Hyperlysinemia, an ultrarare inborn error of metabolism: Review and update.

Familial hyperlysinemia is a rare autosomal recessive disorder due to defects of the AASS (α-aminoadipate δ-semialdehyde synthase) gene, which encodes for a bifunctional enzyme. Two types of hyperlysinemia have been identified namely type 1, due to the deficit of the alfa-ketoglutarate activity, and type 2, due to the deficit of the saccharopine dehydrogenase activity. METHODS: To better characterize the phenotypic spectrum of familial hyperlysinemia type 1, we conducted a systematic review of cases in the literature following PRISMA guidelines. We selected 16 articles describing 23 patients with hyperlysinemia type 1, twelve of whom with homozygous or compound heterozygous mutations in AASS gene. We also included a novel patient with a homozygous c.799C>T; p.(Arg267Cys) mutation in AASS gene. We collected genetic, clinical, brain imaging and electroencephalogram (EEG) features when available. RESULTS: The phenotype of this disease is heterogeneous, ranging from more severe forms with spastic tetraparesis, intellectual disability and epilepsy and mild-moderate forms with only intellectual disability or behavioural problem and/or epilepsy to normal clinical conditions. Only our patient has neuropathy unrelated to infectious event. CONCLUSIONS: We described the heterogeneous phenotypic spectrum of familial hyperlysinemia type 1 and we identified a new symptom, axonal neuropathy, never before described in this condition.

Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH.

Whole exome sequencing (WES) has made the identification of causative SNVs/InDels associated with rare Mendelian conditions increasingly accessible. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative cases, by WES. The opposite workflow may also be applied, according to the familial segregation of the disease. We show preliminary results for a diagnostic application of a single next generation sequencing panel permitting the concurrent detection of LOH and variations in sequences and copy number. This approach allowed us to highlight compound heterozygosity for a CNV and a sequence variant in a number of cases, the duplication of a non-coding region responsible for sex reversal, and a whole-chromosome isodisomy causing reduction to homozygosity for a WFS1 variant. Moreover, the panel enabled us to detect deletions, duplications, and amplifications with sensitivity comparable to that of the most widely used array-CGH platforms.

Maladaptive mood repair, atypical respiratory sinus arrhythmia, and risk of a recurrent major depressive episode among adolescents with prior major depression.

BACKGROUND: Because depressive illness is recurrent, recurrence prevention should be a mainstay for reducing its burden on society. One way to reach this goal is to identify malleable risk factors. The ability to attenuate sadness/dysphoria (mood repair) and parasympathetic nervous system functioning, indexed as respiratory sinus arrhythmia (RSA), are impaired during depression and after it has remitted. The present study therefore tested the hypothesis that these two constructs also may mirror risk factors for a recurrent major depressive episode (MDE). METHOD: At time 1 (T1), 178 adolescents, whose last MDE had remitted, and their parents, reported on depression and mood repair; youths' RSA at rest and in response to sad mood induction also were assessed. MDE recurrence was monitored until time 2 (T2) up to 2 years later. Mood repair at T1 (modeled as a latent construct), and resting RSA and RSA response to sadness induction (RSA profile), served to predict onset of first recurrent MDE by T2. RESULTS: Consistent with expectations, maladaptive mood repair predicted recurrent MDE, above and beyond T1 depression symptoms. Further, atypical RSA profiles at T1 were associated with high levels of maladaptive mood repair, which, in turn, predicted increased risk of recurrent MDE. Thus, maladaptive mood repair mediated the effects of atypical RSA on risk of MDE recurrence. CONCLUSIONS: This study documented that a combination of behavioral and physiological risk factors predicted MDE recurrence in a previously clinically referred sample of adolescents with depression histories. Because mood repair and RSA are malleable, both could be targeted for modification to reduce the risk of recurrent depression in youths.

A patient with partial trisomy 21 and 7q deletion expresses mild Down syndrome phenotype.

