Background
The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in
SUCLA2
or
SUCLG1
. We report here ...25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients.
Patients and results
Of the 71 patients, 50 had
SUCLA2
mutations and 21 had
SUCLG1
mutations. In the newly-reported 20
SUCLA2
patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported
SUCLG1
patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with
SUCLA2
mutations and at birth for
SUCLG1
patients. Median survival was 20 years for
SUCLA2
and 20 months for
SUCLG1
. Notable clinical differences between the two groups were hepatopathy, found in 38 % of
SUCLG1
cases but not in
SUCLA2
cases, and hypertrophic cardiomyopathy which was not reported in
SUCLA2
patients, but documented in 14 % of cases with
SUCLG1
mutations. Long survival, to age 20 years or older, was reported in 12 % of
SUCLA2
and in 10 % of
SUCLG1
patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of
SUCLA2
and 80 % of
SUCLG1
patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found.
Conclusions
To our knowledge, this is the largest study of patients with
SUCLA2
and
SUCLG1
deficiency. The most important findings were a significantly longer survival in patients with
SUCLA2
mutations compared to
SUCLG1
mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with
SUCLG1
mutations, whereas epilepsy was much more frequent in patients with
SUCLA2
mutations compared to patients with
SUCLG1
mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire
SUCLA2
gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known
SUCLA2
founder mutation in the Faroe Islands.
KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism ...responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/−), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.
Although human amniotic fluid does contain different populations of foetal‐derived stem cells, scanty information is available on the stemness and the potential immunomodulatory activity of in vitro ...expanded, amniotic fluid stem cells. By means of a methodology unrequiring immune selection, we isolated and characterized different stem cell types from second‐trimester human amniotic fluid samples (human amniotic fluid stem cells, HASCs). Of those populations, one was characterized by a fast doubling time, and cells were thus designated as fHASCs. Cells maintained their original phenotype under prolonged in vitro passaging, and they were able to originate embryoid bodies. Moreover, fHASCs exhibited regulatory properties when treated with interferon (IFN)‐γ, including induction of the immunomodulatory enzyme indoleamine 2,3‐dioxygenase 1 (IDO1). On coculture with human peripheral blood mononuclear cells, IFN‐γ–treated fHASCs caused significantly decreased T‐cell proliferation and increased frequency in CD4+ CD25+ FOXP3+ regulatory T cells. Both effects required an intact IDO1 function and were cell contact‐independent. An unprecedented finding in our study was that purified vesicles from IFN‐γ–treated fHASCs abundantly expressed the functional IDO1 protein, and those vesicles were endowed with an fHASC‐like regulatory function. In vivo, fHASCs were capable of immunoregulatory function, promoting allograft survival in a mouse model of allogeneic skin transplantation. This was concurrent with the expansion of CD4+ CD25+ Foxp3+ T cells in graft‐draining lymph nodes from recipient mice. Thus fHASCs, or vesicles thereof, may represent a novel opportunity for immunoregulatory maneuvers both in vitro and in vivo.
Abstract Shapiro Syndrome (SS) is a rare condition of spontaneous periodic hypothermia, corpus callosum agenesis (ACC) and hyperhidrosis which can occur at any age. The variant form refers to the ...phenotypic SS without ACC. We reported the case of SS variant on a 4-year-old boy who presented from his first year frequent episodes of hypothermia lasting 2–3 h with core rectal temperatures <35 °C. In order to understand the characteristics of this rare syndrome we searched all the cases present in literature. Fifty-two cases of SS were found in literature. Among all clinical signs, paroxysmal hypothermia seems to be the hallmark of both typical and variant SS. ACC is reported only in 40% of cases of SS. Hyperhidrosis, another hallmark of SS, was present in only 42.3% of the cases and mainly in adult onset. The presence of SS in siblings of different genders suggests an autosomal recessive inheritance model, however a gonadic mosaicism responsible for an autosomal de novo mutation cannot be ruled out. From our review of well documented cases of SS, we conclude that only the episodic and spontaneous paroxysmal hypothermia should be considered the defining hallmark of typical and variant SS. This can be important to define the clinical manifestation of SS improving the early diagnosis.
Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, ...microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype–phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical‐molecular diagnostic criteria.
Background
Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fully reversible motor weakness as a specific symptom of aura. Mutations in the ion ...transportation coding genes CACNA1A, ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy.
Case
Here we report on a three-generation family with five patients having a novel ATP1A2 mutation on exon 19, causing guanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co-segregated in the five living relatives with migraine, four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalized epilepsy with febrile seizures plus (GEFS+).
Conclusions
The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine and epilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lafora disease is a rare recessive form of progressive myoclonic epilepsy, usually diagnosed during adolescence. Patients present with myoclonus, neurological deterioration, and generalized ...tonic-clonic, myoclonic, or absence seizures. Symptoms worsen until death, usually within the first ten years of clinical onset. The primary histopathological hallmark is the formation of aberrant polyglucosan aggregates called Lafora bodies in the brain and other tissues. Lafora disease is caused by mutations in either the EPM2A gene, encoding laforin, or the EPM2B gene, coding for malin. The most frequent EPM2A mutation is R241X, which is also the most prevalent in Spain. The Epm2a
and Epm2b
mouse models of Lafora disease show neuropathological and behavioral abnormalities similar to those seen in patients, although with a milder phenotype. To obtain a more accurate animal model, we generated the Epm2a
knock-in mouse line with the R240X mutation in the Epm2a gene, using genetic engineering based on CRISPR-Cas9 technology. Epm2a
mice exhibit most of the alterations reported in patients, including the presence of LBs, neurodegeneration, neuroinflammation, interictal spikes, neuronal hyperexcitability, and cognitive decline, despite the absence of motor impairments. The Epm2a
knock-in mouse displays some symptoms that are more severe that those observed in the Epm2a
knock-out, including earlier and more pronounced memory loss, increased levels of neuroinflammation, more interictal spikes and increased neuronal hyperexcitability, symptoms that more precisely resemble those observed in patients. This new mouse model can therefore be specifically used to evaluate how new therapies affects these features with greater precision.
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