A FEMALE CASE OF SPINOCEREBELLAR ATAXIA TYPE 10 WITH SUICIDAL BEHAVIOR AND ENDOCRINPATHIES ASSOCIATED WITH A MASSIVE EXPANSION (ATTCT) OF THE GENE ATXN10.

Spinocerebellar ataxia type 10 (SCA10) is characteri- zed by ataxia, psychiatric disorders convulsions, and locus at 22q13.311. It is caused by expansions between 800-4500 pentanucleotide ATTCT repeats in intron 9 of the ATXN10 gene1-2. The ATXN10 gene encodes ataxin-10 protein (known as E46L) involved in neuritogenesis 1. SCA10 has a founder origin in Mexican, Brazilian, Argentine populattons but is rare in others.

Extracranial midline defects in a patient with craniofrontonasal syndrome with a novel EFNB1 mutation.

We report a female patient with craniofrontonasal syndrome (CFNS) who in addition showed other cranial and extracranial midline defects including partial corpus callosum agenesis, ocular melanocytosis, pigmentary glaucoma, duplex collecting system, uterus didelphys, and septate vagina. She was found to have a novel pathogenic variant in exon 5 of EFNB1, c.646G>T (p.Glu216*) predicted to cause premature protein truncation. From our review, we found at least 39 published CFNS patients with extracranial midline defects, comprising congenital diaphragmatic hernia, congenital heart defects, umbilical hernia, hypospadias, and less frequently, sacrococcygeal teratomas, and internal genital anomalies in females. These findings support that the EFNB1 mutations have systemic consequences disrupting morphogenetic events at the extracranial midline. Though these are not rigorously included as midline defects, we found at least 10 CFNS patients with congenital anomalies of the kidney and urinary tract, all females. Additionally, uterus didelphys and ocular melanocytosis observed in our patient are proposed also as a previously unreported EFNB1-related midline defects. In addition, this case may be useful for considering the intentional search for genitourinary anomalies in future patients with CFNS, which will be helpful to define their frequency in this entity.

A clinical report of the massive CAG repeat expansion in spinocerebellar ataxia type 2: Severe onset in a Mexican child and review previous cases.

The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow ocular saccades, nystagmus, ophthalmoplegia, dysarthria, dysphagia, cognitive deterioration, mild dementia, peripheral neuropathy. Infantile onset is a rare presentation that only has been reported in four instances in the literature. In the present work a boy aged 5 years 7 months was studied due to horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. The mother aged 27 years-old presented progressive cerebellar ataxia, dysarthria, dysmetria, dysdiadochokinesis, limb ataxia and olivopontocerebellar atrophy. The molecular analysis was made by identifying the expansion repeats in tandem by long PCR to analyze the repeats in the ATXN2 gene. We found an extreme CAG expansion repeats of ~884 repeats in the child. We describe a Mexican child affected by SCA2 with an infantile onset, associated with a high number of CAG repeats previously no reported and anticipation phenomenon.

[Ataxina-2, nuevo blanco en enfermedades genéticas complejas].

El gen de la ataxina-2 es un blanco en la patogénesis de enfermedades complejas, entre ellas los factores de riesgo cardiovascular y enfermedades neurodegenerativas. El gen ATXN2 tiene un VNTR en el exón 1, cuya expansión por encima de las 30 repeticiones provoca al desarrollo de ataxia espinocerebelosa tipo 2; las repeticiones en rango menor se asocian con diabetes tipo 2 o esclerosis lateral amiotrófica. También este locus está ligado con fenotipos metabólicos e inflamatorios. En conclusión, el gen puede ser utilizado como marcador clínico de fenotipos metabólicos y neurológicos, lo cual está relacionado con su efecto pleiotrópico.

The ataxin 2 gene is a target in the pathogenesis of complex diseases, including cardiovascular risk factors and neurodegenerative diseases. ATXN2 gen has VNTR in exon 1, whose expansion exceeding 30 repetitions leads to the development of spinocerebellar ataxia type 2; lower-range repetitions are associated with type 2 diabetes or amyotrophic lateral sclerosis. This locus is also linked with metabolic and inflammatory phenotypes. In conclusion, this gene can be used as a clinical marker of metabolic and neurological phenotypes, which is related to its pleiotropic effect.

Genetic approach in amyotrophic lateral sclerosis.

