MED12-Related (Neuro)Developmental Disorders: A Question of Causality.

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

MED12 missense mutation in a three-generation family. Clinical characterization of MED12-related disorders and literature review.

Mutations in MED12 gene have been described in association with syndromic and non-syndromic X-linked intellectual disability (XLID). Up to date at least three distinct XLID syndromes have been described: FG syndrome, Lujan-Fryns syndrome (LS) and Ohdo syndrome (OSMKB). In the last years, thanks to the massive use of next generation sequencing techniques (NGS) it has been possible to discover at least 16 others MED12 mutations and to expand the phenotype of MED12-related disorders. Here we report three subjects from a large non-consanguineous family presenting with a mild to severe ID, important speech delay, behavior problems, dysmorphic facial features and hearing loss. NGS allows us to detect the MED12 missense variant c.3883C > T (p.(Arg1295Cys)) carried by the three patients. This variant has been reported in 2016 by Hu et al. in one family from a big cohort of XLID families. This clinical report contributes to expanding the phenotype associated with MED12-mutations.

Neonatal hypotonia and neuromuscular conditions.

The differential diagnosis of neonatal hypotonia is a complex task, as in newborns hypotonia can be the presenting sign of different underlying causes, including peripheral and central nervous system involvement and genetic and metabolic diseases. This chapter describes how a combined approach, based on the combination of clinical signs and new genetic techniques, can help not only to establish when the hypotonia is related to peripheral involvement but also to achieve an accurate and early diagnosis of the specific neuromuscular diseases with neonatal onset. The early identification of such disorders is important, as this allows early intervention with disease-specific standards of care and, more importantly, because of the possibility to treat some of them, such as spinal muscular atrophy, with therapeutic approaches that have recently become available.

CNTNAP1-Related Congenital Hypomyelinating Neuropathy.

BACKGROUND: Congenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life. METHODS: Whole-exome sequencing was performed in two siblings with congenital hypotonia. Detailed phenotyping data were compared with previously reported cases. RESULTS: A novel, heterozygous compound mutation of CNTNAP1 was identified in both siblings. We also reviewed 17 patients harboring 10 distinct mutations from previously published studies. All patients presented with severe hypotonia, respiratory distress, and multiple cranial nerve palsies at birth. Six of 19 patients survived beyond infancy and required chronic mechanical ventilation. Seizures were common in the surviving patients. CONCLUSIONS: These findings suggest that CNTNAP1-related congenital hypomyelinating neuropathy is a distinct form of hereditary neuropathy that affects both the central and peripheral nervous systems with no clear phenotype-genotype correlation. Our findings also indicate that arthrogryposis multiplex congenita and early lethality are not universal outcomes for patients with congenital hypomyelinating neuropathy.

Diagnóstico precoz de enfermedades neuromusculares potencialmente tratables: orientación clínica / Early diagnosis of potentially treatable neuromuscular diseases: clinical guidance

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ßIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy.

ßIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into ßIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na+ channels and no nodal KCNQ2 K+ channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and ßI spectrin can cluster Na+ channels and partially compensate for the loss of AnkG and ßIV spectrin at nodes of Ranvier, AnkR and ßI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K+ channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction.

Congenital Hypotonia in Toddlerhood.

CASE: David is a 22-month-old boy who is new to your practice. He recently moved from a rural area in the Midwest. His father is in the United States Air Force, and his mother works as a full-time homemaker. Their household includes 5 older siblings. The family moves every year because of the father's Air Force placement.David was born full-term in Virginia, with no reported pregnancy complications and no alcohol, tobacco, or drug exposure. He was delivered vaginally, with Apgar scores of 7 and 9, respectively and no respiratory issues. In the newborn nursery, his nurse noted that he was floppy, with generalized low muscle tone. Laboratory work performed included normal thyroid studies and a chromosomal microarray.Because of persistent hypotonia, he was seen by a pediatric neurologist at 9 months of age. A magnetic resonance imaging was performed and was normal, with no structural deficits noted. He was referred to Early Intervention at 6 months, when he was not yet rolling over. He received physical therapy for a few months before the family moved again for his father's next placement.David presents in your office as a sweet nondysmorphic toddler who maintains steady eye contact and smiles responsively. His height, head circumference, and weight are at the 50th percentile. His physical examination is notable for generalized hypotonia, with intact upper and lower deep tendon reflexes. He spontaneously says about 20 words. He turns his head when his name is called and can follow a simple command, such as "clap, clap." He reaches his whole hand toward desired objects and will look at his parents if they are out of reach. He can grasp a block, bang, and transfer objects. He demonstrates an immature pincer grasp. He can roll over and sit independently and is just beginning to pull to a stand. His parents report he has recently restarted Early Intervention, where he is receiving physical, speech, and occupational therapy. His audiology examination is normal.His parents' primary concern today is regarding feeding. David is a picky eater. He has difficulty with new foods and textures. The parents noticed a regression in his tolerance for new foods around the recent move. He eats baby puffs, stage 2 to 3 baby foods, and fruit and vegetable pouches. He does not like soft, sticky foods. He is also reported to have other sensory sensitivities. He does not tolerate loud noises and is bothered by tags in his clothing. You wonder, what further work-up would be helpful for David? How can his feeding issues be addressed?

Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.

Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome.

A novel variant in MED12 gene: Further delineation of phenotype.

MED12 is a multiprotein mediator complex, which has a role in cell growth and differentiation and has been implicated in three distinct X-linked intellectual disability syndromes with distinctive clinical features. These include Opitz-Kaveggia syndrome (FG syndrome), Lujan syndrome, and X-linked Ohdo syndrome. Recently MED12 variants have been implicated in isolated X-linked intellectual disability. We describe a 5-year-old male patient with intellectual disability and facial dysmorphism and a novel variant in MED12 gene identified by Whole Exome Sequencing. His dysmorphic facial features are distinct from the previously described phenotypes. With a strong genotype-phenotype correlation that is already known for MED12, this could be a new phenotype linked to MED12, thus expanding the phenotypic spectrum of MED12-related disorders.

A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.

Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A>G splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK's ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc.

Enfermedad renal por depósito idiopático de cadenas livianas. Caso clínico / Kidney involvement in idiopathic light chain disease. Report of one case

El Mieloma Múltiple (MM) es la gammapatia monoclonal (GM) que más frecuentemente compromete la función renal, no obstante, un número creciente de enfermedades renales asociadas a GM están siendo reconocidas. Las GM son un conjunto de entidades caracterizadas por la producción anómala y secreción a la sangre de una inmunoglobulina (Ig) monoclonal (de un mismo clon de células plasmáticas) o un fragmento de la misma (cadenas pesadas, ligeras o ambas) que puede depositarse en los órganos de forma organizada como cristales, fibrillas o microtúbulos, o de forma no organizada (granular). Esta Ig llega a depositarse principalmente en el riñón, no sólo porque es un órgano muy vascularizado, sino también porque el túbulo renal tiene un papel predominante en el metabolismo de las Igs. El diagnóstico del compromiso renal ha sufrido cambios en las últimas décadas, siendo cada vez más certero debido al desarrollo e implementación rutinaria de distintas técnicas de laboratorio (tinciones con anticuerpos específicos contra cadenas ligeras kappa y lambda, estudio con microscopia electrónica (ME) y el desarrollo de técnicas cada vez más sensibles para detectar el componente monoclonal en sangre u orina). El compromiso renal en estas patologías frecuentemente se asocia a GM malignas, generalmente asociadas a depósitos de cadenas ligeras. Cada vez son más los casos de disfunción renal asociados a GM, y en muchos de estos es evidente el progreso a enfermedad renal terminal y con altas tasas de recurrencia después del transplante renal.

Multiple myeloma (MM) is the monoclonal gammopathy (MG) that most frequently compromises renal function; however, a growing number of renal diseases associated with monoclonal gammopathies are being recognized. Monoclonal gammopathies (MG) are a set of entities characterized by the abnormal production and secretion into the blood of a monoclonal immunoglobulin (Ig) from a single clone of plasma cells or a fragment thereof (heavy, light chains orboth) which can be deposited in the organs in an organized way such as crystals, fibrils or microtubules, orin an unorganized (granular) form. This Ig is mainly deposited in the kidney, not only because it is a very vascularized organ, but also because the renal tubule plays a predominant role in the metabolism of Igs. The diagnosis of renal involvement has undergone changes in the last decades, being more and more certain due to the development and routine implementation of different laboratory techniques (stains with specific antibodies against kappa and lambda light chains, study with electron microscopy (EM), development of increasingly sensitive techniques for detecting the monoclonal component in blood or urine). Renal involvement in these pathologies is often associated with malignant MG, generally associated with light chain deposits. Increasingly, there are cases of renal dysfunction associated with MG, and progression to terminal renal disease and high rates of recurrence after renal transplantation are evident in many of these.

Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy.

tRNA synthetase deficiencies are a growing group of genetic diseases associated with tissue-specific, mostly neurological, phenotypes. In cattle, cytosolic isoleucyl-tRNA synthetase (IARS) missense mutations cause hereditary weak calf syndrome. Exome sequencing in three unrelated individuals with severe prenatal-onset growth retardation, intellectual disability, and muscular hypotonia revealed biallelic mutations in IARS. Studies in yeast confirmed the pathogenicity of identified mutations. Two of the individuals had infantile hepatopathy with fibrosis and steatosis, leading in one to liver failure in the course of infections. Zinc deficiency was present in all affected individuals and supplementation with zinc showed a beneficial effect on growth in one.

Whole Exome Sequencing and Heterologous Cellular Electrophysiology Studies Elucidate a Novel Loss-of-Function Mutation in the CACNA1A-Encoded Neuronal P/Q-Type Calcium Channel in a Child With Congenital Hypotonia and Developmental Delay.

BACKGROUND: A 4-year-old boy born at 37 weeks' gestation with intrauterine growth retardation presented with developmental delay with pronounced language and gross motor delay, axial hypotonia, and dynamic hypertonia of the extremities. Investigations including the Minnesota Newborn Screen, thyroid stimulating hormone/thyroxin, and inborn errors of metabolism screening were negative. Cerebral magnetic resonance imaging and spectroscopy were normal. Genetic testing was negative for coagulopathy, Smith-Lemli-Opitz, fragile X, and Prader-Willi/Angelman syndromes. Whole genome array analysis was unremarkable. METHODS: Whole exome sequencing was performed through a commercial testing laboratory to elucidate the underlying etiology for the child's presentation. A de novo mutation was hypothesized. In attempt to establish pathogenicity of our candidate variant, cellular electrophysiologic functional analysis of the putative de novo mutation was performed using patch-clamp technology. RESULTS: Whole exome sequencing revealed a p.P1353L variant in the CACNA1A gene, which encodes for the α1-subunit of the brain-specific P/Q-type calcium channel (CaV2.1). This presynaptic high-voltage-gated channel couples neuronal excitation to the vesicular release of neurotransmitter and is implicated in several neurologic disorders. DNA Sanger sequencing confirmed that the de novo mutation was absent in both parents and present in the child only. Electrophysiologic analysis of P1353L-CACNA1A demonstrated near complete loss of function, with a 95% reduction in peak current density. CONCLUSIONS: Whole exome sequencing coupled with cellular electrophysiologic functional analysis of a de novoCACNA1A missense mutation has elucidated the probable underlying pathophysiologic mechanism responsible for the child's phenotype. Genetic testing of CACNA1A in patients with congenital hypotonia and developmental delay may be warranted.

Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.

Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.

CDC174, a novel component of the exon junction complex whose mutation underlies a syndrome of hypotonia and psychomotor developmental delay.

Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. Homozygosity mapping identified a single disease-associated locus of 3.5 Mb on chromosome 3. Studies of a Bedouin consanguineous kindred affected with a similar recessive phenotype identified a single disease-associated 18 Mb homozygosity locus encompassing the entire 3.5 Mb locus. Whole exome sequencing demonstrated only two homozygous mutations within a shared identical haplotype of 0.6 Mb, common to both Bedouin and Ethiopian affected individuals, suggesting an ancient common founder. Only one of the mutations segregated as expected in both kindreds and was not found in Bedouin and Jewish-Ethiopian controls: c.1404A>G, p.[*468Trpext*6] in CCDC174. We showed that CCDC174 is ubiquitous, restricted to the cell nucleus and co-localized with EIF4A3. In fact, yeast-two-hybrid assay demonstrated interaction of CCDC174 with EIF4A3, a component of exon junction complex. Knockdown of the CCDC174 ortholog in Xenopus laevis embryos resulted in poor neural fold closure at the neurula stage with later embryonic lethality. Knockdown embryos exhibited a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 and hoxb3. The Xenopus phenotype could be rescued by the human normal, yet not the mutant CCDC174 transcripts. Moreover, overexpression of mutant but not normal CCDC174 in neuroblastoma cells caused rapid apoptosis. In line with the hypotonia phenotype, the CCDC174 mutation caused depletion of RYR1 and marked myopathic changes in skeletal muscle of affected individuals.