Alfonso Romano

Neonatal Urinary Cotinine Correlates With Behavioral Alterations in Newborns Prenatally Exposed to Tobacco Smoke

Altered behavior due to prenatal smoke exposure was examined in 25 neonates born from smoking mothers who consumed at least 5 cigarettes/d during the entire gestation. Data were compared with 25 matched neonates born from nonsmoking mothers. Neonatal behavior was evaluated using the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). Antenatal exposure to tobacco smoke at the end of the pregnancy was determined by measurement of urinary cotinine. Newborns from smoking mothers showed significant lower scores in various BNBAS items compared with neonates from nonsmoking mothers. A strong correlation was observed between infant irritability and urinary cotinine in newborns from smoker and nonsmoking mothers and with number of daily smoked cigarettes and maternal nicotine daily intake of infants exposed to active maternal smoking. Linear regression analysis showed that urinary cotinine was the best predictor of infant irritability (r2 = 0.727). The latter was also associated to the neonates low level of attention and poor response to inanimate auditory stimuli. Among infants from nonsmoking mothers, paternal smoking significantly correlated with infant urinary cotinine and infant irritability, being also the best predictor of irritability (r2 = 0.364). Neonatal behavior can be significantly altered in a dose-dependent manner even after modest prenatal exposure to tobacco smoke.

Long-Term Enzyme Replacement Therapy for Pompe Disease With Recombinant Human Alpha-glucosidase Derived From Chinese Hamster Ovary Cells

Pompe disease is a rare autosomal recessive myopathy due to the deficiency of lysosomal acid alpha-glucosidase. Clinical phenotypes range from the severe classic infantile form (hypotonia and hypertrophic cardiomyopathy), to milder late onset forms (skeletal myopathy and absence of significant heart involvement). Enzyme replacement therapy with recombinant human alpha-glucosidase derived from either rabbit milk or Chinese hamster ovary cells has been introduced and is undergoing clinical trials. Reported is a long-term follow-up of 3 Pompe patients presenting without cardiomyopathy, treated with recombinant human alpha-glucosidase derived from Chinese hamster ovary cells. This study suggests that enzyme replacement therapy can lead to significant motor and respiratory improvement in the subgroup of patients who start the therapy before extensive muscle damage has occurred. The recombinant enzyme derived from Chinese hamster ovary cells, administered at doses significantly higher than previously reported, appears to have the same safety as the drug derived from rabbit milk.

A chaperone enhances blood α-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy.

Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone.

The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann–Pick disease type C after therapy with miglustat†

Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder characterized by defective intracellular lipid trafficking, with secondary accumulation of free cholesterol, sphingosine, and glycosphingolipids. NPC is clinically characterized by a wide spectrum of manifestations with progressive visceral and neurological involvement, including dysphagia. Neurological manifestations represent the most debilitating findings. Swallowing impairment is a frequent cause of morbidity and disability in NPC patients and progressive dysphagia may be considered a marker of neurological progression. Recently substrate reduction therapy with miglustat has been proposed for the treatment of neurological manifestations in NPC patients. This observational study reports on the long‐term use of miglustat in four pediatric patients with NPC and shows the efficacy of the treatment to improve or prevent dysphagia, and persistence after 3 years of treatment or more. We used a videofluoroscopic analysis of liquid barium swallowing to provide additional information on patterns of impairment of the swallowing mechanism and to detect aspiration. In three patients showing dysphagia and aspiration we observed the improvement of the swallowing function and the sustained absence of barium aspiration in the airways after miglustat treatment, while the patient with normal swallowing function at baseline did not show any deterioration. We suggest that the videofluoroscopic study of swallowing should be routinely used to monitor the effects of treatment on swallowing ability in NPC patients.

Partial cerebellar hypoplasia in a patient with Prader-Willi syndrome

UNLABELLED We report a 3-y-old male infant with Prader-Willi syndrome (PWS) caused by a de novo interstitial deletion of 15q11-q13. Additional features included a right cerebellar hemisphere hypoplasia. The extent of deletion was determined by FISH analysis using an SNRPN PW/AS probe that maps in the PWS/AS critical region (CR) and with specific 15q BACs. We unravelled an interstitial 15q11.2-q13.1 deletion spanning about 3 Mb. CONCLUSION To date only a few other PWS patients--including autopsy cases--with CNS structural anomalies have been described. Our case report adds knowledge to the issue of brain involvement in Prader-Willi syndrome. Further MRI studies of PWS patients will be helpful to clarify a correlation between PWS and brain abnormalities.

Early Intervention for Children With Down Syndrome in Southern Italy: The Role of Parent-implemented Developmental Training

The aim of this study was to assess whether parent-implemented developmental training—by means of the Carolina Curriculum for Infants and Toddlers with Special Needs (CCITSN)—could be of greater benefit to young children with Down syndrome (DS) than the standard therapist-implemented treatment provided by the National Health Service of the southern Italian region of Campania (NHST). A total of 47 children with DS were randomly assigned either to the experimental (CCITSN) or to the comparison (NHST) group. Children from both groups were tested periodically with the Brunet-Lézine Psychomotor Development Scale. After completion of the 12-month followup, children in the CCITSN group showed developmental gains over time while children in the comparison group showed a slight but not statistically significant improvement. Moreover, mean developmental quotient scores of the CCITSN group, over the entire study period, were significantly higher than those of the comparison group. A commitment to using parents as interventionists is not a common practice in Italy and many other countries, but may be the most effective and cost-efficient way of providing services to young children with DS and other developmental disabilities.

