Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype

Neuronal migration disorders account for a substantial number of cortical malformations, the most severe forms being represented by lissencephalies. Classical lissencephaly has been shown to result from mutations in LIS1 (PAFAH1B1; MIM#601545), DCX (Doublecortin; MIM#300121), ARX (Aristaless-related homeobox gene; MIM#300382), RELN (Reelin; MIM#600514) and VLDLR (Very low density lipoprotein receptor; MIM#224050). More recently, de novo missense mutations in the alpha-tubulin 1a gene (TUBA1A) located on chromosome 12q13.12, have also been associated with more or less severe defects of cortical development, resulting in complete agyria in the most severe cases of lissencephaly. We report here the cerebral lesions in a 36 weeks’ gestation female foetus with a novel de novo missense mutation in the TUBA1A gene, presenting the most severe antenatal phenotype reported so far. Using routine immunohistochemistry and confocal microscopy, we show evidence for defects in axonal transport in addition to defects in neuronal migration and differentiation, giving new insights to the pathophysiology of this form of lissencephaly.     

Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan

The Cerebellum - Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16), also named as Gordon Holmes syndrome, which is characterized by...     

Spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin micro-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.     

Novel RASA1 mutations in Japanese pedigrees with capillary malformation-arteriovenous malformation

Capillary malformation-arteriovenous malformation (CM-AVM, MIM#608354) is a rare autosomal dominant disorder characterized by multiple cutaneous capillary malformations co-occurring with fast-flow vascular anomalies, such as arteriovenous malformation or fistula. Despite the identification of RASA1 as the first causative gene in Western patients with CM-AVM, there have been no literature reports of Japanese patients with this gene mutation. We herein report two Japanese pedigrees harboring multiple affected members with CM-AVM. Whole-exome sequencing in the two probands identified novel heterozygous mutations in RASA1, which were co-segregated with the disease in each family and were not reported in large-scale sequencing databases. One was a frameshift mutation and the other a splice-site mutation causing aberrant splicing, confirmed by a minigene assay. There were no other genes commonly disrupted among these probands. RASA1 was a major causative gene even in Japanese patients with CM-AVM, although obvious locus heterogeneity was known for this disease.     

A novel MPZ gene mutation in congenital neuropathy with hypomyelination

Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait. Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products. Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN. The authors describe the clinical and morphologic features of a patient with CHN and the identification of a novel Thr124Lys mutation in the MPZ gene.     

Absence of β-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy

While TPM2 mutations identified so far in muscular diseases were all associated with a dominant inheritance pattern, we report the identification of a homozygous null allele mutation in the TPM2 gene in a patient who presented with a recessive form of nemaline myopathy associated with a non-lethal multiple pterygium syndrome (Escobar-MPS MIM# 265000). The TPM2 mutation led to a complete absence of the skeletal muscle isoform of β-tropomyosin not compensated by expression of other β-tropomyosin isoforms. Escobar syndrome has been recently described as a prenatal form of myasthenia associated with recessive mutations in genes of the neuromuscular junction (CHRNG, CHRNA1, CHRND, RAPSN). This observation expands the cause of Escobar variant-MPS to a component of the contractile apparatus. This first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements.     

Update on hereditary neuropathy]

Hereditary neuropathies are classified into several subtypes according to clinical, electrophysiologic and pathologic findings. Recent genetic studies have revealed their phenotypic and genetic diversities. In the primary peripheral demyelinating neuropathies (CMT1), at least 15 genes have been associated with the disorders; altered dosage or point mutation of PMP22, GJB1, MPZ, EGR2, MTMR2, NDRG1, PRX, SOX10, GDAP1 and MTMR13/SBF2. In the primary peripheral axonal neuropathies (CMT2), at least 10 genes have been associated with these disorders; NEFL, KIF1B, MFN2, GAN1, LMNA, RAB7, GARS, TDP1, APTX, and SETX. In addition, some mutations in GJB1, MPZ, GDAP1 and NEFL also present with clinical and electrophysiologic findings of CMT2. Patients with TDP1, APTX or SETX mutations share common clinical findings; autosomal recessive inheritance, cerebellar ataxia, and axonal neuropathy. These genes are suspected to be related to DNA/RNA repair and induce cell death especially in neuronal cells. In addition to the above diseases, we have reported a new type of NMSNP (MIM# * 604484) characterized by proximal dominant neurogenic atrophy, obvious sensory nerve involvement and the gene locus on 3q12.3. Here, we summarize the genetic bases of hereditary neuropathies and attempt to highlight significant genotype-phenotype correlations with a special interest in nonsense-mediated mRNA decay pathway.     

