Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

Emergency management of critically ill adult patients with inherited metabolic disorders.

INTRODUCTION: An increasing number of pediatric patients with inherited metabolic disorders are reaching adulthood. In addition, many patients are diagnosed for the first time in adult life due to improved awareness of these disorders and the availability of advanced diagnostic technology. Knowledge of these inherited metabolic disorders in adults is crucial for the emergency physician to promptly recognize their acute illness and appropriately manage them in the emergency department. OBJECTIVE: This review provides an overview of various inherited metabolic disorders which present to the emergency department with acute metabolic decompensation. EVALUATION AND MANAGEMENT: Acute illness in these patients is often triggered by a catabolic event such as intercurrent illness, fasting, postpartum, or use of certain medication. It may present in a variety of ways related to severe hyperammonemia, metabolic acidosis, leucine encephalopathy or hypoglycemia. In this review, we describe the clinical presentation, evaluation and immediate management of their critical illness in the emergency department. CONCLUSION: Acute metabolic decompensation is a life-threatening condition. The emergency physician is usually the first provider to evaluate these patients when they present to the emergency department. Early recognition of their illness and prompt management of these cases improve patient outcomes.

MYH1 is a candidate gene for recurrent rhabdomyolysis in humans.

Rhabdomyolysis is a serious medical condition characterized by muscle injury, and there are recognized genetic causes especially in recurrent forms. The majority of these cases, however, remain unexplained. Here, we describe a patient with recurrent rhabdomyolysis in whom extensive clinical testing failed to identify a likely etiology. Whole-exome sequencing revealed a novel missense variant in MYH1, which encodes a major adult muscle fiber protein. Structural biology analysis revealed that the mutated residue is extremely well conserved and is located in the actin binding cleft. Furthermore, immediately adjacent mutations in that cleft in other myosins are pathogenic in humans. Our results are consistent with the finding that MYH1 is mutated in rhabdomyolysis in horses and suggest that this gene should be investigated in cases with recurrent rhabdomyolysis.

The neuroimaging findings of monocarboxylate transporter 1 deficiency.

Monocarboxylate transporter 1 (MCT1) deficiency was first described in 2014 by Hasselt et al. as a novel genetic cause of recurrent ketoacidosis. Patients present in the first year of life with acute episodes of ketoacidosis triggered by fasting or infections. Patients with homozygous mutations are known to have a more severe phenotype with mild to moderate developmental delay and an increased prevalence of epilepsy. There is only one recent report of the neuroimaging findings of this disorder as reported by Al-Khawaga et al. (Front Pediatr. 7:299, 2019). We report the neuroimaging abnormalities in two siblings with similar clinical presentation of recurrent ketoacidosis, seizures, and developmental delay. Whole exome sequencing in the younger sibling confirmed a known pathogenic homozygous mutation in MCT1, also known as SLC16A1 gene. Brain MRI showed a similar very distinctive pattern of signal abnormality at the gray-white matter junction, basal ganglia, and thalami in both patients. Both siblings had agenesis of the corpus callosum. Knowledge of this pattern of brain involvement might contribute to an earlier diagnosis and timely management of this rare and under recognized disorder.

Corrigendum: Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation.

This corrects the article DOI: 10.1038/gim.2017.22.

Spectrum of bone marrow pathology and hematological abnormalities in methylmalonic acidemia.

Patients with isolated methylmalonic acidemia (MMA) may present with a wide range of hematological complications including anemia, leukopenia, thrombocytopenia, and pancytopenia. However, there are very limited data on the development of hemophagocytosis or myelodysplasia in these patients. We report three patients with isolated MUT related MMA who presented with severe refractory pancytopenia during acute illness. Their bone marrow examination revealed a wide spectrum of pathology varying from bone marrow hypoplasia, hemophagocytosis to myelodysplasia with ring sideroblasts. We discuss their management and outcome. This report emphasizes the need for bone marrow examination in these patients with refractory or unexplained severe cytopenia, to confirm bone marrow pathology, and to rule out other diseases with similar clinical presentation for a better clinical outcome.

Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation.

PURPOSE: The purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern. METHODS: Exome sequencing of patients from consanguineous families with likely recessive phenotypes was performed. In one family, the genotype of the deceased children was inferred from their parents due to lack of available samples. RESULTS: We describe the identification of 11 recessive variants (5 of which are reported here for the first time) in 11 genes for which only dominant disease or risk alleles have been reported. The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes. CONCLUSION: Our results show that, in the era of genomic sequencing and "reverse phenotyping," recessive variants in dominant genes should not be dismissed based on perceived "incompatibility" with the patient's phenotype before careful consideration.Genet Med advance online publication 06 April 2017.

