Silvio Peluso

Antiphospholipid-Related Chorea

Chorea is a movement disorder which may be associated with immunologic diseases, in particular in the presence of antiphospholipid antibodies (aPL). Choreic movements have been linked to the isolated presence of plasmatic aPL, or to primary, or secondary antiphospholipid syndrome. The highest incidence of aPL-related chorea is detected in children and females. The presentation of chorea is usually subacute and the course monophasic. Choreic movements can be focal, unilateral, or generalized. High plasmatic titers of aPL in a choreic patient can suggest the diagnosis of aPL-related chorea; neuroimaging investigation does not provide much additional diagnostic information. The most relevant target of aPL is β2-glycoprotein I, probably responsible for the thrombotic manifestations of antiphospholipid syndrome. Etiology of the movement disorder is not well understood but a neurotoxic effect of aPL has been hypothesized, leading to impaired basal ganglia cell function and development of neuroinflammation. Patients affected by aPL-related chorea have an increased risk of thrombosis and should receive antiplatelet or anticoagulant treatment.

Benign hereditary chorea: Clinical and neuroimaging features in an Italian family†

Benign hereditary chorea is an autosomal dominant disorder characterized by early onset nonprogressive chorea, caused by mutations of the thyroid transcription factor‐1 (TITF‐1) gene. Clinical heterogeneity has been reported and thyroid and respiratory abnormalities may be present. We describe 3 patients of an Italian family carrying the S145X mutation in the TITF‐1 gene with mild motor delay, childhood onset dyskinesias, and subtle cognitive impairment. A child in the third generation presented with congenital hypothyroidism and neonatal respiratory distress. Imaging studies in 2 patients showed mild ventricular enlargement and empty sella at magnetic resonance imaging and hypometabolism of basal ganglia and cortex at 18‐Fluoro‐2‐deoxy‐glucose positron emission tomography.

TBC1D24 genotype–phenotype correlation: Epilepsies and other neurologic features

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.

The LRRK2 R1441C mutation is more frequent than G2019S in Parkinson's disease patients from southern Italy.

Mutations in the leucine‐rich repeat kinase 2 gene are the most frequent cause of familial and sporadic Parkinsons disease, and G2019S is the most common leucine‐rich repeat kinase 2 mutation across several Mediterranean countries.

The Multiple Faces of Spinocerebellar Ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin‐2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin‐2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin‐2 plays a fundamental role in maintenance of neuronal homeostasis.

The magnetic apraxia of Denny-Brown

Motor apraxia is traditionally defined as a disorder compromising the production of skilled movements. Magnetic apraxia represents a specific subtype, originally described by Denny-Brown.1 It is characterized by prominent and persistent instinctive grasping of hand, mouth, or foot, whenever they make contact or are close to an object. Object manipulation in daily activities is therefore impaired. We report right hand magnetic apraxia in a 58-year-old man with adult-onset Rasmussen encephalitis presenting as corticobasal syndrome2 (video on the Neurology® Web site at Neurology.org). Magnetic apraxia is related to parietal lobe dysfunction and, as other forms of motor apraxia, seems associated with corticobasal syndromes.

Complex phenotype in an Italian family with a novel mutation in SPG3A.

Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations.

Parkinsonism in a pair of monozygotic CADASIL twins sharing the R1006C mutation: a transcranial sonography study.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common hereditary cerebral small vessel disease, is caused by mutations in the NOTCH3 gene on chromosome 19. Clinical manifestations of CADASIL include recurrent transient ischemic attacks, strokes, cognitive defects, epilepsy, migraine and psychiatric symptoms. Parkinsonian features have variably been reported in CADASIL patients, but only a few patients showed a clear parkinsonian syndrome. We studied two patients, a pair of monozygotic twins, carrying the R1006C mutation of the NOTCH3 gene and affected by a parkinsonian syndrome. For the first time in CADASIL patients, we used transcranial sonography (TCS) to assess basal ganglia abnormalities. TCS showed a bilateral hyperechogenic pattern of substantia nigra in one twin, and a right hyperechogenic pattern in the other. In both patients, lenticular nuclei showed a bilateral hyperechogenic pattern, and the width of the third ventricle was slightly increased. The TCS pattern found in our CADASIL patients is characteristic neither for Parkinson’s disease, nor for vascular parkinsonism and seems to be specific and related to the disease-specific pathological features.

Genetic screening for the LRRK2 R1441C and G2019S mutations in parkinsonian patients from campania

BACKGROUND PARK8 is the most common known mendelian form of Parkinsons Disease (PD). It is due to mutations in the leucine-rich repeat kinase 2 (LRRK2) gene and G2019S is considered the most frequent mutation in the Caucasian population, in particular in the Southern Europe and Mediterranean countries. OBJECTIVE We assessed the frequency of the G2019S and R1441C/H/G mutations in 513 (311 M and 202 F) unrelated PD patients from Campania, in Southern Italy. METHODS Three hundreds and thirty-six patients presented a sporadic disease, and 177 had a familial history of PD or tremor. Three hundreds and eighty cases originated from the province of Naples. We compared our LRRK2 mutation carriers to idiopathic PD patients matched for recruiting center, gender, age and age at onset. RESULTS Thirteen patients (8 M and 5 F) carried the R1441C mutation and 4 (3 M and 1 F) the G2019S mutation, all in heterozygous state. All carriers originated from the province of Naples. No carriers of the R1441H or R1441G mutations were found. The LRRK2 mutation carriers were clinically similar to idiopathic PD patients. The R1441C and G2019S mutations are not rare causes of PD in Campania, especially in the province of Naples and among the familial cases, where the overall mutation prevalence is 6.8%. CONCLUSIONS The R1441C prevalence was higher than that of G2019S (2.5% vs 0.8%), underlining the importance of the geographical differencies in LRRK2 mutation frequency for molecular screening and genetic counseling of PD patients.

A case of restless leg syndrome in a family with LRRK2 gene mutation.

Abstract LRRK2 gene mutations (PARK8) are a common cause of genetic Parkinson disease (PD). G2019S, the most frequent mutation, is responsible for both familial and sporadic cases of PD. The clinical picture is usually indistinguishable from that observed in idiopathic PD; however, a wide range of clinical presentations and pathological findings has been described. Restless leg syndrome (RLS) is a disabling sleep-related sensorimotor disorder whose pathogenesis is likely related to dopaminergic dysfunction. We report a 77-year-old woman with RLS and familial history of parkinsonism. The father, one sister, two cousins and one uncle were affected by PD. The proband and her sister were analyzed for mutations in LRRK2 gene and resulted to carry one heterozygous G2019S mutation in LRRK2 gene. The association between RLS and LRRK2 gene mutation may be casual, but it can hypothesized that RLS is a possible phenotypic presentation in PARK8.