Carlo Cianchetti

Increased Sensitivity of the Neuronal Nicotinic Receptor α2 Subunit Causes Familial Epilepsy with Nocturnal Wandering and Ictal Fear

Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor alpha 2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic alpha 2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior.

Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Déjerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q(CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser 44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.

A Mutation in the Dystrophin Gene Selectively Affecting Dystrophin Expression in the Heart

We have previously shown in a large X-linked pedigree that a deletion removing the dystrophin muscle promoter, the first muscle exon and part of intron 1 caused a severe dilated cardiomyopathy with no associated muscle weakness. Dystrophin expression was present in the muscle of affected males and transcription studies indicated that this dystrophin originated from the brain and Purkinje cell isoforms, upregulated in this skeletal muscle. We have now studied dystrophin transcription and expression in the heart of one member of this family. In contrast to the skeletal muscle, dystrophin transcription and expression were absent in the heart, with the exception of the distal Dp71 dystrophin isoform, normally present in the heart. The 43- and 50-kD dystrophin-associated proteins were severely reduced in the heart, despite the presence of Dp71, but not in skeletal muscle. The absence of dystrophin and the down-regulation of the dystrophin-associated proteins in the heart accounted for the severe cardiomyopathy in this family. The mutation present in these males selectively affects dystrophin expression in the heart; this could be secondary to the removal of cardiac-specific regulatory sequences. This family may represent the first example of a mutation specifically affecting the cardiac expression of a gene, present physiologically in both the skeletal and cardiac muscles.

Methylphenidate for pervasive developmental disorders: safety and efficacy of acute single dose test and ongoing therapy: an open-pilot study.

OBJECTIVE The aim of this study was to investigate the effects of ongoing methylphenidate (MPH) on ADHD-related and autistic symptoms in Pervasive Developmental Disorders (PDD) in children who did not present any adverse effects to an initial acute dose administered at the clinic. METHODS Participants included 13 subjects (12 males, with a mean age of 7.9 years) with PDD and moderate to severe hyperactivity/impulsivity. The severity of the symptoms assessment was based on Clinical Global Impression (CGI), Childhood Autism, Child Psychiatric and Conners Parent and Teacher Rating Scales (CPRS). Scores at baseline, and after 1 and 3 months of treatment, were compared to intent-to-treat analyses. RESULTS One (1) hour after a single MPH dose (0.4 mg/kg), 5 subjects exhibited increased hyperactivity, stereotypes, dysphoria, or motor tics and were rated as minimally or much worse on the CGI Global Improvement Scale. They received no further treatment with MPH. Four (4) of the remaining subjects were rated as improved, and four as unchanged; they proceeded to a 12-week open trial of MPH. Two children remained unchanged: they discontinued treatment after 1 week on maximally tolerated doses. However, in group analyses, behavioral measures of hyperactivity and impulsivity improved significantly, while autism core symptom measures were unaffected. No significant adverse effects were observed in any of the 8 subjects. CONCLUSIONS Administering a single MPH test dose may be useful in identifying children with PDD who may benefit from prolonged therapy.

Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments

The clinical and morphological findings of a familial case affected by mental retardation, severe biventricular hypertrophic cardiomyopathy and vacuolar myopathy are reported. The phenotype of this patient is similar to that described by other authors, in which a lysosomal glycogen storage disease with normal acid maltase levels was suspected. However, in our case the vacuoles were stained by several antibodies directed against various sarcolemmal proteins, such as dystrophin and spectrin, and therefore, were not of lysosomal origin. Some of these vacuoles were clearly derived from the splitting of the fibres and invagination of the extracellular space; autophagic vacuoles were not observed. The accumulation of desmin-type, intermediate filaments was demonstrated on immunocytochemistry both in the skeletal and cardiac muscles. A brother of the propositus was also affected by mental retardation, severe cardiomyopathy and died suddenly at the age of 24 yr. A cardiomyopathy and mental subnormality were also present in other male cousins of the proband, while sudden death occurred in several females relatives, whose intelligence was normal. None of these latter individuals was available for further investigation. This report expands the spectrum of desmin associated myopathy and cardiomyopathy to include a familial condition with associated mental retardation.

