Alessandra Rufa

Cerebrotendinous xanthomatosis: heterogeneity of clinical phenotype with evidence of previously undescribed ophthalmological findings.

Cerebrontendinous xanthomatosis (CTX) is a rare autosomal recessive neurometabolic disease involving lipid metabolism. The classical phenotype is characterized by neurological dysfunction, tendon xanthomas and juvenile cataracts. Other ophthalmological findings have occasionally been reported. To gain more insight into the type and frequency of ophthalmological alterations in this multisystem metabolic disorder, we examined 13 CTX patients. Besides cataracts, found in all cases, the second most frequent ocular abnormality was paleness of the optic disk, which was found in 6 patients and was probably previously underestimated. Signs of premature retinal senescence were also observed. We discuss the possible relation between these ocular manifestations and the metabolic defect.

Differences in saccade dynamics between spinocerebellar ataxia 2 and late-onset cerebellar ataxias.

The cerebellum is implicated in maintaining the saccadic subsystem efficient for vision by minimizing movement inaccuracy and by learning from endpoint errors. This ability is often disrupted in degenerative cerebellar diseases, as demonstrated by saccade kinetic abnormalities. The study of saccades in these patients may therefore provide insights into the neural substrate underlying saccadic motor control. We investigated the different extent of saccade dynamic abnormalities in spinocerebellar ataxia type 2 and late-onset cerebellar ataxias, genetically undefined and with prevalent cerebellar atrophy. Reflexive and voluntary saccades of different amplitude (10°-18°) were studied in seven patients with spinocerebellar ataxia 2, eight patients with late-onset cerebellar ataxia and 25 healthy controls. Quantitative analysis of saccade parameters and measures of saccade accuracy were performed. Detailed neurological, neurophysiological and magnetic resonance imaging assessment was obtained for each patient. Genetic and laboratory screening for spinocerebellar ataxias and other forms of late-onset cerebellar ataxias were also performed. A lower peak saccade velocity and longer duration was observed in patients with spinocerebellar ataxia 2 with respect to those with late-onset cerebellar ataxia and controls. Unlike subjects with spinocerebellar ataxia 2, patients with late-onset cerebellar ataxia showed main sequence relationships to similar saccades made by normal subjects. Saccades were significantly more inaccurate, namely hypometric, in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and inaccuracy increased with saccade amplitude. The percentage of hypometric primary saccades and of larger secondary corrective saccades were consistently higher in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and controls. No other significant differences were found between groups. Two different mechanisms were adopted to redirect the fovea as fast and/or accurately as possible to peripheral targets by the two groups of cerebellar patients. Patients with spinocerebellar ataxia 2 maintained accuracy using slow saccades with longer duration. This reflects prevalent degenerative processes affecting the pontine burst generator and leading to saccade velocity failure. On the other hand, patients with late-onset cerebellar ataxia reached the target with a number of fast inaccurate, mostly hypometric saccades. Different degrees of cerebellar oculomotor vermis involvement may account for differences in optimizing the trade-off between velocity and accuracy in the two groups. In addition, as suggested by spinocerebellar patients having slow saccades that are no longer ballistic, visual feedback might be continuously available during the movement execution to guide the eye to its target.

Systemic Blood Pressure Profile in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Background and Purpose— Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic form of subcortical ischemic vascular dementia (SIVD). The most common vascular risk factors are unremarkable in CADASIL; however, studies on systemic blood pressure (BP) changes over time are substantially lacking. Because BP instability is a relevant risk factor for developing or worsening white matter changes in sporadic SIVD, we aimed to study the BP profile of CADASIL to investigate its relationship with cognitive decline and white matter injury. Methods— Twenty-four–hour ambulatory BP monitoring was performed in a group of 14 CADASIL patients (12 males and 2 females) and in a group of 15 healthy age-matched control subjects. The following BP variables were compared between the 2 groups: mean daytime and nighttime systolic, diastolic, and mean arterial BP (SABPday, DABPday, and MABPday, and SABPnight, DABPnight, and MABPnight) and nocturnal percentage decline in arterial BP (%MABP reduction). Cognitive performances were tested by mini mental status examination (MMSE), and brain MRI was performed to extrapolate the T2-weighted lesion volume (LV) in each CADASIL patient. The 24-hour arterial BP variables were compared between CADASIL and controls. In addition, for CADASIL patients only, MMSE, LV, and age were compared with each pressure variable. Results— Patients with CADASIL showed a significant reduction (P<0.05) of SABPday, DABPday, MABPday and %MABP decline with respect to controls. In addition, MMSE of CADASIL subjects correlated significantly (P<0.0001) with daytime MABP. Conclusions— The low systemic BP profile observed in CADASIL patients was specifically attributable to reduced diurnal BP values. This may further affect cerebral hemodynamics and increase the risk of cognitive impairment in these patients. The pathogenesis of abnormal BP profile in CADASIL remains to be clarified. It is likely that central and peripheral mechanisms controlling BP variations are involved.

