Carrier frequency estimation of Zellweger spectrum disorder using ExAC database and bioinformatics tools.

PURPOSE: We aimed to estimate the carrier frequency of Zellweger spectrum disorder (ZSD), a rare autosomal recessive disease, and the associated disease incidence based on data from the Exome Aggregation Consortium (ExAC) of approximately 60,000 individuals. METHODS: We obtained variants from ExAC in 13 PEX genes associated with ZSD. Potentially pathogenic missense variants were identified with computational variant analysis tools according to three stringency levels. Using variants classified as potentially pathogenic, we estimated the carrier frequency and the associated incidence for the entire ExAC population and its subpopulations. We also evaluated variants based on pathogenicity criteria for sequence variant interpretation outlined by the American College of Medical Genetics and Genomics (ACMG) and calculated the carrier frequency and incidence based on those variants. RESULTS: The bioinformatically estimated incidence rate of ZSD in the ExAC population is 1 in 83,841 using our least stringent pathogenicity cutoff. Under clinical guidelines outlined by ACMG, the estimated incidence is 1 in 3,275,751 births. CONCLUSION: We outlined a process for estimating the ZSD disease carrier frequency and incidence in a large consortium using bioinformatics tools. Our results are close to current newborn screening estimates in New York of 1 in 90,000 births, estimated from 1.08 million screenings.

Coagulopathy in Zellweger spectrum disorders: a role for vitamin K.

INTRODUCTION: Zellweger spectrum disorders (ZSDs) are caused by an impairment of peroxisome biogenesis, resulting in multiple metabolic abnormalities. This leads to a range of symptoms, including hepatic dysfunction and coagulopathy. This study evaluated the incidence and severity of coagulopathy and the effect of vitamin K supplementation orally and IV in ZSD. METHODS: Data were retrospectively retrieved from the medical records of 30 ZSD patients to study coagulopathy and the effect of vitamin K orally on proteins induced by vitamin K absence (PIVKA-II) levels. Five patients from the cohort with a prolonged prothrombin time, low factor VII, and elevated PIVKA-II levels received 10 mg of vitamin K IV. Laboratory results, including thrombin generation, at baseline and 72 h after vitamin K administration were examined. RESULTS: In the retrospective cohort, four patients (13.3%) experienced intracranial bleedings and 14 (46.7%) reported minor bleeding. No thrombotic events occurred. PIVKA-II levels decreased 38% after start of vitamin K therapy orally. In the five patients with a coagulopathy, despite treatment with oral administration of vitamin K, vitamin K IV caused an additional decrease (23%) of PIVKA-II levels and increased thrombin generation. CONCLUSION: Bleeding complications frequently occur in ZSD patients due to liver disease and vitamin K deficiency. Vitamin K deficiency is partly corrected by vitamin K supplementation orally, and vitamin K administered IV additionally improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation.

Biochemical and clinical profiles of 52 Tunisian patients affected by Zellweger syndrome.

BACKGROUND: Zellweger syndrome (ZS) is a peroxisome biogenesis disorder attributed to a mutation of the PEX genes family. The incidence of this disease in Africa and the Arab world remains unknown. This contribution is aimed at describing the clinical phenotype and biochemical features in Tunisian patients with ZS in order to improve the detection and management of this severe disorder. METHODS: A total of 52 patients diagnosed with ZS and 60 age- and sex-matched healthy controls were included in this study. Patients were recruited during the past 21 years, and the diagnosis of ZS was based on clinical and biochemical characteristics. Plasma very long chain fatty acids (VLCFA) were analyzed using capillary gas chromatography. The estimated incidence of ZS was calculated using the Hardy-Weinberg formula. RESULTS: The estimated incidence of ZS is 1/15,898 in Tunisia. Age at diagnosis varied between 3 days and 18 months. Severe neurological syndrome, polymalformative features, and hepatodigestive signs were observed in 100%, 67.9%, and 32% of patients, respectively. Values for plasma C26:0 and C26:0/C22:0 and C24:0/C22:0 ratios were noticeably higher in ZS patients than in controls. Distributions of values were completely different for C26:0 (0.10-0.37 vs. 0.001-0.009), C26:0/C22:0 ratio (0.11-1.29 vs. 0.003-0.090), and C24:0/C22:0 ratio (1.03-3.18 vs. 0.4-0.90) in ZS patients versus controls, respectively. CONCLUSIONS: This study highlights the high incidence of ZS in Tunisia and the possibility of simple and reliable biochemical diagnosis, thus permitting early genetic counseling for families at risk.

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population.

BACKGROUND: Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved. METHODS: We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990-2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation. RESULTS: A homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein. CONCLUSION: We report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.

Zellweger syndrome in Saudi Arabia and its distinct features.

Clinical and laboratory findings of Zellweger syndrome (ZS) patients diagnosed at King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia over a period of 10 years are presented in this report. Eleven patients (nine females and two males) from 2 to 4 months old were referred to KFSH & RC for evaluation of hypotonia, seizures, and dysmorphic features. The common clinical findings included high forehead, large fontanelle, shallow orbit ridges, micrognathia, upslanting palebral fissures, epicanthal folds, severe hypotonia, hyporeflexia, pigmentary retinopathy, optic nerve atrophy, complete or partial agenesis of corpus callusum, and failure to thrive. We did not observe any Brushfield spots, any renal and brain cysts, or adrenal insufficiency. Some unique clinical findings were the presence of gallstones, club feet, or bilateral knee or hip dislocation in some patients. All patients had markedly elevated plasma levels of very long chain fatty acids (VLCFA). Electron microscopy performed on liver biopsies of two patients revealed absence of peroxisomes. Biochemical studies of dermal fibroblasts from three patients showed deficient beta-oxidation of lignoceric acid and dihydroxyacetone phosphate acyltransferase (DHAPATase) activity. The tribal living in Saudi Arabia and our observation that 10 of the 11 parents in this study were first-degree relatives and, except for families 1 and 3, each family had at least another baby who died of the same disease. This suggests that the incidence of ZS in Saudi Arabia may actually be higher than our experience at KFSH & RC.

Incidence of peroxisomal disorders in Japan.

Japanese patients with peroxisomal disorders in the pediatric field were screened. Very long chain fatty acid analysis in the serum sphingomyelin was introduced since 1987 and was useful for the first screening of peroxisomal disorders. Seventy-five patients were diagnosed since 1980: 15 patients with Zellweger syndrome, 2 with neonatal adrenoleukodystrophy (ALD), 1 with rhizomelic chondrodysplasia punctata, 1 with Zellweger-like syndrome. 2 with acyl-CoA oxidase deficiency, 2 with bifunctional enzyme deficiency and 52 with X-linked ALD. The incidence of peroxisome-deficient disorders was estimated to be approximately 1 in 800,000 births which is far less than that in the USA. However, the incidence in Okinawa Islands was 1 in 30,000. Japanese Zellweger patients belonged to 5 complementation groups (A, B, C, E, F) and the patients in Okinawa Islands belonged to groups A and C. The results of this screening were useful for genetic counseling, prenatal diagnosis, carrier detection and early medical care of patients with peroxisomal disorders.