Incidence of inherited metabolic disorders in southern Israel: a comparison between consanguinity and non-consanguinity communities.

BACKGROUND: Inherited metabolic disorders (IMDs) are group of rare monogenic diseases, usually derived from reduced or absent activity in a single metabolic pathway. Most of the IMDs are inherited in an autosomal recessive manner. The incidence of IMDs varies from country to country and within different ethnic groups, but data is still scarce. Consanguinity rate among populations is highly contributor factor for IMDs incidence. There are no reports comparing the incidence of IMD in consanguineous and non-consanguineous populations from the same geographic region with the same diagnostic capabilities. Our study objective is to compare the incidence of IMDs between between the relatively low consanguineous Jewish population and the consanguineous Bedouin population, both living in the southern of Israel. RESULTS: During 1990-2017 there were 393,772 live births in the Negev district, of Southern of Israel. Among them 187,049 were of Jewish origin while 206,723 were of Bedouin-Muslim origin. A total of 223 children were diagnosed in this study period with IMDs. Among those 223 children with IMD, 33 were of Jewish origin while the other 190 children were of Bedouin-Muslim origin. The overall incidence for IMDs of the overall Negev population was 56.6/100,000 live birth. The incidence for IMD's among the Bedouin population was significantly higher than among Jewish population. CONCLUSIONS: IMDs are extremely more common in the consanguineous Bedouin compared with the relatively non-consanguineous Jewish population of Southern Israel. Health policy makers should consider these data and prepare educational and genetic counselling problems accordingly.

Adrenal function following ACTH therapy for infantile spasms: A retrospective study.

OBJECTIVE: To determine if treatment with ACTH for infantile spasms (IS) is associated with secondary adrenal insufficiency. PATIENTS AND METHODS: This is a retrospective study of patients diagnosed with infantile spasms and treated with ACTH between 2007 and 2018 at Soroka University Medical Center (SUMC). We reviewed the records of patients who had a post-hormonal laboratory assessment of their adrenal function; either a low dose ACTH test or a random morning cortisol level and looked for laboratory or clinical signs of adrenal insufficiency. RESULTS: Between the years 2007 and 2018, 45 children were diagnosed with IS at our Pediatric Neurology Unit, 20 patients were treated with ACTH, of them 14 children met the inclusion criteria and had a post-treatment laboratory assessment of adrenal function by low dose ACTH test or morning cortisol level. Five children had a normal low dose ACTH test, two had normal morning cortisol level, five were not conclusive, and two had subnormal levels of cortisol. None of the children showed clinical signs of adrenal insufficiency. CONCLUSION: Our study adds to the limited literature on this topic and in contrast to previous publications suggests that adrenal suppression should not occur after ACTH treatment.

Pulmonary involvement in Niemann-Pick C type 1.

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder caused by mutations in either NPC-1 or NPC-2 genes, resulting in abnormal intracellular cholesterol trafficking. The estimated prevalence of NPC disease is 1: 120,000-150,000. Lung involvement has been described in only few patients with NPC, mostly NPC2. We describe a series of 12 patients, originating from six families all homozygotes to the p.R404Q (c.1211G > A) mutation of NPC1 gene; nine of them had significant pulmonary manifestations. All patients were followed in our medical center. Nine of the patients had pulmonary involvement, with recurrent pneumonia as the first manifestation in most, followed by recurrent wheezing episodes and subsequent development of interstitial lung disease with chronic need for oxygen support. Seven patients were reported of having interstitial disease by various imaging modalities.Conclusion: Pulmonary involvement in NPC1 is more common than previously reported. It is characterized as primary obstructive and restrictive lung disease and not only as part of neurologic sequel of NPC. It can lead to respiratory insufficiency and death from respiratory failure. What is Known: • Lung involvement has been described in only few patients with NPC. • Most reported NPC cases with pulmonary involvement were of NPC2. What is New: • Pulmonary involvement in NPC1 is more common than previously reported. • Pulmonary involvement in NPC1 should be considered as part of the disease and be thoroughly assessed and managed.

Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations.

Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.

Effects of a twelve-week randomized intervention of exercise and/or diet on weight loss and weight maintenance, and other metabolic parameters in obese preadolescent children.

AIMS: To compare the short- and long-term effects of intervention programs on body weight and cardiometabolic risk factors. METHODS: 162 obese children (6-11 years) were randomly assigned to three 12-week interventions with a 9-month follow-up period: exercise (E): 90 min moderate exercise 3 days/week (n = 52); diet (D): balanced hypocaloric diet, weekly meetings with dietician (n = 55), and diet + exercise (D+E) (n = 55). Changes in anthropometric variables, cardiometabolic profile and psychological outcome were assessed. RESULTS: At 12 weeks BMI-SDS, cardiometabolic profiles, and psychological score improved in all groups. The decrease in BMI-SDS was greater in D and D+E compared with E (p < 0.001), without a significant difference between the first two groups. Waist circumference and LDL cholesterol decreased more in D+E compared with E (p = 0.026 and p = 0.038, respectively). The increase in adiponectin was greater in D and D+E compared with E (p = 0.004). Anthropometric and cardiometabolic variables regressed without significant differences between groups after 9 months. However, BMI-SDS, body fat percentage and LDL cholesterol were lower compared to baseline. CONCLUSIONS: Diet alone or combined with exercise are the most effective short-term interventions for weight loss and improved cardiometabolic profiles, without a difference between them. In the long term, obese children need the long-term support of maintenance approaches.

Total oxidant-scavenging capacities of plasma from glycogen storage disease type Ia patients as measured by cyclic voltammetry, FRAP and luminescence techniques.

It has been suggested that the very low incidence of atherosclerosis in glycogen storage disease type Ia (GSD Ia) subjects might be attributed to elevated levels of uric acid, one of the potent low molecular- weight antioxidants found in plasma. The present communication describes a use of two analytical methods-cyclic voltammetry and ferric reducing ability of plasma-and also two chemiluminescence methods to evaluate the total oxidant-scavenging capacities (TOSC) of plasma from GSD Ia patients. Our results verified the elevation of TOSC in GSD Ia patients and we propose the inclusion of luminescence and cyclic voltammetry assays as reliable methods for estimating TOSC in a variety of clinical disorders. Our findings with the cyclic voltammetry method add support to the assumption that the elevated uric acid levels might be the main contributor to plasma antioxidant capacity and possible protection against atherosclerosis.

The childhood component of the ICP model is appropriate for growth analysis of short Israeli children.

OBJECTIVE: To determine whether the childhood component of the infancy-childhood-puberty (ICP) model is appropriate for growth analysis of short Israeli children. SUBJECTS AND METHODS: From 204 short, prepubertal children, 2-16 years of age, 1,516 height measurements were analyzed. For each child's measurements, a best-fitted line based on C equation of ICP has been drawn and the distribution of measurement points around that line was calculated. RESULTS: Ninety percent of the measurements were at a distance of no more than +/- 2 cm from the best-fitted ICP line. CONCLUSION: The C component of ICP model can be used as a growth analysis tool for shorter than average, prepubertal, Israeli children, older than 2 years of age.

Carnitine-acylcarnitine translocase deficiency: identification of a novel molecular defect in a Bedouin patient.

Carnitine-acylcarnitine translocase CACT deficiency is a very rare autosomal recessive disease. The neonatal phenotype of CACT deficiency is characterized by hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy and skeletal muscle weakness culminating in early death. The disease is caused by mutations in the CACT gene, which encodes a protein transporting long-chain fatty acid carnitine esters into the mitochondrial matrix. In this report, we describe the first case of CACT deficiency in the Bedouin population in Israel. The patient, the first son of consanguineous parents, was born at term after uneventful delivery. During the second day of life, he developed clinical signs of an acute metabolic crisis with severe hypoglycaemia and hyperammonaemia. Biochemical investigation suggested the diagnosis of CACT deficiency. Genetic molecular analysis confirmed this diagnosis by demonstrating that the affected child was homozygous for a novel missense mutation 793A>G, substituting glutamine by arginine (Q238R) in exon 7 of the CACT gene. Despite medical treatment and adequate nutrition, the patient died at 6 months of age.

