A de novo mutation in the ß-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hereditary leukoencephalopathy that was originally identified by MRI pattern analysis, and it has thus far defied all attempts at identifying the causal mutation. Only 22 cases are published in the literature to date. We performed exome sequencing on five family trios, two family quartets, and three single probands, which revealed that all eleven H-ABC-diagnosed individuals carry the same de novo single-nucleotide TUBB4A mutation resulting in nonsynonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sibling pair revealed maternal mosaicism for the mutation, suggesting that rare de novo mutations that are initially phenotypically neutral in a mosaic individual can be disease causing in the subsequent generation. Modeling of TUBB4A shows that the mutation creates a nonsynonymous change at a highly conserved asparagine that sits at the intradimer interface of α-tubulin and ß-tubulin, and this change might affect tubulin dimerization, microtubule polymerization, or microtubule stability. Consistent with H-ABC's clinical presentation, TUBB4A is highly expressed in neurons, and a recent report has shown that an N-terminal alteration is associated with a heritable dystonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC.

Learning disabilities do not go away: 20- to 25-year study of cognition, academic achievement, and affective illness.

This study was undertaken to establish how the current level of cognitive and academic functioning in adults might correlate with the previous testing performed at a small private school in Dallas, Texas, that serves students with learning disabilities. Each of the 40 participants had been evaluated as students 20 to 25 years previously using the standard cognitive and achievement tests accepted in practice during the 1970s. Additionally, the medical director of the school, a neurologist, had evaluated each student for neurologic and behavioral disorders. At the time of follow-up, the participants were administered a battery of intellectual and achievement measures commensurate with the previous testing and a detailed neurologic and neurobehavioral examination was performed. A significant correlation was found between the original and the current test scores, confirming both that learning disabilities persist into adulthood and that children with affective illness have a significant risk for later recurrent affective illness episodes.

Juvenile Huntington disease exacerbated by methylphenidate: case report.

The authors describe the case of an 8-year-old boy, otherwise healthy, who presented with symptoms consistent with attention-deficit hyperactivity disorder (ADHD) and was started on a trial of methylphenidate. Within 4 weeks, he experienced a rapid decline in fine motor skills, with dysarthria, intention tremor, motor impersistence, and diffusely increased tone. Symptoms persisted despite cessation of methylphenidate. At that time, a paternal history of Huntington disease was disclosed. Molecular analysis revealed an expansion in CAG repeats to 75 copies, within the range characteristic of juvenile Huntington disease. This report raises the possibility that use of dopaminergic agonists in patients with a family history of Huntington disease may lead to clinical exacerbation of motor symptoms and/or unwitting diagnosis in an unprepared family.