Search

Infantile neuroaxonal dystrophy, INAD, is a severe progressive psychomotor disorder with infantile onset and characterized by the presence of axonal spheroids throughout the central and peripheral nervous systems. A subset of INAD patients shows also brain iron accumulation which represents instead the distinctive feature of the idiopathic neurodegeneration with brain iron accumulation, NBIA. These diseases share the same causative gene, PLA2G6, encoding iPLA2-VIA, a calcium-independent phospholipase. Mutations that lead to a complete absence of protein are associated with a severe INAD profile, while compound heterozygous mutations with possibly a residual protein activity are instead associated with the less severe NBIA phenotype. Here we describe two INAD patients both with an unusually rapid disease progression and a peculiar neuroradiological presentation in one of them. Compound heterozygosity for a large intragenic deletion and a nonsense mutation was found in one of them while the other is carrying two novel splice-site mutations. Breakpoint-sequence analysis suggests a non-allelic-homologous-recombination (NAHR) event, probably underlying the rearrangement. These findings, while supporting the genotype-phenotype correlation already observed in INAD patients, provide the first sequence characterization of a genomic rearrangement in PLA2G6 gene, thus orienting the search for missing mutant alleles in PLA2G6 related diseases.

Most patients with an interstitial deletion of 6q16 have Prader-Willi-like phenotype, featuring obesity, hypotonia, short hands and feet, and developmental delay. In all reported studies, the chromosome rearrangement was detected by karyotype analysis, which provides an overview of the entire genome but has limited resolution. Here we describe a detailed clinical presentation of five patients, two of whom were previously reported, with overlapping interstitial 6q16 deletions and Prader-Willi-like phenotype. Our patients share the following main features with previously reported cases: global developmental delay, hypotonia, obesity, hyperphagia, and eye/vision anomalies. All rearrangement breakpoints have been accurately defined through array-CGH at about 100 Kb resolution. We were able to narrow the shortest region of deletion overlap for the presumed gene(s) involved in the Prader-Willi-like syndrome to 4.1 Mb located at 6q16.1q16.2. Our results support the evidence that haploinsufficiency of the SIM1 gene is responsible for obesity in these patients. A possible involvement of the GRIK2 gene in autistic-like behaviour, of POPDC3 in heart development, and of MCHR2 in the control of feeding behaviour and energy metabolism is also hypothesized.

The diagnosis of a subtelomeric rearrangement has immediate impact on counseling, particularly in the case of familial rearrangements. However, the existence of subtelomeric imbalances with absent phenotypic effects may hamper genetic counseling, particularly when the rearrangement has not been previously described. We report on a new subtelomeric polymorphism, consisting of a familial subtelomeric rearrangement of chromosome 19 resulting in distal trisomy for 21q, detected in a child with Angelman Syndrome (AS) due to an UBE3A mutation. This report shows that new, previously unknown, benign subtelomeric variants may complicate the correct clinical diagnosis.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common diagnosis for children and adolescents, although the reported estimates for prevalence are extremely variable worldwide. In the present work we investigate the prevalence of ADHD in a sample of Italian students in a study divided in two phases. In Phase I, a total of 6183 schoolchildren (3178 males and 3005 females, aged range 5-15 years) were screened using the SDAI rating scale for teachers. In Phase II, the parents of children and adolescents who met high screen criteria according to SDAI (cut-off>14; n=471, 7.3%) were invited to complete a specific clinical-diagnostic assessment for ADHD with the help of an experienced clinician. Within the entire sample, 107 children dropped out and 12 had mental retardation, whereas 332 subjects (278 males and 54 females, age range 5-14 years) completed the Phase II of the study. One hundred ninety subjects (163 males and 27 females, male: female ratio 6:1, mean age 8 years) were diagnosed with ADHD, indicating a prevalence of 3%. ADHD subtypes included the following: combined (n=108; 56.8%), inattentive (n=48; 25.2%) and hyperactive/impulsive (n=33; 17.3%). Our findings are in line with other reports of ADHD prevalence in the European Countries, and may contribute to underline the impact of this phenomenon in the population, and the need of achieving an improvement in the quality of the public health mental service for the prevention and treatment of ADHD.