Schwartz-Jampel syndrome. Clinical, electrophysiological and histopathological study of a severe variant.

This report describes a child, offspring of a first cousin marriage, with a severe and progressive disorder of bone and cartilage growth associated with a myotonia-like syndrome. Clinical manifestations of this disease began at birth with marked generalized muscle hypertrophy, stiffness, myotonia and multiple skeletal deformities. Successively severe dwarfism and mental retardation were observed. Neurophysiological studies showed continuous high frequently low voltage activity at rest and myotonic discharges which did not wax and wane. These abnormalities persisted after complete curarization. Muscle biopsy showed mild dystrophic changes. Polymeric glycosaminoglycans and degradation product excretion was normal. These findings are similar to those described in Schwartz-Jampel syndrome, but since the clinical picture was fully expressed at birth and was unusually severe, it is suggested that the patients condition may have represented a severe variant of this syndrome.

Abnormal Phonologic Processing in Familial Lateral Temporal Lobe Epilepsy Due to a New LGI1 Mutation

Summary:  Purpose: Autosomal dominant lateral temporal lobe epilepsy (ADLTLE) is a rare familial epilepsy with onset in adolescence or early adulthood, associated with mutations of LGI1 in most families. We describe the clinical, neuropsychological, and molecular genetic study of a new ADLTLE Italian family.

HLA‐DQB1 genotype in Sardinian multiple sclerosis Evidence for a key role of DQB1 *0201 and *0302 alleles

We studied HLA-DQB1 haplotypes in 103 unrelated multiple sclerosis (UMS) patients and in 26 related (RMS) patients from 12 families from Sardinia, Italy, where the disease was associated with the HLA-DR4 allele. Using polymerase chain reaction and allele-specific oligonucleotide probes, we found in UMS an increased frequency of the DQB1 *0201 (p = 0.010) and DQB1 *0302 (p = 0.025) alleles, whereas the DQB1 *0301 allele was significantly decreased (p = 0.027). In RMS, only the DQB1 *0302 allele was increased (p = 0.047), and no difference was found in the DQB1 *0301 allele. For DQB haplotypes, an increased frequency of DQB1 *0302/*0502 (p = 0.026) and a decreased frequency of DQB1 *0201/*0601 (p = 0.009) and DQB1 *0502/*0502 (p = 0.025) was found in UMS patients, whereas RMS patients showed an increased frequency of DQB1 *0301/*0302 (p = 0.005). Because DQB1 *0201 and *0302 alleles are increased in Caucasian MS patients, where the disease is related to HLA-DR2 and where a primary association with the HLA-DR2, DQB1 *0602 allele has been reported, we conclude that Caucasian and Sardinian populations share HLA-DQB1 *0201 and *0302 alleles in genetic susceptibility to MS.

Therapeutical efficacy of a combination of apomorphine with sulpiride or metoclopramide in parkinsonism

In healthy volunteers the emetic effect of apomorphine (5–10 mg, i.m.) was prevented by haloperidol (2 mg), metoclopramide (10 mg) and sulpiride (100 mg), injected intramuscularly. In parkinsonian patients, apomorphine (1 mg) given alone ameliorated the neurological symptoms (30% improvement in the disability score), but the improvement was accompanied by nausea, vomiting, sedation or sleepiness. Haloperidol (2 mg) prevented not only the emetic effect of apomorphine (10 mg), but also its therapeutic efficacy in parkinsonism. Indeed, the disability score was worsened by the drug combination in some patients. Moreover, after haloperidol, apomorphine produced deep sedation and sleep. By contrast, in parkinsonian patients pretreated with metoclopramide (10 mg) or sulpiride (100 mg), apomorphine (10 mg) markedly diminished tremor and rigidity and failed to produce nausea, vomiting and sleepiness.

Surface Markers on Lymphocytes from Human Cerebrospinal Fluid

Surface markers of cerebrospinal fluid (CSF) cells have been studied in comparison with those of peripheral blood lymphocytes. The great majority (about 95%) of CSF cells bear surface markers of thymu