Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy.

BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

Epilepsy in hemiplegic migraine: Genetic mutations and clinical implications.

Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach.

MYOCLONIC ASTATIC EPILEPSY IN A PATIENT WITH A DE NOVO 4q21.22q21.23 MICRODUPLICATION.

Myoclonicastatic epilepsy (MAE) is a rare form of symptomatic generalized epilepsy of uncertain etiology. To search the possible genetic basis of the disorder, here we investigate a 15 year-old patient with MAE, who is the only person presenting epilepsy in the family. High resolution array-CGH analysis was conducted on DNA extracted from peripheral blood of the patient and the parents. The copy number variant(s) (CNVs) identified were further confirmed by Fluorescent In Situ Hybridization (FISH). The array-CGH identified a de novo microduplication of about 778 Kb in the chromosome region 4q21.22-q21.23, involving 11 genes. This is the first report of a de novo CNV in MAE. The genes involved in the duplication are potential candidates that can be investigated in the future to determine their exact role in the etiopathogenesis of the disorder. However, we suggest performing microarray chromosomal analysis in patients with MAE, since rare de novo CNVs could be identified, and this is known to affect the diagnostic process and recurrence risk assessment.

A novel spinocerebellar ataxia type 15 family with involuntary movements and cognitive decline.

BACKGROUND AND PURPOSE: SCA15 is a recently identified spinocerebellar ataxia with pure cerebellar involvement. Here, we report a novel SCA15 Italian family with atypical clinical features. METHODS: Three affected members from a three-generation family segregating an autosomal dominant cerebellar ataxia underwent clinical examination and genetic tests for hereditary ataxia. RESULTS: All affected members present with cognitive impairment and two of them with mild intermittent involuntary movements in association with the clinical hallmarks of SCA15 (gait ataxia, balance impairment, and dysarthria). Genetic tests detected a large deletion spanning ITPR1 and SUMF1 genes in affected members. CONCLUSION: Our findings help enlarging the clinical spectrum of SCA15.

Prenatal diagnosis and molecular characterization of an interstitial 1q24.3-31.3 deletion: case report and review.

We describe a foetus with an interstitial deletion of 1q detected in amniotic fluid cells and we review the literature of similar pre- and postnatal cases, in order to identify prognostic factors useful for prenatal counselling. Foetal/parents karyotyping and FISH with whole chromosome 1 paint and BAC clone specific for 1q23-32 region were performed. Further 100 Kb resolution array-CGH analysis was executed after pregnancy termination on DNA extracted from foetal skin fibroblasts. Cytogenetic analyses revealed a de novo interstitial deletion involving the long arm of chromosome 1. FISH analysis confirmed that the deletion involves the intermediate 1q31.2 region. Foetal ultrasound (US), performed at 21 weeks of gestation, showed intrauterine growth restriction, shortening of the long bones, echogenic intracardiac focus and mild cerebral ventriculomegaly. Array-CGH localized the deletion in a DNA sequence of about 21 Mb in the 1q24.3-q31.3 region. Our findings, together with available data on patients with 1q deletion, suggest that the most severe phenotypes are not simply associated with larger deletion, and that the results of prenatal US assessment, rather than a fine molecular characterization of the deletion, should be taken into account for prognostic evaluation.

Familial pericentric inversion of chromosome 18: intrafamilial variability of the recombinant dup(18q).

A pericentric inversion of chromosome 18 [inv(18)(p11.32q22)] and its recombinants has been studied in a three-generation family. A mother/son couple, carrying the rec dup(18q), showed dysmorphisms and short stature but only the son had mild mental retardation and speech delay. Karyotype, FISH analysis with subtelomeric probes and a 0.8 Mb array-CGH investigations were used to analyze this recombinant, demonstrating no genomic differences between the two relatives. This is the first observation of familial transmission of a rec dup(18q), showing that this recombinant is associated with a mild phenotype with variable clinical picture.

An intermediate phenotype between Hay-Wells and Rapp-Hodgkin syndromes in a patient with a novel P63 mutation: confirmation of a variable phenotypic spectrum with a common aetiology.

The ankyloblepharon-ectodermal defects-cleft lip and palate (Hay-Wells or AEC) and the Rapp-Hodgkin syndrome (RHS) are rare autosomal dominant ectodermal dysplasias due to mutations in the transcription factor gene P63. Both are caused by mutations affecting SAM or TID domains of TP63 protein. The two disorders share common features and may represent different phenotypic expressions of the same clinical entity. To date more than 20 P63 mutations have been described associated with AEC and RHS, the majority of which are missense or nonsense mutations. Molecular heterogeneity cannot account for the clinical heterogeneity, because the same mutations were observed both in patient with RHS and with AEC syndrome. Here we report on a novel P63 mutation (the first repeat variation described in the gene) in a patient showing overlapping phenotype of AEC and RH syndromes.

