Yoseph Horovitz

TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome

Background The TMEM70 gene defect was recently identified as a novel cause of autosomal recessive ATP synthase deficiency. Most of the 28 patients with TMEM70 disorder reported to date display a distinctive phenotype characterised by neonatal onset of severe muscular hypotonia hypertrophic cardiomyopathy, facial dysmorphism, profound lactic acidosis, and 3-methylglutaconic aciduria. Almost all share a common Roma descent and are homozygous for a single founder splice site mutation. Methods Six new patients from four separate families, with clinical and biochemical diagnosis of ATP synthase deficiency, were studied. TMEM70 sequence analysis of the three exons and their flanking splice junction consensus sequences was performed in all patients. In addition their clinical phenotype and disease course was strictly studied. Results Four novel deleterious homozygous TMEM70 mutations were identified. The previously described clinical spectrum was expanded to include infantile onset cataract, early onset gastrointestinal dysfunction and congenital hypertonia with multiple contractures resembling arthrogryposis. The first characterisation of fetal presentation of the syndrome is also provided, featuring significant intrauterine growth retardation, severe oligohydramnios, fetal hypotonia, and myocardial wall thickening. Conclusions The current report corroborates the previously described unique phenotype of TMEM70 deficiency. The study identifies TMEM70 gene defect as a pan-ethnic disorder and further redefines it as the most common cause of nuclear-origin ATP synthase deficiency.

Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy

Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients’ skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.

Is omitting post urinary-tract-infection renal ultrasound safe after normal antenatal ultrasound? - an observational study

Background: Guidelines recommend obtaining a renal ultrasonogram (RUS) for young children after a first urinary tract infection (UTI). Objective: The aim of the current study was to assess the concordance of prenatal and post-UTI RUS findings in children with a first simple UTI. Methods: This was a prospective study and included all children aged 5 years or younger who were hospitalised with a first simple UTI (determined as clinical response and normalisation of temperature within 48 h on initiation of antibacterial therapy with no complications). Data were collected from each child regarding the results of prenatal and post-UTI RUS. Results: Overall, 250 children were included in the study and the results of late-pregnancy and post-UTI RUS were available for 84% (n = 209). Complete concordance between the two RUS was demonstrated in 96% (n = 201). The predictive value of normal antenatal to normal post-UTI RUS was 96% (95% CI: 93% to 99%). These results include four children with mild transient pelvic dilatation. In eight children in whom renal anomalies were demonstrated only in post-UTI RUS, the influence of these anomalies on the children’s management was negligible. Conclusions: Prenatal-RUS have been performed in most children <5 years old hospitalised with a first simple UTI. Concordance with post-infection tests is very high. Findings which appear only in post-infectious RUS usually have negligible effects on children’s management. Thus, in such children with normal antenatal RUS omitting post-UTI RUS could be considered.

Myopathic form of phosphoglycerate kinase (PGK) deficiency: A new case and pathogenic considerations

We describe an 18-year-old man with muscle cramps and recurrent exertional myoglobinuria, without hemolytic anemia or brain dysfunction. Phosphoglycerate kinase (PGK) deficiency was documented in muscle and erythrocytes and molecular analysis of the PGK1 gene identified a novel mutation, T378P. This is the ninth case presenting with isolated myopathy, whereas most other patients show hereditary non-spherocytic hemolytic anemia alone or associated with brain dysfunction, and a few patients have myopathy plus brain involvement. Although the diverse tissue involvement in PGK deficiency remains unclear, all mutations in myopathic patients tend to cluster in the C terminal domain, adjacent to the substrate-binding pocket. This may lead to a failure in the closure of the N terminal and C terminal domains and loss of stability due to lack of inter-domain communication during the catalytic process.

Expanding the clinical spectrum of SLC29A3 gene defects

H syndrome and pigmented hypertrichosis with insulin dependent diabetes (PHID) are allelic autosomal recessive syndromes reported in the last year to be caused by mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Herein, we report three new patients from a single family who present with phenotypes that associate features of both PHID and H syndrome. Genetic analysis of the SLC29A3 gene revealed that two affected sisters are compound heterozygotes for the previously reported mutations p.G427S and p.G437R, while their nephew was homozygous for the p.G437R mutation. In addition to this intra-familial genetic heterogeneity, these patients demonstrate considerable phenotypic variability. One sister had clinical features consistent with classical PHID phenotype, while her nephews features were in keeping with the diagnosis of H syndrome. The second sister displayed the most severe phenotype which combined diagnostic features from both syndromes. This patient also had features not described previously, including severe seronegative polyarthritis involving large and small joints, and hypogonadotropic hypogonadism. These manifestations may be additional characteristics of the growing clinical spectrum of SLC29A3 defects. This report emphasizes the complex genotype phenotype correlation in SLC29A3 disorders and suggests that other factors are relevant to disease manifestations and severity.

