Arcamone Federico

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.

Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts

Reported are the clinical, neuroradiologic, and molecular findings in 18 patients with megalencephalic leukoencephalopathy and subcortical cysts (MLC) syndrome. Marked clinical intrafamilial and interfamilial variability in mutation-proven cases was found. A broad spectrum of pathogenetic mutations (missense, splice site, insertion, and deletions) were identified in the MLC1 gene, enlarging the spectrum of allelic variants without a straightforward genotype–phenotype correlation. Five patients did not harbor mutations in MLC1, supporting the existence of at least one other MLC locus.

Diffuse structural and metabolic brain changes in Fabry disease.

AbstractObjectivesTo assess structural and metabolic brain changes in subjects affected by Fabry disease (FD) or carrying the disease mutation.BackgroundFD is an X–linked metabolic disorder due to α-galactosidase A deficiency, which leads to storage of glycosphingolipids in many tissues and organs. Previous MR studies have shown structural and metabolic brain abnormalities in FD patients. It is not clear, however, whether tissue damage can be seen in both the brains of hemizygous and heterozygous and whether quantitative MR metrics are useful to monitor disease evolution.Design/MethodsWe studied 4 males and 4 females with FD. Each subject underwent brain proton MRI/MR spectroscopic imaging (MRSI) examinations to obtain measures of total brain volumes, total brain lesion volumes, magnetization transfer ratios (MTr) in WM and central brain levels of N–acetylaspartate (NAA) to creatine (Cr). A second MR examination was performed in five subjects after 2 years.ResultsFocal WM lesions were found in 2 males and 1 female. The MTr values were always low in the WM lesions of FD subjects (p < 0.001) and also were low in the normal–appearing WM of 2 affected males. Total brain volumes were never decreased in FD subjects. Brain NAA/Cr values were significantly (p = 0.005) lower in FD subjects than in normal controls and correlated closely with Rankin scale measures (r = –0.79). On follow–up examinations, no significant MR changes were found. However, the small changes in NAA/Cr correlated closely with changes in Rankin scores (r = –0.86).ConclusionsSubtle structural and metabolic tissue damage can extend beyond WM lesions in FD subjects. Diffuse brain NAA/Cr decrease can be found in FD subjects in relation to the degree of their CNS involvement and its evolution over time.

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.

Tarlov cysts: Clinical evaluation of an italian cohort of patients

Tarlov cyst syndrome is a rare, often asymptomatic disorder, characterised by isolated or multiple nerve-root cysts, usually occurring in the sacral spine, near the dorsal root ganglion, between the perineurium and endoneurium. The cysts may cause lower back pain, sacral radiculopathy, dyspareunia and urinary incontinence. There is little data in the literature on the relationship between Tarlov cysts and symptoms. Here, we report further details on the clinical impact of Tarlov cysts and investigate their pathogenesis and role as a cause of lumbosacral symptoms. We examined 157 patients with MRI evidence of symptomatic Tarlov cysts. Patients underwent complete neurological examination and were scored by the Hamilton Depression Rating Scale and the Visual Analogue Scale. Complete lower limb electromyography was performed in 32 patients. Clinical picture was correlated with size and number of cysts detected by MRI. Family history was recorded for signs of genetic inheritance. Almost all patients suffered perineal or lower back pain; 34 complained of sphincter and 46 of sexual disorders. Hamilton scores were abnormal, and family history was positive in a few cases. The scanty literature on Tarlov cysts mainly regards therapy by a neurosurgical approach. Our results provide new data on clinical impact and possible pathogenetic mechanisms.

Peripheral neuropathy in vanishing white matter disease with a novel EIF2B5 mutation

The authors describe an infant with vanishing white matter disease with demyelinating peripheral neuropathy. Sequence analysis of EIF2B5 gene showed that the patient was a double heterozygote, with novel missense mutation CGA→CAA in codon 269 of exon 6, resulting in the replacement of an arginine residue with glutamine.

Prominent brain axonal damage and functional reorganization in “pure” adrenomyeloneuropathy

