Maddalena Cioni

Spermatogenesis in a man with complete deletion of USP9Y.

Deletions in the azoospermia factor region AZFa on the human Y chromosome and, more specifically, in the region that encompasses the ubiquitin-specific peptidase 9, Y-linked gene USP9Y have been implicated in infertility associated with oligospermia and azoospermia. We have characterized in detail a deletion in AZFa that results in an absence of USP9Y in a normospermic man and his brother and father. The association of this large deletion with normal fertility shows that USP9Y, hitherto considered a candidate gene for infertility and azoospermia, does not have a key role in male reproduction. These results suggest that it may not be necessary to consider USP9Y when screening the Y chromosome of infertile or subfertile men for microdeletions.

Intracellular levels of the LIS1 protein correlate with clinical and neuroradiological findings in patients with classical lissencephaly

We report on the genotype–phenotype correlation in 7 patients with classical lissencephaly carrying a heterozygous subtle mutation in the LIS1 gene. Six patients showed a mutation predicted to encode for a truncated protein, and one mutation altered a splicing site, resulting in skipping of exon 4. Western blot analysis performed on the lymphoblastoid cell line of 2 patients bearing truncating mutations indicated that the mutated allele did not produce a detectable amount of the LIS1 protein; whereas the analysis performed on the fibroblasts from the patient with a splice‐site mutation was suggestive of partial protein synthesis from the mutated allele. Although clinical and magnetic resonance imaging findings of patients with truncating mutations did not differ from those observed in patients with a heterozygous deletion, the patient bearing the exon‐skipping mutation had less severe clinical and brain involvement. Our data suggest that truncating mutations in the LIS1 gene are relatively common among patients with classical lissencephaly not bearing a heterozygous deletion at 17p13.3, and strengthen the relevance of correct intracellular dosage of the LIS1 protein in the neuronal migration process. Ann Neurol 1999;45:154–161

Efficacy and safety of topiramate in infants according to epilepsy syndromes

Studies of the efficacy of topiramate (TPM) in infants and young children are few. Here we report an open, prospective, and pragmatic study of effectiveness of TPM in terms of epilepsy syndromes, in children aged less than 2 years. The median follow-up period was 11 months. We enrolled 59 children in the study: 22 affected by localization-related epilepsy (LRE), 23 by generalized epilepsy, six by Dravets syndrome, and eight with unclassifiable epilepsy. TPM was effective (responders showed a decrease of more than 50% in seizure frequency) in 47% of patients, including 13% who were seizure-free at the last visit. TPM was more effective in localization-related epilepsy (48% of responders) than in generalized epilepsy (32% of responders). In the latter group, 19 patients suffered from infantile spasms. Four of six patients with cryptogenic infantile spasms became seizure-free. Of the 13 patients with symptomatic infantile spasms, only one was seizure-free. Results were poor for patients with Dravets syndrome. In general, TPM was well tolerated. The most frequently reported adverse effects were drowsiness, irritability, hyperthermia, and anorexia. The present study concludes that TPM is effective for a broad range of seizures in infants and young children and represents a valid therapeutic option in this population.

Pseudo-TORCH syndrome or Baraitser–Reardon syndrome: diagnostic criteria

Intracranial calcification and microcephaly, which represent the main clinical features of the TORCH-syndrome, can also be determined by a rare autosomal recessive infection-like condition named pseudo-TORCH syndrome. This emerging entity has been registered in eight families so far. We report on five patients from three unrelated Italian families affected by pseudo-TORCH syndrome. Reevaluation of literature allowed us to draw a specific clinical profile of the syndrome. Indeed, congenital microcephaly, congenital cerebral calcification, spasticity and seizures are the main clinical features, and have been present in almost all patients reported so far. On the contrary, findings resembling congenital infectious diseases including neonatal icterus, hyperbilirubinemia, thrombocytopenia, and hepatomegaly, affect less than half of the patients. Considering the diagnosis of pseudo-TORCH syndrome in patients with neonatal microcephaly and cerebral calcification is necessary since an early diagnosis may allow adequate genetic counseling to the families.

Growth hormone secretion in Prader-Willi syndrome

Prader-Willi Syndrome (PWS) is a multisystem defect characterized by obesity, hypogenitalism and short stature for genetic background. Low GH serum levels have been found in patients with PWS and were related to a hypothalamic-pituitary dysfunction. We studied spontaneous nocturnal GH secretion and GH-response to provocative tests in five patients affected by PWS. We observed in three of them (Group A) abnormally low GH and IGF-1 serum levels. In the other two patients (Group B) GH secretion and IGF-1 serum levels were normal. In all patients no thyroid dysfunction was observed. These data might suggest the presence of two different subgroups of patients affected by PWS, from an endocrinological point of view. An abnormally low GH secretion would be evident only in a subgroup of patients, which appears to be normal in the remaining patients. This casistic is small in number, but if our data will be confirmed by more extensive studies it may be possible to identify a specific population of PWS patients who could benefit from recombinant GH-therapy.