A novel splicing mutation of the ATRX gene in ATR-X syndrome

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X, MIM#301040) is an X-linked recessive condition affecting males. ATR-X is characterized by severe mental retardation, mild HbH disease, dysmorphic facies, and genital and skeletal abnormalities. ATR-X is caused by mutations in the ATRX gene. Most mutations affect two functionally important domains, the ADD domain and the helicase domain. Here, we report on two brothers with the ATR-X phenotype without HbH disease; both had a mutation in the 5' upstream region of the ADD domain of the ATRX gene. This mutation was a G to T nucleotide substitution at the 3' end of exon 5 and resulted in splicing out of exons 5 and 6. Analysis of cDNA structure may clarify genotype-phenotype correlations in ATR-X because splicing mutation could be detectable only by cDNA analysis.     

Comprehensive genetic analyses of PLP1 in patients with Pelizaeus–Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications

Pelizaeus–Merzbacher disease (PMD; MIM#312080) is a rare X-linked recessive neurodegenerative disorder. The main cause of PMD is alterations in the proteolipid protein 1 gene (PLP1) on chromosome Xq22.2. Duplications and point mutations of PLP1 have been found in 70% and 10–25% of all patients with PMD, respectively, with a wide clinical spectrum. Since the underlining genomic abnormalities are heterogeneous in patients with PMD, clarification of the genotype-phenotype correlation is the object of this study. Comprehensive genetic analyses using microarray-based comparative genomic hybridization (aCGH) analysis and genomic sequencing were applied to fifteen unrelated male patients with a clinical diagnosis of PMD. Duplicated regions were further analyzed by fiber-fluorescence in situ hybridization (FISH) analysis. Four novel and one known nucleotide alterations were identified in five patients. Five microduplications including PLP1 were identified by aCGH analysis with the sizes ranging from 374 to 951-kb. The directions of five PLP1 duplications were further investigated by fiber-FISH analysis, and all showed tandem duplications. The common manifestations of the disease in patients with PLP1 mutations or duplications in this study were nystagmus in early infancy, dysmyelination revealed by magnetic resonance imaging (MRI), and auditory brain response abnormalities. Although the grades of dysmyelination estimated by MRI findings were well correlated to the clinical phenotypes of the patients, there is no correlation between the size of the duplications and the phenotypic severity.     

Homozygosity mapping and next generation sequencing for the genetic diagnosis of hereditary ataxia and spastic paraplegia in consanguineous families

IntroductionGenetic inheritance plays key roles in patients with ataxia and/or spastic paraplegia in consanguineous families. This study aims to clarify the genetic spectrum of patients with autosomal recessive hereditary ataxia and spastic paraplegias (AR-HA/HSPs) in consanguineous families.MethodsA total of 36 AR-HA/HSPs consanguineous pedigrees from China were recruited into this study. Next generation sequencing (NGS), guided by homozygosity mapping (HM), was applied to identify the pathogenic variants in known genes or novel candidate genes.ResultsWe totally made molecular diagnosis in 47.2% (17/36) of AR-HA/HSPs families. Among them, 13 AR-HAs carried pathogenic variants in SETX (n = 4), SACS (n = 2), STUB1, HSD17B4, NEU1, ADCK3, TPP1, PLA2G6 and MTCL1, while four AR-HSPs carried pathogenic variants in SPG11, ZFYVE26, ATP13A2 and ABCD1. One homozygous nonsense mutation in MRPS27 was identified in an AR-HA family, which was potentially a novel candidate gene of AR-HA.ConclusionHM and NGS can serve as an efficient molecular diagnostic tool for AR-HA/HSPs in consanguineous families. Our findings provide a better understanding of genetic architecture of AR-HA/HSPs in consanguinity and broaden the clinical-genetic spectrum of the disease.     

