Abnormal Porphyrin Metabolism in Autism Spectrum Disorder and Therapeutic Implications.

Autism spectrum disorder (ASD) is a mosaic of neurodevelopmental conditions composed of early-onset social interaction and communication deficits, along with repetitive and/or restricted patterns of activities, behavior, and interests. ASD affects around 1% of children worldwide, with a male predominance. Energy, porphyrin, and neurotransmitter homeostasis are the key metabolic pathways affected by heavy metal exposure, potentially implicated in the pathogenesis of ASD. Exposure to heavy metals can lead to an altered porphyrin metabolism due to enzyme inhibition by heavy metals. Heavy metal exposure, inborn genetic susceptibility, and abnormal thiol and selenol metabolism may play a significant role in the urinary porphyrin profile anomalies observed in ASD. Altered porphyrin metabolism in ASD may also be associated with, vitamin B6 deficiency, hyperoxalemia, hyperhomocysteinemia, and hypomagnesemia. The present review considers the abnormal porphyrin metabolism in ASD in relation to the potential pathogenic mechanism and discusses the possible metabolic therapies such as vitamins, minerals, cofactors, and antioxidants that need to be explored in future research. Such targeted therapeutic therapies would bring about favorable outcomes such as improvements in core and co-occurring symptoms.

Biochemical, Genetic and Clinical Diagnostic Approaches to Autism-Associated Inherited Metabolic Disorders.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by impaired social interaction, limited communication skills, and restrictive and repetitive behaviours. The pathophysiology of ASD is multifactorial and includes genetic, epigenetic, and environmental factors, whereas a causal relationship has been described between ASD and inherited metabolic disorders (IMDs). This review describes biochemical, genetic, and clinical approaches to investigating IMDs associated with ASD. The biochemical work-up includes body fluid analysis to confirm general metabolic and/or lysosomal storage diseases, while the advances and applications of genomic testing technology would assist with identifying molecular defects. An IMD is considered likely underlying pathophysiology in ASD patients with suggestive clinical symptoms and multiorgan involvement, of which early recognition and treatment increase their likelihood of achieving optimal care and a better quality of life.

The establishment of a population-specific reference value for the ruler drop test for the clinical assessment of reaction time.

BACKGROUND: Reaction time (RT) is the interval between a stimulus and an appropriate voluntary response in an individual. Alcohol is known to result in delayed RT. In Sri Lanka, an alleged drunken driver is legally subjected to a medico-legal examination to confirm or exclude impairment. The guideline for examining a drunk person in Sri Lanka includes the ruler drop test (RDT) as a test of RT. RDT is a simple test of visual reaction time in which the subject attempts to stop a falling ruler, and the height fallen is used to determine the time taken to react to the event. However, a formal study has yet to be carried out to establish population-specific reference values to interpret RDT results. METHODS: A cross-sectional descriptive study was conducted using 903 adults ≥18 years. A nonparametric approach was applied for deriving the reference values based on an inter-percentile interval. RESULTS: The study population consisted of 56.6% females, and the mean age of the participants was 41.6 years. Most (95%) of the study population could catch the ruler at or less than 40.0 cm of average height. The average height on RDT increased from younger to older age groups. However, subgrouping based on other variables, including sex, age, and alcohol consumption, did not show any statistically significant difference. CONCLUSIONS: The population-specific cut-off limit to identify alcohol intoxication by RDT in a Sri Lankan adult is 'average height' >40 cm.

The role of legal medicine professionals in preventing pregnancy and sexually transmitted infections among female victims of sexual assault.

Sexual violence can have an overwhelming impact on the victim's physical and mental health; the consequences include unintended pregnancy and sexually transmitted infections (STIs). Therefore, the examiners must assess victims for possible pregnancy and sexually transmitted infections as a part of the sexual assault examination. This article aims to orient the medico-legal examiners towards their role in preventing unintended pregnancy and sexually transmitted infections among victims of sexual assault. Prompt detection of pregnancy or STIs is critical, as any delay would adversely affect the successful administration of emergency contraception and post-exposure prophylaxis (PEP) against human immunodeficiency virus (HIV) and other sexually transmitted infections.

