Tourniquet-Related Nerve Injury Following Reconstructive Surgery for Wassel Type IV Preaxial Polydactyly of 13-Year-Old Boy: A Case Report.

BACKGROUND Congenital thumb duplication comes under the Wassel type IV classification is the hypoplastic variety, with the extra digit growing from the dominant thumb's soft tissue alone. Excising the hypoplastic finger while reconstructing for the retained one has been the most adopted approach. Tourniquets are commonly utilized tools in orthopedic surgeries to reduce the amount of blood, thus enhancing the visibility. Unfortunately, tourniquet-related nerve injury (TNRI) is gaining more attention as a serious complication of tourniquet use in surgery. CASE REPORT A 13-year-old Asian boy with preaxial polydactyly Wassel type IV of the right hand underwent reconstruction surgery. A pneumatic tourniquet was applied at 200 mmHg on the right mid-upper arm and maintained for 90 min. After the surgery, the patient had total weakness with numbness, tingling, and burning sensation from his right upper arm to his fingertips. The neurological examination and nerve conduction studies (NCS) results were consistent with axonotmesis lesions. Pharmacological and physical rehabilitation therapy had successfully restored full motoric and sensory function after 6 months. CONCLUSIONS Nerve injury should be acknowledged as a possible complication from routinely-utilized tourniquets in orthopedic surgeries. Our cases may expand the need for further studies to establish a guideline for tourniquet use and TRNI management.

Clinical characterizations of three adults with genetically confirmed spinal muscular atrophy: a case series.

BACKGROUND: Spinal muscular atrophy is a recessively inherited autosomal neuromuscular disorder, with characteristic progressive muscle weakness. Most spinal muscular atrophy cases clinically manifest during infancy or childhood, although it may first manifest in adulthood. Although spinal muscular atrophy has come to the era of newborn screening and promising treatments, genetically confirmed spinal muscular atrophy patients are still rare in third world countries, including Indonesia. CASE PRESENTATIONS: We presented three Indonesian patients with spinal muscular atrophy genetically confirmed during adulthood. The first case was a 40-year-old male who presented with weakness in his lower limbs that started when he was 9 years old. At the age of 16 years, he could no longer walk and started using a wheelchair. He first came to our clinic at the age of 38 years, and was diagnosed with spinal muscular atrophy 2 years later. The second patient was a 58-year-old male who presented with lower limb weakness since he was 12 years old. Owing to the geographical distance and financial problems, he was referred to our clinic at the age of 56 years, when he already used a walker to walk. Lastly, the third patient was a 28-year-old woman, who was in the first semester of her second pregnancy, and who presented with slowly progressing lower limb weakness. Her limb weakness began at the age of 8 years, and slowly progressed until she became dependent on her wheelchair 8 years later until now. She had successfully given birth to a healthy daughter 3 years before her first visit to our clinic. All three patients were diagnosed with neuromuscular disorder diseases, with the differential diagnoses of Duchenne muscular dystrophy, spinal muscular atrophy, and Becker muscular dystrophy. These patients were finally confirmed to have spinal muscular atrophy due to SMN1 deletion by polymerase chain reaction and restriction fragment length polymorphism. CONCLUSIONS: Many genetic diseases are often neglected in developing countries owing to the difficulty in diagnosis and unavailable treatment. Our case series focused on the disease courses, diagnosis difficulties, and clinical presentations of three patients that finally lead to diagnoses of spinal muscular atrophy.

Dementia in a patient with autoimmune disease and hypercoagulable state worsened by COVID-19 vaccination: A case report.

Background: Systemic autoimmune disorders are associated with an increased risk of hypercoagulability. The hypercoagulable state in people with systemic autoimmune disorders has lately gained attention. Presentation of case: We presented a 44-year-old male with a chief complaint of progressive difficulty concentrating, memory impairment, and weakness in all limbs. Seven months before admission to our Memory Clinic, the patient began to have infrequent short-term memory loss and sometimes got lost when he went for a drive. Three months later, he complained of feeling dizzy when in a crowd, being unable to watch television for a long time, and easily forgetting. Computed tomography (CT) scan showed brain infarction. After receiving the first dose of COVID-19 vaccine (Sinovac), the patient had difficulty communicating verbally and could only point at objects, as well as tetraparesis. These conditions severely intervened in his daily activities. The patient was then referred to an immunologist and diagnosed with autoimmune disease. In our Memory Clinic, his performances of attention, memory, language, visuospatial, and executive function were very poor. We diagnosed him with autoimmune dementia. The administration of methylprednisolone, mycophenolate mofetil, vitamin D3, donepezil, and memantine could improve his condition. Discussion: Autoimmune disease can cause microvascular thrombosis and microembolism at the central nervous system level, which would cause vascular damage and cognitive impairment leading to brain infarction and dementia. Conclusion: There seems to be a link between autoimmune disease, hypercoagulable state, and dementia, although the magnitude of this link and the underlying processes are not fully understood.

