Maria T. Acosta

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS γ-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors’ institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors’ institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.

Succinic semialdehyde dehydrogenase deficiency in children and adults

Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of γ‐aminobutyric acid. The disorder is detected when 4‐hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic‐clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2‐weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in γ‐aminobutyric acid, γ‐hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems. Ann Neurol 2003;54 (suppl 6):S73–S80

Latent Class Subtyping of Attention-Deficit/Hyperactivity Disorder and Comorbid Conditions

OBJECTIVE Genetic studies of attention-deficit/hyperactivity disorder (ADHD) generally use discrete DSM-IV subtypes to define diagnostic status. To improve correspondence between phenotypic variance and putative susceptibility genes, multivariate classification methods such as latent class analysis (LCA) have been proposed. The aim of this study was to perform LCA in a sample of 1,010 individuals from a nationwide recruitment of unilineal nuclear families with at least one child with ADHD and another child either affected or clearly unaffected. METHOD LCA models containing one through 10 classes were fitted to data derived from all DSM-IV symptoms for ADHD, oppositional defiant disorder, and conduct disorder (CD), as well as seven items that screen for anxiety and depression from the National Initiative for Childrens Healthcare Quality Vanderbilt Assessment Scale for Parents. RESULTS We replicated six to eight statistically significantly distinct clusters, similar to those described in other cross-cultural studies, mostly stable when comorbidities are included. For all age groups, anxiety and depression are strongly related to Inattentive and Combined types. Externalizing symptoms, especially CD, are strongly associated with the Combined type of ADHD. Oppositional defiant disorder symptoms in young children are associated with either conduct disorder or anxiety-related symptoms. CONCLUSIONS Methods such as LCA allow inclusion of information about comorbidities to be quantitatively incorporated into genetic studies. LCA also permits incorporation of milder but still impairing phenotypes than are allowed using the DSM-IV. Such methods may be essential for analyses of large multicenter datasets and relevant for future clinical classifications. This population-based ADHD classification may help resolve the contradictory results presented in molecular genetic studies.

Lovastatin as Treatment for Neurocognitive Deficits in Neurofibromatosis Type 1: Phase I Study

In a neurofibromatosis type 1 murine model, treatment with lovastatin reversed cognitive disabilities. We report on a phase I study examining the safety and tolerability of lovastatin in children with neurofibromatosis type 1. Twenty-four children with neurofibromatosis type 1 underwent a dose-escalation protocol for 3 months to identify the maximum tolerated dose and potential toxicity. Minimal side effects were evident, and no child experienced dose-limiting toxicity. Cognitive evaluations were completed before and after treatment, and the results suggested improvement in areas of verbal and nonverbal memory. Additional analyses, using reliable change indices, indicated improvements exceeding those of test-retest or practice effects in some participants. These observations may be analogous to the improvements observed in a neurofibromatosis type 1 murine model treated with lovastatin, although further study and replication are required. The safety and preliminary cognitive results support the need for a larger phase II trial in this population.

Attention deficit/hyperactivity disorder (ADHD): Complex phenotype, simple genotype?

Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and probably the most controversial. ADHD has been considered a complex genetic trait based upon the absence of a clear-cut boundary between affected and unaffected status. Furthermore, its high comorbidity with other disorders strongly suggests complex epistatic or pleiotropic effects acting in common with the environmental influences. This implies that the same gene or genes is or are associated with different and concurrently occurring phenotypes. In this study, we will review clinical and epidemiological aspects related to the ADHD phenotype, which are considered either as categorical or continuous traits. We also will discuss genetic models underlying the complexity of this behavioral phenotype and the probable role of epistatic interactions between major genes contributing to the ADHD phenotype.

Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1

Aim  Difficulties in neurocognition and social interaction are the most prominent causes of morbidity and long‐term disability in children with neurofibromatosis type 1 (NF1). Symptoms of attention‐deficit–hyperactivity disorder (ADHD) have also been extensively recognized in NF1. However, systematic evaluation of symptoms of autism spectrum disorder (ASD) in children with NF1 has been limited.

Aicardi syndrome: spectrum of disease and long-term prognosis in 77 females

Aicardi syndrome is an X-linked-dominant condition characterized by infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. We reviewed the Aicardi Syndrome Foundations compilation of family-based, self-reported questionnaires for the year 2000. Information was obtained from 77 females with Aicardi syndrome regarding developmental milestones, seizure frequency, seizure classification, antiepileptic drug use, and medical problems. Patient ages ranged from 1 to 25 years (mean = 7.2 years). All patients were significantly developmentally delayed with milestones ranging from 2 to 36 months. Of the patients, 91% attained milestones no higher than 12 months. Seizures were reported in 92% of patients and occurred daily in 67%. Infantile spasms were the most common seizure type observed in 17%, although a variety of other seizure types were also reported. Multiple antiepileptic drugs were used in these patients with 73% of patients taking two or more antiepileptic drugs. Five patients had a vagal nerve stimulator implanted, and one patient underwent a hemispherectomy. The most common medical problems cited included scoliosis, constipation, gastroesophageal reflux, aspiration pneumonia, and otitis media, but overall health was perceived to be good. Our review demonstrates the spectrum of developmental disabilities, epilepsy severity, and prognosis in a large group of Aicardi patients.

Mental, motor, and language development of toddlers with neurofibromatosis type 1.

OBJECTIVE To examine the mental, motor, and language development of toddlers with neurofibromatosis type 1 (NF1). STUDY DESIGN In this cross-sectional study, 39 toddlers with NF1 (aged 21-30 months) and 42 age-matched control children were assessed using the Bayley Scales of Infant Development, Second Edition. Basic vocabulary was assessed with the language subtests from the Wechsler Preschool and Primary Scale of Intelligence, Third Edition. Parents completed questionnaires evaluating the childrens expressive language, behavior, and executive functioning. The χ(2) test, independent t test, Mann-Whitney U test, and analysis of covariance were used to examine differences between the two groups. RESULTS The toddlers with NF1 had significantly poorer mental and motor development than the control participants. Parental responses indicated that most of the children with NF1 had delayed language skills. No differences in behavior and executive functioning were noted between the two groups of children. CONCLUSIONS Children with NF1 as young as age 30 months demonstrate early signs of mental, motor, and language difficulties. Age 2 years may be the appropriate time to perform an initial developmental assessment to identify mental, motor, and language impairments in children with NF1.

A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.