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Natural history of nonketotic hyperglycinemia in 65 patients

From the Department of Pediatrics and Institute of Genetic Medicine (Drs. Hoover-Fong and Hamosh) and School of Public Health (Drs. Hoover-Fong and Shah), Johns Hopkins University, Baltimore, MD; Department of Pediatrics (Dr. Van Hove), University of Colorado Health Sciences Center, Denver, CO; and Department of Pediatrics (Dr. Applegarth, J. Toone), University of British Columbia, Vancouver, British Columbia, Canada.

Address correspondence and reprint requests to Dr. Ada Hamosh, Blalock 1012E, 600 North Wolfe Street, Baltimore, MD 21287; e-mail: ahamosh{at}jhmi.edu

Background: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an autosomal recessive disorder caused by a defect in the glycine cleavage system. NKH is classically associated with neonatal apnea, lethargy, hypotonia, and seizures, followed by severe psychomotor retardation in those who survive.

Methods: To determine the natural history of NKH, the authors mailed a 44-question survey to 170 households in the International NKH Family Network.

Results: Data for 65 patients (36 boys, 29 girls) were collected from 58 families. One-third of the subjects died; 8 girls died during the neonatal period, and 14 patients died thereafter (2 girls, 12 boys). Median age of death for boys was 2.6 years vs <1 month for girls (p = 0.02). Mean birth weight and length, occipitofrontal circumference, and gestation duration were normal. Two-thirds of infants were ventilated during the neonatal period; of these, 40% died. Ninety percent had confirmed seizures, 75% during the first month of life. Interestingly, three NKH patients never developed seizures. An abnormal corpus callosum and/or hydrocephalus were associated with especially poor gross motor and speech development. Of 25 patients living 3 years, 10 were able to walk and say/sign words; all were boys. In six families with more than one affected child, disease course and mortality were similar within each family.

Conclusions: This study reveals a striking and unexpected gender difference in mortality and developmental progress. Of the two-thirds of nonketotic hyperglycinemia patients surviving the newborn period, up to 20% (mostly boys) may learn to walk and communicate by saying or signing words.

Received April 16, 2004. Accepted in final form July 15, 2004.

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