Managing pregnancy in a spinal muscular atrophy type III patient in Indonesia: a case report.

BACKGROUND: Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower motor neurons, leading to progressive muscular atrophy and even paralysis. Spinal muscular atrophy usually associated with a defect of the survival motor neuron 1 (SMN-1) gene. Classification of spinal muscular atrophy is based on the age of onset and maximum motor function milestone achieved. Although spinal muscular atrophy can be screened for in newborns, and even confirmed earlier genetically, this remains difficult in Third World countries such as Indonesia. CASE PRESENTATION: A 28-year-old Asian woman in the first trimester of her second pregnancy, was referred to the neurology department from the obstetric department. Her milestone history showed she was developmentally delayed and the ability to walk independently was reached at 26 months old. At 8 years old, she started to stumble and lose balance while walking. At this age, spinal muscular atrophy was suspected because of her clinical presentations, without any molecular genetic testing. She was married at the age of 25 years and was soon pregnant with her first child. At the gestational age of 32 weeks, her first pregnancy was ended by an emergency caesarean section because of premature rupture of the membranes. In this second pregnancy, she was referred early to the general hospital from the district hospital to receive multidisciplinary care. She and her first daughter underwent genetic testing for spinal muscular atrophy, which has been readily available in our institution since 2018, to confirm the diagnosis and prepare for genetic counseling. CONCLUSIONS: Managing pregnancy in a patient with spinal muscular atrophy should be performed collaboratively. In this case, genetic testing of spinal muscular atrophy and the collaborative management of this patient allowed the clinical decision making and genetic counseling throughout her pregnancy and delivery.

Determining the association between polymorphisms of the DAT1 and DRD4 genes with attention deficit hyperactivity disorder in children from Java Island.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the children. Genetic factor is known one of the factors which contributed in ADHD development. VNTR polymorphism in 3'UTR exon 15 of DAT1 gene and exon 3 of DRD4 gene are reported to be associated in ADHD. In this study we examine the association of ADHD with VNTR polymorphism of DAT1 and DRD4 gene in Indonesian children. Sixty-five ADHD children and 70 normal children (6-13 years of age), were included in the study, we matched by age and gender. ADHD was diagnosed by DSM-IV. We performed a casecontrol study to found the association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes. The 10-repeat allele of DAT1 and 2-repeat allele of DRD4 were higher in Indonesian children. Although the frequency of these allele was higher, but it was similar both in ADHD and control groups. Neither DAT1 nor DRD4 gene showed showed significant difference in genotype distribution and frequency allele between both groups (p > 0.05). No association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes found in Indonesian children. This data suggest that DAT1 and DRD4 do not contribute to etiology of ADHD in Indonesian children. Further studies are needed to clarify association between VNTR polymorphism of DAT1 and DRD4 genetic with ADHD of Indonesian children in larger sample size and family based study.

Attention Deficit/Hyperactivity Disorder (ADHD): age related change of completion time and error rates of Stroop test.

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in children throughout the world. The Stroop test has been widely used for the evaluation of ADHD symptoms. However, the age-related change of the Stroop test results has not been fully clarified until now. METHODS: Sixty-five ADHD and 70 age-matched control children aged 6-13 years were enrolled in this study. ADHD was diagnosed based on DSM-IV criteria. We examined the completion time and error rates of the Congruent Stroop test (CST) and Incongruent Stroop test (IST) in ADHD and control children. RESULTS: No significant difference was observed in the completion time for CST or IST between the ADHD and control children at 6-9 years old. However, ADHD children at 10-13 years old showed significantly delayed completion time for the CST and IST compared with controls of the same age. As for the error rates of the CST and IST, ADHD and control children at 6-9 years old showed no difference. However, error rates of CST and IST in the ADHD children at 10-13 years were significantly higher than those of control of the same age. CONCLUSIONS: Age may influence the results of Stroop test in ADHD children. For the ages of 10-13 years old, the Stroop test clearly separates ADHD children from control children, suggesting that it may be a useful screening tool for ADHD among preadolescent children.

