The many faces of peroxisomal disorders: Lessons from a large Arab cohort
Current Research in Translational Medicine
Alshenaifi J1, Ewida N1, Anazi S1, Shamseldin HE1, Patel N1, Maddirevula S1, Al-Sheddi T1, Alomar R1, Alobeid E1, Ibrahim N1, Hashem M1, Abdulwahab F1, Jacob M2, Alhashem A3,4, Alzaidan HI3,5, Seidahmed MZ6, Alhashemi N7, Rawashdeh R5, Eyaid W8, Al-Hassnan ZN3,5, Rahbeeni Z5, Alswaid A8, Hadid A9, Qari A5, Mohammed DA10, El Khashab HY11,12, Alfadhel M8, Abanemai M13, Sunbul R14, Al Tala S15, Alkhalifi S16, Alkharfi T17, Abouelhoda M1,18, Monies D1,18, Al Tassan N1,18, AlDubayan SH19,20, Kurdi W3,21, Al-Owain M3,5, Dasouki MJ1,2, Kentab AY9, Atyani S22, Makhseed N23, Faqeih E24, Shaheen R1, Alkuraya FS1,3,18.
1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
2 The Newborn Screening and Biochemical Genetics Laboratory, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
3 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
4 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
5 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
6 Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
7 Department of Pediatrics, Royal Hospital, Muscat, Oman.
8 Medical Genetic Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
9 Department of Pediatrics College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
10 Department of Pediatrics, Makkah Maternity and Children’s Hospital, Makkah, Saudi Arabia.
11 Department of Pediatrics Dr. Sulimann AL Habib Medical Group, Riyadh, Saudi Arabia.
12 Department of Pediatrics, Division of Pediatric Neurology Children Hospital, Ain Shams University, Cairo, Egypt.
13 Pediatrics Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
14 Pediatrics Medical Genetic Unit (PMGU), Pediatrics Department, Qatif Central Hospital, Qatif, Saudi Arabia.
15 Armed Forces Hospital Southern Region, Pediatric Directorate and Genetic Unit Khamis Mushayt, Khamis Mushait, Saudi Arabia.
16 Maternity and Children’s Hospital, Dammam, Saudi Arabia.
17 Department of Pediatrics, Sanad Hospital, Riyadh, Saudi Arabia.
18 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
19 Department of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
20 Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts.
21 Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
22 Department of Pediatrics, Mubarak Al-Kabeer Hospital, Kuwait, Kuwait.
23 Pediatric Department, Al-Jahra Hospital, Ministry of Health, Kuwait, Kuwait.
24 Department of Pediatric Subspecialties, Children’s Hospital, Riyadh, Saudi Arabia.
Year of Publication:
Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the “gold standard” very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.