Anna Lia Gabriele

Ophthalmological manifestations in segmental neurofibromatosis type 1

Aims: To study the ophthalmological manifestations in individuals with the typical features of neurofibromatosis type 1 (NF1) circumscribed to one or more body segments, usually referred to as segmental NF1. Methods: Visual acuity and colour tests, visual field examination, slit lamp biomicroscopy of the anterior segment, and a detailed examination of the retina by indirect ophthalmoscopy were performed at diagnosis and follow up in 72 consecutive subjects (29 males, 43 females; aged 1–64 years; mean age 14.6 years) seen at the university departments of paediatrics in Catania and Rome, Italy, during years 1990–2003, who had in restricted body areas: (1) typical pigmentary manifestations of NF1 (café au lait spots and freckling) only (n = 48); (2) NF1 pigmentary manifestations and neurofibromas alone (n = 2); (3) neurofibromas only (n = 15); and (4) plexiform neurofibromas only (n = 7). Results: None of the 72 patients had Lisch nodules in the iris irrespective of age at eye examination or hypertelorism (a “minor” NF1 feature) and none developed typical associated ophthalmological NF1 complications. An additional child had an isolated optic pathways glioma (OPG), which behaved both biologically and radiographically as an NF1 associated OPG. Conclusions: This represents the first systematic study reporting on eye involvement in the largest series of individuals at different ages having segmental NF1. As one of the postulated mechanisms to explain segmental NF1 is somatic mosaicism for the NF1 gene (so far demonstrated only in two patients) the present findings could be explained either by the fact that the eye is too far from the mutated area with NF1 lesions in most cases or by the NF1 (or other “predisposing” or “cooperating”) gene mutation restricted to too few cellular clones or to tissues embryologically different from the eye.

Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke–Davidoff–Masson type in two patients

The term twin spotting refers to phenotypes characterized by the spatial and temporal co‐occurrence of two (or more) different nevi arranged in variable cutaneous patterns, and can be associated with extra‐cutaneous anomalies. Several examples of twin spotting have been described in humans including nevus vascularis mixtus, cutis tricolor, lesions of overgrowth, and deficient growth in Proteus and Elattoproteus syndromes, epidermolytic hyperkeratosis of Brocq, and the so‐called phacomatoses pigmentovascularis and pigmentokeratotica. We report on a 28‐year‐old man and a 15‐year‐old girl, who presented with a previously unrecognized association of paired cutaneous vascular nevi of the telangiectaticus and anemicus types (naevus vascularis mixtus) distributed in a mosaic pattern on the face (in both patients) and over the entire body (in the man) and a complex brain malformation (in both patients) consisting of cerebral hemiatrophy, hypoplasia of the cerebral vessels and homolateral hypertrophy of the skull and sinuses (known as Dyke–Davidoff–Masson malformation). Both patients had facial asymmetry and the young man had facial dysmorphism, seizures with EEG anomalies, hemiplegia, insulin‐dependent diabetes mellitus (IDDM), autoimmune thyroiditis, a large hepatic cavernous vascular malformation, and left Legg‐Calvé‐Perthes disease (LCPD) [LCPD‐like presentation]. Array‐CGH analysis and mutation analysis of the RASA1 gene were normal in both patients.

Neurofibromatosis type 1 and infantile spasms

BackgroundThere is no agreement on the prevalence, natural history and outcome of infantile spasms (IS) in neurofibromatosis type 1 (NF1). By contrast, its prevalence and outcome are well characterised in the setting of other neurocutaneous disorders (e.g. tuberous sclerosis).Materials and methodsThe aim of the present study was to try to establish a genotype–phenotype correlation in IS in the setting of NF1. A retrospective (years 1990–2000) and prospective (years 2000–2006) study in three paediatric centres in Italy were taken as referral populations for: (1) children with NF1 and (2) neurological problems in childhood.ResultsTen NF1 patients have had IS. The calculated population-based: (1) prevalence of IS in NF1 (0.76%) was higher than the reported frequency of IS in the general population (0.02–0.05%) and (2) frequency of NF1 in the IS series in two out of three centres (0.62–0.90%) was lower than the estimated frequencies in the literature (1.5–3.0%). Patients had psychomotor delay preceding the spasms (50%), symmetrical spasms (50%), typical (80%) and modified (20%) hypsarrhythmia and foci of spikes and waves and a good response to corticosteroid treatment (50%). Outcome was good in 30%. Imaging revealed high-signal foci in atypical locations (sub-cortical and central brain regions). Deoxyribonucleic acid analysis revealed three novel NF1 gene mutations without genotype–phenotype correlation.ConclusionEven though the combination of IS and NF1 does not seem to be coincidental, it is certainly an unusual event in NF1—rarer than in other neurocutaneous disorders. Spasms in NF1 are not associated with specific genetic defects.

Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia

Mutations in the SPG4 gene are the most common causes of hereditary spastic paraplegia (HSP) accounting for up to 40% of autosomal dominant (AD) forms and 12-18% of sporadic cases. The phenotype associated with HSP due to mutations in the SPG4 gene tends to be pure. There is increasing evidence, however, of patients with complicated forms of spastic paraplegia in which SPG4 mutations were identified. A cohort of 38 unrelated Italian patients with spastic paraplegia, of which 24 had a clear dominant inheritance and 14 were apparently sporadic, were screened for mutations in the SPG4 gene. We identified 11 different mutations, six of which were novel (p.Glu143GlyfsX8, p.Tyr415X, p.Asp548Asn, c.1656_1664delinsTGACCT, c.1688-3C>G and c.*2G>T) and two exon deletions previously reported. The overall rate of SPG4 gene mutation in our patients was 36.8% (14/38); in AD-HSP we observed a mutation frequency of 45.8% (11/24), in sporadic cases the frequency was 21.4% (3/14). Furthermore, we found a mutational rate of 22.2% (2/9) and 41.4% (12/29) in the complicated and pure forms, respectively. The results underlie the importance of genetic testing in all affected individuals.

Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus

Hereditary spastic paraplegias are neurodegenerative disorders characterized clinically by progressive spasticity of the lower limbs. They are inherited as autosomal dominant, autosomal recessive, and X-linked traits. Four Italian families with autosomal recessive pure spastic paraplegia are reported. We show evidence of linkage to the SPG5 locus on chromosome 8p and our data reduce the candidate interval for SPG5 to the11-cM interval spanned by D8S285 and D8S544. We also report the search for mutations in five genes located in the region and their exclusion as candidates for SPG5.

A novel mutation in the CLN1 gene in a patient with juvenile neuronal ceroid lipofuscinosis

Abstract. We describe the clinical, neuropathological and molecular findings from a patient affected with neuronal ceroid lipofuscinosis with a juvenile onset (JNCL). She was a 9-year-old right-handed girl with a normal birth and early developmental milestones. At the age of 4 the early symptoms began. Skin biopsy showed granular osmiophilic deposits (GRODs).Because JNCL with GRODs is caused by mutations in the CNL1 gene, we performed a molecular investigation by direct sequencing of nine exons of the CNL1 gene. This analysis revealed a novel mutation in homozygous form in the exon 7 that caused an aminoacid substitution at codon 222 (Leu → Pro). Direct sequencing of the exon 7 in both parents showed the same substitution in heterozygous form.

A novel point mutation in PMP22 gene in an Italian family with hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited disorder characterized by recurrent sensory or motor dysfunction. In 85% of HNPP cases the genetic defect is a 1.4 Mb deletion on chromosome 17p11.2, encompassing the PMP22 gene. Point mutations in the PMP22 gene responsible for HNPP phenotypes are rare. We investigated a 17-years-old girl who led to our detecting a novel mutation in PMP22 gene. The mutation was also detected in her father and corresponded to a deletion of one tymidine at position 11 in exon2 (c.11delT). This novel mutation creates a shift on the reading frame starting at codon 4 and leads to the introduction of a premature stop at codon 6.

Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia.

Spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin (SPG4), a member of the AAA protein family. A cohort of 34 unrelated Italian patients with pure spastic paraplegia, of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic, were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography. We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia. We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene (one missense mutation, c.1304 C>T; one nonsense mutation, c.807C>A; two frameshift mutations, c.1281dupT, c.1514_1515insATA; and one splicing mutation, c.1322-2A>C). The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44.4%. This study contributes to expand the spectrum of SPG4 mutations in Italian population.

First evidence of a pathogenic insertion in the NOTCH3 gene causing CADASIL

CADASIL (OMIM 125310) is an increasingly recognised adult-onset autosomal-dominant vascular disease that is characterised by recurrent transient ischaemic attacks and strokes (43% of patients), vascular dementia (6%), migraine with aura (40% of patients) and psychiatric disturbances (9% of patients); epilepsy has been reported in 2–10% of subjects.1 All patients revealed prominent signal abnormalities on brain magnetic resonance imaging (MRI)—leukoencephalopathy on T2- and small subcortical infarcts on T1-weighted images.2 The pathological hallmark of CADASIL is a non-amyloid and non-arteriosclerotic angiopathy, which predominantly affects the small penetrating brain arteries. Vascular lesions are characterised by degeneration and loss of smooth-muscle cells and by the presence of granular osmiophilic material (GOM) accumulating within the smooth-muscle-cell basement membrane and the surrounding extracellular matrix. Examination of several peripheral organs revealed vessel changes, including the presence of GOM deposits, providing evidence that CADASIL is a systemic arteriopathy.3 It has been reported that CADASIL is caused by single missense mutations, small in-frame deletions or splice-site mutations in the NOTCH3 gene encoding a transmembrane receptor (http://www.hgmd.cf.ac.uk/ac/gene.php?gene = NOTCH3). Almost all previously reported mutations resulted in an odd number of cysteine residues within one of the 34 epidermal growth factor (EGF)-like repeats in the …

A Simple Method for Diagnosis of Autosomal Recessive Spinal Muscular Atrophy by Denaturing High-Performance Liquid Chromatography

Autosomal recessive spinal muscular atrophy is caused by mutations in the survival motoneuron (SMN ) gene. There are two nearly identical copies of this gene present on chromosome 5q13; however, only the telomeric copy of this gene is affected in spinal muscular atrophy. In this study, we describe a new method to detect SMN gene deletion by denaturing high-performance liquid chromatography, which is also simple to perform but is faster and more specific. (J Child Neurol 2003;18:269—271).