Acute renal failure and 2,8-dihydroxyadeninuria

We report the case of a 65 year old man, with a history of recurrent urolithiasis, who was referred for an acute renal failure. Investigations deny obstructive or glomerular involvement. 2,8-Dihydroxyadeninuria was diagnosed with the help of crystalluria. This rare metabolic disease is due to a deficiency of adenine phosphoribosyltransferase, a purine salvage enzyme. Allopurinol, a low purine diet and high fluid intake made possible the nearly entire regression of renal failure.     

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos

Microphthalmia is a developmental eye defect that is highly variable in severity and in its potential for systemic association. Despite the discovery of many disease genes in microphthalmia, at least 50% of patients remain undiagnosed genetically. Here, we describe a cohort of 147 patients (93 families) from our highly consanguineous population with various forms of microphthalmia (including the distinct entity of posterior microphthalmos) that were investigated using a next‐generation sequencing multi‐gene panel (i‐panel) as well as whole exome sequencing and molecular karyotyping. A potentially causal mutation was identified in the majority of the cohort with microphthalmia (61%) and posterior microphthalmos (82%). The identified mutations (55 point mutations, 15 of which are novel) spanned 24 known disease genes, some of which have not or only very rarely been linked to microphthalmia (PAX6, SLC18A2, DSC3 and CNKSR1). Our study has also identified interesting candidate variants in 2 genes that have not been linked to human diseases (MYO10 and ZNF219), which we present here as novel candidates for microphthalmia. In addition to revealing novel phenotypic aspects of microphthalmia, this study expands its allelic and locus heterogeneity and highlights the need for expanded testing of patients with this condition.     

Genetic profiling of children with advanced cholestatic liver disease

Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers. Recent advances in the genetic classification of this group of disorders promise a highly personalized management although the genetic heterogeneity also poses a diagnostic challenge. Using a next‐generation sequencing‐based multi‐gene panel, we performed retrospective analysis of 98 pediatric patients who presented with advanced cholestatic liver disease. A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39. We find no evidence to support mono‐allelic phenotypic expression in the carrier parents despite the severe nature of the respective mutations, and no evidence of oligogenicity. The high‐carrier frequency of the founder mutations identified in our cohort (1 in 87) suggests a minimum incidence of 1:7246, an alarmingly high disease burden that calls for the primary prevention through carrier screening.     

Difficulties in diagnosing an aortic arch thrombus

INTRODUCTION: Thrombosis of the aortic arch is a rare and often underdiagnosed source of peripherical arterial embolic events. EXEGESIS: We report a case with a non-typical initial clinical presentation of polyarteritis nodosa. A mobile thrombus in the aortic arch was secondarily suspected when disseminated arterial embolism appeared. Transthoracic echocardiography failed twice to diagnosticate the source of embolism. The diagnosis was only performed with transesophageal echocardiography and confirmed by computed tomography and magnetic resonance imaging of the thoracic aorta. The thrombus completely disappeared after six months of oral anticoagulant therapy. CONCLUSION: Although rare, this diagnosis mustn't be disregarded in an etiologic view of recurrent and disseminated peripherical ischemic events (even clinically silent ones) under penalty of detrimental functional consequences due to a delayed diagnosis.     

Autozygome maps dispensable DNA and reveals potential selective bias against nullizygosity

PurposeCopy number variants are an important source of human genome diversity. The widespread distribution of hemizygous copy number variants in the DNA of healthy humans suggests that haploinsufficiency is largely tolerated. However, little is known about the extent to which corresponding nullizygosity (two-copy deletion) is similarly tolerated.MethodsWe analyzed a cohort of first cousin unions to enrich for shared parental hemizygous events and tested their Mendelian inheritance in offspring.ResultsAnalysis of autozygous DNA blocks (autozygome) in the offspring not only proved an efficient method of mapping “dispensable” DNA but also revealed potential selective bias against the occurrence of nullizygous changes. This bias was not restricted to genic copy number variants and was not accounted for by a high rate of miscarriages.ConclusionsThe autozygome is an efficient way to map dispensable segments of DNA and may reveal selective bias against nullizygosity in healthy individuals.Genet Med 2012:14(5):515–519     

The many faces of peroxisomal disorders: Lessons from a large Arab cohort

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the “gold standard” very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.     

