Novel PTEN mutations in neurodevelopmental disorders and macrocephaly.

Somatic mutations of the phosphatase and tensin (PTEN) gene have been frequently detected in many types of human cancer. However, germline mutations can determine multiple hamartoma syndromes and, as more recently ascertained, syndromes clinically characterized by autism associated with macrocephaly. To determine whether germline mutations of PTEN may lead to different phenotypes, we screened all the nine exons of the PTEN gene in 40 patients with neurodevelopmental disorders, with or without features of autism spectrum disorder, associated with macrocephaly. Three novel de novo missense mutations were found (p.H118P, p.Y176C, p.N276S) in two severely mentally retarded patients with autism and in a subject with neurodevelopmental disorders without autistic features. Our results provide evidence that PTEN germline mutations may sustain a more wide phenotypical spectrum than previously suggested.

Neurocutaneous syndrome with mental delay, autism, blockage in intracellular vescicular trafficking and melanosome defects.

We evaluated a 11-year-old male patient with mental delay, autism and brownish and whitish skin spots. The former resembled those of neurofibromatosis, the latter those of tuberous sclerosis. The patient received a complete clinical work-up to exclude neurofibromatosis, tuberous sclerosis, or any other known neurocutaneous disease, with biochemistry, chromosome analysis and analysis of skin specimens. Being all the other tests not significant, two main ultrastructural defects were observed. The first was a blockage in intracellular vescicular trafficking with sparing of the mitochondria; the second an aberrant presence of melanosomes in vacuoles of several cell lines and abnormal transfer of these organelles to keratinocytes. This patient presented with a unique clinical picture distinct from neurofibromatosis or tuberous sclerosis or any other known neurocutaneous disease. The ultrastructural abnormalities suggested a defect in cell trafficking involving several cell lines and compartments.

Occipital intermittent rhythmic delta activity only following eye closure in atypical CNS Salmonellosis.

OBJECTIVE: A statement recently published on the base of a large retrospective analysis, report that the occipital intermittent rhythmic delta activity (OIRDA) "is associated with epilepsy but not acute encephalopathy" [Gullapalli and Fountain. J Clin Neurophysiol 2003;20:35-41]. Our aim is to report, the exception from a child with an intermittent fever, in which the finding of an occipital intermittent rhythmic delta activity (OIRDA) following the eye closure in the EEG recording was the first clinical sign addressing to a CNS involvement. METHODS: To review the record from a five-year-old girl with a normal basal electroencephalogram and OIRDA that only appeared following eye closure. RESULTS: We found OIRDA associated with atypical CNS Salmonellosis. Brain MRI and CSF examination confirmed an acute encephalopathy, which was due to Salmonella infection. The only symptoms of the infection were episodes of nightly fever that had lasted for four weeks, sometimes associated with headache and vomiting. Both OIRDA only induced by eye closing and other symptoms disappeared after starting antimicrobial therapy. CONCLUSIONS: OIRDA only following eye closure is a non-specific abnormality and the present findings, based on a single case, merely indicate that intracranial infection is among the possible causes. SIGNIFICANCE: The new clinical association is certainly worth recording, as the presence of this electrophysiological sign may provoke clinicians to then delve further into a diagnostic work up.

Lamotrigine treatment in childhood drug resistant epilepsy.

The clinical response to lamotrigine has been evaluated in a group of 63 drug resistant epileptic children in an open add-on trial. A negative response was observed in 30 subjects. In 11 patients, after an initial improvement lasting a mean period of 8 months, seizures recurred with the same frequency present before the beginning of the treatment. Twenty-two patients responded to lamotrigine treatment. Period of observation in the responsive group ranged from 1 year to 3 years. Response was complete in 16 patients and in the other 6 a 50% to 90% decrease of seizures was obtained. A complete normalization of the electroencephalogram (EEG) was registered in 10 cases after a mean period of 5 months of therapy. Side effects were mild and limited to 12 patients. Improvement was obtained in social and academic performance. Writing ability improved in one case. Lamotrigine can be considered a useful drug in the therapeutic armamentarium for childhood drug resistant epilepsy.

The syndrome of inv dup (15): clinical, electroencephalographic, and imaging findings.

The clinical and laboratory data of four pediatric patients and one adult patient with inverted duplication (inv dup) (15) are reported. The most evident findings were dysmorphic features with frontal bossing; genital abnormalities, such as macropenis or hypospadias; mental retardation; autistic behavior; and seizures. Two additional adults with inv dup (15) from other institutions were also diagnosed in our laboratory. Seizures and mental retardation were the reasons for their referral. The clinical picture of inv dup (15) seems to be quite variable since the phenotype can also be normal. However, karyotyping and fluorescent in-situ hybridization, focused in particular on chromosome 15, appear to be indicated in patients with dysmorphic phenotypes, such as the one present in our patients, and in subjects with early-onset seizures and psychomotor retardation with autistic features.

