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As editors and authors, we reflect on this project, conceptualized to blend the salient clinical and exciting scientific advances that are on full display, from common to unique, in the field of inherited metabolic movement disorders. It is the province of the neurologist (pediatric and adult), geneticist, movement disorder specialist, developmentalist, radiologist, pathologist, physiatrist, therapist, educator, parent, advocate … indeed, the scope of this work is beyond provincial but instead universal. We have endeavored to encapsulate in this monograph a comprehensive approach to the somewhat peculiar but frankly permeating intersection of the inherited errors of metabolism and movement disorders.
Inherited metabolic movement disorders are an important and evolving group of disorders that bridge two subspecialty areas: childhood-onset movement disorders and inborn errors of metabolism. Individually, many of these disorders are rare but in aggregate they represent a substantial clinical burden. It is in their complex nature that they require a multidisciplinary approach that includes pediatricians, neurologists, and geneticists among others.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. The primary precursor of GABA is glutamate, the major excitatory neurotransmitter in the brain. Glutamate is converted into GABA via glutamate decarboxylase (GAD). GABA-transaminase (GABA-T) metabolizes GABA to succinic semialdehyde, which is rapidly metabolized to succinic acid by succinic semialdehyde dehydrogenase (SSADH) and then enters the tricarboxylic acid (TCA) cycle (Figure 23.1).
Inherited metabolic movement disorders are a significant and rapidly evolving field of study, linking two subspecialty areas of childhood-onset movement disorders and inborn errors of metabolism. Increasing the chance of early recognition of inherited metabolic movement disorders can have significant therapeutic implications for patients. Containing information on new disorders of post-translational modification and autophagy and their identification and treatment, there is thorough coverage of disorders of amino acids, energy metabolism, and lysosomal storage, amongst others. This key resource explores future directions in the field including next-generation genetic sequencing and novel therapeutic approaches such as deep brain stimulation. Supplementary videos are available on Cambridge Core, accessible via the code printed inside the cover. This essential text bridges the gap in communication between experts in genetic-metabolic medicine and movement disorder neurology. With an emphasis on treatable conditions that should not be missed, this volume guides you through various disorders from a clinical, biochemical and genetic perspective.
Succinic semialdehyde dehydrogenase (SSADH) deficiency (γ-hydroxybutyric aciduria) is a rare neurometabolic disorder of γ-aminobutyric acid degradation. While neurological manifestations, such as developmental delay, are typical during infancy, limited data are available on adolescent and adult symptomatology.
We overview the phenotype of 33 adolescents and adults (10.1–39.5 years of age, mean: 17.1 years, 48% females) with SSADH deficiency. For this purpose, we applied a database with systematic questionnaire-based follow-up data.
Sixty-six percent of patients (n=21) presented by 6 months of age, 14% from 6–12 months of age, 5% from 1–2 years of age, and 14% from 2–4 years of age, mean age at first symptoms was 11±12 months. However, mean age at diagnosis was 6.6±6.4 years of age. Presenting symptoms encompassed motor delay, hypotonia, speech delay, autistic features, seizures, and ataxia. Eighty-two percent demonstrated behavioral problems, such as attention deficit, hyperactivity, anxiety, or aggression, and 33% had ≥3 behavior problems. Electroencephalograms showed background slowing or epileptiform discharges in 40% of patients. Treatment approaches are then summarized.
The variable phenotype in SSADH deficiency suggests the likelihood that this disease may be under-diagnosed. Families of patients with SSADH deficiency should be counseled and supported regarding the anticipated persistence of various neuropsychiatric symptoms into adulthood.