Type I Sialidosis: A Clinical, Biochemical and Neuroradiological Study

We report biochemical, morphological and neuroradiological findings in a 40-year-old woman affected with type I sialidosis. The clinical symptoms, consisting of a cerebellar syndrome, were first noted at the age of 17 years. The macular cherry-red spot was first observed after 23 years of disease. A CT scan performed at 21 years of age showed enlargement of the fourth ventricle. Nuclear magnetic resonance imaging of the brain performed at the age of 40 showed severe atrophy of the cerebellum and pontine region; atrophy of cerebral hemispheres and of the corpus callosum was also observed. We emphasize the prolonged course of illness in this patient, observed over a long period of time. Of particular interest is the neuroradiological study showing our findings both at the beginning of the disease and after 20 years.

Two novel HTRA1 mutations in a European CARASIL patient

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary, nonhypertensive cause of recurrent lacunar stroke and cognitive decline associated with alopecia, spondylosis deformans, and lumbago.1 The disease has been linked to mutations in the HTRA1 gene, encoding for serine protease HTRA1, loss of which causes dysregulation of transforming growth factor-β signaling.2

A case of ethambutol-induced optic neuropathy harbouring the primary mitochondrial LHON mutation at nt 11778

Sirs: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited form of acute central visual loss that occurs predominantly in healthy young men. Several mitochondrial point mutations associated with the disease have been described, but the pathogenetic link between the genetic defect, environmental factors and the disease is still poorly understood. The influence of several toxic, nutritional and genetic factors on onset and evolution of LHON has been debated [1, 3–5, 9]. Recent studies indicate the presence of primary point mutations that are pathogenetic and secondary mutations whose role is still unclear [5]. We report a case of ethambutol-induced optic neuropathy in a patient carrying the 11778 LHON mutation. The patient is a 53-year-old man who had been healthy until the age of 51, when he developed pulmonary tuberculosis (TBC). He was treated with ethambutol (1500 mg/day) and isoniazid (200 mg/day) for 10 months, and streptomycin (1000 mg/day) for 1 month. After 8 months of therapy the patient developed a subacute bilateral visual loss diagnosed as toxic retrobulbar neuritis. The drug therapy was discontinued. The family history revealed that a maternal uncle, deceased at 60 years, had developed a severe, irreversible visual loss with subacute onset at the age of 20 years. For further evaluation, the patient was admitted to our department. Neurological examination was normal except for the presence of mild bitemporal pallor of the optic discs, more evident in the right eye. Routine blood chemistry, creatine-kinase, aldolase, carnitine, lactic and pyruvic acid, vitamin E, vitamin B12, folic acid levels and lysosomal enzymes were normal. Electromyogram (EMG), nerve conduction velocities, brainstem auditory evoked resfouces (BAERs) and electrocardiogram (ECG) were normal. Visual evoked potentials were severely reduced in the right eye and absent in the left eye. The best corrected visual acuity was 20/40 in the right and 8/200 in the left eye. Slight temporal pallor and circumpapillary microangiopathy, more evident in the left eye, were noted. Fluorescein angiography in the early phase demonstrated increased tortuosity of vessels around the disc without dye leakage. Molecular analysis of mitochondrial DNA demonstrated a homoplasmic mutation at nt 11778. Other primary mutations at nt 3460 and nt 14484 [8] were absent. Two years after suspension of therapy, in spite of a subjective partial improvement, visual acuity was substantially unchanged. Visual evoked potientals did not show any recovery. The 11778 mtDNA mutation is one of the so-called primary mutations and accounts for over 50% of LHON probands [5]. All studies to date have shown that recovery of bilateral optic neuropathy, when caused by the mt 11778 mutation, is exceptional [1, 8]. Although exclusively found in affected families, the presence of a primary LHON mutation does not necessarily imply that a patient will develop the disease [6–8]. Our patient developed bilateral optic neuropathy after 8 months of drug therapy for pulmonary tuberculosis. Ethambutol by itself can cause optic neuropathy, which is usually reversible after discontinuation of therapy. The development of visual loss is dosage-dependent; the dose received by the patient (20 mg/kg per day) is estimated to produce a risk of optic neuropathy lower than 5% [2]. The pathogenesis of LHON is still unclear, and several toxic, nutritional, autoimmune and genetic factors have been proposed as precipitating factors, presumably as additional stressors on an already compromised mitochondrial energy production system [1, 3, 4, 7, 9]. To our knowledge, an association between ethambutol therapy and Leber’s optic neuropathy has not been described before. In our patient, both ethambutol and the 11778 mutation have a role in the pathogenesis of optic neuropathy. It is difficult, at the moment, to determine which one was the primary trigger. In conclusion, this case is an example of the interaction of exogenous toxic and genetic factors in the manifestation of clinical symptoms. It suggests that a full history and neurogenetic analysis may help in diagnosis and therapy.

