Liver involvement in neuroblastoma amplified sequence gene deficiency is not limited to acute injury: Fibrosis silently continues.

Biallelic mutations in neuroblastoma amplified sequence gene (NBAS) is a rare disease which is characterized by recurrent liver failure (RALF). We reported the novel mutations, clinical characteristics and long-term outcomes of 5 patients with novel biallelic NBAS variants. Four patients (80%) had acute, episodic liver crises (LC) triggered by fever, with a median age of onset of 8.5 months. The median age in the last episode was 34 months. Median number of liver episodes was 4. The course of ALF was complicated by hepatic encephalopathy and hypoglycaemia in all patients with ALF. Two patients recovered with conservative treatment, 2 required liver transplantation (LT) and 1 died during the fourth episode. Long-term post-transplant follow-up showed normal liver function and histology. There is no hepatic or extrahepatic recurrence after LT. Non-transplanted patients exhibited fibrosis in either biopsy or elastography. Despite a reduction in the frequency of clinically significant episodes, patients may exhibit ongoing liver injury and fibrosis. An acute on chronic liver failure with predominant cholestasis can be an alternative presentation.

Clinical Features and Molecular Genetics of Autosomal Recessive Ataxia in the Turkish Population.

BACKGROUND: Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of inherited neurodegenerative disorders. The aim of this study was to present the clinical and genetic features of patients with ataxia complaints and those genetically diagnosed with ARCAs. MATERIALS AND METHODS: Thirty-one children with ARCA were retrospectively analyzed. RESULTS: Fourteen (45.2%) were boys and 17 (54.8%) were girls with the mean age at onset of symptoms of 46.13 ± 26.30 months (12-120 months). Of the 31 patients, 21 (67.7%) were from consanguineous marriages. Eight patients had Friedreich's ataxia, five had ataxia telangiectasia, three had L-2-hydroxyglutaric aciduria, three had Joubert syndrome, two had neuronal ceroid lipofuscinosis, two had megalencephalic leukoencephalopathy with subcortical cysts, two had ataxia with ocular motor oculomotor apraxia type 1, one had cytochrome c oxidase deficiency, one had autosomal recessive spastic ataxia of Charlevoix-Saguenay, one had Niemann-Pick type C, one had congenital disorders of glycosylation, one had adrenoleukodystrophy, and one had cobalamin transport disorder. CONCLUSION: The prevalence of hereditary ataxia can vary among countries. The consanguineous marriage is an important finding in these diseases. These genetic tests will increase the number of ARCA patients diagnosed.

Can untreated PKU patients escape from intellectual disability? A systematic review.

BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 µmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.

Late-Onset Leigh Syndrome due to NDUFV1 Mutation in a 10-Year-Old Boy Initially Presenting with Ataxia.

Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. The onset of clinical features is typically between 3 and 12 months of age; however, a later onset has been described in a few patients. Complex I deficiency is reported to be the most common cause of mitochondrial disorders. We described a patient with a late-onset LS, who presented with gait ataxia, caused by complex I deficiency (NDUFV1 gene).

Spinocerebellar Ataxia-21 in a Turkish Child.

Hereditary cerebellar ataxias are genetically heterogeneous disorders. Autosomal recessive spinocerebellar ataxia-21 (SCAR21) is a neurologic disorder characterized by the onset of cerebellar ataxia, recurrent episodes of liver failure, peripheral neuropathy, and learning disabilities. Herein, we reported a case presented with gait and balance problems, swallowing difficulties, mild delayed motor development, and mild learning disability with SCAR21 that confirmed by mutation analysis in a Turkish child. To the best of our knowledge, this is the first case of SCAR21 from Turkey.

Brown-Vialetto-Van Laere syndrome: two siblings with a new mutation and dramatic therapeutic effect of high-dose riboflavin.

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible.

Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome.

CONTEXT: Gordon Holmes syndrome (GHS) is characterized by cerebellar ataxia/atrophy and normosmic hypogonadotropic hypogonadism (nHH). The underlying pathophysiology of this combined neurodegeneration and nHH remains unknown. OBJECTIVE: We aimed to provide insight into the disease mechanism in GHS. METHODS: We studied a cohort of 6 multiplex families with GHS through autozygosity mapping and whole-exome sequencing. RESULTS: We identified 6 patients from 3 independent families carrying loss-of-function mutations in PNPLA6, which encodes neuropathy target esterase (NTE), a lysophospholipase that maintains intracellular phospholipid homeostasis by converting lysophosphatidylcholine to glycerophosphocholine. Wild-type PNPLA6, but not PNPLA6 bearing these mutations, rescued a well-established Drosophila neurodegenerative phenotype caused by the absence of sws, the fly ortholog of mammalian PNPLA6. Inhibition of NTE activity in the LßT2 gonadotrope cell line diminished LH response to GnRH by reducing GnRH-stimulated LH exocytosis, without affecting GnRH receptor signaling or LHß synthesis. CONCLUSION: These results suggest that NTE-dependent alteration of phospholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to nHH.

Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature.

Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by an early-infancy-onset diabetes mellitus associated with a variety of multisystemic clinical manifestations. Here, we present six patients with WRS, carrying the same homozygous mutation (EIF2AK3-W522X), from two unrelated Turkish families. This is the largest series of patients with the same mutation for this rare syndrome. In this communication we compare clinical features of these six patients with the other 34 patients who have been reported to date, and review the clinical features of WRS. All WRS patients presented first with symptoms of insulin dependent diabetes mellitus, with a mean age at onset of 2 months. All patients had skeletal dysplasia or early signs of it, and growth retardation. Many of the patients with WRS have been reported to have developmental delay, mental retardation, and learning difficulties; in contrast, none of our patients showed abnormal development at age up to 30 months. Acute attacks of hepatic failure were reported in 23 cases out of 37 patients; in 15 of those 23 cases an acute attack of renal failure accompanied the liver failure. Exocrine pancreatic deficiency has been reported in only four cases other than our four patients. Central hypothyroidism was observed in six of 28 cases. We propose that central hypothyroidism is not a component of WRS, but rather a reflection of euthyroid sick syndrome. Four of our patients experienced severe neutropenia, compared to only five of the 27 other cases, suggesting that the W522X mutation may be specifically associated with neutropenia. Other than the consistent features of diabetes mellitus and epiphyseal dysplasia, WRS patients are otherwise characterized by extensive phenotypic variability that correlates poorly to genotype.

Ambulatory blood pressure monitoring and serum nitric oxide concentration in type 1 diabetic children.

Blood pressure can be determined more precisely with the use of 24 hours ambulatory measurement in type 1 diabetics. Nitric oxide (NO) has been suggested to be responsible for the vascular changes described in early diabetic nephropathy. We aimed to investigate serum NO concentration along with ambulatory blood pressure monitoring (ABPM) parameters in type 1 diabetic patients and to find out whether there are correlation between serum NO level and ABPM parameters. Forty type 1 diabetic subjects and 35 controls were enrolled. Diabetic subjects were grouped as microalbuminuric (n=16) and normalbuminuric (n=24). Casual and ambulatory blood pressure parameters and serum NO concentrations were measured in all study population. Microalbuminuric subjects had higher nighttime systolic blood pressure (SBP), 24 hours diastolic blood pressure (DBP) and 24 hours mean arterial pressure (MAP) than controls. Both microalbuminuric and normalbuminuric subjects had also significantly higher nighttime DBP and nighttime MAP than controls. Serum NO concentrations were higher in normalbuminuric and microalbuminuric subjects than controls. Serum NO concentrations were positively correlated with daytime DBP and MAP, nighttime SBP, DBP and MAP, and 24 hours DBP and MAP in microalbuminuric subjects. Serum NO concentrations were also positively correlated with nighttime DBP in normalbuminuric subjects. Multiple linear regression analysis revealed that serum NO(2)- + NO(3)- concentrations and 24 hours DBP were independently associated with the development of microalbuminuria. Albuminuria seems to be closely associated with serum NO concentrations and ABPM parameters in type 1 DM patients. A prospective follow-up study on diabetic patients with normo- and micro- albuminuria is needed to confirm the predictive values of increased NO concentrations and ABPM parameters on the development of albuminuria.

TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction.

The timely secretion of gonadal sex steroids is essential for the initiation of puberty, the postpubertal maintenance of secondary sexual characteristics and the normal perinatal development of male external genitalia. Normal gonadal steroid production requires the actions of the pituitary-derived gonadotropins, luteinizing hormone and follicle-stimulating hormone. We report four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss-of-function mutations in TAC3 (encoding Neurokinin B) or its receptor TACR3 (encoding NK3R). Neurokinin B, a member of the substance P-related tachykinin family, is known to be highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of gonadotropin-releasing hormone secretion. These findings implicate Neurokinin B as a critical central regulator of human gonadal function and suggest new approaches to the pharmacological control of human reproduction and sex hormone-related diseases.