The Rationale for Vitamin, Mineral, and Cofactor Treatment in the Precision Medical Care of Autism Spectrum Disorder.

Children with autism spectrum disorder may exhibit nutritional deficiencies due to reduced intake, genetic variants, autoantibodies interfering with vitamin transport, and the accumulation of toxic compounds that consume vitamins. Importantly, vitamins and metal ions are essential for several metabolic pathways and for neurotransmitter functioning. The therapeutic benefits of supplementing vitamins, minerals (Zinc, Magnesium, Molybdenum, and Selenium), and other cofactors (coenzyme Q10, alpha-lipoic acid, and tetrahydrobiopterin) are mediated through their cofactor as well as non-cofactor functions. Interestingly, some vitamins can be safely administered at levels far above the dose typically used to correct the deficiency and exert effects beyond their functional role as enzyme cofactors. Moreover, the interrelationships between these nutrients can be leveraged to obtain synergistic effects using combinations. The present review discusses the current evidence for using vitamins, minerals, and cofactors in autism spectrum disorder, the rationale behind their use, and the prospects for future use.

Non-specificity of symptoms in infantile-onset Pompe disease may delay the diagnosis and institution of treatment.

Pompe disease is an autosomal-recessive inherited disorder of glycogen metabolism due to lysosomal acid alpha-glucosidase deficiency. The infantile-onset form is rapidly fatal if left untreated and presents with respiratory symptoms, a typical encounter during infancy. We discuss two infants presenting with respiratory symptoms since early infancy and found to have cardiomegaly, hypotonia, elevated muscle enzymes, leading to the diagnosis of Pompe disease with genetic confirmation. However, both infants expired before the enzyme replacement therapy due to complications of irreversible muscle damage despite supportive medical care. Presentation with respiratory symptoms common during childhood, absence of alarming symptoms such as hypoglycaemia, ketoacidosis or encephalopathy, and relative rarity of Pompe disease can contribute to lapses in the early diagnosis as observed in the index patients. Thus, these cases emphasise the importance of vigilant assessment of common paediatric presentations, which may be presenting symptoms of underlying sinister pathologies.

A rare co-occurrence of duchenne muscular dystrophy, congenital adrenal hypoplasia and glycerol kinase deficiency due to Xp21 contiguous gene deletion syndrome: case report.

BACKGROUND: Contiguous gene deletion syndromes are rare genomic disorders caused by deletion of large segments of DNA resulting in co-occurrence of apparently unrelated multiple clinical phenotypes. We report a boy with contiguous gene deletion involving Xp21 genomic location. CASE PRESENTATION: A Sri Lankan boy with developmental delay and failure to thrive first presented at three years of age with hypovolaemia, hyperpigmentation and drowsiness. Investigations done at that time revealed hypoglycaemia, hyponatraemia, hyperkalaemia, low cortisol, low aldosterone, high ACTH and low 17-hydroxyprogesterone. He was diagnosed to have primary adrenal insufficiency. During follow-up at five years, he was noted to have progressive difficulty in walking, waddling gait, hypotonia, calf hypertrophy and positive Gower's sign. His creatine kinase was very high, and the electromyogram showed myopathy. Genetic analysis revealed hemizygous deletion involving the final 35 exons of the dystrophin gene confirming the diagnosis of Duchenne muscular dystrophy. Further investigations revealed pseudohypertriglyceridemia, large glycerol peak on urine organic acid analysis and hemizygous deletion of the glycerol kinase gene confirming glycerol kinase deficiency. Based on the presence of Duchenne muscular dystrophy, glycerol kinase deficiency and probable congenital adrenal hypoplasia along with genetic confirmation of deletions involving dystrophin and glycerol kinase genes, the diagnosis of Xp21 contiguous gene deletion syndrome was made. CONCLUSIONS: We report a child with contiguous gene deletion syndrome who was initially diagnosed as having isolated primary adrenal insufficiency probably due to congenital adrenal hypoplasia. Later he was confirmed to have Duchenne muscular dystrophy and glycerol kinase deficiency, as well. This case report highlights the importance of pre-emptive evaluation and identification of genetic defects when patients present with seemingly unrelated diseases that could aid in accurate diagnoses of contiguous gene deletion syndromes.