Neurophysiologic studies in congenital insensitivity to pain with anhidrosis.

Thirteen patients with congenital insensitivity to pain and anhidrosis, carrying a mutation at the TRK-A gene, were studied. Neurologic examination revealed vestigial pain sensitivity, suggesting an incomplete involvement of the affected nerves. All 13 patients manifested normal electrophysiologic studies but striking absence of sympathetic skin responses. We suggest the use of the sympathetic skin response test in the clinical evaluation of patients suspected of having congenital insensitivity to pain and anhidrosis.

A recessive contiguous gene deletion of chromosome 2p16 associated with cystinuria and a mitochondrial disease.

Deletions ranging from 100 Kb to 1 Mb--too small to be detected under the microscope--may still involve dozens of genes, thus causing microdeletion syndromes. The vast majority of these syndromes are caused by haploinsufficiency of one or several genes and are transmitted as dominant traits. We identified seven patients originating from an extended family and presenting with a unique syndrome, inherited in a recessive mode, consisting of cystinuria, neonatal seizures, hypotonia, severe somatic and developmental delay, facial dysmorphism, and lactic acidemia. Reduced activity of all the respiratory chain enzymatic complexes that are encoded in the mitochondria was found in muscle biopsy specimens of the patients examined. The molecular basis of this disorder is a homozygous deletion of 179,311 bp on chromosome 2p16, which includes the type I cystinuria gene (SLC3A1), the protein phosphatase 2Cbeta gene (PP2Cbeta), an unidentified gene (KIAA0436), and several expressed sequence tags. The extent of the deletion suggests that this unique syndrome is related to the complete absence of these genes' products, one of which may be essential for the synthesis of mitochondrial encoded proteins.

Micropituitarism and cortical dysplasia: an unknown association of two uncommon CNS disorders.

We describe a case of two known pathologies of the CNS in an unusual association: the concomitant presentation of the micropituitarism and cortical dysplasia. To our knowledge, this association is unreported to date.

Continuous glucose monitoring in children with glycogen storage disease type I.

Glycogen storage disease type I (GSD I) is characterized by impaired production of glucose from glycogenolysis and gluconeogenesis resulting in severe fasting hypoglycaemia. The aim of the present study was to examine the efficacy of a continuous subcutaneous glucose monitoring system (CGMS MiniMed), to determine the magnitude and significance of hypoglycaemia in GSD I and to evaluate the efficacy of its dietary treatment. Four children with GSD I were studied over a 72-h period. Results indicated that the values recorded with continuous subcutaneous glucose monitoring were highly correlated with paired blood glucose values measured by glucometer. Significant periods of asymptomatic hypoglycaemia were noted, especially during night-time. The study suggests that repeated continuous subcutaneous glucose monitoring may serve as a useful tool for the assessment of the long-term management of GSD I patients.

A novel mutation causing complete thyroxine-binding globulin deficiency (TBG-CD-Negev) among the Bedouins in southern Israel.

T4-binding globulin (TBG) is the major thyroid hormone transport protein in human serum. Inherited TBG abnormalities do not usually alter the metabolic status and are transmitted in X-linked inheritance. A high prevalence of complete TBG deficiency (TBG-CD) has been reported among the Bedouin population in the Negev (southern Israel). In this study we report a novel single mutation causing complete TBG deficiency due to a deletion of the last base of codon 38 (exon 1), which led to a frame shift resulting in a premature stop at codon 51 and a presumed truncated peptide of 50 residues. This new variant of TBG (TBG-CD-Negev) was found among all of the patients studied. We conclude that a single mutation may account for TBG deficiency among the Bedouins in the Negev. This report is the first to describe a mutation in a population with an unusually high prevalence of TBG-CD.

Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.

Congenital insensitivity to pain with anhidrosis (CIPA), a rare and severe disorder, comprises absence of sensation to noxious stimuli, inability to sweat, and recurrent episodes of hyperthermia. It has a relatively high prevalence in the consanguineous Israeli-Bedouins. Clinical studies of 28 patients are reported here. Using the linkage analysis approach, we linked the disease in 9 of 10 unrelated Israeli-Bedouin families with CIPA to the TrkA gene, which encodes the receptor for nerve growth factor. In one family, linkage was excluded, implying that another gene, yet unidentified, is involved. Two new mutations in the tyrosine kinase domain of the TrkA gene were identified in our CIPA patients: a 1926-ins-T in most of the southern Israeli-Negev CIPA patients, and a Pro- 689-Leu mutation in a different isolate of Bedouins in northern Israel. Eight prenatal diagnoses were made in the southern Israeli-Negev Bedouins, two by linkage analysis and six by checking directly for the 1926-ins-T mutation. Three polymorphisms in the TrkA protein kinase encoding domain were also observed.

Prenatal diagnosis of hypoparathyroidism retardation and dysmorphism (HRD) syndrome.

We used linkage analysis for prenatal diagnosis of the recently reported hypoparathyroidism, retardation, and dysmorphism (HRD) syndrome. Five cases from four families were evaluated. Three fetuses were carriers and were born healthy. Two fetuses were affected but the parents decided not to terminate the pregnancies. The diagnosis of HRD syndrome was confirmed in these newborns. This is the first report about prenatal diagnosis of HRD syndrome.

Blood lipids and endothelial function in glycogen storage disease type III.

We have assessed early indicators of arterial disease in patients with glycogen storage disease type III (GSD III; McKusick 232400), investigating the plasma lipid and lipoprotein profile and endothelial function. Eleven patients, aged 10-39 years, were recruited together with age-, sex- and smoking status-matched controls. Brachial artery responses were assessed by high-resolution ultrasonographic measurement of the diameter of the brachial artery at baseline, after reactive hyperaemia and in response to sublingual glyceryl trinitrate (GTN). The means of plasma cholesterol (total and HDL and LDL subfractions), triglycerides, apo-A1, apo-B, Lp(a) and the atherogenic index were similar in both groups. Cardiac troponin I was below the lower limits of detection (< 0.03 g/L) in all subjects. The GSD III patients had similar body mass index (BMI) and brachial artery diameter to the control group (BMI 22.6 +/- 5.6 vs 22.3 +/- 5 kg/m2; brachial artery diameter 3.4 +/- 0.5 vs 3 +/- 0.7 mm). When compared to the baseline diameter, the maximal flow-mediated dilatation of the brachial artery after reactive hyperaemia was 9.3% +/- 2.1% (mean +/- SD) in the GSD III patients and 6.5% +/- 3.5% in the control group, a difference of 1.8% (95% CI 0.07% to 5.5%). The maximal dilatation of the brachial artery after GTN administration was 18.3% +/- 6.4% in the GSD III patients and 17.9% +/- 6.5% in the control group, a difference of 0.4% (95% CI-6.9% to 7.7%). In conclusion, we found no evidence of abnormal plasma lipid and lipoprotein profile or endothelial dysfunction in patients with GSD III. They are unlikely to be at increased risk of premature atherosclerosis.

Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain.