COVID-19 in Unvaccinated patients with inherited metabolic disorders: A single center experience.

Patients with certain inherited metabolic disorders (IMD) are at high risk for metabolic decompensation with exposure to infections. The COVID-19 pandemic has been particularly challenging for health care providers dealing with IMD patients, in view of its unpredictable consequences in these patients. There is limited data in literature on evaluating the impact and the outcome of COVID-19 infection in these patients. This cross-sectional retrospective study on a large cohort of unvaccinated IMD patients, reviewed the incidence of COVID-19 infection, disease manifestation and outcome during the pandemic between November 2019 and July 2021. In this cohort of 1058 patients, 11.7% (n = 124) were infected with COVID-19. Their median age was 16 years (age range 2-42); 57% (n = 71) were males. Post-exposure positive test was noted in 78% (n = 97) patients, while 19% (n = 24) had symptomatic diagnosis and three patients tested positive during pre-hospital visits screening. Most patients, 68.5% (n = 85) had mild COVID-19 related symptoms such as fever, cough, headache and diarrhea while 13.7% (n = 17) patients had no symptoms. Of twenty-two patients (17.7%) who required hospitalization, 16 were adults with various intoxication and energy metabolism disorders, who developed IMD related complications such as metabolic acidosis, hyperammonemia, acute pancreatitis, hypoglycemia, rhabdomyolysis and thrombosis. Ten patients needed intensive care management. The cohort death rate was 2.4% (3 patients). Overall, the clinical course of COVID-19 infection in these IMD patients was relatively mild except for patients with intoxication and energy metabolism disorders who had high risk of developing acute metabolic decompensation with severe complications.

Inherited metabolic disorders and dyslipidaemia.

Monogenic dyslipidaemia is a diverse group of multisystem disorders. Patients may present to various specialities from early childhood to late in adult life, and it usually takes longer before the diagnosis is established. Increased awareness of these disorders among clinicians is imperative for early diagnosis. This best practice review provides an overview of primary dyslipidaemias, highlighting their clinical presentation, relevant biochemical and molecular tests. It also addresses the emerging role of genetics in the early diagnosis and prevention of these disorders.

Inherited Metabolic Disorders in Adults: A view from Saudi Arabia.

The incidence of inherited metabolic disorders (IMD) in Saudi Arabia is one of the highest in the world. Early diagnosis and advances in the treatment of these diseases have led to improved survival of these patients resulting in a rapidly growing number of adults with IMD. This is the first report from a single tertiary care center, on the experience of managing a large cohort of adult patients with a wide range of IMD. We describe the common IMD seen in adult patients in Saudi Arabia, highlighting the variations from the Caucasian populations, and unique challenges in providing care to these adults. We mention the pitfalls causing the delay in the diagnosis particularly in cases of late-onset IMD in adults. We also discuss some unusual complications seen in adult patients during the course of their disease. We describe the role of genetic prevention services in Saudi Arabia and the importance of research in this field.

Optic neuropathy in classical methylmalonic acidemia.

Background: Classical MMA, caused by methylmalonyl-CoA mutase deficiency, may result in late-onset dysfunction in several organ systems. To date, 10 cases of optic neuropathy have been reported. The prevalence of optic neuropathy in visually asymptomatic patients has not been determined. This study sought to identify overt and subclinical optic neuropathy in a cohort with classical MMA. Methods and Materials: Neuroophthalmic examinations were performed on 21 patients identified with classical MMA, older than 10years. Diagnosis of optic neuropathy was determined by a combination of visual acuity, optic nerve appearance and electrodiagnostic tests. Tabulated data were analyzed for association of variables using SAS software. Significance was set at p < .05. Results: Two-thirds were Saudi nationals and one third, Syrian. Age range was 11-29years. Eleven (52.4%) patients had optic neuropathy. Nine (81.8%) of these were bilateral, seven (57.9% to 63.6%) reported decreased vision and four (33.1% to 36.4%) were asymptomatic. Two patients had catastrophic vision loss, following acute metabolic crises. Sixteen patients had chronic renal impairment while three had renal hypertension. Seventeen patients had short stature and eight, chronic pancreatitis. Methylmalonic acid levels ranged from 82 to 3,324µmol/L (Normal<1µmol/L). There was a significant association between optic neuropathy and female gender (p = .011) and none with age, nationality, renal impairment, pancreatitis or specific genotype. Conclusion: Optic neuropathy was a frequent finding in classical MMA. It was often bilateral and some cases were sub-clinical, lacking visual symptoms. These findings have important management implications. Full ophthalmic evaluations should be performed early and regularly in patients with MMA, even when patients are asymptomatic.

