Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

Natural Course of Neonatal Progeroid Syndrome

Several progeroid disorders presenting a specific “old-man” appearance since birth or childhood have been described. Here, five patients with a history of severe intrauterine and postnatal growth retardation and pseudohydrocephaloid cranium noted after birth that were suggestive of neonatal progeroid syndrome (NPS) or Wiedemann-Rautenstrauch syndrome are reported. We discuss the natural course of the syndrome. Methods: A series of anthropometric measurements, imaging, dual energy X-ray absorptiometry, and endocrine investigations to assess metabolic complications such as hyperinsulinemia and dyslipidemia were performed on these five patients who were followed for 1-7 years. Screening of inborn errors, karyotyping, chromosomal breakage rates and DNA mutational studies with direct sequencing of LMNA, ERCC8 and ZMPSTE24 genes were also performed. Results: Generalized lipodystrophy was noted in all patients except for regions such as the cheeks, hands and feet. All cases had failure to thrive, microcephaly, ear dysplasia, laryngomalacia, hearing impairment, gastro-esophageal reflux disease, constipation, abnormal dentition, dermatitis/acrodermatitis enteropathica, hyperpigmentation of the skin, very low insulin-like growth factor I levels with delayed bone age, relative hypolipidemia, initial camptodactyly/joint contracture, progressive kyphoscoliosis, osteoporosis with loose joints, ventriculomegaly, and generalized organic aciduria. Other findings included inguinal hernia, hypothyroidism or persistent hyperthyrotropinemia, cryptorchidism, hip dysplasia, growth hormone deficiency, cloudy cornea with congenital glaucoma, neonatal teeth, cardiac defects, basal ganglia calcification and seizure disorder. These patients with NPS did not show hyperinsulinemia or dyslipidemia. Their karyotypes were all normal, while the chromosomal breakage test showed markedly increased breakage rates in four patients. LMNA, ERCC8, or ZMPSTE24 gene mutations could not account for the disorders in these patients. Four patients died after sepsis or aspiration pneumonia at the age of 1.1, 4, 6.2 and 7.5 years. Conclusion: Increased chromosomal breakage and the presence of basal ganglia calcification after early childhood suggest that DNA repair defects are involved in the pathogenesis of this disorder. This rare disorder represents a complex of symptoms with unknown cause and pathogenesis, and more than one disease may account for the clinical variability of NPS

Maple Syrup Urine Disease Complicated with Kyphoscoliosis and Myelopathy

Maple syrup urine disease (MSUD) is an autosomal recessive aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids (BCAAs: leucine, isoleucine, and valine). Accumulation of their corresponding keto-acids leads to encephalopathy if not treated in time. A newborn male patient was suspected to have MSUD after tandem mass study when he presented symptoms and signs suggestive neonatal sepsis, anemia, and diarrhea. Food restriction of BCAAs was started; however, acrodermatitis enteropathica-like skin eruptions occurred at age 2 months. The skin rashes resolved after adding BCAAs and adjusting the infant formula. At age 7 months, he suffered from recurrent skin lesions, zinc deficiency, osteoporosis, and kyphosis of the thoracic spine with acute angulation over the T11-T12 level associated with spinal compression and myelopathy. After supplementation of zinc products and pamidronate, skin lesions and osteopenia improved gradually. Direct sequencing of the DBT gene showed a compound heterozygous mutation [4.7 kb deletion and c.650-651insT (L217F or L217fsX223)]. It is unusual that neurodegeneration still developed in this patient despite diet restriction. Additionally, brain and spinal magnetic resonance imaging, bone mineral density study, and monitoring of zinc status are suggested in MSUD patients

Amelioration of Hypophosphatemic Rickets and Osteoporosis With Pamidronate and Growth Hormone in Lowe Syndrome

The oculocerebrorenal syndrome of Lowe, an X-linked multisystem disorder, was diagnosed in a male patient who presented with typical abnormalities of the eyes, kidneys and nervous system. Besides congenital cataracts, renal tubular dysfunction and psychomotor retardation, the patient had also suffered from profound failure to thrive, growth hormone deficiency, severe osteoporosis with hypophosphatemic rickets, and progressive renal dysfunction since early childhood, which were attributed to the metabolic derangements following Fanconi syndrome. Direct sequencing of the OCRL1 gene (responsible for the oculocerebrorenal syndrome of Lowe) revealed a de novo c.2282_2283insT in exon 20, which resulted in premature termination of translation (D762X). After monthly intravenous administration of pamidronate since the age of 17.8 years, his urine creatinine clearance and tubular resorption of phosphate increased slightly and bone mineral density was much improved (Z score increased from −7.3 to −3.3) without deterioration of renal function. Simultaneous growth hormone therapy enhanced the positive response. The beneficial osseous and renal effects of the bisphosphonate, along with growth hormone treatment in Lowe syndrome with hypophosphatemia, may be related to reduced renal calcium and phosphate excretion

