplasia endocrina múltiple tipo 1.

BACKGROUND: The clinical features of multiple endocrine neoplasia type-1 (MEN-1) syndrome are hyperplasia or adenoma of the parathyroid glands, pituitary adenoma and gastroenteropancreatic endocrine tumors. This syndrome is due to mutations in the MEN1 gene, located on the q13 region of chromosome 11. Prognosis depends on tumoral growth and metastatic potential. PATIENTS AND METHOD: We reviewed the medical records of the members of a family (6 men and 2 women) with MEN-1 syndrome diagnosed between 1995 and 2007 in Hospital Donostia, San Sebastian (Spain). Familial study of all patients and family members (19 cases from 2 generations) was performed in 2 phases. The first phase consisted of mutation screening and the second of multiplex ligation-dependent probe amplification (MLPA) to detect deletions. RESULTS: Screening of mutations identified no pathogenic variants in the proband of this family. MLPA revealed a deletion affecting exons 1 and 2 of the MEN1 gene. Of the 10 family members with this molecular alteration, 8 had at least one phenotypic feature of this syndrome (hyperparathyroidism in 8, prolactinomas in 2, and gastrinomas in 3) after 12 years of follow-up. CONCLUSION: We discuss the clinical forms of MEN-1 syndrome in this family and the molecular alteration found. Study of MEN1 gene deletions should be incorporated into routine molecular screening.

Prenatal diagnosis in myotonic dystrophy type 1. Thirteen years of experience: implications for reproductive counselling in DM1 families.

OBJECTIVES: To analyse the results obtained from prenatal diagnoses in myotonic dystrophy type 1 (DM1) performed in our hospitals during the last 13 years. METHODS: Molecular analyses were conducted on chorionic villi or cultured amniotic fluid samples obtained for prenatal diagnosis of DM1. CTG expansion was analyzed by polymerase chain reaction (PCR) and Southern blot techniques. RESULTS: From 154 prenatal diagnoses performed in 13 years, 51% were found to be healthy and 49% affected. Considering the 75 carriers of the mutation, in 65.3% of the cases, the mother was the transmitting parent versus 36.5% of fathers. From these female transmissions, 31/49 foetuses had expansion in the neonatal form range, namely, congenital myotonic dystrophy (CMD). CONCLUSIONS: In our series, no significant deviation of the 50% expected frequency of transmission in autosomal dominant disorder was seen. We show that when the disease is transmitted by a male, the mean intergenerational variation is minimal (mean = 56 CTG, SD = 177 CTG). However, this does not occur in the affected mothers, where the mean intergenerational expansion is very high (mean = 948 CTG, SD = 815 CTG) and the difference is statistically significant (t-Student p < 0.0001). Our data have important implications for the genetic counselling of DM1 families.

A common haplotype associated with the Basque 2362AG --> TCATCT mutation in the muscular calpain-3 gene.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by any of over 150 mutations in the calpain-3 (CAPN3) gene. Of those, 2362AG --> TCATCT is particularly prevalent in Basque patients, and this mutation was hypothesized to have arisen in the Basque Country. To explore the natural history of this mutation, we genotyped 65 Basque and non-Basque patients with LGMD2A who carry the 2362AG --> TCATCT mutation for four microsatellites within or flanking the gene. A particular haplotype was found in three-fourths of the patients and was assumed to be ancestral. From the average number of recombinations and mutations accumulated from this ancestral haplotype, the age of the 2362AG ----> TCATCT mutation was estimated to be 50 generations (i.e., 1,250 years), which is more recent than the Paleolithic Basque heritage. The subsequent spread of the 2362AG --> TCATCT mutation can be related to gene flow out of the Basque Country, even across a cultural border.