Homocystinuria with transverse sinus thrombosis.

A case of cerebral venous thrombosis caused by undiagnosed homocystinuria is reported. The pitfalls regarding the diagnosis of a potentially medically treatable condition are discussed. Cerebral venous thrombosis in children has a variable type of onset and a multiplicity of causes. This type of pathology, although not frequent, is more common than previously thought. Among the different etiologies, undiagnosed homocystinuria is not routinely considered. We report a case of venous thrombosis of the left transverse cerebral sinus in a girl with drug-resistant partial epilepsy and homocystinuria. This diagnosis was considered and confirmed after the appearance of acute cerebral symptoms caused by venous thrombosis.

Lamotrigine in typical absence epilepsy.

Lamotrigine (LTG) is an anti-epileptic drug effective in partial seizures and generalized epilepsy. There is growing evidence of the usefulness of LTG in childhood (CAE) orjuvenile (JAE) absences resistant to previous treatment. In this study all patients were identified using strict diagnostic criteria and subdivided into two groups. (1) Eight patients affected by absence seizures resistant to valproic acid or ethosuximide, received LTG as an-add-on therapy, (2) seven patients affected by typical absence seizures not previously treated, received LTG monotherapy after the diagnosis. In the patients with resistant absence seizures, a full control of seizures was obtained. In five of them, after a mean period of 12.5 months, the previous anti-epileptic drugs were withdrawn leaving the patients on LTG monotherapy. In one patient, absences relapsed and valproic acid was therefore added again to LTG to regain control of the seizures. In six of the seven patients on LTG monotherapy after the diagnosis, a full control of seizures was obtained. In the seventh patient the drug was stopped due to a skin rash. In conclusion LTG appears to be effective in resistant absence seizures in combination with valproic acid. Moreover, our preliminary data suggest that lamotrigine might be used as monotherapy in typical absence seizures. The advantages and disadvantages of LTG monotherapy in this type of epilepsy are discussed.

Clinical and EEG findings in 18 cases of late infantile neuronal ceroid lipofuscinosis.

The objective of this study was to present clinical and electroencephalographic findings in 18 cases with late infantile neuronal ceroid lipofuscinoses, focusing on features that assist early diagnosis. Clinical and EEG findings have been described in the past for classic types, but several variants have recently been reported. The authors reviewed the clinical and EEG findings of 18 childhood onset neuronal ceroid lipofuscinoses cases. In the late infantile neuronal ceroid lipofuscinoses type, both typical and variant cases have been observed. In this type, the presence of a particular pseudoperiodic EEG pattern that we found in 15/18 patients and observed in the first stages of the disease could be useful in early diagnosis, especially if associated with the absence of sleep spindles. A precise nosological classification, based both on clinical and instrumental findings is the prerequisite for a correct genotype-phenotype correlation that could greatly improve our knowledge of this disease, providing a better understanding of pathogenesis and increasing our ability to treat it.

Diagnosis of Angelman syndrome: clinical and EEG criteria.

In order to evaluate which diagnostic criteria can be indicative for an early diagnosis of Angelman syndrome (AS), 144 children with severe epilepsy and mental retardation were evaluated. In 10 of them the diagnostic criteria indicated by Williams were present. Of the remaining 134 patients we were able to diagnose one 15-year-old patient with AS, on the basis of the EEG findings, even though the typical clinical features of the syndrome were absent. In all patients the diagnosis of AS was confirmed by fluorescent in situ hybridization (FISH) in 10 patients and by methylation analysis in one patient. AS is very likely when both typical clinical and EEG findings are present. Nevertheless, it must be considered in all patients affected by severe epilepsy and mental retardation, when the EEG pattern is sufficiently indicative, and FISH and/or molecular analysis should be performed even in absence of typical clinical signs.

Early-onset seizure variant of Rett syndrome: definition of the clinical diagnostic criteria.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder affecting almost exclusively females. Among Rett clinical variants, the early-onset seizure variant describes girls with early onset epilepsy and it is caused by mutations in CDKL5. METHODS: Four previously reported girls and five new cases with CDKL5 mutation, ranging from 14 months to 13 years, were evaluated by two clinical geneticists, classified using a severity score system based on the evaluation of 22 different clinical signs and compared with 128 classic Rett and 25 Zappella variant MECP2-mutated patients, evaluated by the same clinical geneticists. Clinical features were compared with previously described CDKL5 mutated patients. Both the statistical and the descriptive approach have been used to delineate clinical diagnostic criteria. RESULTS: All girls present epilepsy with onset varying from 10 days to 3 months. Patients may present different type of seizures both at onset and during the whole course of the disease; multiple seizure types may also occur in the same individual. After treatment with antiepileptic drugs patients may experience a short seizure-free period but epilepsy progressively relapses. Typical stereotypic hand movements severely affecting the ability to grasp are present. Psychomotor development is severely impaired. In the majority of cases head circumference is within the normal range both at birth and at the time of clinical examination. CONCLUSION: For the practical clinical approach we propose to use six necessary and eight supportive diagnostic criteria. Epilepsy with onset between the first week and 5 months of life, hand stereotypies, as well as severe hypotonia, are included among the necessary criteria.