Pasireotide and octreotide in the treatment of severe late dumping syndrome.

Hypoglycemia due to late dumping is a significant problem postoesophagectomy but may not always be diagnosed sufficiently early. It can be difficult to treat and may severely compromise quality of life. The combination of diazoxide and octreotide or more probably pasireotide may transform the patient's life and should be considered in all problematic cases.

Juvenile hemochromatosis and hepatocellular carcinoma in a patient with a novel mutation in the HJV gene.

Juvenile hemochromatosis is a rare but the most severe form of hereditary hemochromatosis which develops due to mutations in the HJV or HAMP genes. It presents in the early adulthood mainly as cardiomyopathy, hypogonadism and liver fibrosis. Unlike hereditary hemochromatosis due to HFE mutation, hepatocellular carcinoma is not known to be associated with juvenile hemochromatosis. Here, we report a patient of Arab ancestry who presented with severe cardiomyopathy. Sequence analysis of the HJV gene followed by homozygosity mapping, identified a previously undescribed homozygous missense variation in exon 3 (c.497A > G; p.H166R) in both the proband and his clinically asymptomatic brother. The former, later developed hepatocellular carcinoma. To the best of our knowledge, neither the mutation identified in our patient, nor a case of juvenile hemochromatosis with hepatocellular carcinoma has been reported before.

Depression in adult patients with biotin responsive basal ganglia disease.

Biotin responsive basal ganglia disease (BBGD), is a potentially treatable inherited metabolic disorder which clinically presents as sub-acute encephalopathy in children. Early diagnosis and treatment of this disorder results in good clinical recovery in childhood. However, there is no report in the literature on the long term outcome of these treated patients in adult life. We report two patients with BBGD who were metabolically stable on treatment and developed depression later in life. These cases highlight the association of depression with basal ganglia disorders and demonstrate that depression is the potential long term complication of BBGD.

Fibrolamellar hepatocellular carcinoma mimicking ornithine transcarbamylase deficiency.

We report an unusual case of recurrent non-hepatic hyperammonaemic encephalopathy in an adult patient. She had a previous history of treated fibrolamellar hepatocellular carcinoma (FLC). This posed a diagnostic challenge, as she had normal liver function tests and normal looking liver on imaging but with extra hepatic metastases. This case highlights the importance of measuring plasma ammonia levels in all patients presenting with unexplained acute confusion. Clinical awareness of non-hepatic hyperammonaemic encephalopathy can contribute to early diagnosis and timely initiation of life-saving treatment. Delay in treatment results in irreversible brain damage, deep coma and death. Treatment of hyperammonaemia must begin prior to confirmation of aetiology, for a favourable outcome. This case also highlights the need for further research to understand the exact mechanism of hyperammonaemia in hepatocellular carcinoma.

Effect of order of draw of blood samples during phlebotomy on routine biochemistry results.

AIM: To investigate whether incorrect order of draw of blood samples during phlebotomy causes in vitro potassium ethylenediaminetetraacetic acid EDTA (kEDTA) contamination of blood samples. METHODS: Serum kEDTA, potassium, calcium, magnesium, alkaline phosphatase, zinc and iron concentrations were measured in blood samples drawn before and after collecting blood into kEDTA containing sample tubes by an experienced phlebotomist using the Sarstedt Safety Monovette system. RESULTS: EDTA was undetectable in all samples. The concentrations of other analytes were similar in blood samples drawn before and after collection of the EDTA blood sample. CONCLUSION: Order of draw of blood samples using the Sarstedt Safety Monovette system has no effect on serum biochemistry results, when samples are taken by an experienced phlebotomist.

Ethnic differences in umbilical cord blood vitamin D and parathyroid hormone--South Asians compared to Whites born in the UK.

Serum calcium, 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were measured in umbilical cord blood samples taken from 54 White and 22 South Asian babies born in the UK during the summer months. South Asians had lower serum calcium (p < 0.0027) and 25OHD (p < 0.0002) than Whites. Serum PTH was low in all subjects, but South Asians had relatively higher concentrations of serum PTH (p < 0.001) than Whites. The lower vitamin D and calcium in South Asian newborns is not associated with secondary hyperparathyroidism as previously reported but may still explain their increased prevalence of neonatal hypocalcaemia and rickets.