A novel mutation in the SDHD gene responsible for familial paraganglioma. Medical and psychological implications.

Familial paragangliomas/pheochromocytomas are dominantly inherited disorders characterized by the development of highly vascularized tumors of the head and neck, derived from non-chromaffin cells of the extra-adrenal paraganglia, and tumors with endocrine activity, derived from chromaffin cells, usually located in the adrenal medulla and pre- and para-vertebral thoracoabdominal regions. Germline inactivating heterozygous mutations in one of the genes encoding for succinate dehydrogenase subunits B, C or D (SDHB, SDHC or SDHD) are responsible for hereditary paragangliomas (PGLs), accounting for nearly 70% of familial cases. Particularly in the SDHD gene, different types of mutations have been found, nevertheless, alterations other than point mutations and deletion leading to missense/nonsense/splicing mutations are extremely rare. Here we report a family with multiple cases of PGL which co-segregates with a novel SDHD gene mutation predictable to give rise to an abnormal gene product (CybS). The identification of the molecular event responsible for PGL in our family made genetic counseling particularly useful for younger first degree relatives at risk to develop this late-onset disease.

Paracentric inversion of Yq and review of the literature.

We report on the second prenatal diagnosis of familial paracentric inversion of the long arm of Y chromosome [46, X, inv(Y)(q11.2q12)]. The anomaly was detected through an amniocentesis performed because of advanced maternal age. The inversion has been detected by standard GTG banding methods and better characterized by FISH with painting probe and specific satellite probes DYZ1 and DYZ3. The inversion derived from phenotypically normal father. Pregnancy was uneventful and an healthy child was born. We discuss the issue concerning genetic prenatal counselling of this rare condition and we report the clinical follow up of the child.

Prenatal diagnosis of a de novo satellited chromosome 18 (18ps) associated with 18p deletion.

De novo satellited non-acrocentric chromosomes are very rare findings in prenatal diagnosis. Here we report the first case of a de novo 18ps, associated with del(18p), detected at prenatal diagnosis. A 37 years old woman underwent Chorionic Villus Sampling (CVS) for advanced maternal age. Cytogenetic analysis on direct CVS preparation (CVSc) revealed a male karyotype with a nonfamilial satellited 18ps and a reciprocal translocation t(17;19)(P11.1;q11) of maternal origin. The mesenchimal CVS culture (CVSm) showed a mosaic of cell lines with various involvement of chromosome 18: 18ps [36/70]/ r(18) [25/70]/ del(18p) [3/70]/ -18 [6/70]. Amniotic fluid cells (AFC) confirmed the homogeneous karyotype found at CVSc. The molecular cytogenetic characterization, performed on AFC, allowed the following diagnosis: 46,XY, +15, dic(15;18)(p11.1;p11.2), t(17;19)(p11.1;q11)mat. ish dic(15;18)(tel 18p-, D15Z1+, wcp18-, wcp 18+, D18Z1+, tel 18q+). The foetal autopsy disclosed subtle facial dysmorphisms and corpus callosum hypoplasia. In case of prenatal detection of de novo terminal ectopic NORs an accurate cytogenetic and molecular analysis should be performed in order to rule out subtle unbalancements.

FGFR3 mutation in thanatophoric dysplasia type 1 with bilateral cystic renal dysplasia: coincidence or a new association?

Thanatophoric dysplasia (TD) is a lethal dwarfism condition due to missense mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Examination of TD patients reveals mainly the involvement of the skeletal system and the brain, but also renal and cardiovascular anomalies have been described. We report the prenatal detection of TD type 1 (TD1) associated with bilateral cystic renal dysplasia (CRD) Potter's type II, in which the molecular analysis reveals the typical Arg248Cys substitution in the FGFR3 gene. CRD has not been previously described in TD or other conditions due to FGFR3 mutations, but occurs in Apert syndrome (due to FGFR2 mutations). The possible involvement of renal developmental defect in FGFR3 mutations is discussed.

Aicardi syndrome associated with autosomal genomic imbalance: coincidence or evidence for autosomal inheritance with sex-limited expression?

Aicardi syndrome (AIS), a rare neurodevelopmental disorder thought to be caused by an X-linked dominant mutation, is characterized by 3 main features: agenesis of corpus callosum, infantile spams and chorioretinal lacunae. A genome-wide study of a girl with AIS lead us to identify a 6q deletion;12q duplication, derived from a maternal 6q;12q translocation. The two intellectually impaired brothers of the proband showed the same genomic anomalies, but not the constellation of features characterizing the AIS. This could be either a coincidental observation of 2 rare conditions, but can also suggest an alternative hypothesis for the genetic etiology of AIS, indicating the existence of a subset of autosomal genes whose mutation could act in a sex-confined manner.