Analysis of disease characteristics of a large patient cohort with congenital generalized lipodystrophy from the Middle East and North Africa.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by a near-total absence of adipose tissue and is associated with organ system abnormalities and severe metabolic complications. Here, we have analyzed the disease characteristics of the largest CGL cohort from the Middle East and North Africa (MENA) who have not received lipodystrophy-specific treatment. METHODS: CGL was diagnosed clinically by treating physicians through physical assessment and supported by genetic analysis, fat loss patterns, family history, and the presence of parental consanguinity. Data were obtained at the time of patient diagnosis and during leptin-replacement naïve follow-up visits as permitted by available medical records. RESULTS: Data from 43 patients with CGL (37 females, 86%) were collected from centers located in eight countries. The mean (median, range) age at diagnosis was 5.1 (1.0, at birth-37) years. Genetic analysis of the overall cohort showed that CGL1 (n = 14, 33%) and CGL2 (n = 18, 42%) were the predominant CGL subtypes followed by CGL4 (n = 10, 23%); a genetic diagnosis was unavailable for one patient (2%). There was a high prevalence of parental consanguinity (93%) and family history (67%) of lipodystrophy, with 64% (n = 25/39) and 51% (n = 20/39) of patients presenting with acromegaloid features and acanthosis nigricans, respectively. Eighty-one percent (n = 35/43) of patients had at least one organ abnormality; the most frequently affected organs were the liver (70%, n = 30/43), the cardiovascular system (37%, n = 16/43) and the spleen (33%, n = 14/43). Thirteen out of 28 (46%) patients had HbA1c > 5.7% and 20/33 (61%) had triglyceride levels > 2.26 mmol/L (200 mg/dl). Generally, patients diagnosed in adolescence or later had a greater severity of metabolic disease versus those diagnosed during childhood; however, metabolic and organ system abnormalities were observed in a subset of patients diagnosed before or at 1 year of age. CONCLUSIONS: This analysis suggests that in addition to the early onset of fat loss, family history and high consanguinity enable the identification of young patients with CGL in the MENA region. In patients with CGL who have not received lipodystrophy-specific treatment, severe metabolic disease and organ abnormalities can develop by late childhood and worsen with age.

Familial Screening for the Prevention of Rare Diseases: A Focus on Lipodystrophy in Southern Saudi Arabia.

BACKGROUND: Lipodystrophy is a relatively rare, complex disease characterised by a deficiency of adipose tissue and can present as either generalised lipodystrophy (GLD) or partial lipodystrophy (PLD). The prevalence of this disease varies by region. This study aimed to identify the genetic variations associated with lipodystrophy in the southern part of Saudi Arabia. METHODOLOGY:  We conducted a retrospective study by recruiting nine patients from six families, recruiting the proband whole exome sequencing results or any other genetic test results, screening other family members using Sanger sequencing and analysing the carrier status of the latter. These patients were recruited from the Endocrinology and Diabetes Clinic at Jazan General Hospital and East Jeddah Hospital, both in the Kingdom of Saudi Arabia. RESULT: Eight patients were diagnosed with GLD, and one was diagnosed with PLD. Of the six families, four were consanguineously married from the same tribe, while the remaining belonged to the same clan. The majority of GLD patients had an AGPAT2 c.158del mutation, but some had a BSCL2 c.942dup mutation. The single PLD case had a PPARG c.1024C > T mutation but no family history of the disease. In all families evaluated in this study, some family members were confirmed to be carriers of the mutation observed in the corresponding patient. CONCLUSION:  Familial screening of relatives of patients with rare, autosomal recessive diseases, such as lipodystrophy, especially when there is a family history, allows the implementation of measures to prevent the onset or reduced severity of disease and reduces the chances of the pathogenic allele being passed onto future generations. Creating a national registry of patients with genetic diseases and carriers of familial pathogenic alleles will allow the assessment of preventive measures and accelerate disease intervention via gene therapy.

Burden of Illness of Type 2 Diabetes Mellitus in the Kingdom of Saudi Arabia: A Five-Year Longitudinal Study.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is associated with huge clinical and economic burden in the Kingdom of Saudi Arabia (KSA) which can be curtailed by efficacious treatment. In order to achieve this, current treatment pathways for T2DM and associated costs need to be assessed. METHODS: A longitudinal cohort review was conducted to collect country-specific and patient-specific clinical data, over a minimum observation period of 5 years in the KSA. Patient demographics, clinical characteristics and treatment patterns were recorded. The IQVIA Core Diabetes Model (CDM) version 9.5 Plus was used to assess the burden of illness, which included long-term projections of clinical (life expectancy [LE], quality-adjusted life-years [QALYs], event rates of diabetes-related complications) and direct medical cost (per-patient annual or lifelong [50 years]) outcomes of the most commonly used first-line (1st-line) regimens for T2DM from a payer perspective in the KSA. RESULTS: Data were collected from a subpopulation of 638 patients from 15 participating centres. There was an equal gender representation with a majority of the patients belonging to Arabian/Saudi ethnicity (71.0%). Biguanides (81.5%), sulfonylureas (51.6%), dipeptidyl peptidase 4 (DPP4) inhibitors (26.2%) and fast-acting insulins (17.2%) were the most prescribed 1st-line agents. The most frequently used 1st-line regimens resulted in an estimated LE of 25-28 years, QALYs of 18-21 years and lifelong total cost of illness of 201,377-437,371 Saudi Arabian riyal (53,700-116,632 US dollars). CONCLUSION: Our study addresses gaps in the current research by providing a complete landscape of baseline demographic, clinical characteristics and treatment patterns from a heterogeneous group of patients with T2DM in the KSA. Additionally, the burden of illness analysis using CDM showed substantially higher cost of T2DM care from a payer perspective in the KSA.

A homozygous mutation in the insulin gene (INS) causing autosomal recessive neonatal diabetes in Saudi families.

PURPOSE: Insulin gene (INS) mutations are a rare cause of permanent neonatal diabetes and mature-onset diabetes of the young (MODY10). Homozygous mutations have been reported to cause diabetes by decreasing insulin biosynthesis through distinct mechanisms. In this study, we report a homozygous mutation c.-331C>G in the INS gene causing autosomal recessive neonatal diabetes in Saudi families and share our experience with diagnosis and management. METHODS: We retrospectively reviewed all cases diagnosed with diabetes during the first week of life. We identified 18 cases, and all underwent genetic testing to identify the cause. Most had mutations in common genes (9 in KCNJ11 and 5 in ABCC8). The inclusion criterion for this study was a mutation in the INS gene. RESULTS: Four patients from 3 Saudi families had mutations in the INS gene. All patients were born with low birth weight and were diagnosed with neonatal diabetes at the age of 2 days. Sanger sequencing analysis identified a homozygous INS pathogenic promoter variant, c.-331C>G. All patients were managed by insulin therapy. Two patients had persistent diabetes and in 2 cases diabetes resolved. CONCLUSION: This report indicates that a homozygous mutation in the INS gene is a probable and important cause of neonatal diabetes in Saudi Arabia. The c.-331C>G variant in the INS gene identified in our study showed variability both within and between families and different outcomes ranging from early resolution of diabetes after 2 months of life to permanent diabetes.