The superoxide dismutase type 1 (SOD1) gene is the first responsible gene mapped in amyotrophic lateral sclerosis type 1 (ALS1), and it codes for the enzyme SOD1, the function of which is to protect against damage mediated by free radicals deriving from oxygen. Its pathophysiological mechanism in ALS1 is related to ischemia. Several molecular studies of the SOD1 gene show that point mutations are the most frequent. The most common mutations in familial cases are p.A4V, p.I113Y, p.G37R, p.D90A and p.E100G, which account for more than 80% of cases, although intronic mutations have also been described as responsible for ALS1. Sporadic cases are explained by mutations in other genes such as SETX and C9orf72. ALS1 is a complex disease with genetic heterogeneity. On the other hand, familial and sporadic cases have a different etiology, which is explained by molecular heterogeneity and multiple pathogenic mechanisms that lead to ALS1; oxidative stress and ischemia are not the only cause. In Mexico, ALS molecular genetics studies are scarce. Clinical studies show an increase in cytokines such as adipsin in cerebrospinal fluid.

Aproximación genética en la esclerosis lateral amiotrófica.

The superoxide dismutase type 1 (SOD1) gene is the first responsible gene mapped in amyotrophic lateral sclerosis type 1 (ALS1), and it codes for the enzyme SOD1, the function of which is to protect against damage mediated by free radicals deriving from oxygen. Its pathophysiological mechanism in ALS1 is related to ischemia. Several molecular studies of the SOD1 gene show that point mutations are the most frequent. The most common mutations in familial cases are p.A4V, p.I113Y, p.G37R, p.D90A and p.E100G, which account for more than 80% of cases, although intronic mutations have also been described as responsible for ALS1. Sporadic cases are explained by mutations in other genes such as SETX and C9orf72. ALS1 is a complex disease with genetic heterogeneity. On the other hand, familial and sporadic cases have a different etiology, which is explained by molecular heterogeneity and multiple pathogenic mechanisms that lead to ALS1; oxidative stress and ischemia are not the only cause. In Mexico, ALS molecular genetics studies are scarce. Clinical studies show an increase in cytokines such as adipsin in cerebrospinal fluid.

El gen SOD1 es el primer gen responsable mapeado en la esclerosis lateral amiotrófica tipo 1 (ELA1) y codifica para la enzima superóxido dismutasa tipo 1 (SOD1), cuya función es proteger del daño mediado de los radicales libres derivados del oxígeno; su mecanismo fisiopatológico en ELA1 se relaciona con isquemia. Diversos estudios moleculares del gen SOD1 muestran que las mutaciones puntuales son las más frecuentes. Las mutaciones más comunes en los casos familiares son p.A4V, p.I113Y, p.G37R, p.D90A y p.E100G, que explican más de 80 % de los casos, aunque también se han descrito mutaciones intrónicas como responsables de esclerosis lateral amiotrófica tipo 1. Los casos esporádicos se explican por mutaciones en otros genes como SETX y C9orf72. ELA1 es una enfermedad compleja con heterogeneidad genética. Por otra parte, los casos familiares y esporádicos tienen etiología distinta, lo cual se explica por la heterogeneidad molecular y múltiples mecanismos patogénicos que conducen a ELA1; el estrés oxidativo y la isquemia no son la única causa. En México son escasos los estudios de genética molecular de esclerosis lateral amiotrófica. Los estudios clínicos muestran incremento de citocinas como la adipsina en el líquido cefalorraquídeo.

Epidemiología genética sobre las teorías causales y la patogénesis de la diabetes mellitus tipo 2.

Diabetes mellitus type 2 (DM2) is a worldwide public health problem. The etiology of the disease is multifactorial and is characterized by great heterogeneity of metabolic disorders. The most common are the insufficient production of insulin, insulin resistance and impaired incretin system. The specialist must understand the multi-causal nature of DM2 in the post-genomic era. This nature is determined by the additive effect of genes and environment, so there is no simple genetic epidemiological model to explain the inheritance pattern. Hence the need to establish the proportion of disease that is determined by genes and the contribution of environmental factors, the combination of which regulates the threshold or tolerance level for diabetes development. Given this complexity in DM2 in this work are discussed the various existing theories of causality of this disease, which will permit us to understand the interaction between the environment and the human genome, and also to know how risk factors or predisposition to this disease influence, laying the grounds that delimit environment interaction with the genome.