Late Relapse of Herpes Simplex Virus Encephalitis in a Child Due to Reactivation of Latent Virus: Clinicopathological Report and Review

A child suffered from herpes simplex virus encephalitis at the age of 6 months; a late relapse occurred 8.5 years after the initial episode, the longest latency period reported. Radiologic and autopsy findings suggest local reactivation of latent herpes simplex virus as the cause of relapse. All cases of late relapse of herpes simplex virus encephalitis in the last 15 years are reviewed, with emphasis on clinical characteristics and possible mechanisms.

Pylephlebitis due to perforated appendicitis in a teenager

Pylephlebitis, a septic thrombophlebitis of the portal vein, is a life-threatening complication of intraabdominal infections, commonly associated with acute appendicitis in children, and diverticulitis in adults. A 13-year-old boy was admitted for high fever and jaundice. On the fifth day of hospitalization, ultrasound Doppler flow and Computer Tomography scan studies showed thrombosis of the portal vein and acute appendicitis. The patient was treated with antibiotics, anticoagulation and laparotomy with appendectomy. No thrombophilic risk factors were diagnosed. Our aim is to improve physicians’ awareness of this complication and emphasize the importance of early diagnosis and appropriate therapy in children in order to reduce serious complications and long-term sequels.

Eosinophilic Pericarditis—A Rare Complication of Idiopathic Hypereosinophilic Syndrome in a Child

We describe an 18-month-old child with idiopathic hypereosinophilic syndrome (IHES) who presented with fever, and cervical lymphadenoathy. Chest X-ray showed marked cardiomegaly, and echocardiogram revealed large pericardial effusion. Other causes of pericarditis were excluded. Despite the initiation of steroid therapy, signs of impending cardiac tamponade developed. Pericardiocentesis yielded bloody fluid with a white blood count of 14,800/mm3, of which 23% were eosinophils. The child recovered after pericardial drainage and prolonged systemic steroid therapy. Eosinophilic pericarditis is a rare but potentially dangerous complication of IHES.

Acute human parvovirus B-19 infection in hospitalized children: A serologic and molecular survey.

Background: The extent and clinical manifestations of acute human parvovirus B19 (B19) infection were assessed in previously healthy hospitalized children admitted with clinical syndromes potentially associated the virus. Patients and Methods: The study was prospective and was conducted between October 2002 and August 2004 in the pediatric departments of 3 hospitals in Israel. The survey included previously healthy children who were hospitalized with 1 or more of the following acute diseases: acute nonallergic exanthema, fever for >1 week, aplastic anemia or pancytopenia, acute nonbacterial arthropathy, immune thrombocytopenic purpura (ITP), Henoch-Schönlein purpura (HSP) and aseptic meningitis. A control group of children with a proven, non-B19 infection was also studied. Serum samples obtained from each child on admission were tested for B19 DNA by real-time PCR and B19 IgM by ELISA. Acute B19 infection was defined by the following criteria: positive serum B19-DNA and/or B19 IgM, negative serum B19 IgG, and no other proven infection. Results: Overall, 167 children were included in the study. The mean age was 5.5 ± 4.6 years (range, 0.5–17), males and females equally divided. Acute B19 infection was demonstrated in 12.6% (n = 21) of the children. Both tests were performed in 19 children and were positive in 10 (53%). In 7 and 2 children, only B19-DNA or B19 IgM, respectively, was positive. Acute B19 infection was documented in 27% (10/39) of children who presented with a variety of acute exanthema diseases; 9% (5/57) of children with acute arthropathy (all 5 had transient synovitis); 10% (2/21) of children with fever >1 week, both presented as mononucleosis syndrome; and in 44% (4/9) of children with transient pancytopenia or aplastic anemia. No acute B19 infection was demonstrated in 15 children with ITP, 9 with HSP, and 6 with aseptic meningitis and among 70 children in the control group. By logistic regression analysis, manifestations significantly associated with acute B19 infection were exanthema (OR 2.9; 95% CI = 1.1–7.5), anemia (OR 6.35; 95% CI = 2.2–18.2) and leucopenia (OR 4.14; 95% CI =1.2–14.2). Conclusions: Acute B19 infection was documented among 12.6% of children hospitalized with clinical syndrome potentially associated with the virus. Clinical and laboratory features associated with acute B19 infection were exanthema, anemia and leucopenia. Determination of both serum B19-DNA and serum B19 IgM should be performed for the accurate diagnosis of acute B19 infection.

Secondary diabetes mellitus: late complication of glycogen storage disease type 1b.

We report a 22 year-old male with glycogen storage disease type 1 (GSD-1) who developed diabetes mellitus secondary to pancreatic islet beta-cell insufficiency. Diabetes mellitus should be considered among the late complications of GSD-1. The pathogenesis of the conversion, from a disease characterized by hypoglycemia to a disease dominated by hyperglycemia, is discussed.