Spinal muscular atrophy patient detection and carrier screening using dried blood spots on filter paper.

AIM: Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder. It is caused by mutations in the SMN1, and its clinical severity is modified by copy number variations of the SMN2. According to previous studies, deletion of SMN1 exon 7 is the most frequently observed in patients with SMA. Therefore, molecular analyses exploiting this genetic lesion could be beneficial in the diagnosis of SMA. Unfortunately, in many geographical regions, physicians do not have the latest molecular screening technologies at their immediate disposal. Thus, to overcome this issue, we developed an SMA-diagnosing system using dried blood spots (DBS) placed on filter paper to facilitate remote diagnosis. METHODS: In this study, we validate the applicability of DBS on Flinders Technology Associates (FTA) filter paper for detecting SMN1 exon 7 deletions and copy number variations of SMN1 and SMN2. To detect exon 7 deletions in SMN1, polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis was conducted by using DNA extracted from the DBS on FTA filter paper that had been stored at room temperature for a period of up to 4 years. To determine the copy numbers of SMN1 and SMN2, we carried out SYBR green-based real-time PCR by using the same blood specimens. RESULTS: The results obtained from the DBS on FTA filter paper were in complete concordance with those analyses using fresh blood specimens. This indicates that DBS on filter papers is a reliable method for SMA patient detection and carrier screenings. CONCLUSION: The SMA-diagnosing system, combined with the mailing of DBS on filter paper, will be beneficial for patients suffering from neuromuscular disorders in areas with limited or no access to diagnostic facilities with molecular capabilities.

Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is caused by loss of the survival motor neuron gene, SMN1. SMA treatment strategies have focused on production of the SMN protein from the almost identical gene, SMN2. Valproic acid (VPA) is a histone deacetylase inhibitor that can increase SMN levels in some SMA cells or SMA patients through activation of SMN2 transcription or splicing correction of SMN2 exon 7. It remains to be clarified what concentration of VPA is required and by what mechanisms the SMN production from SMN2 is elicited. We observed that in two fibroblast cell lines from Japanese SMA patients, more than 1mM of VPA increased SMN2 expression at both the transcript and protein levels. VPA increased not only full-length (FL) transcript level but also exon 7-excluding (Δ7) transcript level in the cell lines and did not change the ratio of FL/Δ7, suggesting that SMN2 transcription was mainly activated. We also found that VPA modulated splicing factor expression: VPA increased the expression of splicing factor 2/alternative splicing factor (SF2/ASF) and decreased the expression of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). In conclusion, more than 1mM of VPA activated SMN2 transcription and modulated the expression of splicing factors in our SMA fibroblast cell lines.

Acetaminophen administration in a patient with Gilbert's syndrome.

The patient was an 8-year-old Japanese girl with Gilbert's syndrome (GS). Based on the DNA analysis, she was homozygous for a T-to-G transversion at nucleotide position 1456 in the UGT1A1 gene, leading to the substitution of aspartate for tyrosine at position 486 of the UGT1A1 enzyme. Because this mutation is located in an exon common to UGT1A genes, all the UGT1A enzymes may be affected. It is well-known that UGT1A1, UGT1A6 and UGT1A9 enzymes glucuronidate acetaminophen. To evaluate acetaminophen tolerance in the patient, serum acetaminophen levels were determined after oral administration of acetaminophen (15 mg/kg). The maximum serum acetaminophen level reached (12.8 µg/mL) was far below the toxic level. The finding suggested that the usual therapeutic dose of acetaminophen is safe for the GS patient. The combination of mutation analysis in UGT1A1 and acetaminophen loading test may be useful to avoid adverse effect in GS patients.

Diagnosis of spinal muscular atrophy via high-resolution melting analysis symmetric polymerase chain reaction without probe: a screening evaluation for SMN1 deletions and intragenic mutations.