CT and MRI of Wernicke’s encephalopathy

The purpose of this pictorial essay is to present the computed tomography (CT) and magnetic resonance imaging (MRI) findings of Wernicke’s encephalopathy, a rare, severe, acute neurological syndrome due to thiamine (vitamin B1) deficiency, associated with high morbidity and mortality. The classical clinical triad, which includes ocular signs, altered consciousness and ataxia, can be found in only one-third of patients. Although chronic alcoholic patients are the most commonly affected, Wernicke’s encephalopathy may complicate malnutrition conditions in nonalcoholic patients, in whom it is greatly underestimated. CT and above all MRI of the brain play a fundamental role in diagnosing the condition and ruling out other diseases. MRI is the most sensitive technique and is required in all patients with a clinical suspicion of Wernicke’s encephalopathy. Medial thalami, mamillary bodies, tegmentum, periaqueductal region, and tectal plate are typical sites of abnormal MRI signal. The dorsal medulla, red nuclei, cranial nerve nuclei, cerebellum, corpus callosum, frontal and parietal cerebral cortex are less common sites of involvement although they are more frequently affected in nonalcoholic patients. Paramagnetic contrast material may help to identify lesions not otherwise visible.RiassuntoLo scopo di questa rassegna iconografica è presentare i possibili reperti alla tomografia computerizzata (TC) e alla risonanza magnetica (RM) dell’encefalopatia di Wernicke, una rara grave sindrome neurologica acuta da deficit di tiamina (vitamina B1), con elevate morbilità e mortalità. La triade sintomatologica classica comprende disturbi oculari, alterazioni della coscienza e atassia, ma si presenta soltanto in un terzo dei pazienti. L’encefalopatia di Wernicke colpisce più frequentemente soggetti etilisti cronici, ma può complicare molte condizioni di malnutrizione in soggetti non-etilisti cronici, nei quali è spesso sottostimata. Lo studio dell’encefalo mediante TC e, soprattutto, RM riveste un ruolo fondamentale nell’orientamento diagnostico e nell’esclusione di altra patologia. La RM presenta elevata sensibilità e deve quindi essere eseguita in tutti i pazienti con sospetto clinico di encefalopatia di Wernicke. Le sedi tipiche di alterazione del segnale RM sono nuclei mediali del talamo, corpi mammillari, tegmento, sostanza grigia periacqueduttale e lamina quadrigemina. Sedi meno tipiche di interessamento, e più frequentemente coinvolte nei pazienti non-etilisti, sono la porzione dorsale del bulbo, il nucleo rosso e i nuclei dei nervi cranici, il cervelletto, il corpo calloso e la corteccia fronto-parietale. Il mezzo di contrasto paramagnetico può mostrare la presenza di lesioni non altrimenti evidenti.

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.

Plasma Levels of Asymmetric Dimethylarginine in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarct and Leukoencephalopathy

Background: Asymmetric dimethylarginine (ADMA) is a marker of endothelial dysfunction and a new independent risk factor for adverse cerebrovascular events in small vessel disease. Conversely, L-arginine (LARG) may have a protective role. Methods: To assess ADMA, LARG levels and LARG/ADMA ratio in 16 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and normal controls, and to look for possible correlations with white matter changes. Plasma levels of ADMA and LARG were assayed by high-performance liquid chromatography in all subjects. The overall T1 and T2 lesion load was obtained from brain MRI of patients with CADASIL. Results: ADMA plasma concentrations (1.5 ± 2.0 µM) were significantly higher (p < 0.05) in CADASIL patients than in controls (0.35 ± 0.075 µM). Analyzing only CADASIL subjects, an inverse borderline-significant correlation was found between LARG/ADMA (190 ± 20) and T2-weighted lesion volumes (57.9 ± 46.5; r = –0.578, p = 0.024). Conclusion: Our results may indicate the possible coexistence of endothelial dysfunction in CADASIL patients, broadening the range of potentially pathogenetic mechanisms in this disease and providing insights for future therapeutic strategies.

Spastic paraplegia in ‘dominant optic atrophy plus’ phenotype due to OPA1 mutation

Sir, We read the papers by Yu-Wai-Man et al. (2010) and Marelli et al. (2011) with much interest. The authors described three families with dominant optic atrophy plus phenotype due to OPA1 mutations presenting spastic paraplegia among the extra-ocular neurological features. Two families, reported by Yu-Wai-Man et al . (2010), harboured a deletion c.876-878del(TGT) and a nonsense GTPase mutation c.899C>T, respectively, both resulting in premature termination codons. The affected members presented neuropathy in addition to spastic paraplegia and dominant optic atrophy. Marelli et al. (2011) described a third family in which a missense mutation c.1652G>A in the dynamin domain was associated with Behr syndrome. We report here, a patient in whom a deletion c.2708_2711delTTAG of OPA1 was associated with dominant optic atrophy, spastic paraplegia, Duane retraction syndrome, migraine with atypical aura, patent foramen ovale and muscle fibre abnormalities. Considering the previous reports, we extend the mutations of OPA1 as possibly responsible for dominant optic atrophy plus phenotypes presenting spastic paraplegia, and identify some features shared by patients with optic atrophy plus and spastic pyramidal involvement. The proband, a 28-year-old Italian female belonging to a family from Sicily, has suffered from loss of central vision due to optic atrophy since childhood. She was referred to our unit for the onset, appeared a few years earlier, of slowly progressive …