Acute myocardial infarction. Analysis of the activities of the ambulance "R"]

Frequency of emergency calls for ambulance help to patients with acute myocardial infarction (MI) as well as a number of infarct complications and the influence of immediate professional help on survival of prehospital phase of acute MI is reviewed. The diagnosis of acute MI was based on a typical history of chest pain and electrocardiographic findings. Acute MI was also diagnosed in all cases of sudden cardiac death. Out of 3674 calls for ambulance help, MI was diagnosed in 379 patients what amounts for 10.1% of all interventions in life-threatening cases and for 61% of patients with acute MI in the analysed period of time. Complicated MI was observed in 61.7% of all patients, including 70.5% of men and 49.3% of women. Arrhythmic complications occurred in 54.5% of patients. Ventricular ectopic activity was the most frequent arrhythmia and amounted to 46.6%. The II0 or III0 atrioventricular block occurred in 4.5% of patients. Haemodynamic complications occurred in 12.3% of cases. Sudden cardiac death occurred in 23.6% of patients with acute MI, including 21.9% cases of ventricular fibrillation or flutter and 1.7% of asystole. 28.5% of those patients were successfully resuscitated. 61% of patients died in the prehospital phase of acute MI including 63.4% of males and 57.2% of females. Out of 61% of patients who died before admission to the hospital, 53% had died before ambulance team arrived and 7.9 died being under the care of the ambulance team. 80% of patients who survived prehospital phase of acute MI were admitted to the hospital within 60 min after the call for the ambulance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical and genetic features of anoctaminopathy in Saudi Arabia

Objectives:

Characterization of the phenotypic, pathological, radiological, and genetic findings in 2 Saudi Arabian families with anoctaminopathies, and limb girdle muscular dystrophy type 2L (LGMD2L).

Methods:

Over a 2-year period from December 2010 to January 2013, the clinical presentations were analyzed and all genes responsible for limb girdle muscular dystrophy (LGMD) were screened in families seen at King Faisal Specialist Hospital and Research Centre, a tertiary care hospital in Riyadh, Saudi Arabia. Out of 66 families with LGMD, we identified 2 families (3.1%) with anoctaminopathy, ANO5 muscular dystrophy.

Results:

In the first case, a man presented with asymmetrical calves’ muscles weakness and atrophy, which was first noted at age 39. The creatinine kinase (CK) level was >20x normal, muscle biopsy showed necrotizing myopathic changes, and an MRI of the legs showed fatty-tissue replacement to muscle tissue with volume loss involving the gastrocnemius and soleus muscles in an asymmetrical fashion. Minimal disease progression was noted over 18 years of follow up. Exercise induced recurrent rhabdomyolysis was noted over the last 2 years. A novel ANO5 gene mutation (Arg58Trp) was found. In the second family, a male presented at the age of 41 with asymptomatic hyperCkemia and intermittent dyspnea. Over 10 years follow up, he became disabled with muscle cramps, rhabdomyolysis, myoglobinurea, and difficulty ambulating. Muscle biopsy showed necrotizing myopathy and perivascular and interstitial amyloid deposit in skeletal muscle. A homozygous deletion of 11.9 Kb encompassing exon 13 to exon 17 was found in the ANO5 gene. Full cardiac investigations were normal in both patients.

Conclusion:

The prevalence of LGMD2L is approximately 3.1% in a Saudi Arabian native LGMD cohort. Slowly progressive, late onset, and asymmetrical weakness was the salient features in these 2 families. The genetic findings were novel and will add to the spectrum of ANO5 known mutations.Anoctamin is a protein involved in the calcium-activated chloride channel and named as such because it contains 8 transmembrane domains that are anions (ano “anion” and octa=8). The exact function of anoctamin 5 (ANO5) proteins are still not exactly known. It is possibly involved in cell membrane repair.1 An autosomal recessive mutation in ANO5 causes limb girdle muscular dystrophy type 2L (LGMD2L). This condition is characterized by proximal weakness affecting the pelvic girdle and leg muscles, or with only distal weakness known as non-dysferlin Miyoshi muscular weakness type 3 (MMD3).2-4 Anoctamin related muscle disorder was first described in 14 French Canadian patients in 2007.2 Subsequently, only a few cases were described from different ethnic groups.3-15 Cases of isolated hyperCKemia and pseudo metabolic myopathy were also reported to be caused by ANO5 gene mutations (MIN# 608662). In this communication, we describe the clinical and genetic findings in 2 native Arab patients who presented with a long history of exercise intolerance and high CK, and were found to have ANO5 related muscular dystrophy.     

SARS-CoV-2–Related Acute Respiratory Distress Syndrome Uncovers a Patient with Severe Combined Immunodeficiency Disease

Journal of Clinical Immunology -