An infant with a neurodegenerative disorder accompanied by lactic acidemia is described. In muscle homogenate, the activity of lipoamide dehydrogenase (LAD), the third catalytic subunit of pyruvate dehydrogenase complex (PDHc), alpha-ketoglutarate dehydrogenase complex (KGDHc), and branched-chain keto acid dehydrogenase complex was reduced to 15% of the control. The activity of PDHc was undetectable and the activity of KGDHc was 2% of the control mean. The immunoreactive LAD protein was reduced to about 10% of the control. Direct sequencing of LAD cDNA revealed only one mutation, substituting Asp for Val at position 479 of the precursor form. The mutation resides within the interface domain and likely perturbs stable dimerization. The phenotypic heterogeneity in LAD deficiency is not directly correlated with the residual LAD activity but rather with its impact on the multienzymatic complex activity.

Zinc supplementation increases the level of serum insulin-like growth factor-I but does not promote growth in infants with nonorganic failure to thrive.

We investigated in a randomized double-blind placebo-controlled study the effects of zinc supplementation (2 mg/kg/day) for 12 weeks on growth, serum insulin-like growth factor-I (IGF-I) and insulin-like factor binding protein-3 (IGFBP-3) on 3- to 9-month-old infants with nonorganic failure to thrive (NOFTT). 25 infants completed the study, 14 received zinc supplementation (group A), and 11 received placebo (group B). The control group for baseline measurements was composed of 10 age-matched normal growing infants. There were no significant changes in weight for age, length for age, or weight for length during the entire study period in either group A or B. Serum IGF-I levels at baseline were similar in all the groups. After 12 weeks of therapy, serum IFG-I levels increased significantly only in the zinc-supplemented group, from 40.3 +/- 7 ng/ml at baseline to 65 +/- 8 ng/ml (p < 0.05). There was a marked difference in serum IGF-I levels between the zinc-supplemented group and the placebo group after 12 weeks: 65 +/- 8 vs. 49.4 +/- 5 ng/ml (p = 0.058, 95% CI of difference 9.88-21.31). No change was demonstrated in serum IGFBP-3 levels in either study group. We conclude that although zinc supplementation increased serum IGF-I levels, it did not improve the growth parameters of infants with NOFTT.

Once versus twice daily injections of growth hormone in children with idiopathic short stature.

The aim of this study was to compare the growth response of 22 short pre-pubertal children without growth hormone deficiency, treated with a single daily growth hormone injection (group A), to the growth response of 27 similar children, treated with the same daily dose divided into 2 subcutaneous injections per day (group B), for 1 y, in a randomized study. GH treatment significantly promoted growth parameters, height standard deviation score and height velocity standard deviation score in both groups. Serum insulin-like growth factor I was also increased. There were no significant differences in growth response, serum IGF-I levels, or the advance in bone age between the two study groups after 1 y of GH therapy. We conclude that twice daily s.c. growth hormone injections provide no advantages over once daily injection of the same dose in promoting the linear growth of short children without growth hormone deficiency.

Homozygosity and linkage-disequilibrium mapping of the syndrome of congenital hypoparathyroidism, growth and mental retardation, and dysmorphism to a 1-cM interval on chromosome 1q42-43.

The syndrome of hypoparathyroidism associated with growth retardation, developmental delay, and dysmorphism (HRD) is a newly described, autosomal recessive, congenital disorder with severe, often fatal consequences. Since the syndrome is very rare, with all parents of affected individuals being consanguineous, it is presumed to be caused by homozygous inheritance of a single recessive mutation from a common ancestor. To localize the HRD gene, we performed a genomewide screen using DNA pooling and homozygosity mapping for apparently unlinked kindreds. Analysis of a panel of 359 highly polymorphic markers revealed linkage to D1S235. The maximum LOD score obtained was 4.11 at a recombination fraction of 0. Analysis of three additional markers-GGAA6F06, D1S2678, and D1S179-in a 2-cM interval around D1S235 resulted in LOD scores >3. Analysis of additional chromosome 1 markers revealed evidence of genetic linkage disequilibrium and place the HRD locus within an approximately 1-cM interval defined by D1S1540 and D1S2678 on chromosome 1q42-43.