Francesco Sicurelli

A Rett syndrome MECP2 mutation that causes mental retardation in men

Objective: To characterize the clinical features of a new type of X-linked mental retardation associated with MECP2 mutation in the index family. Background: MECP2 mutations, originally described in a high percentage of patients with classic Rett syndrome, were considered lethal in men. The authors recently described a novel A140V MECP2 missense mutation in an Italian family with X-linked semidominant mental retardation. Methods: The neurologic features of six symptomatic relatives (two women and four men) carrying the mutation were compiled. Laboratory investigations included EEG, EMG, conduction velocity (CV) of peripheral nerves, brain MRI, and 1H-MR spectroscopy. Results: Mental retardation and signs of neurologic impairment were present in all the affected members, but more pronounced in men. Neurologic features included slowly progressive spastic paraparesis/pyramidal signs (6/6), distal atrophy of the legs (6/6), ataxia (2/6), and postural tremor of the hands (3/6). Speech was preserved (6/6) but was dysarthric in the oldest brothers (2/6). Mild dysmorphic features were present in all cases. Conclusion: The neurologic disorder associated with A140V MECP2 mutation is not necessarily lethal in men, but they are more severely affected than women of the same family.

Cerebrotendinous xanthomatosis: 11-year treatment with chenodeoxycholic acid in five patients. An electrophysiological study

We report the electrophysiological follow-up of five cerebrotendinous xanthomatosis patients treated for 11 years with chenodeoxycholic acid (CDCA). Nerve conduction velocity (NCV) was reduced in three cases. P100 latency of visual evoked potentials was delayed in four cases, interpeaks I-III and I-V of brainstem auditory evoked potentials (BAEPs) was increased in two and interpeak N13-20 of upper limb somatosensory evoked potentials (SEPs) was slowed in one. After 4 months of therapy with CDCA, NCV was normal and did not show any significant change during the 11 years of observation. Central motor conduction time of motor evoked potentials (MEPs) and N24-P40 interpeak latency of lower limb SEPs were increased in five and four cases, respectively, in spite of 2/3-year treatment with CDCA. Improvement of evoked potentials, especially of MEPs and SEPs, was slower and continued over the whole 11-year period. The size of xanthomas slightly decreased in some patients during treatment and the clinical manifestations stabilized, avoiding progressive worsening, but there was no significant improvement in neurological deficit. Two sisters of patients who never took CDCA showed progressive worsening of clinical manifestations, upper limb SEPs and BAEPs.

Protocol of outcome evaluation for surgical release of carpal tunnel syndrome.

OBJECTIVETo propose and apply a protocol for assessing the outcome of surgery for carpal tunnel syndrome. METHODSThe protocol included a patient questionnaire that was self-administered before and 1 and 6 months after the operation to assess severity of symptoms (Boston questionnaire) and staging according to clinical (Giannini) and electrophysiological (Padua) severity scales. RESULTSThe results of a prospective series of 323 hands undergoing surgery for carpal tunnel syndrome by the mini-incision of the palm technique are reported. CONCLUSIONThe method was found to be valid, precise, reliable, and straightforward, enabling a comparison of the results from different patient series and different operating techniques.

Spinocerebellar Ataxia Type 2 (Sca2) Associated with Retinal Pigmentary Degeneration