Background: Cerebral involvement is usually absent in pure adrenomyeloneuropathy (AMN). Recently, nonconventional MR studies have reported brain abnormalities in patients with pure AMN, providing evidence that occult cerebral involvement may occur in this disease. It remains unclear, however, whether these brain abnormalities reflect centripetal extension of spinal cord long-tract axonopathy or can be the expression of a pathologic process largely involving the brain. Methods: Conventional MRI and proton MR spectroscopic imaging (1H-MRSI) data of four patients with pure AMN were compared to those of four men with spinal cord injury (SCI) and 10 age-matched healthy men (HM). Resonance intensity areas of N-acetylaspartate (NAA) and choline were calculated as ratios to creatine (Cr) in voxels located in white matter (WM) regions. Functional MRI (fMRI) data during simple motor task were obtained in a separate session in three patients with AMN and three age-matched HM. Results: Conventional MRI examinations were normal in all patients. On 1H-MRSI, NAA/Cr values were lower in all WM regions of patients with AMN than in those of patients with SCI (p < 0.05) and HM (p < 0.01). In contrast, patients with SCI showed NAA/Cr values lower than HM only in the periventricular WM (p = 0.04). At fMRI, patients with AMN showed a more pronounced activation than HM in all movement-associated cortical regions contralateral to the hand moved and an exclusive voxel activation of the primary motor, somatosensory, and posterior parietal cortices ipsilateral to the hand moved. Conclusions: CNS damage in pure adrenomyeloneuropathy is not confined exclusively to spinal cord and seems to primarily involve the brain. GLOSSARY: 1H-MRSI = proton MR spectroscopic imaging; AC = anterior commissure; AMN = adrenomyeloneuropathy; BOLD = blood oxygenation level dependent; BR = brisk reflexes; Cho/Cr = choline to creatine ratio; Cr = creatine; DTI = diffusion tensor imaging; EA = endocrine abnormalities; FLAIR = fluid-attenuated inversion recovery; fMRI = functional MRI; FMRIB = Functional Magnetic Resonance Imaging of the Brain; FILM = FMRIB’s improved linear model; Fr-WM = frontal WM; HM = healthy men; Lac = lactate; MD = motor deficits; NAA = N-acetylaspartate; Naa/Cr = N-acetylaspartate to creatine ratio; PC = posterior commissure; PD = proton density; Post-WM = deep posterior WM; Pv-WM = periventricular WM; SA = sensory abnormalities; SCI = spinal cord injury; SP = spastic paraparesis; Sph Dis = sphincteric disturbances; VLCFA = very-long-chain fatty acids; VOI = volume of interest; WM = white matter.

Cavernous sinus syndrome due to neurosarcoidosis in adolescence: a diagnosis not to be missed

Cavernous sinus syndrome (CSS) is a pathological condition characterized by usually unilateral painful ophthalmoplegia associated with headache, diplopia, ptosis, pupillary changes, trigeminal nerve dysfunction and retroorbital pain. Primitive or metastatic malignancies, vascular abnormalities and inflammatory processes are the most common causes of CSS [1]. Differential diagnosis between the various conditions may be tangled; in this respect, laboratory and brain MRI findings are discriminatory [2]. We describe here a rare case of unilateral CSS as the presenting sign of neurosarcoidosis in adolescence. A 16-year-old female referred to our neuro-ophthalmological outpatient service for right ptosis, non-reacting midriasis, pain during eye movements, cephalalgia, and diplopia. She also referred mild exertional dyspnea and fatigue in the last months. Neurological and neuro-ophthalmological examinations showed complete right III cranial nerve palsy with non-reacting midriasis, congested right optic disc with a normal neurorim, in absence of other neurological defects. Visual field was normal, while visual evoked potential showed delayed latency of P100 in the right eye. Head MRI (Fig. 1) showed a pachymeningeal thickening of the right cavernous sinus region, extending toward ipsilateral orbital fissures and oval foramen, and an analogous focal pachymeningeal thickening in both the temporal regions. All these lesions showed gadolinium enhancement. Autoimmune screening, thyroid function, hematological testing and Mantoux reaction were normal. While serum ACE and lysozyme dosage were in the normal range, serum chitotriosidase was increased (64 nmol/h/ml, cut-off limit 48.8 nmol/h/ ml) [3]. Cerebrospinal fluid (CSF) analysis and investigation for Mycobacterium tuberculosis, neurotropic viruses and culture for bacteria were negative. Pulmonary function tests (PFTs) were normal, but diffusing capacity of lung for carbon monoxide (DLCO) was reduced (57% of predicted). Chest high-resolution CT scan (HRCT) showed a mild parenchymal involvement with peripheral and perifissural micronodules suggestive of sarcoidosis. Bronchoalveolar lavage (BAL) revealed an increased percentage of lymphocytes with high CD4/CD8 ratio (macrophages 46.5%, lymphocytes 46.5%, neutrophils 3.5%, eosinophils 3%, basophils 0.5%; CD4/CD8 lymphocytes ratio 3.98). Therefore, diagnosis of pachymeningeal and lung sarcoidosis was considered consistent and pulsed intravenous corticosteroid therapy (1 g/day) for 5 days, followed by oral therapy, was introduced. The therapy achieved a rapid, marked and durable improvement of symptoms. Six-month follow-up showed resolution of all clinical aspects, with only remaining reactingmidriasis, complete disappearance of meningeal thickening at MRI and DLCO improvement (70% pred.). Steroid therapy was tapered till complete suspension 24 months F. Rosini and D. Bennett equally contributed to the present paper.

