Efrat Ben-Shalom

Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation

The mitochondrial respiratory chain comprises 85 subunits, 13 of which are mitochondrial encoded. The synthesis of these 13 proteins requires many nuclear‐encoded proteins that participate in mitochondrial DNA replication, transcript production, and a distinctive mitochondrial translation apparatus. We report a patient with agenesis of corpus callosum, dysmorphism, and fatal neonatal lactic acidosis with markedly decreased complex I and IV activity in muscle and liver and a generalized mitochondrial translation defect identified in pulse‐label experiments. The defect was associated with marked reduction of the 12S rRNA transcript level likely attributed to a nonsense mutation in the MRPS16 gene. A new group of mitochondrial respiratory chain disorders is proposed, resulting from mutations in nuclear encoded components of the mitochondrial translation apparatus. Ann Neurol 2004;56:734–738

Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids

In an infant who suffered from prolonged icterus and hepatocellular dysfunction we detected an increase of citrulline and dibasic amino acids in plasma and urine. The amino acid levels along with all the abnormal liver tests normalized upon replacing breast-milk by formula feeding; there was no relapse after human milk was tentatively reintroduced. A novel mutation, a approximately 9.5-kb genomic duplication, was identified in the citrin gene (SLC25A13) resulting in the insertion of exon 15. No mutation was detected in the CAT2A specific exon of the SLC7A2 gene which encodes for the liver transporter of cationic amino acids. This is the first report of infantile citrin deficiency in non-Asian patients.

Dent’s disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg?

Dent’s disease is an X-linked proximal tubulopathy. It often manifests in childhood with symptoms of Fanconi syndrome and low-molecular-weight proteinuria. We describe four boys from three unrelated families whose only presenting symptoms of Dent’s disease were nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis. In all families, a causal mutation in the CLCN5 gene, encoding a voltage-gated chloride transporter and chloride-proton exchanger, was identified. All three mutations are pathogenic: two are novel (p.Asp727fs and p.Trp122X), and one is a recurrent mutation, p.R648X. Given the atypical phenotype of these patients with Dent’s disease, it is possible that this clinical entity is markedly underdiagnosed and that our report represents only the tip of the iceberg. The diagnosis of Dent’s disease should be considered in all patients with nephrotic-range proteinuria without hypoalbuminemia or edema. Establishing the diagnosis of Dent’s disease will prevent the administration of unnecessary immunosuppressive medications with their undesirable side effects.

N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy

Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N‐acetylglutamate, is synthesized from acetyl‐CoA and glutamate in a reaction catalyzed by N‐acetylglutamate synthase (NAGS). We have identified the putative human NAGS gene and report the first mutation in this gene in a family with carbamylglutamate responsive hyperammonemia and normal activity of the urea cycle enzymes. Mutation analysis has a higher diagnostic specificity than the enzymatic assay in NAGS deficiency. A therapeutic trial with carbamylglutamate is recommended whenever hyperammonemia without an organic aciduria, increased orotate excretion, or diagnostic amino acidemia/uria is detected.

Primary hyperoxalurias: diagnosis and treatment

Primary hyperoxalurias (PH) comprise a group of three distinct metabolic diseases caused by derangement of glyoxylate metabolism in the liver. Recent years have seen advances in several aspects of PH research. This paper reviews current knowledge of the genetic and biochemical basis of PH, the specific epidemiology and clinical presentation of each type, and therapeutic approaches in different disease stages. Potential future specific therapies are discussed.

Congenital analbuminemia with acute glomerulonephritis: a diagnostic challenge

Congenital analbuminemia is a rare autosomal recessive disease in which albumin is not synthesized. Patients with this disorder generally have minimal symptoms despite complete absence of the most abundant serum protein. We report a family in which the proband presented with acute glomerulonephritis and was found to have underlying congenital analbuminemia. Consequently, the patient’s two older sisters were diagnosed with the same condition. Sequencing of the human serum albumin gene was performed, and a homozygous mutation in exon 3 was found in all three patients. Together with these three patients of Arab ethnicity, this mutation, known as Kayseri, is the most frequently described mutation in congenital analbuminemia. This article discusses clinical features and diagnostic challenges of this disorder, particularly in this case, where concomitant renal disease was present.

TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae.

Eosinophilia in a peritoneal dialysis patient: Answers

Icodextrin is a starch-derived glucose polymer used in peritoneal dialysis dialysate to treat volume overload by increasing ultrafiltration in patients with end-stage renal disease. Reported adverse reactions to icodextrin are mild and rare and mainly consist of skin rash that resolves spontaneously after discontinuation of treatment. We describe a young patient with extreme eosinophilia that appeared with the use of icodextrin, disappeared after its discontinuation, and reappeared after a rechallenge with the drug. The eosinophilia was not associated with peritonitis, was asymptomatic, and fully resolved after discontinuation of the drug. Severe eosinophilia can potentially cause tissue damage in several organs, which would indicate that blood eosinophil count is recommended in routine complete blood counts while icodextrin peritoneal dialysis is being administered.

A non-resolving skin lesion in hemodialysis patient: Questions

A 6-year-old boy treated with chronic hemodialysis, presented with an ulcerative lesion on his left fifth toe (Fig. 1). He had presented at 4 months of age with end-stage kidney disease and was diagnosed with primary hyperoxaluria type 1 (PH1) due to homozygous mutation in AGXT. He has been treated since with chronic hemodialysis six days per week, through a central venous catheter. He was afebrile and hemodynamically stable. Physical examination was remarkable for short stature, severe hepatosplenomegaly, and bone deformities due to recurrent pathological fractures. The central venous catheter exit site looked well with no signs of infection. Ophthalmological examination revealed retinal oxalate deposits and bilateral macular fibrosis. His skin lesion was suspected to be pyogenic granuloma and repeated topical application of silver nitrate was unsuccessful. Local excision of the entire lesionwas performed. Microscopic examination of the lesion is shown (Fig. 2).

A non-resolving skin lesion in hemodialysis patient: Answers

1. The histological examination revealed calcium-oxalate crystal deposition, as part of systemic oxalosis at the base of ulcerated skin with superficial acute inflammation. 2. Systemic oxalosis appears when glomerular filtration rate (GFR) falls below 30–40 ml/min/1.73 m and results in calcium oxalate depositions in various organs including heart, blood vessels, bone, joints, retina, thyroid gland, and skin. 3. The definitive treatment of primary hyperoxaluria type 1 (PH1) is liver transplantation. In the case of end-stage kidney disease, combined (or sequential) renal and liver transplantation is the only curative modality.