Troyer syndrome: a combination of central brain abnormality and motor neuron disease?

Hereditary spastic paraplegia is a group of clinically and genetically heterogeneous disorders consisting of pure and complicated forms. A variant with the additional features of severe atrophy of the small hand muscles, dysarthria, mental retardation, and short stature has been termed Troyer syndrome (MIM#275900) after the name of Old Order Amish families suffering from these symptoms. We report here an Austrian family with two individuals who exhibit all the features of Troyer syndrome, and provide additional data on this disorder. Electrophysiological studies showed chronic denervation and reduced motor nerve conduction velocities but normal sensory potentials. Muscle biopsy revealed a neurogenic pattern while the sural nerve was normal on histological examination. Brain abnormalities on magnetic resonance imaging consisted of a thin corpus callosum with a poorly developed cingulate gyrus and mild periventricular signal hyperintensities. These findings characterize the Troyer syndrome as a disorder of the first and second motor neuron with additional damage in the brain. The morphological features observed in this family may contribute to the grouping and subsequent understanding of complicated forms of hereditary spastic paraplegia, together with similar observations in other, more recently reported families. Received: 24 September 1998 Received in revised form: 23 December 1998 Accepted: 30 December 1998     

Polycystin-1 can interact with homer 1/Vesl-1 in postnatal hippocampal neurons

Polycystin-1 (PC-1) has been identified as critical to development of the nervous system, but the significance of PC-1 expression in neurons remains undefined, and little is known of its roles outside the kidney, where mutation results in autosomal dominant polycystic kidney disease (ADPKD). In kidney, PC-1 interacts with cadherins, catenins, and its cognate calcium channel polycystin-2 (PC-2), which in turn interacts with a number of actin-regulatory proteins. Because some of the proteins that interact with PC-1 in kidney also participate in synaptic remodeling and plasticity in the hippocampus, we decided to test PC-1's potential to interact with a recently discovered type of plasticity-associated protein (homer 1a/Vesl-1S) in postnatal mouse hippocampus. Homer 1a/Vesl-1S is an activity-induced protein believed to participate in synaptic remodeling/plasticity responses to temporal lobe seizure and learning. Here we report the following. 1) PC-1 contains a homer-binding motif (PPxxF), which lies within its purported cytoplasmic domain. 2) Immunoreactivity for PC-1 (PC-1-ir) is highly colocalized with homer 1a immunoreactivity (H1a-ir) in primary cultured hippocampal neurons. 3) PC-1-ir and H1a-ir are present and appear to be colocalized in mouse hippocampus but not cortex on postnatal day 2 (P2), when higher frequencies of spontaneous activity are normal for hippocampus compared with cortex. 4) An endogenous PC-1-ir band with the correct size for the reported C-terminal G-protein-sensitive domain cleavage product of PC-1 (approximately 150 kDa) coimmunoprecipitates with endogenous homer 1/Vesl-1 proteins from mouse brain, suggesting that PC-1 can interact with homer 1/Vesl-1 proteins in postnatal hippocampal neurons.     

CYP1A1 and GSTM1/T1 Genetic Variation in Predicting Risk for Cerebral Infarction

Cytochrome P450 1A1 (CYP1A1) is involved in the production of arachidonic acid-derived vasoactive substance. We hypothesized that CYP1A1 polymorphism might be related to pathological conditions associated with cerebral infarction (CI). We investigated the effect of genetic polymorphism in the 3′-flanking region (T6235C) of CYP1A1 gene in 353 patients with CI and 376 controls. The distributions of T6235C CYP1A1 genotypes in patients with (TT: 36.0%; TC/CT: 64.0%; n = 353) and without CI (TT: 44.7%; TC/CT: 55.3%; n = 376) indicate that the C allele is associated with CI (P = 0.017, odds ratio (O.R.) = 1.44; 95% confidence interval (C. I.) = 1.07–1.94). Furthermore, we examined whether the glutathione S-transferase (GST) gene, which is one of detoxification enzyme, influence the risk of CI. GST M1 null genotype increased the relative risk for the CI in the subjects with the CYP1A1 C allele (P = 0.015, O.R. = 1.47; C. I. = 1.08–2.00). We conclude that T6235C CYP1A1 polymorphism is a risk factor for the development of CI and suggest that GST polymorphism contribute to the odds of CI.     