Autosomal dominant spinocerebellar ataxias (SCAs) are a clinical and molecular heterogeneous group of neurodegenerative disorders caused by expansion of an unstable CAG (polyglutamine) trinucleotide repeat. The cloning of the genes responsible and the characterization of the mutation now permit a reliable diagnosis. A wide spectrum of clinical phenotypes has been observed within families with the same genotype, and common pathologic and phenotypic features can be produced by different genetic abnormalities. A new classification based on clinical and molecular findings has recently been proposed [1]. Specific ocular findings contribute to the characterization of different SCA phenotypes and retinal dystrophy is well known to be associated with the SCA7 phenotype [2]. We describe a family with dominant ataxia associated with a SCA2 mutation in which the index case presented with retinal degeneration. The patient is a 48-year-old woman who presented at 28 years of age with night blindness. At the age of 32 years she began to have gait instability, speech difficulty and hearing loss. She was first admitted to our department at 36 years of age. Neurological examination showed severe gait ataxia, dysarthria, hypotonia and hyperreflexia. An ocular motility study demonstrated a considerable alteration in the fast component, saccades were slow especially in the vertical plane, pursuit was moderately decreased, and the vestibular ocular reflex was intact. Typical retinitis pigmentosa, optic atrophy and macular changes were observed on fundoscopy. Bright flash electroretinogram (ERG) in a full dark-adapted state was not recorded in either eye. A slight sensory neuropathy was evident on EMG. CT scan of the brain showed cerebellar atrophy. Because of the presence of other cases in the family, who had already died, with gait disturbances and not well-defined ocular impairment, hereditary dominant ataxia was diagnosed. Polymerase chain reaction analysis of the CAG repeats of the SCA7 gene was performed, but the alleles were found to be in the normal size range. The SCA2 mutation subsequently tested showed one expanded allele of 41 CAG. Clinical examination and molecular analysis were extended to the other family members: the only younger symptomatic brother and her 2 asymptomatic children. The 45-year-old brother had complained of mild gait instability since the age of 30 years. Neurological examination showed mild ataxia, dysarthria and slow saccades. MRI showed cerebellar atrophy. Slight sensory neuropathy was evident on EMG. Fundoscopy was normal. ERG disclosed a slight a and b wave amplitude reduction. Molecular analysis revealed 41 CAG repeats in the SCA2 expanded allele. Neurological examination of both children (a 27year old female and a 25-year-old male) showed hypotonia, mild instability of gait and slow saccades which was more evident in the son. Normal fundoscopy associated with a regular retinal response on ERG and cerebellar atrophy on MRI were observed in both children. Molecular analysis revealed a SCA2 expanded allele of 38 CAG and 43 CAG repeats, respectively. The ocular involvement in SCA2 is typically characterized by severe impairment of the fast eye component, and saccadic system is much more compromised [3]. Optic atrophy and retinal degeneration are not usually considered part of SCA2 phenotype [4]. The exact mechanism behind retinal dystrophies following SCAs mutations is still unknown, but polyglutamine-related toxicity has been proposed as cause of photoreceptors and ganglion cell damage in the SCA7 phenotype [5, 6]. The presence of retinal dystrophy, associated with hereditary ataxia was suggestive of an underlying common pathogenetic mechanism in the index case. Although evident, retinal pigmentary changes were not seen in the symptomatic brother, a decreased ERG response was suggestive of mild retinal involvement. Further examination should be necessary in all affected members. Babovic-Vuksanovic et al. [7] described retinitis pigmentosa associated with an extreme CAG repeat expansion in an infant with SCA2. ERG alterations have been reported in 6 patients with the SCA1 mutation without retinal changes [8], and optic atrophy has even been reported as an atypical finding in SCA1 patients [9]. In conclusion, our family suggests that: (1) although retinal degeneration is part of the SCA7 phenotype, other SCA mutations should be screened for when the SCA7 molecular investigation is negative, and (2) the clinical heterogeneity within families is often not only related to the CAG expansion size. As recently suggested by Subramony and Filla [10], the specific diagnosis of a SCA subtype on a clinical basis alone is often prone to error.

Peripheral neuropathy in CADASIL

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary cerebral microangiopathy associated with mutations in the Notch 3 gene. The clinical phenotype is characterized by cerebral impairment even though typical microvascular changes are diffuse.ObjectiveTo assess peripheral neuropathy in patients with CADASIL.Patients and MethodsWe enrolled eleven CADASIL patients with variable phenotype including clinical signs of peripheral nerve involvement. In all patients electromyography and nerve conduction velocities were performed. Peripheral nerve biopsy was performed in three cases.ResultsWe found sensory motor neuropathy in 7/11 patients. Nerve biopsy revealed axonal and demyelinated findings.ConclusionOur findings suggest that peripheral neuropathy may be part of the CADASIL phenotype.