BACKGROUND: Down syndrome (DS) is the most common aneuploidy in live-born individuals and it is well recognized with various phenotypic expressions. Although an extra chromosome 21 is the genetic cause for DS, specific phenotypic features may result from the duplication of smaller regions of the chromosome and more studies need to define genotypic and phenotypic correlations. CASE REPORT: We report on a 26 year old male with partial trisomy 21 presenting mild clinical symptoms relative to DS including borderline intellectual disability. In particular, the face and the presence of hypotonia and keratoconus were suggestive for the DS although the condition remained unnoticed until his adult age array comparative genomic hybridization (aCGH) revealed a 10.1 Mb duplication in 21q22.13q22.3 and a small deletion of 2.2 Mb on chromosomal band 7q36 arising from a paternal translocation t(7;21). The 21q duplication encompasses the gene DYRK1. CONCLUSION: Our data support the evidence of specific regions on distal 21q whose duplication results in phenotypes recalling the typical DS face. Although the duplication region contains DYRK1, which has previously been implicated in the causation of DS, our patient has a borderline IQ confirming that their duplication is not sufficient to cause the full DS phenotype.

De novo 15.5-Mb Interstitial Deletion in 5p in a Male Ascertained by Oligospermia.

We describe a case of a 34-year-old male presenting with oligospermia and an otherwise normal phenotype. Investigation with array-based comparative genomic hybridization (aCGH) revealed an interstitial deletion of about 15.5 Mb in chromosome 5p13.3p14.3. We compared the phenotype of our patient with recently reported patients studied by aCGH, who show an overlapping deletion. We also analyzed the gene content of the deleted region in order to propose a possible involvement of specific genes in the clinical phenotype.

Partial trisomy 2p and partial monosomy 2q arising from a paternal intrachromosomal 2q-into-2p between-arm insertion and paracentric inversion: molecular cytogenetic characterization of a four-break rearrangement.

We report on a 26-month-old boy with an interstitial duplication of 2p22.3p22.2 and an interstitial deletion of 2q14.1q21.2. The abnormality was derived from his father having a balanced paracentric inversion and pericentric insertion. The deletion in the child was identified by cytogenetic analysis and characterized in more detail by molecular cytogenetics and array comparative genomic hybridization. The latter revealed a 20-Mb deletion in the long arm and a 5.6-Mb duplication in the short arm of chromosome 2. Fluorescence in situ hybridization in paternal chromosomes characterized an intrachromosomal insertion of 2q14.1q21.2 into 2p23; additionally a paracentric inversion of 2p13p23 was observed. The boy with the unbalanced karyotype suffered from severe psychomotor retardation, thrombophilia due to protein C deficiency, and hypertrophic cardiomyopathy and also had phenotypic abnormalities. Most of these features have previously been described in individuals with interstitial deletion of 2q14.1.

First trimester diagnosis of 13q-syndrome associated with increased fetal nuchal translucency thickness. Clinical findings and systematic review.

13q-syndrome is a rare chromosomal disorder caused by partial deletion of the long arm of chromosome 13 with variable phenotypic presentation. Further sonographic features involve fetal growth restriction, bradycardia, encephalocele, facial dysmorphism and upper extremity deformity. We report a case of 13q-syndrome presenting as increased nuchal translucency diagnosed by chromosome studies and confirmed by array comparative genomic hybridization (CGH) analysis in the first trimester of pregnancy. Pregnancy was terminated at 14 weeks' gestation. The parents did not give consent for a postmortem examination. Furthermore we performed a systematic review of the international literature on previous cases of 13q-syndrome diagnosed prenatally. Our case emphasizes the importance of a detailed 11-14 week ultrasound assessment in diagnosing fetal chromosomal aberrations in combination with the modern aspects of array CGH, thus providing more precise and rapid prenatal diagnosis.

