Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families.

AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.

Altered myogenesis and premature senescence underlie human TRIM32-related myopathy.

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.

A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain.

MYH7 gene mutations are associated with wide clinical and genetic heterogeneity. We report a novel founder mutation in MYH7 in Southern Spain (Andalucía). We studied two index patients and 24 family members from two apparently independent families by physical examination, serum creatine-kinase, muscle MRI, sequencing studies and genetic linkage analysis. Sixteen individuals were heterozygous for a (p.R1560P) variant in the MYH7 gene. Haplotype was consistent with a common ancestor for the two families. The patients displayed the classic Laing distal myopathy phenotype, with hanging first toe as the initial presentation, even in mildly affected patients who declared themselves asymptomatic, although neck flexor weakness was revealed as an early sign in some cases. MRI showed that the sartorius was the first muscle involved, even in two out of three asymptomatic carriers. Our findings support the novel variant p.R1560P in MYH7 as a founder mutation in Andalucía. The early involvement of the sartorius muscle in MRI may be useful as an indicator of affection status.

Desmoplastic astrocytoma: new insights into its clinical profile, diagnosis, and treatment.

BACKGROUND: Desmoplastic astrocytoma (DA) is a rare intracranial tumor which usually affects pediatric patients. The aim of this study is to describe the clinical features and management of DA based on a joint analysis of the cases reported in the scientific literature. MATERIAL AND METHODS: A thorough review was carried out, gathering those pathologically proven DAs reported since the first description of this entity. Two new own cases were included in order to illustrate this review. Epidemiological, clinical, radiological, therapeutic, and follow-up data were analyzed with the software SPSS version 20. RESULTS: A total of 52 DAs were recorded. Most cases occurred in the first 2 years of life, although older patients were also reported. Patients mainly presented symptoms and signs of elevated intracranial pressure. According to their radiological features, we were able to classify DAs in four main groups, with distinct differential diagnosis and prognosis. After treatment, 14.2 % of patients presented persistent neurological impairment and the mortality rate was close to 10 %. CONCLUSION: DAs can be diagnosed at any age from birth to adolescence. These neoplasms can show up a wider range of radiological morphologies than previously thought. Surgery represents the treatment of choice for DAs, although chemotherapy can also be useful in the setting of recurrence or progression of the disease. Those DAs lacking classic radiological features, especially type 4 tumors, were linked with a poorer clinical outcome.

Developmental study of vitamin C distribution in children's brainstems by immunohistochemistry.

Vitamin C (Vit C) is an important antioxidant, exerts powerful neuroprotective brain effects and plays a role in neuronal development and maturation. Vit C is present in brain tissue at higher concentrations than in other organs, but its detailed distribution in brain is unknown. Immunohistochemical detection of this vitamin has been performed by using a highly specific antibody against Vit C. The aim of the present work was to analyze the distribution of Vit C in children's brainstems during postnatal development, comparing two groups of ages: younger and older than one year of life. In general, the same areas showing neurons with Vit C in young cases are also immunostained at older ages. The distribution of neurons containing Vit C was broader in the brainstems of older children, suggesting that brainstem neurons maintain or even increase their ability to retain Vit C along the life span. Immunohistochemical labeling revealed only cell bodies containing this vitamin, and no immunoreactive fibers were observed. The distribution pattern of Vit C in children's brainstems suggests a possible role of Vit C in brain homeostatic regulation. In addition, the constant presence of Vit C in neurons of locus coeruleus supports the important role of Vit C in noradrenaline synthesis, which seemed to be maintained along postnatal development.