Atypical BECTS and homocystinuria.

Reported is an association of atypical benign childhood epilepsy with centrotemporal spikes (BECTS) and homocystinuria in three apparently healthy children with borderline intelligence, two of whom had difficult-to-control seizures. In all three, EEG were suggestive of BECTS, although the clinical features were not. Homocystinuria could not be diagnosed for several years, pending metabolic evaluation.

Vigabatrin treatment in children.

Sixty-nine children, aged from 2 months to 16 years and suffering from different types of drug-resistant epileptic seizures, mostly complex partial and secondary generalised, were recruited in an open, uncontrolled, prospective study of treatment with vigabatrin (gamma-vinyl GABA). Following a 3-month baseline observation period, the initial dose of vigabatrin of 10 mg/kg per day was progressively increased up to a maximum of 140 mg/kg per day, in addition to the conventional concomitant therapy. Sixteen patients showed a > or = 50% reduction in seizure frequency compared with the baseline, with complete control of seizures in nine cases. In 14 other patients, no substantial change in seizure frequency was observed, although an improvement in psychological performance after vigabatrin treatment warranted further continuation of the drug. In 35 patients vigabatrin was discontinued because of lack of efficacy (22 cases) and/or increased seizure frequency (13 cases). The clinical and biological tolerance of vigabatrin was remarkably good.

The FBN1 (R2726W) mutation is not fully penetrant.

The R2726W mutation in the fibrillin 1 (FBN1, Marfan syndrome) gene segregates with isolated skeletal features of Marfan syndrome and/or high stature. Here we report a family in which two out of four individuals, an 18-year-old son and his mother, a 41-year-old woman, had the R2726W mutation of FBN1. Both family members carrying the mutation were of average height. The son had a Marfan-like phenotype, but his mother did not. The FBN1 R2776W mutation, which is associated with skeletal features of Marfan syndrome, appears incompletely penetrant. Consequently, genetic counselling in the presence of this mutation is difficult.

Neuronal ceroid lipofuscinoses: clinical and EEG findings in a large study of Italian cases.

We reviewed the clinical and EEG features of 30 Italian patients with childhood-onset neuronal ceroid lipofuscinosis (NCL). The outcome and the EEG pattern of the 4 infantile NCL cases were classic, although the age at onset of symptoms varied from 1.0 to 3.5 years. This latter finding is unusual and has not been reported for other Italian patients. Both typical and variant cases of late-infantile NCL (LINCL) were observed. This NCL type represents the most common form in our country, and was the largest group (18 cases) in our study. A particular pseudoperiodic EEG pattern was observed in 15 of the 18 patients with LINCL. This pattern may be useful in early diagnosis, especially if associated with the absence of sleep spindles. In the 8 cases with juvenile NCL, clinical and EEG findings were similar to those reported in the literature.

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.

Blood pressure in the small-for-gestational age newborn.

AIM: The aim of the paper is to verify the existence of an inverse correlation between birth weight and blood pressure (BP) in neonates, infants and adolescents. METHODS: BP was measured at 7 days, 3, 6, 9, 12 months and 7-18 years in 432 subjects born at term at the Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena; 228 of these subjects were small for gestational age (SGA) and 204 appropriate for gestational age (AGA). For small babies, BP was measured with a DYNAMAP oscillometer which provides digital visualisation of systolic, diastolic and mean arterial pressure and heart rate. In older children, a mercury sphygmomanometer was used. Statistical analysis was carried out with SPSS 8.01 software using the Kolmogorov-Smirnov test for normality of populations. RESULTS: Statistical analysis did not reveal any significant differences between SGA and AGA subjects in the various age classes of the first 12 months of life. Significant correlation was found between 7 and 18 years with differences in the various age classes for systolic pressure. Subjects with normal birthweight had lower systolic and diastolic BP. SGA males had higher risk of high systolic and diastolic pressure, whereas SGA females were only at higher risk for elevated diastolic pressure. CONCLUSIONS: SGA subjects should be monitored for BP and life-style between 7 and 18 years to risk of cardiovascular disease.