Identification of de novo mutations and rare variants in hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart malformations, characterized by underdevelopment of the structures in the left heart-aorta complex. The majority of cases are sporadic. Although multiple genetic loci have been tentatively implicated in HLHS, no gene or pathway seems to be specifically associated with the disease. To elucidate the genetic basis of HLHS, we analyzed 53 well-characterized patients with isolated HLHS using an integrated genomic approach that combined DNA sequencing of five candidate genes (NKX2-5, NOTCH1, HAND1, FOXC2 and FOXL1) and genome-wide screening by high-resolution array comparative genomic hybridization. In 30 patients, we identified two novel de novo mutations in NOTCH1, 23 rare patients inherited gene variants in NOTCH1, FOXC2 and FOXL1, and 33 rare patients mostly inherited copy-number variants. Some of the identified variations coexisted in the same patient. The biological significance of such rare variations is unknown, but our findings strengthen the role of NOTCH pathway in cardiac valve development, indicating that HLHS is, at least in part, a 'valve' disease. This is the first report of de novo mutations associated with isolated HLHS. Moreover, the coexistence of multiple rare variants suggests in some cases a cumulative effect, as shown for other complex disease.

Association of the GABRD gene and childhood-onset mood disorders.

The chromosome 1p36 region was previously indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the gamma-aminobutyric acid A (GABA(A)) delta receptor subunit gene, GABRD, as a susceptibility gene to childhood-onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for the association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global chi(2) test for haplotypes = 12.746, 3 df, P = 0.0052). Furthermore, significant evidence of association was only observed in male subjects (n = 438) when the results were analyzed by sex (chi(2) = 9.000 1 df, P = 0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female-female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD; however, this gene may not explain the previous linkage finding.

Mutation screen and association analysis of the glucocorticoid receptor gene (NR3C1) in childhood-onset mood disorders (COMD).

Depressive disorders are highly heterogeneous psychiatric disorders involving deficits to cognitive, psychomotor, and emotional processing. Considerable evidence links disruption to the hypothalamic-pituitary-adrenal (HPA) axis to the etiology of depression, with specific deficits reported in glucocorticoid receptor (GR)-mediated negative feedback. Given the role of GR-mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene (NR3C1) act to increase susceptibility. Maternal behavior in rats epigenetically alters a NGF1-A transcription factor binding-site in the promoter region of the GR gene, providing a mechanism by which environmental cues can regulate GR expression and thus response to stress. The analogous region of the human GR gene (NR3C1) has not been studied, but it is possible that polymorphisms in this region may alter the binding of transcription factors known to regulate GR expression. In this study, we have performed bioinformatic analyses on the promoter region of NR3C1 to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing high-performance liquid chromatography (DHPLC) and direct re-sequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1 in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorders (COMD). Single-marker analysis provided little evidence for an association of this gene with COMD, but multi-marker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Role of high-resolution ultrasound in guiding treatment of idiopathic plantar fasciitis with minimally invasive techniques.

PURPOSE: The aim of this study was to assess the reliability of peri-fascial oedema as a sonographic criterion for selecting the most appropriate treatment (ultrasound-guided corticosteroid injection or ultrasound-guided extracorporeal shock wave therapy) of idiopathic plantar fasciitis (IPF). MATERIALS AND METHODS: Sixty-four patients with a clinical diagnosis of unilateral refractory IPF, treated conservatively for at least 8 weeks, were studied with high-resolution ultrasound (HRUS). Pain intensity was evaluated with a visual analogue scale (VAS). HRUS was used to confirm IPF and identify the presence of peri-fascial oedema. Patients with an HRUS diagnosis of IPF were grouped according to the presence (A) or absence (B) of peri-fascial oedema and then randomly allocated to treatment with corticosteroid injection (1) or extracorporeal shock wave therapy (2). Clinical and HRUS follow-up was performed 6 weeks after treatment. RESULTS: HRUS confirmed IPF in 68,97% of patients and identified peri-fascial oedema in 53.33%. Clinical and sonographic improvements were observed in 87.5% and 37.5% of patients in subgroups A1 and A2, respectively, and in 35.71% and 92.85% of those in subgroups B1 and B2, respectively. CONCLUSIONS: The presence of peri-fascial oedema may represent an effective criterion for guiding treatment decisions towards HRUS-guided corticosteroid injection.

Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients.

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.

Association study of the adrenergic receptors and childhood-onset mood disorders in Hungarian families.

The adrenergic system has been implicated in the etiology of depression based on a number of lines of evidence, particularly, the mechanism of some classes of antidepressants which increase the synaptic levels of norepinephrine. Further, several genome scans for mood disorders, both unipolar and bipolar, have indicated linkage to the chromosomal regions of 5q23-q33.3, 8p12-p11.2, 4p16, and 10q24-q26, the location of the adrenergic receptors alpha1B (ADRA1B), beta3 (ADRB3), alpha2C (ADRA2C), alpha2A (ADRA2A), and beta1 (ADRB1). In this manuscript, we report on the relationship of the adrenergic receptors and depression using a family based association approach and 189 families (223 affected children) with childhood-onset mood disorder (COMD) collected in Hungary. We found no significant evidence for an association with any of the 24 markers, in total, tested across these genes using single marker analysis or haplotypes of markers across these genes. The results in the present sample indicate that these nine genes are unlikely to be major susceptibility genes contributing to COMD.

Association study of CREB1 and childhood-onset mood disorders.

Several lines of evidence suggest that the cellular pathways involved in synaptic plasticity contribute to the risk of depression. These findings include the evidence that chronic antidepressant treatment upregulates the cAMP signal transduction cascade resulting in increased expression and function of the cAMP responsive element binding protein (CREB), a transcription factor that increases the expression of key growth factors involved in synaptogenesis and neurogenesis. Recently, linkage to CREB1 was reported for early-onset depression in families recruited from the Pittsburgh area. This finding was significant only in female sibling pairs from those families. Two specific DNA variants, -656G/A and a C insertion/deletion in intron 8, were identified in CREB1 that co-segregated with depression in two of the families. We sought to investigate the relationship of CREB1 to childhood-onset mood disorders (COMD) using a sample of 195 nuclear families (225 affected children) collected in Hungary. We genotyped the two CREB1 DNA variants previously identified as linked to depression as well as three additional polymorphisms spanning the gene. In addition, we genotyped the -656G/A DNA change and the intron 8 polymorphism in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matched controls, and examined the distribution of alleles. The -656A allele was not observed in our samples and there was no evidence for association of the intron 8 polymorphism in either the sample from Pittsburgh (chi(2) = 0.061, 1 d.f., P = 0.803) or Hungary (chi(2) = 0.040, 1 d.f., P = 0.842). We found no evidence for an association with the other three polymorphisms or with the haplotypes of these markers. Further, we found no sex-specific relationship. Our results, therefore, do not support the previous evidence for this gene as a major factor contributing to depression.

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (chi2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.

Manipulative therapy in the treatment of benign cervicobrachialgia of mechanical origin.

The authors compared two methods of rehabilitation, traditional physical therapy and manual therapy, in the treatment of benign cervicobrachialgia of mechanical origin, typical of young subjects, generally consequent to mild and moderate trauma, occasional strain or incorrect posture repeated in time. A MID (minor intervertebral deficit) is at its origin, characterized by the absence of objective instrumental signs (X-ray, CT scan, MRI) and it is only diagnosed based on clinical history and accurate physical examination of the spine segment involved. A sample of 80 patients was divided at random into two groups: the first group was submitted to traditional physiotherapy, the second to manipulative therapy carried out according to the French method of R. Meigne. The results obtained, which were evaluated by univaried ANOVA and Student's "t" test statistical analysis, showed the greater effectiveness of manipulative treatment, in the short term and in the long term.