The role of 18FDG, 18FDOPA PET/CT and 99mTc bone scintigraphy imaging in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocitosis, characterized by multisystemic xanthogranulomatous infiltration by foamy histiocytes that stain positively for CD68 marker but not express CD1a and S100 proteins. Etiology and pathogenesis are still unknown and only about 500 cases are related in the literature. Multisystemic involvement leads to a wide variety of clinical manifestations that results in a poor prognosis although recent advances in treatment. We present the clinical, nuclear medicine findings and therapeutic aspects of a serie of 6 patients with histopathological diagnosis of ECD, who have undergone both bone scintigraphy (BS) and 18F-fluorodeoxyglucose (18FDG)-PET/CT scans in our institution. A complementary 18F-fluorodopa (18FDOPA)-PET/CT was performed in one case. Three different presentations of the disease were observed in our casuistic: most indolent form was a cutaneous confined disease, presented in only one patient. Multifocal involvement with central nervous system (CNS) preservation was observed in two patients. Most aggressive form consisted in a systemic involvement with CNS infiltration, presented in three patients. In our experience neurological involvement, among one case with isolate pituitary infiltration, was associated with mortality in all cases. 18FDG-PET/CT and BS were particularly useful in despite systemic involvement; locate the site for biopsy and the treatment response evaluation. By our knowledge, 18FDOPA-PET/CT not seems useful in the initial staging of ECD. A baseline 18FDG-PET/CT and BS may help in monitoring the disease and could be considered when patients were incidentally diagnosed and periodically 18FDG-PET/CT must be performed in the follow up to evaluate treatment response.

Distribution of peptidergic populations in the human dentate gyrus (somatostatin [SOM-28, SOM-12] and neuropeptide Y [NPY]) during postnatal development.

The postnatal development of the human hippocampal formation establishes the time and place at which we start autobiographical memories. However, data concerning the maturation of the neurochemical phenotypes characteristic of interneurons in the human hippocampus are scarce. We have studied the perinatal and postnatal changes of the dentate gyrus (DG) interneuron populations at three rostrocaudal levels. Immunohistochemically identified neurons and fibers for somatostatin (SOM-12 and SOM-28) and neuropeptide Y (NPY) and the co-localization of SOM-28 and NPY were analyzed. In total, 13 cases were investigated from late pregnancy (1 case), perinatal period (6 cases), first year (1 case), early infancy (3 cases), and late infancy (2 cases). Overall, the pattern of distribution of these peptides in the DG was similar to that of the adult. The distribution of cells was charted, and the cell density (number of positive cells/mm(2)) was calculated. The highest density corresponded to the polymorphic cell layer and was higher at pre- and perinatal periods. At increasing ages, neuron density modifications revealed a decrease from 5 postnatal months onward. In contrast, by late infancy, two immunoreactive bands for SOM-28 and NPY in the molecular layer were much better defined. Double-immunohistochemistry showed that NPY-positive neurons co-localized with SOM-28, whereas some fibers contained only one or other of the neuropeptides. Thus, this peptidergic population, presumably inhibitory, probably has a role in DG maturation and its subsequent functional activity in memory processing.

Developmental study of the distribution of hypoxia-induced factor-1 alpha and microtubule-associated protein 2 in children's brainstem: comparison between controls and cases with signs of perinatal hypoxia.

Perinatal asphyxia and hypoxia are common causes of morbidity in neonates. Prenatal birth associated with hypoxemia often results in several disorders because of the lack of oxygen in the brain. Survival rates from perinatal hypoxia have improved, but appropriate treatments for recovery are still limited, with great impact on patients, their families, society in general and health systems. The aim of this work is to contribute to a better understanding of the cellular mechanisms underlying the brainstem responses to hypoxia. For this purpose, distributions of two proteins, hypoxia-inducible factor-1 alpha (HIF-1α) and microtubule-associated protein 2 (MAP-2) were analyzed in brainstems of 11 children, four of them showing neuropathological evidence of brain hypoxia. They were included in control or hypoxic groups, and then in several subgroups according to their age. Immunohistochemical labeling for these proteins revealed only cell bodies containing HIF-1α, and both cell bodies and fibers positive for MAP-2 in the children's brainstems. The distribution of HIF-1α was more restricted than that of MAP-2, and it can be suggested that the expression of HIF-1α increased with age. The distribution pattern of MAP-2 in the medulla oblongata could be more due to age-related changes than to a response to hypoxic damage, whereas in the pons several regions, such as the nucleus ambiguus or the solitary nucleus, showed different immunolabeling patterns in controls and hypoxic cases. The distribution patterns of these two proteins suggest that some brainstem regions, such as the reticular formation or the central gray, could be less affected by conditions of hypoxia.