Copolymer-1

Copolymer 1 (Cop-1) is a mixture of synthetic polypeptides composed of four amino acids. Cop-1 was very effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Two principal mechanisms have been proposed to explain the suppressive activity of Cop-1 in EAE and in multiple sclerosis (MS): the induction of antigen-specific suppressor T cells and the interference with T-cell activation by competition with myelin antigens in binding to the major histocompatibility complex class II molecules. Clinical trials with Cop-1 have demonstrated that Cop-1 positively alters the course of relapsing-remitting multiple sclerosis (MS) by both reducing the relapse rate and slowing the progression of disability. In a 2-year multi-centre, randomized, double-blind, placebo-controlled trial of 251 patients, Cop-1 was shown to reduce relapses by an average of 29% when compared with placebo. A preliminary study on patients with relapsing-remitting MS treated with Cop-1 showed a reduced number of new enhancing lesions on MRI as well as a reduced accumulation of lesion load during Cop-1 treatment. Antibodies to copolymer-1, which are found during Cop-1 treatment, do not interfere with its clinical effects. The side effects of Cop-1 are minimal and acceptable. In vitro and in vivo animal studies have shown a very good safety profile of Cop-1 which is devoid of teratogenic or mutagenic effects. Cop-1 joins interferon beta as a good candidate for treatment of relapsing-remitting MS.     

DRB1*1502-DQB1*0601-DQA1*0103 and DRB1*04-DQB1*0302 in Jewish hypersomnolent patients

OBJECTIVES: Narcolepsy is a sleep disorder with a genetic association with the haplotype DRB1*1501, DQA1*0102, DQB1*0602. This haplotype has been described in different ethnic groups suffering from narcolepsy (Japanese, Caucasian, African Americans, Jews). In a recent study we have found the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in three patients with hypersomnolence. The similarity of this haplotype to the narcoleptic haplotype DRB1*1501, DQB1*0602 and DQA1*0102 has raised the question of whether this haplotype is a marker for sleepiness, or rather indicates a variant of non-cataplectic narcolepsy. This study was conducted to further investigate this question. METHODS: HLA-DNA analysis was carried out in 20 healthy Jewish patients (age 23.9+/-6.3 years; 13 Ashkenazi, seven non-Ashkenazi) who had objective measures of hypersomnolence. All underwent whole-night polysomnography, multiple sleep latency test and tissue typing. RESULTS: HLA-DNA analysis revealed HLA-DR2 in eight patients of whom five (25%) carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103 (vs. 1.4% in the Israeli population, P<0.0001). Six patients were diagnosed as non-cataplectic narcoleptics. Five of them carried the haplotype DRB1*1502, DQB1*0601, DQA1*0103. Forty percent of the patients carried the haplotype DRB1*04, DQB1*0302, which was not statistically different from its prevalence in the healthy Israeli population (25%). CONCLUSIONS: This is the first report describing the haplotype DRB1*1502, DQB1*0601, DQA1*0103 in narcoleptic patients (non-cataplectic). This haplotype is close but different from the already known narcoleptic haplotype DRB1*1501, DQA1*0102, DQB1*0602. We assume that this haplotype represents a variant of non-cataplectic narcolepsy rather than association with hypersomnolence. However, in order to conclude whether this haplotype is a marker for the lack of cataplexy, or represents a variant of non-cataplectic narcolepsy, a larger group of patients should be investigated.     

