Al-Aqeel Sewairi syndrome, MIMfi605156, a prototype for personalized medicine for the study and prevention of genetic metabolic disorders in Saudi Arabia

Middle Eastern cultures are tribal and heavily consanguineous. Marriage between cousins has been part of the culture for millennia, leading to 'founder' effect and a large number of autosomal diseases. In Saudi Arabia, like other Middle Eastern countries, first-cousin marriages account for almost 60-70% of all marriages, leading to uniquely common disorders which are either rare by Western standards or completely unknown. Most of these disorders lead to physical and mental handicap; affected children have poor development and reduced mental capacity. Therefore, accurate diagnosis of the exact molecular defect and prevention is the main aim of our management of these children. Applying personalized genomics for the diagnosis, prevention and treatment of our patients with genetic metabolic disorders in accordance with our Islamic ethical guidelines is our most important strategy in managing our patients. An example of such an application in Saudi Arabia is the previously described novel autosomal recessive osteolysis/ arthritis syndrome, multicentric osteolysis nodulosis with arthritis [MONA] [NOA] [Al-Aqeel Syndrome] [MIM#605156], a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, patients have large, painful to touch palmar and plantar pads; they are also found to have hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia. The syndrome is caused by inactivating mutations in the MMP2 gene, for which we have established prevention and therapeutic strategy. We have also established with other colleagues the exact genetic defect after establishing the accurate diagnosis and the systematic prevention of genetic disorders by pre-implantation genetic diagnosis with a success in over 160 cases in which the result was the birth of normal children, including patients with Al-Aqeel Sewairi syndrome. We are also establishing stem cell therapy for Genetic Metabolic disorders, with Al-Aqeel Sewairi syndrome as the prototype for such promising modality for treatment of mental and physical handicap in children. These strategies must be done in accordance with our ethical and religious background, with priorities given to the rights of patients and families to know and to make their own decisions as dictated by our Islamic ethics. Personalized medicine includes diagnostic and prognostic approaches, and must include personalized preventive and therapeutic strategies in accordance with our Islamic ethical standards

Human cloning, stem cell research. An Islamic perspective

The rapidly changing technologies that involve human subjects raise complex ethical, legal, social, and religious issues. Recent advances in the field of cloning and stem cell research have introduced new hopes for the treatment of serious diseases. But this promise has raised many complex questions. This field causes debate and challenge, not only among scientists but also among ethicists, religious scholars, governments, and politicians. There is no consensus on the morality of human cloning, even within specific religious traditions. In countries in which religion has a strong influence on political decision making, the moral status of the human embryo is at the center of the debate. Because of the inevitable consequences of reproductive cloning, it is prohibited in Islam. However, stem cell research for therapeutic purposes is permissible with full consideration, and all possible precautions in the pre-ensoulment stages of early fetus development, if the source is legitimate

Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy. the first genetic defect of matrix metalloproteinase 2 gene

We report a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, they had large, painful to touch palmar and plantar pads. Hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia. Using a genome-wide search for microsatellite markers from 11 members of the family from the Armed Forces Hospital and King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, localized the disease gene to chromosome 16q12-21. Haplotype analysis with additional markers narrowed the critical region to 1.2cM and identified the matrix metalloproteinase 2 [MMP-2], [gelatinase A, collagenase type IV, EC 3.4, 24,24] gene as a disease candidate at Mount Sinai School of Medicine, New York, United States of America in April 2000. Some affected individuals were homoallelic for a nonsense mutation [TCA>TAA] in codon 244 of exon 5, predicting the replacement of a tyrosine residue by a stop codon in the first fibronectin type II domain [Y244X]. Other affected members had a missense mutation in exon 2 arginine 101-histidine [R101H] leading to no MMP-2 enzyme activity in serum or fibroblast or both of affected individuals. In other affected members, a non-pathogenic homoallelic GT transversion resulted in the substitution of an aspartate with a tyrosine residue in codon 210 of exon 4 [D210Y]. The MMP-2-null mouse has no developmental defects, but are small, which may reflect genetic redundancy. The discovery that deficiency of this well-characterized gelatinase/collagenase results in an inherited form of an osteolytic and arthritic disorder provides an invaluable insights for the understanding of osteolysis and arthritis and is the first genetic evidence that MMP2 deficiency is important in growth and development

