Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients.
OBJECTIVE
Molybdenum cofactor deficiency (MoCD) and Sulfite oxidase deficiency (SOD) are rare autosomal recessive conditions of sulfur-containing amino acid metabolism with overlapping clinical features and emerging therapies. The clinical phenotype is indistinguishable and they can only be differentiated biochemically. MOCS1, MOCS2, MOCS3, and GPRN genes contribute to the synthesis of molybdenum cofactor, and SUOX gene encodes sulfite oxidase. The aim of this study was to elucidate the clinical, radiological, biochemical and molecular findings in patients with SOD and MoCD.


METHODS
Detailed clinical and radiological assessment of 9 cases referred for neonatal encephalopathy with hypotonia, microcephaly, and epilepsy led to a consideration of disorders of sulfur-containing amino acid metabolism. The diagnosis of six with MoCD and three with SOD was confirmed by biochemical tests, targeted sequencing, and whole exome sequencing where suspicion of disease was lower.


RESULTS
Novel SUOX mutations were detected in 3 SOD cases and a novel MOCS2 mutation in 1 MoCD case. Most patients presented in the first 3 months of life with intractable tonic-clonic seizures, axial hypotonia, limb hypertonia, exaggerated startle response, feeding difficulties, and progressive cystic encephalomalacia on brain imaging. A single patient with MoCD had hypertrophic cardiomyopathy, hitherto unreported with these diseases.


CONCLUSIONS
Our results emphasize that intractable neonatal seizures, spasticity, and feeding difficulties can be important early signs for these disorders. Progressive microcephaly, intellectual disability and specific brain imaging findings in the first year were additional diagnostic aids. These clinical cues can be used to minimize delays in diagnosis, especially since promising treatments are emerging for MoCD type A.
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt. Electronic address: dr_mahazaki@yahoo.com.
Maha S
MS
Zaki
Pediatric Department, Neurometabolic Clinic, Cairo University, Cairo 12613, Egypt.
Laila
L
Selim
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Hala T
HT
El-Bassyouni
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Mahmoud Y
MY
Issa
Pediatric Department, Neurometabolic Clinic, Cairo University, Cairo 12613, Egypt.
Iman
I
Mahmoud
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Samira
S
Ismail
Pediatric Department, Neurometabolic Clinic, Cairo University, Cairo 12613, Egypt.
Mariane
M
Girgis
Pediatric Neurology Department, Faculty of Medicine, Sohag University, Sohag 82524, Egypt.
Abdelrahim A
AA
Sadek
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, CA 92093, USA.
Joseph G
JG
Gleeson
Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Mohamed S
MS
Abdel Hamid
D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000503:physiopathology; D003067:Coenzymes / Q000235:genetics; D004534:Egypt; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D008297:Male; D008664:Metal Metabolism, Inborn Errors / Q000235:genetics / Q000503:physiopathology; D008667:Metalloproteins / Q000235:genetics; D000090006:Molybdenum Cofactors; D008983:Molybdoferredoxin / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011621:Pteridines; D050876:Sulfite Oxidase / Q000172:deficiency* / Q000235:genetics
D003067:Coenzymes; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D008983:Molybdoferredoxin; D011621:Pteridines; D050876:Sulfite Oxidase; C022261:molybdopterin
Epilepsy; MOCS1 gene; MOCS2 gene; Microcephaly; Molybdenum cofactor deficiency; SUOX gene; Sulfite oxidase deficiency