Cardiovascular effects of centrally applied endothelin-1 1-31 and its relationship to endothelin-1 1-21 in rats

Endothelin-1(1-31) (ET-1(1-31)) is a novel member of the endothelin family, which comprises 31 amino acids and derived from the selective hydrolysis of big ET-1 by chymase. Although ET-1(1-31) has been reported to be involved in biological effects via direct or indirect (converting to ET-1(1-21)) mechanisms, the cardiovascular effects of central ET-1(1-31) are not fully identified. The present study was designed to comparatively investigate the cardiovascular effects of intracerebroventricular (icv) application of ET-1(1-31) or ET-1(1-21) in anesthetized rats. Injection (icv) of ET-1(1-31) (500 pmol) produced a biphasic blood pressure response: an initial increase (from 118+/-8 to 138+/-14 mmHg, P<0.05) followed by a sustained decrease in BP (from 118+/-8 to 58+/-9 mmHg, P<0.05), which was very similar to BP response to icv injection of big ET-1 (500 pmol) or ET-1(1-21) (25 pmol)(.) The cardiovascular effects of icv injection of ET-1(1-31) or ET-1(1-21) were completely antagonized by ET(A) receptor antagonist BQ123 but not ET(B) receptor antagonist BQ788. Furthermore, pretreatment with ET converting enzyme inhibitor phosphoramidon (10 nmol) abolished the cardiovascular effects evoked by icv injection of ET-1(1-31) or big ET-1. In conclusion, the current data showed that central ET-1(1-31) produced the similar cardiovascular effects as those of central ET-1(1-21), and suggesting that the central cardiovascular effects of ET-1(1-31) resulted from it converting to ET-1(1-21) and then activating ET(A) receptors.     

Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings

ABSTRACT: BACKGROUND: Velo-cardio-facial syndrome (VCFS, MIM#192430) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in adolescents with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased photometric indices of WM microstructure (FA, AD and RD), particularly in WM tracts to the frontal lobe, and that these measures that would be correlated with cognitive functioning. METHODS: For the current study, thirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each subject, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (pFDR<0.05), we assessed the correlations of FA, AD, and RD with neuropsychological measures. RESULTS: In VCFS individuals as compared to unaffected siblings, we found decreased FA in the uncinate fasciculus, decreased RD in the right posterior corona radiata, and decreased AD in multiple WM tracts (bilateral superior and posterior corona radiata, dorsal cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, superior cerebellar peduncle, posterior thalamic radiation, and left anterior corona radiata, retrolenticular part of internal capsule, external capsule, sagittal stratum). We also found significant correlations of AD and RD with measures of executive function, IQ, working memory, and/or social cognition. CONCLUSIONS: Our results suggest that adolescents with VCFS display abnormal WM connectivity from/to frontal lobe, as well as temporal, parietal, occipital areas and the cerebellum. Future studies could focus on the developmental trajectory of WM in VCFS, the association of WM alterations with psychiatric disorders, and the effects of candidate genes within the 22q11.2 region on WM anomalies.     

Expression of inducible nitric oxide synthase, interleukin-1 and caspase-1 in HIV-1 encephalitis

Inflammatory cytokines and enzymes such as IL-1 and inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of AIDS dementia, a condition associated with infection of the CNS cells by the HIV-1. In this report, we investigated the expression of iNOS, IL-1, and caspase-1 (interleukin-1 converting enzyme) in HIV-1 encephalitis (HIVE) by immunocytochemistry and analyzed their expression with respect to HIV-1 infection and glial activation. In HIVE, all three molecules were expressed at high levels in areas of HIV-1 infection (microglial nodules with HIV-1 p24 immunoreactivity) and in areas of diffuse white matter gliosis. Expression was cell-type specific, with IL-1 and caspase-1 being expressed in macrophages and microglia, and iNOS in activated astrocytes. Multinucleated giant cells, a hallmark of virally infected cells, showed intense staining for both IL-1 and caspase-1, suggesting induction of these molecules by HIV-1. Double immunocytochemistry demonstrated a regional co-localization of astrocyte iNOS and microglial IL-1 and caspase-1. These results support the notion that autocrine and paracrine interactions between HIV-1 infected macrophages and microglia, activated microglia, and astrocytes lead to expression of proinflammatory and neurotoxic molecules. iNOS and caspase-1 may provide additional therapeutic targets for HIVE.