Ethical guidelines in genetics and genomics. an islamic perspective

We are at a time of unprecedented increase in knowledge of rapidly changing technology. Such biotechnology especially when it involves human subjects raises complex ethical, legal, social and religious issues. A World Health Organization expert consultation concluded that "genetics advances will only be acceptable if their application is carried out ethically, with due regard to autonomy, justice, education and the beliefs and resources of each nation and community." Public health authorities are increasingly concerned by the high rate of births with genetic disorders especially in developing countries where Muslims are a majority. Therefore, it is imperative to scrutinize the available methods of prevention and management of genetic disorders. A minimum level of cultural awareness is a necessary prerequisite for the delivery of care that is culturally sensitive, especially in Islamic countries. Islam presents a complete moral, ethical, and medical framework, it is a religion which encompasses the secular with the spiritual, the mundane with the celestial and hence forms the basis of the ethical, moral and even juridical attitudes and laws towards any problem or situation. Islamic teachings carry a great deal of instructions for health promotion and disease prevention including hereditary and genetic disorders, therefore, we will discuss how these teachings play an important role in the diagnostic, management and preventive measures including: genomic research; population genetic screening pre-marital screening, pre-implantation genetic diagnosis; assisted reproduction technology; stem cell therapy; genetic counseling and others

Carnitine palmityl transferase I deficiency in a Saudi family

Carnitine palmityl transferase I is the key enzyme in the carnitine dependent transport of long chain fatty acids across the mitochondrial inner membrane and its deficiency results in a decrease rate of fatty acids beta-oxidation with decreased energy production. We reported a family of 3 affected siblings who are the product of a first degree cousin marriage. The first 2 presented with typical Reye-like syndrome with unconsciousness, hepatomegaly, hypoglycemia, hyperammonemia and very high liver enzymes. Liver biopsy showed steatosis. On screening of the complete family, the 3rd sibling was found to have hepatomegaly. The 3 siblings showed an acyl carnitine profile with very high free carnitine with almost absent long chain acyl carnitines, suggestive of carnitine palmityl transferase I deficiency. This was confirmed by enzyme analyses in fibroblast cultures. These patients were effectively treated with a diet high in carbohydrate, low in long chain fatty acids with medium chain triglycerides. In conclusion, carnitine palmityl transferase I deficiency is an important cause of Reye-like syndrome, which may be treated easily with very good results if detected early in life

Cystinosis: the importance of early diagnosis

Cystinosis is a leading cause of Fanconi syndrome in childhood. We report a 7-year-old Pakistani boy who presented at the age of 5 months with vomiting, failure to thrive and rickets. At the age of 15 months he had typical biochemical findings of Fanconi syndrome and was prescribed electrolyte supplements. At the age of 6 years he presented to us with photophobia and renal failure in addition to the previous complaints, and was found to have hazy corneas. Cystinosis was suspected and confirmed by finding typical corneal and bone marrow cystine crystals. Leukocyte cystine was 7.3 nmol 0.5 cystine/mg protein [normal < 0.2]. The patient was started on L-thyroxine, 1 -alpha-cholecalciferol, in addition to electrolyte supplements and it was planned to start him on phosphocysteamine and to proceed to renal transplant. However, his renal failure was rapidly progressive. At the age of 7 years, after taking phosphocysteamine for 10 days, he was admitted with epistaxis and haematemesis; he required haemodialysis, bled massively into his chest after central line insertion and died within 2 months after suffering from severe hypoxic brain damage. We conclude although Cystinosis is a leading cause of Fanconi syndrome in North America, it is quite rare in Saudi Arabia. Second, Cystinosis is a generalized disease, and the involvement of the blood vessels might have led to the intrathoracic bleeding in our patient. Third, the importance of early diagnosis and treatment is stressed