Lung involvement in Niemann-Pick disease type C1: improvement with bronchoalveolar lavage

AbstractProgressive lung infiltration is a major cause of death in Niemann–Pick disease type A and B (NPA, NPB) and in the recently defined type C2. In type C1 (NPC1), the main manifestations are neurological. We report a patient with a classic, neurological, late infantile form of NPC1 disease, carrying the mutation P474L and the variant I642M in the NPC1 gene, who suffered recurrent respiratory manifestations. Bronchoalveolar lavage of a lung segment due to deteriorating respiratory condition revealed many foamy macrophages and was followed by an improvement in symptoms. Pneumopathy may therefore be considered a feature of NPC1 disease for which a partial bronchoalveolar lavage could be a useful treatment.

Rapidly progressive neurodegeneration in a case with the 7472insC mutation and the A7472C polymorphism in the mtDNA tRNAser(UCN) gene

The authors report the clinical, neuroimaging, muscle biopsy and mtDNA findings in a patient affected by bilateral hearing loss and mental retardation since infancy, presenting at age 31 years with a rapid deterioration of mental status and ataxia leading to vegetative condition and death at the age of 32 years. Clinical and genetic studies have been also performed in the mother, affected by neurosensorial hearing loss. Muscle biopsy showed severe mitochondrial alterations in the propositus and evidence of mitochondrial alterations in his mother. Direct mtDNA sequencing in all family members revealed the known 7472insC mutation and the recently described A7472C sequence variation in the tRNA(Ser(UCN))gene. RFLP-PCR confirmed the heteroplasmic nature of the two mutations and failed to find the second transversion in 200 controls. The percentage of mutant genomes harbouring 7472insC ranged from 3 to 7% in asymptomatic family members to 70% in the proband and his mother, whereas the percentage of A7472C mutant genomes was about 90% in all maternal relatives except the proband (56%) and his sister (5%). In conclusion, this is the first report of a rapidly progressive encephalopathy in association with the 7472insC mutation in mtDNA, combined with an A>C variation at the same nucleotide with a possible suppression effect on the pathogenic mutation.

Leukoencephalopathy as a rare complication of hepatitis C infection.

We report the case of a 64-year-old female patient with hepatitis C infection (HCV), who developed Sjögren’s disease and sensory peripheral neuropathy. Clinical conditions worsened over three years with central nervous system involvement characterised by transient third cranial nerve paresis and mild selective impairment of attention and memory. Brain magnetic resonance imaging showed diffuse periventricular and lobar white matter hyperintensity. Laboratory findings included mixed cryoglobulinaemia (type II), cryocrit 1.47%, low serum levels of complement C4 and high levels of rheumatoid factor, HCV 1b genotype, high HCV mRNA levels in serum and cerebrospinal fluid. Skin biopsy showed evidence of vasculitis. After one year of plasmapheresis, immunosuppressant therapy and occasional corticosteroid treatment, neurological symptoms improved, skin biopsy changed and inflammation parameters normalised, suggesting that neurological symptoms might be related to the high levels of mixed cryoglobulins.

Peripheral neuropathy in late-onset Krabbe disease: report of three cases

Late-onset Krabbe disease may have variable misleading clinical manifestations and be a puzzling problem for physicians. We report clinical and peripheral nerve studies of three patients with adult-onset Krabbe disease. Two cases had a predominantly spastic paraparesis; in one case, the symptoms mimicked a cerebrovascular disorder. Predominantly, demyelinating neuropathy was observed in one case and axonal neuropathy in two cases. In all cases, no typical intracytoplasmic inclusions were found. These observations suggest that peripheral neuropathy in adult-onset Krabbe disease has variable clinical and pathological characteristics, different from those described in the classic form.

Recurrent venous thrombosis including cerebral venous sinus thrombosis in a patient taking sildenafil for erectile dysfunction

Acquired or hereditary prothrombotic risk factors may lead to cerebral venous sinus thrombosis (CVST), particularly when other predisposing factors coexist. A 57-year-old man experienced right leg deep venous thrombosis, severe thrombosis of the haemorrhoid plexus and CVST over a 12-month period during which he was taking sildenafil regularly twice a week. Sildenafil is a phosphodiesterase 5 (PDE5)-inhibitor used for erectile dysfunction (ED). A slight reduction in antithrombin III and free protein S levels was demonstrated. After suspension of sildenafil and six months on oral anticoagulants, clinical improvement was obtained. Recurrent venous thrombosis, including CVST, may complicate prolonged treatment with PDE5-inhibitors in subjects at risk. Periodic monitoring of clotting factors is recommended in these subjects.