The natural history of a disease is defined as its progression over time, in the absence of treatment. Thus, for inherited inborn errors of metabolism, which are normally identified and treated in childhood, it is often unknown. A group of physicians from Canada recently described in the journal Neurology some features of the natural history in adulthood of succinic semialdehyde dehydrogenase (SSADH) deficiency, an autosomal recessive disorder characterized by the lack of the enzyme involved in the degradation of the neurotransmitter GABA, which in turn leads to an accumulation of gamma-hydroxybutyric acid. The symptoms, which include seizures, cognitive deficiency and epilepsy, among others, can vary from patient to patient and are not specific. In addition, SSADH deficiency is a disorder only recently discovered, for which only 450 cases have been reported so far. For these reasons, even if the diagnosis is made usually at around 2 years of age, some cases may remain undiagnosed for a long time. As for example in the case of a 63-year-old man who was finally diagnosed for SSADH deficiency after repeated admissions to hospital for seizures and episodes of altered consciousness. Upon the identification of SSADH deficiency in this patient, the researchers tried to delineate the natural history of the disorder, taking advantage of a database collecting 112 patients with SSADH deficiency. Only for 25 patients aged 18 years or older the clinical data from adulthood were available, and the majority of them (60%) suffered from epilepsy. By contrast, other manifestations such as anxiety, obsessive-compulsive behaviors, hyperactivity and sleep disturbance were quite common but present in half or less than half of the patients. Therefore, from this small cohort of subjects and from the observation that epilepsy is more frequent in adults than in children, the authors hypothesize that SSADH patients may exhibit progressive hyperexcitability. MAIN MESSAGES Physicians should never exclude inherited inborn errors of metabolism or other genetic and childhood-onset pathologies when adult patients have symptoms that are unexplained. Indeed, not only several diseases have just been identified, but patients may have been misdiagnosed in the past, because the specific tests did not exist or were not accurate enough at the onset of the disease. The identification of undiagnosed adult patients suffering from rare diseases could be essential to determine the natural history of these disorders. Reference: Lapalme-Remis S et al. Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Neurology. 2015 Sep 8;85(10):861-5