Eye movement abnormalities in a patient with Zellweger spectrum disorder

Dear Sir, Zellweger spectrum disorders (ZSDs) are included in peroxisomal biogenesis disorders, a wide spectrum of diseases due to mutations in genes (PEX), leading to loss of peroxisomal metabolic functions. ZSDs have an autosomal recessive transmission and encompass a continuum of three different phenotypes, i.e. Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. The onset is in the newborn period or later in childhood. Though the prognosis is usually poor, milder phenotypes with clinical heterogeneity have been reported [1]. Visual system abnormalities, including retinal degeneration, optic nerve atrophy, cataracts, corneal changes and glaucoma are commonly described in ZSDs [2]. Moreover, pendular nystagmus (PN) is almost always present [3]. However, given the precocious appearance of hypovision and the usually young age of the patients, little is known about quantitative eye movements features in the various phenotypes of ZSDs. We examined the eye movements features of a 56-yearold man, already diagnosed as having a peculiar mild phenotype of ZSD caused by two heterozigous mutations of the PXMP3 (PEX2) gene (c.355 C[T (p.Arg119X) and c.865_866insA (p.Ser289-LysfsX36), with onset at age 3 years and slow progression. Neurological examination showed predominant cerebellar signs as gait ataxia, dysartria, dysmetria, and gaze-evoked nystagmus, mild retinopathy and bilateral neurorim pallor with preserved good visual acuity, hypoacusia, generalized areflexia, and bilateral pes cavus; brain MRI revealed marked atrophy of cerebellum, cerebellar peduncles and brainstem, particularly of pons, and moderate atrophy of the supratentorial regions, with no signal abnormalities in the white matter. Patient’s detailed clinical and biochemical aspects have already been described [1]. Eye movements were recorded by means of an eye tracker device (ASL 504, Applied Science Laboratories, Bedford, MA, USA). An interactive procedure based on nine static points of calibration was performed to ensure a minimization of spatial error. The subject’s head movements were minimized by a chinrest. We recorded horizontal (target of 10 and 18 of amplitude) and vertical (8 ) visually guided saccades, elicited, after the disappearance of the central fixation target (1500 ms) and a period of Gap (200 ms), by a peripheral target appearing randomly at left–right or up–down position for 1500 ms. The antisaccade task was analogous to the horizontal visually-guided task, but the subject had to make a saccade opposite to the target. In the fixation task, the patient was required to hold his eye still in response to target in central (90 s) and eccentric (10 –18 , 15 s each) position. Standard saccadic parameters of horizontal and & A. Rufa rufa@unisi.it

Hydroxychloroquine neuromyotoxicity: a case with rapid course and complete recovery

Hydroxychloroquine (HCQ), a 4-aminoquinoline, with addition of a hydroxyl group initially used as antimalarial agent, is now mainly utilized for the long-term management of rheumatological disorders such as rheumatoid arthritis (RA) and lupus erythematosus (SLE). Its toxicity against retina, heart, skin, nervous system and muscle is documented [1]. HCQ myopathy may onset from months (at least six) to years after drug intake with symptoms characterized by aspecific mild to moderate proximal muscle weakness with normal or slightly increased creatine kinase (CK) levels [2– 5]. We report a case of severe neuromyopathy with a very early diagnosis, rapid and complete recovery followed 2 weeks after HCQ discontinuation. A 63-year-old Italian woman was referred to us for severe and generalized weakness, with more evident involvement of lower limbs, progressing from 3 weeks, associated with gait disturbance and falls. The patient, with a history of rheumatoid arthritis, has been treated with HCQ for the last 2 months (from September to November 2013, 200 mg twice a day). In the previous 4 years, she assumed Salazopyrin with poor improvement. She received also ramipril and bisoprolol for hypertension from many years. Family history was negative for neuromuscular disorders. On admission to our Department, the patient complained tingling of distal districts of all limbs and diffuse wasting. Neurological examination presented waddling gait, possible with unilateral support. Muscle strength evaluated in proximal and distal muscles of the upper and lower limbs (graded according to the Medical Research Council scaleMRC), showed severe muscle weakness mainly at the girdles (2/5 vs 1/5 at upper limbs and 4/5 vs 2/5 at lower limbs, in distal and proximal district, respectively). Deep tendon reflexes were normal in the upper limbs, decreased in the lower. Serum CK, lactate dehydrogenase (LDH) and aldolase levels were normal. Nerve conduction velocity study (NCS) showed mild multiple mononeuropathies of the sensory median and sural nerves and motor tibial nerve. Standard needle electromyography (EMG) of trapezius, deltoid, brachial biceps, rectus femoris and tibialis anterior muscles showed myopathic pattern (polyphasic motor unit action potentials of short duration and low amplitude, and early recruitment at full effort). Deltoid muscle biopsy showed variation in fiber sizes with rare regeneration. Ultrastructural analysis detected diffuse agglomerates of lipofuscin-like membrane-bound electron-dense material (Fig. 1). Suspecting an iatrogenic myopathy, HCQ was discontinued and replaced with Salazopyrin. Two months (February 2014) later the patient referred a rapid improvement of all symptoms; neurological examination showed recovery of muscle strength in all districts, with evidence only of mild weakness to the upper right limb that completely disappeared in June 2014 (MRC in proximal and distal & A. Federico federico@unisi.it