Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia.

OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. RESULTS: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5µmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292-303.

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

[Current indications for invasive prenatal diagnosis. New proposals based on the experience of Institute Nacional de Perinatología]. / Indicaciones actuales para el diagnóstico prenatal invasivo. Nuevas propuestas basadas en la experiencia del Instituto Nacional de Perinatología.

BACKGROUND: Invasive prenatal diagnosis (IPD) allows identification of fetal diseases, mainly aneuploidy. With the addition of first-trimester prenatal screening and structural ultrasound, IPD indications have changed. OBJECTIVE: To describe the current indications for IPD in pregnant patients at INPer. METHODS: Descriptive and retrospective study. We reviewed medical records of patients in which IPD was performed during a period of 2.5 years. RESULTS: A total of 339 studies were performed: 81% by amniocentesis (AC), 13% by chorionic villus sampling (CVS) and 6% by cordocentesis or somatocentesis. The most common indications for AC were: advanced maternal age (AMA) (43%), fetuses with multiple defects by ultrasonido (23%) and presence of soft markers for aneuploidies (9%). For CVS were: cystic hygroma (24%). Increased nuchal translucency (NT) (24%), and AMA (18%). When the indication was only AMA, 1.5% of fetus presented aneuploidy. In women under 38 years and normal ultrasoud, chromosomal abnormalities were not detected. The increased NT in women <35 years had a 21% detection and in patients > 35 years it increased to 33%. CONCLUSIONS: We observed that the group who had normal translucencia nucal and AMA presented a low risk of chromosomal abnormalities. In the presence of an increased NT, 33% of fetuses were affected, so that measuring TN is considered the best non invasive PD tool. The average age with cytogenetic abnormalities was above 38 years, so we suggest to offer IPD in women above 38 years-old.

iPSC-based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation.

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.

Disgenesia gonodal pura 46XX / Gonadal disgenesia pure 46XX

Se describe el caso de una paciente de 22 años de edad, ty con fenotipo femenino, sin estigmas somáticos, desarrollo mamario normal, vello axilar y púbico escaso y genitales externos normales, que acudió a consulta por esterilidad. El estudio hormonal mostró hipogonadismo hepergonadotropo. El cariotipo en linfocitos de sangre periférica fue 46XX; la citología de la mucosa oral y vaginal fue positiva. En la laparoscopia se observaron bandas blanquecinas en el sitio de los ovarios, la biopsia mostro estroma ovárico fibroso, sin folículos primordiales. Se estableció el diagnóstico de disgenesia gonadal pura 46XX. Este síndrome se conoce desde 1990 y hasta ahora solamente se ha informado de aproximadamente 130 casos. Se exponen los datos clínicos, hormonales, citogenéticos e histológicos del padecimiento.

La inseminación artificial como tratamiento de la pareja estéril: informe preliminar / Artificial insemination as treatment for sterile couples: preliminary report

El propósito de este estudio fue demostrar la utilidad de la inseminación artificial intrauterina en parejas con esterilidad que no lograron el embarazo mediante relaciones sexuales e inductores de la ovulación. El estudio fue de tipo prospectivo, longitudinal, abierto, en la Clínica de Esterilidad e Infertilidad del Hospital Central Militar, en un periodo de tres años. El tamaño de la muestra fue de 120 parejas. El estudio se realizó en tres etapas: cada una tuvo una duración aproximada de tres ciclos (tres meses). Previamente se realizó laparoscopía pélvica