Milky pleural effusion in a neonate and approach to investigating chylothorax.

Neonatal chylothorax is a rare presentation leading to significant respiratory distress, thus requiring timely diagnosis. A preterm neonate was resuscitated and ventilated, following which she clinically improved but subsequently developed respiratory distress with a right-sided pleural effusion. Interestingly, thoracentesis fluid appeared 'milky' with elevated triglycerides and lymphocytes, suggesting chylothorax. As fluid triglyceride level was lower than the established diagnostic criterion for chylothorax (1.24 mmol/L), a high fluid-to-serum triglyceride ratio was used as a surrogate diagnostic marker, later confirmed by lipoprotein electrophoresis. As observed in the index patient, a critically ill neonate would have a lower-than-average fat intake leading to less chylomicron production, thus lower triglyceride levels in chyle than expected, which may still fail to meet the amended cut-off limit. This case highlights the challenges in diagnosing neonatal chylothorax due to the lack of age-specific triglyceride levels in chyle and low oral fat intake in critically ill patients.

Patient with respiratory distress, facial oedema and refractory hypokalaemia.

Small cell lung carcinoma, when associated with co-occurrence of complications such as paraneoplastic syndrome and superior vena cava syndrome, poses a greater management challenge to the clinical team. We report a 56-year-old man who was eventually diagnosed with stage III small cell lung carcinoma, presenting with respiratory distress, facial and upper body oedema, proximal muscle weakness, hypokalaemia, new-onset hypertension and hyperglycaemia. His medical management was complicated by associated superior vena cava syndrome and Cushing's syndrome leading to refractory hypokalemia, immunosuppression and depression. Although the patient improved clinically and biochemically with the chemotherapy and other treatments, the development of neutropenic pneumonia led to his demise. This case highlights the importance of a multidisciplinary approach to achieve better patient care and the need for good clinical vigilance to identify possible humoral manifestations of aggressive malignancies such as small cell carcinoma of the lung to assist their early detection.

A study into blood alcohol concentration in fatal accidents among vulnerable road users in a tertiary care hospital Sri Lanka.

Reckless driving behaviour associated with alcohol has been well known. In Sri Lanka, research on blood alcohol concentration (BAC) in road fatalities is scares. Thus, we studied the BAC in vulnerable road users (VRUs) encountered in medico-legal autopsies. A retrospective descriptive study based on case records of VRU fatalities from 2005 to 2012 referred for a tertiary care unit for post-mortem examination was conducted. A pro-forma was developed to extract data from the post-mortem blood alcohol reports. Data were analysed using percentages and p-values. There were 119 cases from the 328 autopsies to investigate blood alcohol tests. A total of 51% (n = 61) out of 119 had BAC above 80 mg/100 ml and mean level was 103 mg/100 ml. 2/3 of pedestrians had a BAC above 80 mg/100 ml with a mean level of 139 mg/dl. The highest mean blood alcohol (158 mg/dl) was reported from three-wheeler users. Majority of cases with more than 80 mg/100 ml BAC was reported in the age group of 40-60 years, while 40% of the elderly too had a BAC above 80 mg/100 ml. The comparison between pedestrians having above 80 mg/100 ml of BAC with that of other VRUs (active road users) showed a significant statistical difference (p = 0.017). The study results suggest that alcohol influence among pedestrians represent a significant risk factor for fatal road traffic accidents.