[(CAG)n polymorphism of the ATXN2 gene, a new marker of susceptibility for type 2 diabetes mellitus]. / El polimorfismo (CAG)n del gen ATXN2, nuevo marcador de susceptibilidad para diabetes mellitus tipo 2.

OBJECTIVE: Estimate whether there is an association between the (CAG)n repeat in the ATXN2 gene in the Mexican population and type 2 diabetes mellitus (DM). METHODS: Epidemiological case-control study, including healthy people and diabetics. (CAG)n expansion was detected by end-point polymerase chain reaction (PCR). PCR outputs were analyzed by electrophoresis (PAGE 8%) and silver nitrate staining. RESULTS: (CAG)n nucleotide allele distribution in the study population was similar to that reported in central Mexico. The 22-repeat allele is the most frequent; however, there is an association with carriers of long repeats in the normal range with diabetes. CONCLUSIONS: The results suggest that the (CAG)n repeat of the ATXN2 gene could be a causal factor for type 2 DM.

Anti-cyclic citrullinated peptide antibodies and rheumatoid factor sera titers in leprosy patients from Mexico.

Leprosy offers a broad spectrum of altered immunological sceneries, ranging from strong cell-mediated immune responses seen in tuberculoid leprosy (TT), through borderline leprosy (BB), to the virtual absence of T cell responses characteristic in lepromatous leprosy (LL). The exact mechanism of autoantibodies production remains unknown in leprosy and other chronic inflammatory diseases and also the contribution of these antibodies to the pathogenesis of the disease. The aim of this study is to evaluate the frequency and profiles of serum anti-cyclic citrullinated peptide antibodies (a-CCP), rheumatoid factor (RF) and its relationship with leprosy spectrum. Serum samples from 67 leprosy patients (54 LL, 5 TT and 8 BB) and 46 clinically healthy subjects (CHS) from the same endemic region were investigated. The clinical chart and questionnaire were used to obtain clinical information. Anti-cyclic citrullinated peptide antibodies (a-CCP) were measured by enzyme-linked immunosorbent assay, whereas the rheumatoid factor (RF) levels were measured by nephelometric method. The mean age of patients was 51.5 ± 13 years. Sera levels of a-CCP where higher in leprosy patients than in CHS (5.9 ± 11.6 vs. 0.3 ± 0.29) (P < 0.0001); the same pattern was found for RF sera titers without reaching statistical significance (16.8 ± 22.5 vs. 9.9 ± 3) (P = NS). We did not find a correlation between a-CCP and RF Rho =0.02786 (IC 95%) P = 0.8229. However, LL patients had higher a-CCP and RF levels than TT patients. Although an absence in correlation was observed, the serum levels of a-CCP antibodies and RF appeared to be useful in distinguishing LL from TT patients with a limited significance in detecting reactional leprosy patients.

Umbilical cord disruption sequence caused by long cord in two unrelated infants with amyoplasia.

Encirclement of a fetal body part by the umbilical cord with or without vascular obstruction in either the umbilical cord or the encircled fetal part is considered an umbilical cord loop (UCL). Significant disruption of the encircled fetal parts is recognized as the umbilical cord disruption sequence (UCDS). UCL around fetal parts is an occasional anomaly in infants with amyoplasia. We report on 2 patients with amyoplasia and damage to the fetal limbs caused by UCDS and a long umbilical cord. Patient 1 showed two deep constrictions on the left lower limb caused by UCL with an intact skin and a mild mark of constriction on the left wrist. The umbilical cord in patient 2 produced 5 entanglements around the left thigh which resulted in a deep groove extending down to the femur and also showed an exposed fracture and gangrene of the entire lower limb with an unusual congenital paraumbilical "stoma" that corresponded to the afferent loops of a jejunal atresia. The UCDS in infants with amyoplasia has been associated with short umbilical cords, whereas in patients without congenital contractures, the UCDS or UCL has been related to long umbilical cords. Our observations of UCDS in patients with amyoplasia but with long umbilical cords suggest the influence of both pathogenic factors or the existence of additional mechanisms. Evidence in patient 2 may support a vascular pathogenesis.

New subtype of familial achondrogenesis type IA (Houston-Harris).

