Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.

We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging. An essential role for DDHD2 in the human CNS, and perhaps more specifically in synaptic functioning, is supported by a reduced number of active zones at synaptic terminals in Ddhd-knockdown Drosophila models. All identified mutations affect the protein's DDHD domain, which is vital for its phospholipase activity. In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy, which provides an applicable diagnostic biomarker that can distinguish the DDHD2 phenotype from other complex HSP phenotypes. We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease.

Differing definition-based prevalence of metabolic syndrome in the women of Oman family study: a function of multiparity.

OBJECTIVE: The aim of this study was to investigate causes of the prevalence of the metabolic syndrome in multiparous Omani Arab women using the International Diabetes Federation definition (IDF). RESEARCH DESIGN AND METHODS: Of 392 married women (mean age 40 years), 354 (90%) were multiparous with an average parity of 8. They were divided into four parity groups: Para 0, Para 1-3, Para 4-6, and Para >6. Body mass index (BMI), waist circumference, fasting, and 2-hour glucose and insulin, plasma lipids, serum leptin, and homeostasis model assessment for insulin resistance (HOMA-IR) and blood pressure (BP) were measured. RESULTS: In the whole cohort, the IDF definition identified 28% women with the metabolic syndrome, whereas it identified 48% in Para >6. In comparison, the National Cholesterol Education Program (NCEP) definition identified 21% and 39%, respectively (kappa = 0.642). Waist circumference was positively associated with the number of live births (beta = 0.78, p = 0.0001). Compared to other individual IDF criteria, only age-adjusted large waist circumference carried the highest risk for having the metabolic syndrome in all groups (odds ratio [OR], 2.3, 95% confidence interval [CI], 1.0-5.4, 3.2, CI, 1.3-8 and 4.8, CI, 2.1-11.2). CONCLUSION: The high prevalence of the metabolic syndrome in multiparous Omani Arab women appeared to be influenced by the parity-related large waist circumference. The high dependency of the IDF criteria on waist circumference for the definition of the metabolic syndrome in this population has led to the misclassification of such women.

Heritability of determinants of the metabolic syndrome among healthy Arabs of the Oman family study.

The metabolic syndrome, as defined by the International Diabetes Federation, was investigated in five large, extended, highly consanguineous, healthy Omani Arab families of a total of 1277 individuals. Heritability (h2) of the phenotypic abnormalities that make up the syndrome and other related traits was estimated by variance decomposition method using SOLAR software. The overall prevalence of the syndrome was 23%. The prevalence of abnormalities making the syndrome in a descending order were: obligatory waist circumference, hypertension, raised fasting blood glucose, low serum high-density lipoprotein (HDL), and raised serum triglycerides (TGs). Highly significant, but widely spread, h2 values were obtained for: height (0.68), weight (0.68), BMI (0.68), serum HDL (0.63), serum leptin (0.55), percentage body fat (0.53), total serum cholesterol (0.53), fasting serum insulin (0.51), homeostasis model assessment-insulin resistance index (0.48), serum TG (0.43), waist circumference (0.40), diastolic blood pressure (0.38), and 2-hour glucose level (0.17), whereas for the metabolic syndrome itself, h2 was 0.38. The wide spread of h2 results (0.07 to 0.68) indicates that some determinants, such as weight, BMI, and HDL level, are under significant genetic influence among the Omani Arabs. Other determinants such as insulin resistance, abdominal obesity, diastolic blood pressure, and TG levels seem to be more environmentally driven.