Transient neonatal hypothyroidism after gestational exposure to amiodarone: A follow-up of two cases

Amiodarone (AMD) is an antiarrhythmic drug which contains 37% of iodine. It can reach the fetus by transplacental passage and induce fetal hypothyroidism. Since in some pregnant women AMD represents a cardinal therapeutic opportunity, it is necessary to establish not only the risk of teratogenicity linked to fetal AMD exposure but also to evaluate the psychomotor development of children with neonatal thyroid dysfunction related to fetal AMD exposure. We report on two cases involving children with an AMD gestational exposure and transient neonatal hypothyroidism, who were followed-up until the age of 4 years 8 months and 5 years 6 months, respectively. Denver’s developmental milestone test and Whechsler Preschool and Primary Scale of Intelligence (WPPSI) were administered to the patients in accordance to their age. A normal psychomotor development was observed in both patients with full scale IQ score, verbal and performance IQ scores within normal range. In conclusion, if these data were validated by larger studies, it might not be obligatory to discontinue AMD administration in cardiopathic pregnant women, since mental impairment may not necessarily occur in children with transient neonatal hypothyroidism caused by fetal AMD exposure. However, the evaluation of the thyroid function of these children is imperative.

Chromosome 18 aberrations and epilepsy: A review

Epilepsy is commonly observed in patients with chromosomal aberrations. We evaluated epilepsy and electroencephalographic (EEG) features in a group of patients carrying aberrations of chromosome 18. Fourteen patients were recruited: five with an 18p deletion syndrome (18pDS); six with an 18q deletion syndrome (18qDS); two with trisomy 18p syndrome; and one with a 45,XY,t(17‐18) (cen‐q11.2) karyotype. Patients with 18pDS had neither epilepsy nor EEG anomalies; four patients with 18qDS had epilepsy with partial seizures occurring during infancy or early childhood. Partial seizures were also present in both patients with trisomy 18p. By contrast, mixed seizures were observed in the patient carrying a translocation between chromosomes 17 and 18. Our data and a re‐evaluation of the literature suggest that epilepsy is infrequent in patients with 18pDS. Conversely, partial seizures and focal EEG anomalies may be observed in those with patients with 18qDS. Our observations suggest that the haplo‐insufficiency of genes located on the long arm of chromosome 18 is more likely to be associated with epilepsy, than is haplo‐insufficiency of genes located on the short arm. While further EEG/clinical investigations are needed to validate these observations, this study indicates a possible relationship between chromosome 18 genes and epilepsy.

Schinzel–Giedion syndrome: a further cause of West syndrome

Schinzel-Giedion syndrome (SGS) is a rare disorder with a likely autosomal recessive pattern of inheritance which is characterized by several facial dysmorphisms, midface hypoplasia, multiple skeletal anomalies including short and sclerotic skull base, short neck, and post-axial polydactyly. Cardiac and urogenital malformations are also present. Thirty-three cases have been described so far. We report on a boy affected by SGS in whom a long-term EEG follow-up showed a progressive deterioration of the background bioelectric activity ending, at the age of 19 months, with a hypsarrhythmic pattern clinically correlated with severe and refractory infantile spasms. EEG deterioration and neuroradiological findings, which showed progressive brain atrophy, confirm the neurodegenerative nature of SGS. We also re-evaluated all the published cases and found that 33% of patients with SGS experienced neonatal seizures and another 25% developed West syndrome in the following months. The seizures appeared extremely refractory to several anticonvulsive treatments. In conclusion, we believe that SGS should be included among the causes of secondary West syndrome.

3.2 Mb microdeletion in chromosome 7 bands q22.2–q22.3 associated with overgrowth and delayed bone age

We report a patient with mental retardation, epilepsy, overgrowth, delayed bone age, peculiar facial features, corpus callosum hypoplasia, enlarged cisterna magna and right cerebellar hypoplasia. Array-CGH analysis revealed the presence of a de novo 3.2 Mb interstitial deletion of the long arm of chromosome 7 involving bands q22.2-q22.3. The rearrangement includes 15 genes and encompasses a genomic region that represents a site of frequent loss of heterozygosity in myeloid malignancies. Four genes are implicated in the control of cell cycle: SRPK2, MLL5, RINT1 and LHFPL3. Haploinsufficiency of these genes might therefore be associated with overgrowth and could confer susceptibility to cancers or other tumours, so that attention to this possibility would be appropriate during regular medical review. In conclusion, array-CGH analysis should be performed in patients with overgrowth where the known causes have already been excluded, because some still unclassified overgrowth syndromes may be caused by subtle genomic imbalances.

Pontocerebellar hypoplasia type 2: further clinical characterization and evidence of positive response of dyskinesia to levodopa.

Pontocerebellar hypoplasia type 2 (PCH2) is a very rare autosomal recessive disorder. We report two unrelated female patients born to consanguineous parents presenting with this condition. Patient 1 showed a classical clinical/neuroradiological phenotype of PCH2 with dyskinesia/dystonia. Patient 2 had a neonatal onset of PCH2 with polyhydramnios, apneic spells, myoclonus, and an akinetic/rigidity condition. Neuroradiologically, patient 2 showed extensive pancerebral degeneration. Based on these observations, and in accordance with the published cases, two groups of PCH2 patients may be defined: (a) patients with dyskinesia/dystonia, severe hypoplasia of the infratentorial structures and less severe involvement of the supratentorial brain; and (b) patients with polyhydramnios, neonatal onset with tremulousness (hyperekplexia), no spontaneous activity, absence of dyskinesia and pancerebral degeneration. Finally, we report a dramatic positive response of the patient with dyskinesia/dystonia to levodopa treatment, and discuss the associated physiopathological implications.