Background and objectives Pallister–Killian syndrome (PKS) is a rare genetic disorder caused by a tissue-limited mosaic supernumerary isochromosome 12p. Typical facial dysmorphisms, pigmentary abnormalities, and some major malformations are frequently present. Neurological manifestations include mental retardation, hypotonia, and seizures. Epilepsy incidence ranged from 39 to 59% in a previously reported series. No specific clinical and EEG phenotype has ever been reported to describe seizure features, electroclinical patterns, and response to therapy in PKS. Methods This was a multicentre study conducted on 13 Italian children with PKS, as diagnosed by clinical phenotype and confirmed in cultured fibroblasts. All patients underwent several polygraphic video-EEG recordings and brain magnetic resonance imaging. Results and conclusions All the patients presented with epilepsy and seizures that started at a mean age of 19 months. In six cases, epilepsy started with epileptic spasms (ES) combined with focal seizures in another case. In four cases, seizures were focal, and this was followed by ES in two patients. In only two cases, epilepsy started with myoclonic seizures, and spasms were never observed. The study provides further evidence that epilepsy is a part of the phenotype of PKS, although a specific clinical and EEG pattern could not be identified. Our cases show how ES with late- or first-year onset is the most common type of seizure. Despite a variable prognosis in terms of response to therapy, a significant proportion of patients achieved good seizure control.

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS., Author Summary Terminal chromosome deletions are among the most commonly observed rearrangements detected by cytogenetics and may result in several well-known genetic syndromes. We used 22q13 deletions to study how these types of chromosome abnormalities arise. Children with Phelan/McDermid syndrome, caused by deletion of the terminal portion of chromosome 22, experience developmental delay, absent or severely delayed speech, and frequent behavioral problems. Lack of one copy of SHANK3, a key gene for the correct development and organization of brain synapses, is very likely the basis of the syndrome's major neurological features. Deletion of additional genes probably causes more complex phenotypes in subjects with larger deletions. We also studied patients who only lack a portion of SHANK3 and demonstrated that small, hard-to-detect deletions of this gene may cause substantial clinical problems. Until now, the 22q distal deletion had been only diagnosed in very young people. We studied a large group of patients of different ages and discovered that all adult patients face progressive cognitive decline. Our study demonstrates that deletion of the terminal portion of chromosome 22, a prototype for terminal deletions in human chromosomes, can occur in several ways. Mosaic deletions of different size can also form in early embryogenesis.

Cohen syndrome is a rare, clinically variable autosomal recessive disorder characterized by mental retardation, postnatal microcephaly, facial dysmorphisms, ocular abnormalities and intermittent neutropenia. Mutations in the COH1 gene have been found in patients from different ethnic origins. However, a high percentage of patients have only one or no mutated allele. To investigate whether COH1 copy number changes account for missed mutations, we used multiplex ligation-dependent probe amplification (MLPA) to test a group of 14 patients with Cohen syndrome. This analysis has allowed us to identify multi-exonic deletions in 11 alleles and duplications in 4 alleles. Considering our previous study, COH1 copy number variations represent 42% of total mutated alleles. To our knowledge, COH1 intragenic duplications have never been reported in Cohen syndrome. The three duplications encompassed exons 4–13, 20–30 and 57–60, respectively. Interestingly, four deletions showed the same exon coverage (exons 6–16) with respect to a deletion recently reported in a large Greek consanguineous family. Haplotype analysis suggested a possible founder effect in the Mediterranean basin. The use of MLPA was therefore crucial in identifying mutated alleles undetected by traditional techniques and in defining the extent of the deletions/duplications. Given the high percentage of identified copy number variations, we suggest that this technique could be used as the initial screening method for molecular diagnosis of Cohen syndrome.

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Contains fulltext : 69539.pdf (Publisher’s version ) (Closed access) BACKGROUND: Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects, as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. OBJECTIVE: To describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and to report on the molecular characterisation of the deletion size. Results and CONCLUSIONS: The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in 10 of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalities to a 360 kb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.