Pyridoxine-Responsive Homocystinuria with Ruptured Sinus of Valsalva in a Chinese Boy

Homocystinuria (McKusick 236200) is an inborn error of amino acid metabolism. The frequency of the condition has been estimated at one in 2000000 population in Taiwan by newborn screening. We report one such case who had congenital aneurysm of aortic sinus and sudden rupture of sinus of Valsalva. The patient is a 14-year-old Chinese male who had presented with marfanoid habitus, pectus excavatum and mental retardation but no lens subluxation. He came to visit us owing to acute onset of chest pain, dyspnoea and development of a loud to-and-fro murmur with thrill and heave . Echocardiography showed ruptured aortic sinus of Valsalva and prolapse of right coronary cusp into right ventricle (RV) with systolic (mainly) and diastolic flow from aorta into RV (pressure gradient 117 mmHg), as well as ventricular septal defect (VSD, 2.0 cm in diameter) and dilation of both ventricles and aorta. Resection of the ruptured aneurysm of the aortic sinus of Valsalva, repair of VSD and aortic valvuloplasty and aortoplasty were done smoothly. Histological examination revealed myxoid degeneration with mild mononuclear cell infiltration. There was no evidence of infective endocarditis. Chromosome study, including fragile X, was normal. Urine tests with both silver-nitroprusside and cyanide- nitroprusside were positive . Plasma methioine was 5.2μmol/L (normal 3.4- 27.8), homocystine 35μmol/L (normal 0.3-5.8) detected following immediate precipitation of protein after blood-sampling ( Gaull et al 1974). After 2 weeks' intake of pyridoxine (100 mg/day) the homocystine disappeared and both urine tests became negative. Aneurysm of the aortic sinus as a complication of Marfan syrfan syndrome or secondary to infective endocarditis has been reported (Arey 1984), but not in homocystinuria

Different Gene Preferences of Maple Syrup Urine Disease in the Aboriginal Tribes of Taiwan

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism caused by a deficiency of the branched-chain α-ketoacid dehydrogenase (BCKD) complex. Mutations in any one of the three different genes encoding for the BCKD components, namely, BCKDHA, BCKDHB, and DBT, may be responsible for this disease. In Taiwan, few MSUD cases were diagnosed clinically, and most of these patients are from Aboriginal tribes. Materials and methods: To identify and detect the carrier frequency of MSUD in Taiwanese Aboriginal tribes, we performed biochemical and molecular studies from peripheral blood in MSUD patients and dried blood on filter paper in the enrolled screened populations. Results: Homozygous A208T and I281T of BCKDHA were found in two patients from Hans (non-Aboriginal Taiwanese), respectively; compound heterozygous mutations of the DBT gene [4.7 kb deletion/c.650-651insT (L217F or L217fsX223) and c.650-651insT/c.88-89delAT] were found in two patients from Amis, respectively, after direct DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism studies. There were no cases of deleted 4.7-kb heterozygote out of 302 normal people (Hans, n = 125; Atayal, n = 156; and Saisiyat, n = 21); by contrast, the DBT mutations c.650-651insT and deleted 4.7-kb heterozygote were noted in 2/121 and 1/121, respectively, from the general population of the Amis, a southeastern Taiwanese tribe. Conclusion: Although the Taiwanese Austronesian Aboriginal tribes are considered to share a common origin, different gene preferences of MSUD were noted. The novel DBT mutation c.650-651insT was more prevalent than the deleted 4.7-kb heterozygote in the Amis population. The reported 4.7-kb deletion indicating a possible founder mutation may be preserved in the southern and eastern, but not in northern Aboriginal tribes of Taiwan

Clinical Variability in Neonatal Progeroid Syndrome

　　The neonatal progeroid syndrome (NPS) was characterized by Wiedemann. NPS differs from the well-known Hutchinson- Gilford progeria, which is not apparent at birth. We report on a Chinese infant girl with a progeroid appearance, multiple anomalies, and severe growth retardation since birth. Thus, our patient has the phenotype of Wiedemann- Reutenstrauch syndrome without intrauterine growth retardation (IUGR ), but with laryngomalacia, camptodactyly, and recurrent skin infection. Our patient brings further evidence of autosomal-recessive inheritance and suggests clinical variability.#1914