A further contribution to the delineation of the 17q21.31 microdeletion syndrome: Central nervous involvement in two Italian patients

The 17q21.31 microdeletion syndrome is a genetic disorder characterized by intellectual disability, facial dysmorphisms and a typical behavioral phenotype. Patients are usually described as friendly and cooperative but they can also show behavioral problems such as hyperactivity, bad humor, temper tantrums and poor interaction. Central nervous system involvement includes callosal dysgenesis/absence, enlargement of lateral ventricles and abnormalities of cyngulate gyrus. We report on two Italian patients with the 17q21.31 microdeletion syndrome better emphasizing neuroimaging and neuropsychological characteristics. In particular, we carried out an assessment of intellectual efficiency and behavior that turned out to be within the mild-moderate range of mental retardation, as already reported in the literature. To the best of our knowledge this is the first report of a patient with the 17q21.31 microdeletion and a Chiari malformation type 1 coexisting with a mild anomaly of medulla oblongata. This malformation should be considered in patients with the 17q21.31 microdeletion syndrome, presenting suggestive symptoms (headache, neck pain, cerebellar signs or muscle weakness).

Congenital Fiber Type Disproportion Myopathy: Report of a Case with Late Onset and Myalgia

From the Department of Clinical Neurophysiology, the Department of Pediatrics, the Department of Neurology, Second School of Medicine, University of Naples, Naples, Italy, and the Department of Neurology, University of Messina, Messina, Italy. Correspondence to: Lucio Santoro, MD, Cattedra di Neurofisiopatologia, Università degli Studi di Napoli, II Facoltà di Medicina e Chirurgia, via Sergio Pansini n.5, Nuovo Policlinico, 80131 Napoli, Italy. Received for publication February 1984, revised April 1984, and accepted July 1984. QSINCE THE FIRST DESCRIPTION of congenital fiber type disproportion myopathy (CFTDM) by Brooke and Engel,’ a few additional cases have been reported,2-’:! but only one is in the pediatric literature.’ o

Lack of red hair phenotype in a North-African obese child homozygous for a novel POMC null mutation: nonsense-mediated decay RNA evaluation and hair pigment chemical analysis.

cytokines from the nervous system itself. Proinflammatory cytokines, including IL-1b and tumour necrosis factor-a, are upregulated in response to trauma to the nerve and can act directly on receptors expressed by cells of the nervous system. It was shown in various experiments that exogenous IL-1b can directly induce hyperalgesia when injected into a peripheral nerve in mice, and mice with genetically impaired IL-1 signalling do not develop neuropathic pain behaviour. Experiments with IL-1RA also showed that mice treated with IL-1RA, compared with placebo, did not exhibit an allodynic response, and IL-1RA also reduced allodynia in mice with established allodynic response. There are no human studies of IL-1RA in patients with neuropathic pain to date. Our patient had recurrent urticarial rash, joint pain and fatigue with an IgM paraprotein compatible with Schnitzler’s syndrome. That the diagnosis was only made 2 years after the onset of her illness as a result of repeated serum electrophoresis and immunofixation highlights the importance of having a high clinical suspicion. Her intercostal neuralgia responded within 48 h to anakinra suggesting that IL-1 plays an important role in the development of neuropathic pain and Schnitzler’s syndrome. It is not clear whether this effect is due to the reduction of inflammation around the nerve or is a direct effect on IL-1 signalling in the neurons.

Myasthenia gravis in a patient affected by glycogen storage disease type Ib: A further manifestation of an increased risk for autoimmune disorders?

SummaryGlycogen storage disease type Ib (GSD Ib, OMIM 232220) is an inborn disorder of glucose metabolism, caused by mutations in the G6PT gene, encoding a glucose 6-phosphate transporter (G6PT). GSD Ib is mainly associated with fasting hypoglycaemia and hepatomegaly. Most GSD Ib patients also show neutropenia and neutrophil dysfunction and therefore are at risk of developing severe infections and inflammatory bowel disease (IBD). An increased risk for autoimmune disorders, such as thyroid autoimmunity and Crohn-like disease, has also been demonstrated, but no systematic study on the prevalence of autoimmune disorders in GSD Ib patients has ever been performed. We describe a 25-year-old patient affected by GSD Ib who developed ‘seronegative’ myasthenia gravis (MG), presenting with bilateral eyelid ptosis, diplopia, dysarthria, severe dysphagia, dyspnoea and fatigue. The repetitive stimulation of peripheral nerves test showed signs of exhaustion of neuromuscular transmission, particularly evident in the cranial area. Even in the absence of identifiable anti-acetylcholine receptor antibodies, seronegative MG is considered an autoimmune disorder and may be related to the disturbed immune function observed in GSD Ib patients.