AIM: Spinal muscular atrophy (SMA) is a well-defined autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. The most frequently observed mutation is a deletion of exon 7, which has been documented in >95% of SMA patients. A novel technique for detecting mutations known as high-resolution melting analysis (HRMA) has rapidly become the tool of choice for screening pathogenic genetic variants. In the present study, we attempt to validate the applicability of HRMA to the detection of exon 7 deletions and other intragenic mutations in SMN1. RESULTS: Three primer sets were adopted in our HRMA screening for deletion of SMN1 exon 7. In screening attempts utilizing two primer sets, the results of HRMA were not compatible with those obtained by polymerase chain reaction-restriction fragment length polymorphism. Therefore, we applied a modified protocol using revised primer sets, which resulted in an absolute compatibility of results between HRMA and polymerase chain reaction-restriction fragment length polymorphism. With regard to screenings for intragenic mutations in SMN1 exon 3, two primer sets were adopted for use in HRMA. In the initial HRMA screening using the first primer set, we failed to identify any intragenic mutations; however, when using a revised primer set, HRMA successfully detected the presence of a c.275G>C mutation. CONCLUSION: HRMA is a simple but versatile tool to add to the existing arsenal of diagnostic techniques that could aid clinicians/researchers in diagnosing SMA. However, as we demonstrate in the present study, the design and selection of primers is of monumental importance in ensuring the successful application of HRMA to screening for pathogenic variants.

Herbal Medicine Containing Licorice May Be Contraindicated for a Patient with an HSD11B2 Mutation.

Licorice ingestion, as well as mutations in the HSD11B2 gene, inhibits 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) enzyme activity, causing the syndrome of apparent mineral corticoid excess (AME). However, the combined effect of licorice ingestion and an HSD11B2 mutation has never been reported, until now. In this study, we demonstrated that licorice ingestion can produce overt hypertension in an individual without medical history of hypertension who is heterozygous for wild-type and mutant HSD11B2 genes. Our patient was a 51-year-old female with serious hypertension who had been taking herbal medicine containing licorice for more than one year. She was clinically diagnosed as having licorice intoxication, because she did not present with hypertension after ceasing the herbal medicine. Molecular analysis showed that she carried a missense mutation, c.40C>T, in HSD11B2. In conclusion, licorice ingestion is an environmental risk factor for hypertension or AME state in patients with a mutation in HSD11B2. Carrying a mutation in HSD11B2 is, conversely, a genetic risk factor for licorice-induced hypertension or AME state. Herbal medicine containing licorice may, therefore, be contraindicated in patients with an HSD11B2 mutation.

Generalized epilepsy with febrile seizures plus (GEFS+) spectrum: clinical manifestations and SCN1A mutations in Indonesian patients.

Generalized epilepsy with febrile seizures plus (GEFS+) is a childhood genetic epilepsy syndrome. GEFS+ includes a wide spectrum of clinical manifestations, and SCN1A mutations have frequently been reported among the GEFS+-related gene abnormalities. In this study, to clarify the distributions of the clinical subtypes, we analyzed 34 families with GEFS+ in Indonesia using the hospital records of the patients and questionnaires for the family members. The number of patients with febrile seizures plus (FS+), FS+ and afebrile generalized/partial seizures, borderline severe myoclonic epilepsy in infancy (SMEB) and severe myoclonic epilepsy in infancy (SMEI) were 9, 11, 7, and 7, respectively. Most patients had a family history of febrile seizures. Next, we performed molecular analyses to clarify the contributions of SCN1A mutations to the development of the GEFS+ subtypes. Only 3 of 34 probands showed SCN1A mutations. These mutations were two missense mutations, p.V1612I and p.C1756G, in two patients with SMEI and SMEB, and one silent mutation, p.G1762G, in a patient with FS+ and afebrile partial seizures. In conclusion, the majority of GEFS+ patients in Indonesia were not associated with SCN1A mutations. To detect the GEFS+-causing mutations, we must search and analyze other genes in these patients.

Novel mutations in 21 patients with tuberous sclerosis complex and variation of tandem splice-acceptor sites in TSC1 exon 14.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, mental retardation, skin lesions, and tumors in various organs. However, TSC is sometimes difficult to diagnose because of its broad phenotypic spectrum. In such cases, it is essential to find a mutation in the disease-causing genes, TSC1 and TSC2. In this study, we analyzed 21 TSC patients from 16 families using a combination method of DHPLC and nucleotide sequencing. We identified 16 novel mutations in the 16 families: nine mutations in TSC1 (1 insertion, 7 deletion and 1 nonsense mutations) and seven mutations in TSC2 (2 insertion, 2 deletion, 1 missense mutations and 2 splicing abnormalities). We also tested the possibility of very short alternative splicing due to a variation of the tandem splice-acceptor sites of TSC1 exon 14 in a patient. RT-PCR and sequencing analysis indicated that no alternative splicing occurred in the patient. In conclusion, we confirmed the diagnosis of all patients using mutation analysis and clarified that variation of the tandem splice-acceptor sites in TSC1 exon 14 does not cause a splicing abnormality.