Angiopatía amiloidea cerebral, hemorragias cerebrales de repetición y síndrome de Down / Cerebral amyloid angiopathy, recurrent intracerebral haemorrhages and Down's syndrome

Los pacientes con síndrome de Down en la edad media de la vida desarrollan demencia con cambios anatomopatológicos propios de la enfermedad de Alzheimer. La angiopatía amiloidea cerebral (AAC) puede manifestarse por hemorragias intracerebrales de localización lobular, únicas o múltiples, simultáneas o de repetición. La AAC se asocia frecuentemente con la enfermedad de Alzheimer. Sin embargo, la relación entre AAC y síndrome de Down es poco conocida. Aunque existen unos criterios diagnósticos de AAC relacionada con hemorragia intracerebral lobular, en la actualidad el diagnóstico definitivo de esta entidad es anatomopatológico. Aportamos el caso de un varón con síndrome de Down y hemorragias intracerebrales lobulares de repetición que en el estudio post mortem mostró alteraciones en los vasos leptomeníngeos y corticales características de AAC, así como cambios anatomopatológicos compatibles con enfermedad de Alzheimer que afectaban especialmente a la corteza entorrinal e hipocampo. Se discute la relación patogénica entre la proteína ²-amiloide, los alelos de la APOE, la AAC, la enfermedad de Alzheimer y el síndrome de Down (AU)

Middle-age Down's syndrome patients develop dementia with antomicopathological changes that are characteristic for Alzheimer's disease. Cerebral amyolid angiopathy (CAA) most commonly manifests itself as a lobar intracerebral haemorrhage that tends to recur. Multiple haemorrhages may occur simultaneously. CAA is frequently associated with Alzheimer's disease, however the relationship between CCA and Down's syndrome is poorly know. Although there are established clinical criteria for the diagnosis of CAA related to lobar intracerebral haemorrhage, definitive CAA needs anatomicopathologial confirmation. This paper presents the case of a male with Down's syndrome and recurrent lobar intracerebral haemorrhage. An autopsy showed lesions in leptomeningeal and cortical arteries which are characteristic of CAA in addition to anatomicopathological changes of Alzheimer s disease that were mostly seen in entorhinal cortex and hippocampus. The paper also discusses the pathological association between beta-amyloid protein, apolipoprotein alleles, CAA, Alzheimer's disease and Down's syndrome (AU)

[Cerebral amyloid angiopathy, recurrent intracerebral haemorrhages and Down's syndrome]. / Angiopatía amiloidea cerebral, hemorragias cerebrales de repetición y síndrome de Down.

Middle-age Down's syndrome patients develop dementia with antomicopathological changes that are characteristic for Alzheimer's disease. Cerebral amyolid angiopathy (CAA) most commonly manifests itself as a lobar intracerebral haemorrhage that tends to recur. Multiple haemorrhages may occur simultaneously. CAA is frequently associated with Alzheimer's disease, however the relationship between CCA and Down's syndrome is poorly know. Although there are established clinical criteria for the diagnosis of CAA related to lobar intracerebral haemorrhage, definitive CAA needs anatomicopathologial confirmation. This paper presents the case of a male with Down's syndrome and recurrent lobar intracerebral haemorrhage. An autopsy showed lesions in leptomeningeal and cortical arteries which are characteristic of CAA in addition to anatomicopathological changes of Alzheimer s disease that were mostly seen in entorhinal cortex and hippocampus. The paper also discusses the pathological association between beta-amyloid protein, apolipoprotein alleles, CAA, Alzheimer's disease and Down's syndrome.