Eng-King Tan

Variability and validity of polymorphism association studies in Parkinson’s disease

Background: In recent years, interest in gene–environment interactions has spurred a great number of association studies on polymorphism of different genes. Objective: To review case-control studies of genetic polymorphisms in PD, and perform meta-analysis of individual gene polymorphism. Methods: The authors searched the Medline database (PubMed) for publications (English language) from January 1966 to November 1999 for association studies in PD. The key words used were “PD” and “polymorphism.” The authors supplemented the search with relevant references quoted in these published articles. Those with four or more independent studies of a specific gene polymorphism were subjected to meta-analysis, with the exception of cytochrome-P450 enzyme polymorphisms, for which meta-analyses results were already available in the literature. Results: The authors identified 84 studies on 14 genes, including dopamine receptors (DRD2 and DRD4), dopamine transporter (DAT), monoamine oxidase (MAOA and MAOB), catechol-O-methyltransferase (COMT), N-acetyltransferase 2 (NAT2), APOE, glutathione transferase (GSTT1, GSTM1, GSTP1, and GSTZ1), and mitochondrial genes (tRNAGlu and ND2). Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT)n polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNAGlu (OR = 3.0). No significant differences were found for the other genes. Conclusion: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNAGlu. Although significant association does not imply a causal relationship between the presence of the polymorphisms and PD pathogenesis, their pathophysiologic significance should be studied further.

Polymorphism of NACP-Rep1 in Parkinson’s disease: An etiologic link with essential tremor?

Article abstract An allele (263bp) of the nonamyloid component of plaques (NACP)-Rep1 polymorphism has shown association with sporadic PD in a German population. The authors studied this polymorphism in 100 American PD patients and 100 healthy controls. The authors also studied 46 essential tremor (ET) and 55 Huntington’s disease (HD) patients. Allele 263bp was significantly higher in PD patients (OR = 3.86) and ET patients (OR = 6.42) but not HD patients, compared with healthy controls. The association of allele 263bp with PD and ET suggests a possible etiologic link between these two conditions.

Bilateral hemifacial spasm: A report of five cases and a literature review

We describe five patients with bilateral hemifacial spasm evaluated in a Movement Disorders Clinic to illustrate the clinical characteristics and to draw attention to the differential diagnosis of this condition. All patients had unilateral onset followed by bilateral, asymmetric, and asynchronous facial contractions. The mean age of the patients (4 women and 1 man) was 70.6 years (range, 54–81 yrs), and the mean duration of symptoms was 17 years (range, 2–30 yrs). The facial twitching started in the left eyelid in all cases and the opposite side of the face began to twitch on the average 8.4 years (range, 0.2–15 yrs) later. Imaging studies revealed tortuous vertebrobasilar arteries in three patients. Four patients were successfully treated with botulinum toxin injections. Bilateral hemifacial spasm is a rare, peripherally induced disorder that must be differentiated from tics, dystonia including blepharospasm and other cranial dystonia, and other facial dyskinesias. Botulinum toxin injection appears to be the treatment of choice.

Restless Legs Syndrome: Clinical Features and Treatment

Restless legs syndrome (RLS), widely recognized as a definite clinical entity, has an estimated prevalence of 1 to 15% in different ethnic populations. However, it remains an underdiagnosed condition and its symptoms are frequently ascribed to stress and anxiety. Advancement in modern imaging techniques and clinical drug trials provide evidence of an impaired dopaminergic system in RLS. Management involves investigating and correcting treatable secondary causes, avoidance of aggravating factors, and pharmacologic therapy. Recent controlled trials have demonstrated the effectiveness of dopamine agonists such as pramipexole and pergolide. Additional research is needed to further elucidate the pathophysiology of RLS, through obtaining post-mortem specimens and refinement of neuroimaging and neurophysiologic techniques. Isolation of specific genetic loci in familial cases would enable better characterization of distinct clinical and genetic subsets of RLS and result in better understanding of this disease at the molecular level.

Rheumatologic serologies in secondary restless legs syndrome

Diagnostic criteria for restless legs syndrome (RLS) have been established; however, the pathophysiology of this common condition remains elusive. Several secondary forms of RLS potentially include renal failure, iron deficiency, pregnancy, and neuropathy. RLS has also been reported in approximately 25% of patients diagnosed with rheumatoid arthritis and Sjögrens syndrome. We performed clinical and serologic evaluations on 68 patients diagnosed with RLS to determine how many may have concurrent rheumatologic disease that could be causing their RLS symptoms. We compared these with other postulated secondary causes of RLS. No patient had clinical evidence of rheumatologic disease, and only four had any positive serologic evaluations (two positive SSA/SSB and two mildly elevated RF titers). Three of these had a positive family history for RLS. Patients without a family history of RLS did have lower ferritin levels, more cases of neuropathy, and an older age at symptom onset. We do not think rheumatologic disease represents a significant secondary cause of RLS and do not recommend serologic investigation unless there are overt clinical signs. In contrast, our study suggests that neuropathy and serum iron deficiency do represent secondary forms of RLS.

X-linked adrenoleukodystrophy: spinocerebellar variant

The phenotypic variability in X-linked adrenoleukodystrophy (X-ALD) can be wide and varied. Rarely, it can present with clinical signs of spinocerebellar degeneration. There are very few reported cases of selective predominant white matter disease of the cerebellum in these patients. We report a patient with a rare variant of adult onset ALD who was previously diagnosed as spinocerebellar ataxia. He was a 24-year-old male who had delayed developmental milestones, developed signs of spinocerebellar degeneration (SCD) after 10 years of Addisons disease. Serial Magnetic Resonance Imaging (MRI), revealed cerebellar and pontine white matter disease but sparing the cerebral cortex and supratentorial white matter. His diagnosis of X-ALD was subsequently confirmed by the elevated serum very long chain fatty acids. This patient illustrates the unusual clinical presentation and imaging features of X-ALD and the importance of considering X-ALD in the clinical context of spinocerebellar degeneration. Early recognition of this rare variant would allow proper genetic counselling and institution of dietary therapy and/or bone marrow transplantation.

Alcohol dehydrogenase polymorphism and Parkinson's disease

A particular alcohol dehydrogenase (ADH) polymorphism (allele A1) in the promoter region of the gene has been recently demonstrated to be associated with increased risk of Parkinsons disease (PD). In a case control study, we examine frequencies of ADH A1 allele in 100 PD patients (i.e. 200 alleles), 100 diseased controls (i.e. 200 alleles), and 194 healthy controls (i.e. 388 alleles). In addition, we study possible association of a combined non-amyloid component of plaque (NACP-Rep 1) allele and ADH A1 allele with risk of PD. There was no statistical significance of the frequencies of ADH A1 allele between PD patients 12/200 (6%), diseased controls 13/200 (6.5%), and healthy controls 20/388 (5.2%). No strong evidence of an association was found between ADH A1 allele and PD susceptibility in our study patients. There was also no suggestion of linkage disequilibrium between NACP-Rep 1 and ADH A1 alleles.