BACKGROUND: Achondrogenesis is a skeletal dysplasia characterized primarily by short stature, severe micromelia, short and narrow chest, prematurity, polyhydramnios, fetal hydrops, and in utero or neonatal death. Based on the radiological and histopathological findings, there are three types of achondrogenesis: type 1A (Houston-Harris), type 1B (Fraccaro) and type 2 (Langer-Saldino). CLINICAL CASE: A premature female product was studied whose clinical, radiological and histopathological characteristics were compatible with achondrogenesis Type 1A. The family information allowed us to conclude that the 4 products of the 6 previous pregnancies were affected. Statistical analysis in at least 4 families previously described, including this family case showed significant differences between expected and observed number of members, being incongruent with an autosomal recessive mode of inheritance previously reported. CONCLUSIONS: therefore, it could be considered a new subtype of achondrogenesis type 1A due to the presence of a preferential germline mutation.

INTRODUCCIÓN: La acondrogénesis es una displasia esquelética que se caracteriza principalmente por talla baja, micromelia grave, tórax corto y estrecho, prematurez, polihidramnios, hidropesía fetal y muerte fetal in utero o neonatal. Según los hallazgos radiológicos e histopatológicos existen tres tipos de acondrogénesis: tipo 1A (Houston-Harris), tipo 1B (Fraccaro) y tipo 2 (Langer-Saldino). CASO CLÍNICO: Se sometió a estudio a un producto femenino prematuro cuyas características clínicas, radiológicas e histopatológicas fueron compatibles con acondrogénesis tipo 1A. La información familiar permitió concluir que los cuatro productos de los seis embarazos previos se encontraban afectados. El análisis estadístico en por lo menos cuatro familias previamente descritas, incluyendo este caso familiar, mostró diferencias significativas entre el número de miembros esperado y el observado, siendo incongruente con el modo de herencia autosómico recesivo previamente reportado. CONCLUSIONES: Podría considerarse un nuevo subtipo de acondrogénesis tipo 1A debida a la presencia de una mutación germinal preferencial.

New subtype of familial achondrogenesis type IA (Houston-Harris). / Nuevo subtipo de acondrogénesis familiar tipo IA (Houston-Harris)

Background: Achondrogenesis is a skeletal dysplasia characterized primarily by short stature, severe micromelia, short and narrow chest, prematurity, polyhydramnios, fetal hydrops, and in utero or neonatal death. Based on the radiological and histopathological findings, there are three types of achondrogenesis: type 1A (Houston-Harris), type 1B (Fraccaro) and type 2 (Langer-Saldino). Clinical case: A premature female product was studied whose clinical, radiological and histopathological characteristics were compatible with achondrogenesis Type 1A. The family information allowed us to conclude that the 4 products of the 6 previous pregnancies were affected. Statistical analysis in at least 4 families previously described, including this family case showed significant differences between expected and observed number of members, being incongruent with an autosomal recessive mode of inheritance previously reported. Conclusions: therefore, it could be considered a new subtype of achondrogenesis type 1A due to the presence of a preferential germline mutation.

Introducción: La acondrogénesis es una displasia esquelética que se caracteriza principalmente por talla baja, micromelia grave, tórax corto y estrecho, prematurez, polihidramnios, hidropesía fetal y muerte fetal in utero o neonatal. Según los hallazgos radiológicos e histopatológicos existen tres tipos de acondrogénesis: tipo 1A (Houston-Harris), tipo 1B (Fraccaro) y tipo 2 (Langer-Saldino). Caso clínico: Se sometió a estudio a un producto femenino prematuro cuyas características clínicas, radiológicas e histopatológicas fueron compatibles con acondrogénesis tipo 1A. La información familiar permitió concluir que los cuatro productos de los seis embarazos previos se encontraban afectados. El análisis estadístico en por lo menos cuatro familias previamente descritas, incluyendo este caso familiar, mostró diferencias significativas entre el número de miembros esperado y el observado, siendo incongruente con el modo de herencia autosómico recesivo previamente reportado. Conclusiones: Podría considerarse un nuevo subtipo de acondrogénesis tipo 1A debida a la presencia de una mutación germinal preferencial.

Prevalence of orofacial clefts and risks for nonsyndromic cleft lip with or without cleft palate in newborns at a university hospital from West Mexico.

