Abnormalities of vestibular-evoked myogenic potentials in idiopathic Parkinson's disease are associated with clinical evidence of brainstem involvement.

Brainstem degeneration in Parkinson's disease (PD) may explain the occurrence of many non-motor symptoms in this condition. Purposes of the present work were to investigate brainstem function in PD through a battery of vestibular-evoked myogenic potentials (VEMP) allowing a comprehensive brainstem exploration and to correlate VEMP findings with symptoms related to brainstem involvement. Cervical (cVEMP), masseter (mVEMP) and ocular (oVEMP) VEMPs were investigated in 24 PD patients and compared with those recorded in 24 age-matched controls. Presence of symptoms ascribable to brainstem dysfunction, such as daytime sleepiness, REM sleep behavior disorder and depression, was investigated through Epworth Sleepiness Scale, Parkinson's Disease Sleep Scale, REM Sleep Disorder Screening Questionnaire (RBD-SQ) and Geriatric Depression Scale. Postural instability was additionally assessed through mini-BESTest. The frequency of alteration of VEMPs in patients was 83.3 % when considering the whole set and 41.7 % for cVEMP, 66.7 % for mVEMP and 45.8 % for oVEMP. This was significantly different from controls, with absence being the prevalent alteration in PD. A significant inverse correlation between the number of altered VEMPs and mini-BESTest and a direct correlation with RBD-SQ were found. The VEMP battery under study allowed the identification of brainstem dysfunctions in PD patients, which correlated with clinical tests suggestive of postural and REM sleep disorders. VEMPs might represent a valuable tool of brainstem assessment in PD.

Novel SPAST deletion and reduced DPY30 expression in a Spastic Paraplegia type 4 kindred.

BACKGROUND: The hereditary spastic paraplegias (HSPs) are pleiomorphic disorders of motor pathway and a large number of affected genes have been discovered. Yet, mutations in SPG4/SPAST represent the most frequent molecular etiology in autosomal dominant (AD) patients and sporadic cases. We describe a large, AD-HSP Sardinian family where 5 out of several living members harbored a novel deletion affecting also the 5'UTR of SPAST and resulting in reduced expression of DPY30, the gene located upstream SPAST in a head-to-head manner. CASE PRESENTATION: A 54-year-old woman manifested leg stiffness at age 39 and required a cane to walk at age 50. Neurological examination disclosed mild spasticity and weakness in the legs, hyperreflexia in all limbs, and bilateral Babinski sign. She also complained of urinary urgency, but no additional neurological symptoms or signs were detected at examination. The clinical examination of 24 additional relatives disclosed three further affected individuals, two men and one woman. In the four symptomatic patients the initial manifestations were walking abnormalities and leg stiffness with a mean age at onset (SD) of 46.75 (5.44) years (range 39-51). The mean disease duration was 13.2 (13.4) years (range 6-35), and it correlated well with clinical severity (SPRS score) (r = 0.975, p = 0.005). One patient was confined to bed and displayed knee and ankle contractures, another case needed a cane to walk, and two individuals were able to walk without aids. Interestingly, a patient had also had a miscarriage during her first pregnancy.Gene testing revealed an heterozygous deletion spanning from the 5'-UTR to intron 4 of SPAST in the affected individuals and in one clinically unaffected woman. In three affected patients, the deletion also determined low mRNA levels of SPAST and DPY30, a component of the Set1-like multiprotein histone methyltransferase complex located upstream, head-to-head with SPAST. CONCLUSION: Together with data described in a Japanese family, our findings seem to suggest that genes close to spastin might be candidates in modulating the clinical phenotype. This report endorses future research on the role of neighboring genes as potential players in SPG4 disease variability.

Restless legs syndrome and periodic limb movements after ischemic stroke in the right lenticulostriate region.

We report the first instance of restless legs syndrome (RLS) associated with periodic limb movements (PLM) and disruption of sleep architecture occurring in a patient following ischemic infarction in the right lenticulostriate region. Recently, a role for the basal ganglia-brainstem system in the control of motor behaviors and in the regulation of awake-sleep states has been proposed. The purported roles of these structures may be relevant in explaining the occurrence of the RLS in our patient. The discrete brain localization observed in this patient may be a clue to a better understanding of the pathophysiology of RLS and PLM.

Three sisters with very-late-onset major depression and parkinsonism.