Molecular genetic analysis of normosmic hypogonadotropic hypogonadism in a Turkish population: identification and detailed functional characterization of a novel mutation in the gonadotropin-releasing hormone receptor gene.

BACKGROUND/AIMS: Currently known mutations account for less than 15% of cases with normosmic hypogonadotropic hypogonadism (nIHH). The objective of the study was to identify novel hereditary associations in the pathogenesis of nIHH. METHODS: We investigated 26 Turkish patients with nIHH (21 males and 5 females) from 22 families. The coding regions of the GnRH receptor, GnRH1, GPR54, and KISS1 genes were directly sequenced. RESULTS: In two sisters, a novel homozygous missense mutation, R139C, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified. The R139C mutation almost completely abolished plasma membrane expression while having little effect on GnRH-binding affinity. The mutant receptor expression was rescued by a membrane-permeant, non-peptide GnRH receptor antagonist IN3. CONCLUSIONS: Consistent with the previous studies we were able to find mutations in only 7.6% of a well-defined group of patients with nIHH, which further suggests that yet unidentified genetic associations to explain nIHH exist.

Bone calcium changes during diabetic ketoacidosis: a comparison with lactic acidosis due to volume depletion.

In this study, we aimed to compare bone calcium system changes from children with diabetic ketoacidosis or acute metabolic acidosis due to dehydration to find out the relative contribution of metabolic acidosis and diabetes-related factors on expected negative calcium balance. We studied a set of non-invasive parameters of bone remodeling in 16 children with diabetic ketoacidosis due to new onset type 1 diabetes and 25 children with acute metabolic acidosis due to dehydration complicating acute gastroenteritis before and after the correction of acidosis. The two groups of subjects were matched for age, sex, pubertal status, and degree of metabolic acidosis and dehydration. A group of 18 age and sex-matched healthy children served as the control group. Plasma ionized calcium levels were increased in both groups, significantly more so in diabetic ketoacidosis. While osteoblastic markers, osteocalcin and alkaline phosphatase, were depressed to a comparable degree in both groups, urinary calcium/creatinine ratio and hydroxyproline excretion were significantly greater in diabetic ketoacidosis. No significant changes in calcitrophic hormone (intact PTH, calcitonin, 25-hydroxy vitamin D3) levels were observed. All study parameters except for serum phosphate levels behaved in parallel in both clinical conditions, and abnormalities disappeared with the correction of acidosis except for IGF-1, which remained low in diabetic subjects. In conclusion, our results suggest that, in diabetic ketoacidosis, the observed severe negative calcium balance occurred through diminished bone formation mediated by metabolic acidosis per se and increased bone mineral dissolution and bone resorption because of severe insulin deficiency and secondarily via metabolic acidosis. Observed changes appear to be independent of calcitrophic hormones.

Bone mineral changes in acute metabolic acidosis due to acute gastroenteritis.

We studied bone mineral metabolism changes complicated by acute gastroenteritis in a clinical acute metabolic acidosis milieu where we observed hypercalcemia, hypercalciuria, and elevated urinary hydroxyproline excretion. Serum magnesium and plasma osteocalcin, alkaline phosphatase, and IGF-1 levels were decreased. No significant changes in serum inorganic phosphate and plasma PTH, calcitonin, or 25-hydroxy vitamin D3 levels were detected. All abnormalities disappeared with the correction of acidosis. Observed hypercalcemia seems to be the result of increased calcium efflux from bone due to metabolic acidosis-induced catabolism of type 1 collagen and decreased osteoblastic activity. This study provides data regarding acute metabolic acidosis-induced changes in noninvasive parameters of bone modeling, assessed for the first time in humans.

Three children with triple A syndrome due to a mutation (R478X) in the AAAS gene.

OBJECTIVE: To investigate the phenotype and genotype of 3 unrelated children with triple A syndrome from southern Turkey. METHODS: The coding sequence of the AAAS gene was sequenced including exon-intron boundaries. Haplotype analysis using markers from AAAS region was performed in order to assess potential founder effects. RESULTS: In all 3 patients, the identical nonsense mutation (R478X) in exon 16 of the AAAS gene was identified. The patients who may be distantly related appeared phenotypically similar with the classical triad of the triple A syndrome (adrenal insufficiency, alacrima and achalasia) with dermatological manifestations while lacking neurological features except for mild mental retardation. CONCLUSION: The R478X mutation tends to result in a rather severe phenotype although genotype-phenotype relationships cannot be drawn due to the small number of patients.