We determined the overall prevalence of typical orofacial clefts and the potential risks for nonsyndromic cleft lip with or without cleft palate in a university hospital from West México. For the prevalence, 227 liveborn infants with typical orofacial clefts were included from a total of 81,193 births occurred during the period 2009-2016 at the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Guadalajara, Jalisco, Mexico). To evaluate potential risks, a case-control study was conducted among 420 newborns, including only those 105 patients with nonsyndromic cleft lip with or without cleft palate (cases), and 315 infants without birth defects (controls). Data were analyzed using multivariable logistic regression analysis expressed as adjusted odds ratio with 95% confidence intervals . The overall prevalence for typical orofacial clefts was 28 per 10,000 (95% confidence interval: 24.3-31.6), or 1 per 358 live births. The mean values for the prepregnancy weight, antepartum weight, and pre-pregnancy body mass index were statistically higher among the mothers of cases. Infants with nonsyndromic cleft lip with or without cleft palate had a significantly higher risk for previous history of any type of congenital anomaly (adjusted odds ratio: 2.7; 95% confidence interval: 1.4-5.1), history of a relative with cleft lip with or without cleft palate (adjusted odds ratio: 19.6; 95% confidence interval: 8.2-47.1), and first-trimester exposures to progestogens (adjusted odds ratio: 6.8; 95% CI 1.8-25.3), hyperthermia (adjusted odds ratio: 3.4; 95% confidence interval: 1.1-10.6), and common cold (adjusted odds ratio: 3.6; 95% confidence interval: 1.1-11.9). These risks could have contributed to explain the high prevalence of orofacial clefts in our region of Mexico, emphasizing that except for history of relatives with cleft lip with or without cleft palate, most are susceptible of modification.

A de novo interstitial 6q deletion in a boy with a split hand malformation.

We report on a de novo interstitial deletion of (6)(q15q22.2) in a 5-year-old boy with developmental delay, microcephaly, facial dysmorphism, cryptorchidism, congenital heart defect, and split-hand malformation. Previous reports and this patient suggest that 6q21 may contain a gene or genes related either directly or indirectly to limb development.

Microcephaly, distinctive facies, single atrium, postaxial polydactyly, skeletal defects and mental retardation: a new familial faciocardiomelic syndrome?

Three siblings with postaxial polydactyly type A, congenital heart defect (single atrium), mental retardation, microcephaly, a distinctive facial appearance, skeletal anomalies and neonatal macrosomy were studied. Comparison with other cardiomelic syndromes previously described in the literature lead us to conclude that this is a new faciocardiomelic syndrome probably inherited as an autosomal recessive trait.

[Anterior cervical hypertrichosis: case report]. / Hipertricosis cervical anterior: caso dínico.

The non-syndromic anterior cervical hypertrichosis (OMIM N° 600457) is a genetic disorder characterized by a patch of hair at the level of the laryngeal prominence. We present a 12-year-old boy with anterior cervical hypertrichosis and mild generalized hypertrichosis. He has no neurological, ophthalmological or skeletal anomalies. The clinical follow up is 10 years.

La hipertricosis cervical anterior no sindrómica (OMIM N° 600457) es un desorden genético caracterizado por un parche de pelo a nivel de la prominencia laríngea. Se presenta a un niño de 12 años de edad con hipertricosis cervical anterior e hipertricosis generalizada leve, sin alteraciones neurológicas, oftalmológicas ni esqueléticas, en seguimiento clínico por un lapso de 10 años.

Microsatellite analysis in Turner syndrome: parental origin of X chromosomes and possible mechanism of formation of abnormal chromosomes.

Turner syndrome is a chromosomal disorder in which all or part of one X chromosome is missing. The meiotic or mitotic origin of most cases remains unknown due to the difficulty in detecting hidden mosaicism and to the lack of meiotic segregation studies. We analyzed 15 Turner patients, 10 with a 45,X whereas the rest had a second cell line with abnormal X-chromosomes: a pseudodicentric, an isochromosome, one large and one small ring, and the last with a long arm deletion. Our aims were: to detect X cryptic mosaicism in patients with a 45,X constitution; to determine the parental origin of the abnormality; to infer the zygotic origin of the karyotype and to suggest the timing and mechanism of the error(s) leading to the formation of abnormal X chromosomes from maternal origin. Molecular investigation did not revealed heterozygosity for any microsatellite, excluding X mosaicism in the 45,X cases. Parental origin of the single X chromosome was maternal in 90% of these patients. Three of the structurally abnormal Xs were maternally derived whereas the other two were paternal. These results allowed us to corroborate breakpoints in these abnormal X chromosomes and suggest that the pseudodicentric chromosome originated from post-zygotic sister chromatid exchange, whereas the Xq deleted chromosome probably arose after a recombination event during maternal meiosis.