Familiar Parkinson's disease has an age of onset from the second to the sixth decade, whereas Wilson's disease (WD) usually presents in the first decade of life. We studied three sisters with a form of very-late-onset major depression and parkinsonism with probable linkage to ATP7B gene. Molecular studies demonstrated a nucleotide deletion at the 5'UTR region in a single allele of ATP7B gene. They did not have a family history of WD, or markers indicative for copper deposition in peripheral tissues. We suggest that single allele mutations of ATP7B gene may confer a susceptibility for late-onset major depression and parkinsonism.

Effects of topiramate in patients with cerebellar tremor.

PURPOSE: To evaluate the safety and potential beneficial effect of topiramate (TPM) as monotherapy or adjunctive therapy to carbamazepine (CBZ) in patients with cerebellar tremor. METHODS: Nine patients with cerebellar tremor participated a 4-week, open-label, prospective-controlled trial. TPM was given as monotherapy (n=7 cases), or in combination with CBZ (n=2 cases), at dosages ranging from 25 mg twice daily to 100 mg twice daily. The severity of tremor was assessed clinically on a 0-4 scale, by tremograms, by the Patients Global Impressions Scale, and by a "free writing" task at baseline and after 4 weeks. RESULTS: TPM was discontinued in four patients due to adverse effects (sedation=2; cognitive impairment=2; increased aggressiveness=2; asthenia=1). During TPM, all patients improved. The mean tremor amplitude, compared with the baseline period, was reduced from 20% to 75%. After TPM, mean clinical scores of postural tremor and kinetic tremor decreased from 2.1+/-0.8 to 0.9+/-0.9 and from 2.1+/-1 to 1.4+/-1 (P<.05), respectively. All patients with head tremor improved. Writing, eating, and drawing were improved with TPM. Four patients chose to keep taking the drug. CONCLUSIONS: Our study indicates that TPM may be useful for the management of cerebellar tremors. A prospective placebo-controlled trial of TPM in this kind of tremor is warranted. TPM dosages should be titrated slowly to avoid the potential side effects of the drug. The range and the frequency of adverse events might limit the clinical usefulness of TPM.

Infantile-onset ascending hereditary spastic paralysis: a case report and brief literature review.

BACKGROUND: Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early-onset autosomal recessive motor neuron disease associated with mutations in ALS2. AIM: We studied a 17-year-old boy who had features of IAHSP. We also reviewed the current literature on ALS2-related syndromes. METHODS: Clinical and neuroimaging studies were performed. Blood DNA analyses were combined with mRNA studies in cultured skin fibroblasts. RESULTS: Like previously described cases, the patient presented with severe spastic paraparesis and showed rapid progression of paresis to the upper limbs. He also developed bulbar involvement and severe scoliosis during childhood. In blood DNA we identified a novel splice-site homozygous mutation in ALS2 (c.3836+1G > T), producing exon skipping in fibroblast mRNA and predicting premature protein truncation. CONCLUSIONS: This case adds to the allelic heterogeneity of IAHSP. Review of the pertinent literature indicates a fairly homogeneous clinical picture in IAHSP that should facilitate molecular confirmation and prevention of long-term complications.

The high prevalence of hereditary spastic paraplegia in Sardinia, insular Italy.

The few epidemiological studies conducted to date on the heterogeneous group of hereditary spastic paraplegias (HSPs) indicate a prevalence of 1.27-12.1 per 100,000. This study aims to explore the epidemiological, clinical, and genetic variability of HSPs among Sardinians, a population of peculiar ethnicity.A population-based prevalence study was performed in north-western Sardinia between January 2000 and December 2010. Multiple sources were used for case ascertainment. Familial and sporadic cases were diagnosed according to generally accepted criteria, and clinical diagnoses were validated by expert neurological examination. Clinical data and pedigree information were recorded and blood samples drawn for genetic testing.Sixty-seven HSP patients were included in the study: 59 belonged to 11 families with autosomal dominant transmission (AD-HSP), three cases were from two unrelated autosomal recessive families, and the remaining five cases were apparently sporadic. On 31 December 2010, the total crude prevalence was 19.9 per 100,000 (95 % CI 18.4-21.4), while the crude prevalence of AD-HSP was 17.5 (24.4 M, 15.7 F; M:F ratio 1.55). The mean age at examination was 48.4 years, and the mean age at onset of HSP was 36.6 years. A molecular diagnosis was obtained in 82.1 % of the cases (52 cases with mutations in SPAST/SPG4, two in SPG7, and one in SPG11).The prevalence of HSP among Sardinians is high compared with other Western European populations. The multiple search strategy used in this study and the specific socio-demographic characteristics of Sardinians may account for this finding.