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 nonsy-nonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sib-ling 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 non-synonymous change at a highly conserved asparagine that sits at the intradimer interface of a-tubulin and b-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 dys-tonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC [MIM 612438]) is a rare leukodystro-phy described by Van der Knaap et al. in 2002. 1 To date, only 22 individual cases have been reported. It is character-ized by variable onset (from infancy to childhood), devel-opmental delay, extrapyramidal movement disorders (dys-tonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises), progressive spastic tetraplegia, ataxia, and, more rarely, seizures. 1 MRI plays a fundamental role in the diagnostic work-up because neuroradiological find-ings are pathognomonic; diagnostic criteria include the combination of hypomyelination, cerebellar atrophy, and absence or disappearance of the putamen, 1 all features that have been comprehensively confirmed in a recent au-topsy case. 2 The disease appears to be sporadic in nature given that there are no previously published sibling groups. The lack of familial groups has thus far foiled at-tempts at identifying a causative mutation or rare variant. It has also been somewhat uncertain whether H-ABC represents a single disorder or the common neuroradio-logic manifestations of a heterogeneous group of disorders. The reported finding of low levels of 5-methyltetrahydro-folate in the cerebrospinal fluid (CSF) of one affected