The Utilization of MS-MLPA as the First-Line Test for the Diagnosis of Prader–Willi Syndrome in Thai Patients

Prader–Willi syndrome (PWS) is a genetic disorder caused by the expression disruption of genes on the paternally inherited allele of chromosome 15q11.2-q13. Apart from clinical diagnostic criteria, PWS is confirmed by genetic testing. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is one of the molecular techniques used to analyze this syndrome. This study aimed to evaluate the concordance of the test results of MS-MLPA with conventional techniques in the diagnosis of PWS in Thai patients. Forty leftover specimens from routine genetic testing (MS-PCR and FISH) were tested to obtain MS-MLPA results. By comparison, perfect concordance was shown between the result of MS-MLPA and those of conventional techniques. In conclusion, MS-MLPA is an accurate and cost-effective assay that can be used to confirm PWS diagnosis with explicit deletion of affected genes.

Comparative diagnostic sensitivity of the substantia nigra transcranial sonography and salivary gland biopsy in patients with Parkinson’s disease

Parkinsons disease is a chronic neurodegenerative disease, the diagnosis of which remains challenging at the early stages, although clinical diagnostic criteria are developed. The diagnostic accuracy is only 58% for patients at early Parkinsons disease stages. The sensitivity and specificity of transcranial sonography of the substantia nigra used for Parkinsons disease verification is about 85% and 71%, respectively. It has been shown that the aggregates of -synuclein in the nerve fibers in major salivary glands may be seen in Parkinsons disease patients. The availability of the salivary glands for morphological study made it possible to investigate the approaches of the in vivo histological diagnosis of Parkinsons disease based on the detection of -synuclein aggregates in the nerve fibers innervating the glands. Aim: To evaluate and compare the sensitivity of transcranial sonography of the substantia nigra and sublingual salivary gland biopsy. Materials and methods: Six patients with clinically verified Parkinsons disease were enrolled. Evaluation of the neurological state using special scales, transcranial sonography of the substantia nigra and sublingual salivary gland biopsy was performed. Results: Mean age of patients was 59 [58; 60.7] years, mean disease duration period was 5 [3; 7.75] years and the mean HoehnYahr stage was 2.25 [2; 2.5]. Hyperechogenicity of the substantia nigra was found in 3 of 6 patients and the substantia nigra sensitivity was shown to be 50%. Sublingual salivary gland biopsy was positive for -synuclein in 6 of 6 patients and the sensitivity of method was shown to be 100%. No adverse events after biopsy were registered. Conclusion: The sensitivity of sublingual salivary gland biopsy was higher than those of transcranial sonography of the substantia nigra, which indicates the prospect of using the biopsy method as a more sensitive diagnostic tool in Parkinsons disease (1 table, bibliography: 19 refs)

Presence of Skin α-Synuclein Deposits Discriminates Parkinson’s Disease from Progressive Supranuclear Palsy and Corticobasal Syndrome

Background: Previous studies reported skin phosphorylated α-synuclein (p-syn) deposits in Parkinson’s disease (PD) patients but not in patients with parkinsonism due to tauopathies, although data on the latter are limited. Objective: We aimed to assess the presence of skin p-syn deposits in patients with clinical diagnosis of parkinsonism usually due to tauopathy and PD. Methods: We consecutively recruited 26 patients, 18 fulfilling clinical diagnostic criteria of progressive supranuclear palsy (PSP) and 8 of corticobasal syndrome (CBS), 26 patients with PD, and 26 healthy controls (HC). All subjects underwent skin biopsy to study p-syn deposits in skin nerves by immunofluorescence. Results: Skin p-syn deposits were present in only two of the PSP/CBS patients and none of the HC. Conversely, all PD patients showed p-syn deposition (p < 0.001, Chi-square). The two p-syn positive patients were diagnosed with PSP and CBS, respectively. Although clinical and MRI findings supported these diagnoses, both patients had some atypical features more typical of synucleinopathies. Conclusion: The detection of skin p-syn deposits may help in the differential diagnosis of parkinsonism. Indeed, in this study, all PD patients and only two out of 26 with a clinical diagnosis of PSP/CBS had skin p-syn deposits. Furthermore, these two patients showed clinical features that could suggest an atypical synucleinopathy presentation or a mixed pathology.

An atypical presentation of a pathogenic STK11 gene variant in siblings not fulfilling the clinical diagnostic criteria for Peutz-Jeghers Syndrome

Objectives To report an atypical presentation of a pathogenic STK11 gene variant in siblings not fulfilling the clinical diagnostic criteria for Peutz-Jeghers Syndrome (PJS). Case presentation Two siblings presented with prepubertal gynaecomastia and bilateral macro-orchidism, without mucocutaneous pigmentation or gastrointestinal symptoms. There was no family history of PJS. Sibling 1 had unilateral gynaecomastia. Sibling 2 had bilateral gynaecomastia, advanced bone age and bilateral testicular microlithiasis, not indicative of a large-cell calcifying Sertoli cell tumour. Genetics revealed a paternally inherited heterozygous pathogenic STK11 variant (910C>T) in both siblings. The diagnosis was confirmed following the identification of multiple intestinal polyps in their father. Conclusions Prepubertal gynaecomastia and prepubertal macro-orchidism (testicular enlargement without virilisation), always warrant endocrinological investigation, with PJS being an important differential diagnosis. Children may not fulfil the clinical criteria for a diagnosis of PJS at presentation. Genetic testing and gastroenterological investigation of parents may aid diagnosis.

Biomarkers for Ehlers-Danlos Syndromes: There Is a Role?

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS—classic and hypermobile—by trying to identify possible biomarkers that could be of great help to confirm patients’ diagnosis and their follow up.

Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

Clinical Presentation of Parkinson’s Disease: Experience of using Movement Disorder Society Clinical Diagnostic Criteria for Parkinson’s Disease

Aims: Parkinson’s disease (PD) is a common neurodegenerative disorder. As no definite diagnostic tests are available, diagnosis is done mostly clinically. UK Brain Bank criteria is commonly used globally for that purpose. In this study we used Movement Disorder Society (MDS) Clinical Diagnostic Criteria to diagnose PD and document the clinical presentations. Study design: Descriptive cross-sectional study. Methodology: This study was carried out in the department of neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from May 2018 to April 2019. Total 42 patients (4 clinically established and 38 clinically probable PD) were enrolled as study population according to Movement Disorder Society (MDS) Clinical Diagnostic Criteria - 2015 for PD. Their patterns of clinical presentation were recorded. Results: Among the PD patients, 31 were male and 11 were female. Mean age of all patients was 59.43 ± 11.34 years. The most common presenting feature was tremulous movement (90.5%) followed by slowness of movement (40.5%). Only 9% patients had early onset PD. All patients had history of positive response to dopaminergic therapy with documented resting tremor in 95.2%, and end-of-dose wearing off in 75.6%. Constipation was the commonest (69%) non motor symptom followed by sleep dysfunction (64.3%) & depression (50%). On examination- 100% patients had bradykinesia, 97.6% rest tremor, 95.2% rigidity, 21.4% mild dementia and 4.8% moderate dementia. Also 26.2% patients were found to have postural hypotension. 4 patients had red flag features- urinary retention was found in three patients and one patient suffered from recurrent early fall. Conclusion: MDS Clinical Diagnostic Criteria help in accurate diagnosis of PD and include more clinical features which will help in formulating management plan.