PEDIATRICS Vol. 99 No. 4 April 1997, pp. 567-574

The Clinical Phenotype of Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria): Case Reports of 23 New Patients

Received May 20, 1996; accepted Aug 21, 1996.

K. Michael Gibson^*, Ernst Christensen, Cornelis Jakobs^§, Brian Fowler, Michael A. Clarke^¶, Gerhard Hammersen^#, Klaus Raab^#, Joyce Kobori^**, Allie Moosa, Brigitte Vollmer^§§, Eva Rossier^||, A. Kimberly Iafolla^¶¶, Dietrich Matern^##, Oebele F. Brouwer^***, Janice Finkelstein, Fuat Aksu^§§§, Hans-Peter Weber, Jan A. J. M. Bakkeren^{¶¶, ¶}, Fons J. M. Gabreels^{¶¶, ¶}, Daniel Bluestone^{##, #}, Todd F. Barron^{***, *}, Pierre Beauvais^, , Daniel Rabier^{§§§, §}, Cesar Santos^, , Richard Umansky^{¶¶, ¶¶}, and Willy Lehnert^##

From the ^* Institute of Metabolic Disease, Baylor University Medical Center and Baylor Research Institute, and Department of Neurology, University of Texas Southwestern Medical Center, Dallas;  Division of Clinical Genetics, Department of Pediatrics, University of Copenhagen, Copenhagen, Denmark; ^§ Division of Clinical Chemistry and Pediatrics Department, Free University Hospital, Amsterdam, the Netherlands;  Basler Children's Hospital, University of Basel, Basel, Switzerland; ^¶ Division of Pediatric Neurology, Booth Hall Children's Hospital, University of Manchester School of Medicine, Manchester, United Kingdom; ^# Cnopf'sche Children's Hospital, Evangelical-Lutheran-Diakoniewerk Neuendettelsau, Nuremburg, Germany; ^** Division of Pediatric Genetics, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA;  Department of Pediatrics, Kuwait University Faculty of Medicine, Safat; ^§§ Children's Hospital, Department of Neuropediatrics, Eberhard-Karls-Universitat, Tubingen, Germany; ^|| Institute of Anthropology and Human Genetics, Department of Clinical Genetics, University of Tubingen, Tubingen, Germany; ^¶¶ Division of Pediatric Genetics and Metabolic and Neonatal-Perinatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC; ^## Children's Hospital, Albert-Ludwigs University, Freiburg, Germany; ^*** Division of Child Neurology, Department of Neurology, University Hospital Leiden, the Netherlands;  Center for Medical Genetics, Johns Hopkins Hospital, Baltimore, MD; ^§§§ Department of Neuropediatrics, Vestische Children's Hospital, University of Witten/Herdecke, Datteln, Germany;  Children's Hospital, Lüdenscheid, Germany; ^¶¶ ¶ Division of Clinical Genetics and Child Neurology, Department of Pediatrics, University Hospital, Nijmegen, the Netherlands; ^## # Division of Child Neurology, Department of Neurology and Pediatrics, University of California Medical Center, San Francisco; ^*** * Division of Pediatric Neurology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey;   Department of Pediatric Neurology, Armand Trousseau Hospital, Paris, France; ^§§§ § Medical Biochemistry Laboratory, Necker Hospital for Sick Children, Paris, France;   Section of Pediatric Neurology, Department of Neurology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC; and ^¶¶ ¶¶ Children's Hospital Oakland, Child Development Center, Oakland, CA.

Objectives.  To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients.

Patients.  The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric aciduria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families.

Outcome Measurements.  The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients.

Conclusions.  Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

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