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

Author:

Gibson K. Michael1,Christensen Ernst2,Jakobs Cornelis3,Fowler Brian4,Clarke Michael A.5,Hammersen Gerhard6,Raab Klaus6,Kobori Joyce7,Moosa Allie8,Vollmer Brigitte9,Rossier Eva10,Iafolla A. Kimberly11,Matern Dietrich12,Brouwer Oebele F.13,Finkelstein Janice14,Aksu Fuat15,Weber Hans-Peter16,Bakkeren Jan A. J. M.115,Gabreels Fons J. M.115,Bluestone Daniel126,Barron Todd F.131,Beauvais Pierre142,Rabier Daniel153,Santos Cesar164,Umansky Richard1111,Lehnert Willy12

Affiliation:

1. 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 Pediatric Neurology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey;

2. Division of Clinical Genetics, Department of Pediatrics, University of Copenhagen, Copenhagen, Denmark; Department of Pediatric Neurology, Armand Trousseau Hospital, Paris, France;

3. Division of Clinical Chemistry and Pediatrics Department, Free University Hospital, Amsterdam, the Netherlands; Medical Biochemistry Laboratory, Necker Hospital for Sick Children, Paris, France;

4. Basler Children's Hospital, University of Basel, Basel, Switzerland; Section of Pediatric Neurology, Department of Neurology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC; and

5. Division of Clinical Genetics and Child Neurology, Department of Pediatrics, University Hospital, Nijmegen, the Netherlands; Division of Pediatric Neurology, Booth Hall Children's Hospital, University of Manchester School of Medicine, Manchester, United Kingdom;

6. Cnopf'sche Children's Hospital, Evangelical-Lutheran-Diakoniewerk Neuendettelsau, Nuremburg, Germany; Division of Child Neurology, Department of Neurology and Pediatrics, University of California Medical Center, San Francisco;

7. Division of Pediatric Genetics, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA;

8. Department of Pediatrics, Kuwait University Faculty of Medicine, Safat;

9. Children's Hospital, Department of Neuropediatrics, Eberhard-Karls-Universitat, Tubingen, Germany;

10. Institute of Anthropology and Human Genetics, Department of Clinical Genetics, University of Tubingen, Tubingen, Germany;

11. Division of Pediatric Genetics and Metabolic and Neonatal-Perinatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC; Children's Hospital Oakland, Child Development Center, Oakland, CA.

12. Children's Hospital, Albert-Ludwigs University, Freiburg, Germany;

13. Division of Child Neurology, Department of Neurology, University Hospital Leiden, the Netherlands;

14. Center for Medical Genetics, Johns Hopkins Hospital, Baltimore, MD;

15. Department of Neuropediatrics, Vestische Children's Hospital, University of Witten/Herdecke, Datteln, Germany;

16. Children's Hospital, Lüdenscheid, Germany;

Abstract

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.

Publisher

American Academy of Pediatrics (AAP)

Subject

Pediatrics, Perinatology and Child Health

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