Acquired cerebellar lesions in adults and children can lead to the development of a complex behavioural pattern termed ‘Cerebellar Cognitive Affective Syndrome’ (Schmahmann and Sherman, Brain, [1998][1]; 121: 561–79), which is characterized by reduced cognitive efficiency associated with specific neuropsychological deficits (executive and visuospatial disorders), expressive language disorders (mild agrammatism and anomia) and affective disorders with blunting of affect. It is not known whether a symptomatological picture such as this can also be found in congenital cerebellar malformations. We studied the behavioural developmental profile of 27 patients including children and adults with congenital malformations confined to the cerebellum, the largest studied sample to date. Extensive clinical and neuropsychological investigations highlight the presence of a wide range of disorders supporting the important role played by the cerebellum in the acquisition of higher-order cognitive and affective skills. The type and extent of cerebral reorganization processes in the presence of malformative lesions are difficult to predict and may possibly account for the variability of clinical phenotypes. It is, therefore, more difficult to identify a syndromic picture defined as exactly as is the case with acquired lesions. However, the pattern of deficits that we document is in remarkable agreement with the general profile of the Cerebellar Cognitive Affective Syndrome. Malformations affecting the cerebellar vermis induce affective and social disorders and evolve towards more unfavourable pictures often associated with an autistic symptomatology. Malformations of cerebellar hemispheres are more frequently associated with selective neuropsychological deficits involving mainly executive functions and visuospatial and linguistic abilities. Motor deficits are generally less severe, and tend to improve slowly and progressively, in some cases reaching almost complete functionality. Finally, the overall favourable evolution with an onset of skills in advanced age in a consistent subset of subjects suggests that individual follow-ups should be performed in order to monitor the quality and stability of impairments and acquired abilities over time. [1]: #ref-67

This study reports the clinical features of 63 patients with agenesis of the corpus callosum who received in-depth genetic, clinical, and laboratory testing with the aim to contribute to a better description of the large spectrum of associated malformations and to assist clinicians in the diagnosis. Thirty patients manifested complete agenesis and 33 patients displayed partial agenesis. Other associated nervous system malformations were detected in 14 patients with partial agenesis of the corpus callosum (mostly correlated to posterior fossa malformations) and in 10 patients with complete agenesis (more frequently associated with malformations of cortical development). Involvement of organs and apparatus other than the nervous system was present in 41 patients (ascribed to known syndromes in 21 cases). Cytogenetically detectable chromosomal abnormalities (7 patients) and subtelomeric rearrangements (3 patients) were found. Neuromotor skills were impaired in almost all cases (58/63). Mental retardation of different severity was present in 52 cases, whereas 2 patients were borderline and 9 patients had normal intelligence quotient. This study demonstrates that there is no unique prognosis for agenesis of the corpus callosum as this condition is associated with a broad range of clinical manifestations, oscillating between the limits of the norm and severe psychomotor delay.

It has recently been demonstrated that patients with Angelman's syndrome who exhibited a deletion on cytogenetic tests show more severe clinical pictures with drug-resistant epilepsy than patients with Angelman's syndrome not carrying the deletion. To verify if this difference in clinical severity can be attributed to genes for the three γ-aminobutyric acid (GABA)A receptor subunits ( GABRB3, GABRA5, GABRG3) located in the deleted region, a possible modification of peripheral markers of the GABAergic system was investigated in 12 subjects with Angelman's syndrome and 20 age-matched subjects (8 with idiopathic epilepsy and 12 not affected by neurologic diseases). The results confirmed a more severe clinical picture, and epilepsy syndrome in particular, in Angelman's syndrome patients with deletions versus patients without deletions. In contrast, biochemical study (based on dosage of plasma levels of GABA and diazepam binding inhibitor, an endogenous ligand of GABAA and peripheral benzodiazepine receptors, showed contradictory results: patients with Angelman's syndrome showed significantly higher levels of GABA and diazepam binding inhibitor than patients without neurologic impairment but significantly lower levels than epileptic controls. ( J Child Neurol 2003; 18: 21—25).

We studied the case of a girl with a partial 9p duplication, dup(9)(p22.1 --> p13.1). Molecular cytogenetics studies defined the chromosome 9 rearrangement as a direct duplication of 20 Mb from D9S1213 to D9S52. Microsatellite analysis demonstrated the presence of a double dosage of the paternal alleles and demonstrated that the duplication occurred between sister chromatids. The patient's phenotype was almost normal, with a few minor anomalies (dolichocephaly, crowded teeth, high arched palate) and normal IQ. The breakpoint's location in this patient and previously reported cases suggest that the critical region for the 9p duplication syndrome lies within a 6-Mb portion of chromosome 9p22 between markers D9S267 and D9S1213.