Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

Rhombencephalosynapsis is a midline brain malformation characterized by missing cerebellar vermis with apparent fusion of the cerebellar hemispheres. Rhombencephalosynapsis can be seen in isolation or together with other central nervous system and extra-central nervous system malformations. Gómez-López-Hernández syndrome combines rhombencephalosynapsis with parietal/temporal alopecia and sometimes trigeminal anaesthesia, towering skull shape and dysmorphic features. Rhombencephalosynapsis can also be seen in patients with features of vertebral anomalies, anal atresia, cardiovascular anomalies, trachea–oesophageal fistula, renal anomalies, limb defects (VACTERL) association. Based on a comprehensive evaluation of neuroimaging findings in 42 patients with rhombencephalosynapsis, we propose a spectrum of severity, ranging from mild (the partial absence of nodulus, anterior and posterior vermis), to moderate (the absence of posterior vermis with some anterior vermis and nodulus present), to severe (the absence of posterior and anterior vermis with some nodulus present), to complete (the absence of the entire vermis including nodulus). We demonstrate that the severity of rhombencephalosynapsis correlates with fusion of the tonsils, as well as midbrain abnormalities including aqueductal stenosis and midline fusion of the tectum. Rhombencephalosynapsis is also associated with multiple forebrain abnormalities including absent olfactory bulbs, dysgenesis of the corpus callosum, absent septum pellucidum and, in rare patients, atypical forms of holoprosencephaly. The frequent association between rhombencephalosynapsis and aqueductal stenosis prompted us to evaluate brain magnetic resonance images in other patients with aqueductal stenosis at our institution, and remarkably, we identified rhombencephalosynapsis in 9%. Strikingly, subjects with more severe rhombencephalosynapsis have more severely abnormal neurodevelopmental outcome, as do subjects with holoprosencephaly and patients with VACTERL features. In summary, our data provide improved diagnostic and prognostic information, and support disruption of dorsal–ventral patterning as a mechanism underlying rhombencephalosynapsis.

In the large group of genetically undetermined infantile-onset mitochondrial encephalopathies, multiple defects of mitochondrial DNA-related respiratory-chain complexes constitute a frequent biochemical signature. In order to identify responsible genes, we used exome-next-generation sequencing in a selected cohort of patients with this biochemical signature. In an isolated patient, we found two mutant alleles for EARS2, the gene encoding mitochondrial glutamyl–tRNA synthetase. The brain magnetic resonance imaging of this patient was hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim and symmetrical signal abnormalities of the thalami, midbrain, pons, medulla oblongata and cerebellar white matter. Proton magnetic resonance spectroscopy showed increased lactate. We matched this magnetic resonance imaging pattern with that of a cohort of 11 previously selected unrelated cases. We found mutations in the EARS2 gene in all. Subsequent detailed clinical and magnetic resonance imaging based phenotyping revealed two distinct groups: mild and severe. All 12 patients shared an infantile onset and rapidly progressive disease with severe magnetic resonance imaging abnormalities and increased lactate in body fluids and proton magnetic resonance spectroscopy. Patients in the ‘mild’ group partially recovered and regained milestones in the following years with striking magnetic resonance imaging improvement and declining lactate levels, whereas those of the ‘severe’ group were characterized by clinical stagnation, brain atrophy on magnetic resonance imaging and persistent lactate increases. This new neurological disease, early-onset leukoencephalopathy with thalamus and brainstem involvement and high lactate, is hallmarked by unique magnetic resonance imaging features, defined by a peculiar biphasic clinical course and caused by mutations in a single gene, EARS2, expanding the list of medically relevant defects of mitochondrial DNA translation.

Mutations in dynamin 2 (DNM2) lead to dominant intermediate Charcot–Marie–Tooth neuropathy type B, while a different set of DNM2 mutations cause autosomal dominant centronuclear myopathy. In this study, we aimed to elucidate the disease mechanisms in dominant intermediate Charcot–Marie–Tooth neuropathy type B and to find explanations for the tissue-specific defects that are associated with different DNM2 mutations in dominant intermediate Charcot–Marie–Tooth neuropathy type B versus autosomal dominant centronuclear myopathy. We used tissue derived from Dnm2-deficient mice to establish an appropriate peripheral nerve model and found that dominant intermediate Charcot–Marie–Tooth neuropathy type B-associated dynamin 2 mutants, but not autosomal dominant centronuclear myopathy mutants, impaired myelination. In contrast to autosomal dominant centronuclear myopathy mutants, Schwann cells and neurons from the peripheral nervous system expressing dominant intermediate Charcot–Marie–Tooth neuropathy mutants showed defects in clathrin-mediated endocytosis. We demonstrate that, as a consequence, protein surface levels are altered in Schwann cells. Furthermore, we discovered that myelination is strictly dependent on Dnm2 and clathrin-mediated endocytosis function. Thus, we propose that altered endocytosis is a major contributing factor to the disease mechanisms in dominant intermediate Charcot–Marie–Tooth neuropathy type B.

The peripheral manifestations of the inherited neuropathies are increasingly well characterized, but their effects upon cranial nerve function are not well understood. Hearing loss is recognized in a minority of children with this condition, but has not previously been systemically studied. A clear understanding of the prevalence and degree of auditory difficulties in this population is important as hearing impairment can impact upon speech/language development, social interaction ability and educational progress. The aim of this study was to investigate auditory pathway function, speech perception ability and everyday listening and communication in a group of school-aged children with inherited neuropathies. Twenty-six children with Charcot–Marie–Tooth disease confirmed by genetic testing and physical examination participated. Eighteen had demyelinating neuropathies (Charcot–Marie–Tooth type 1) and eight had the axonal form (Charcot–Marie–Tooth type 2). While each subject had normal or near-normal sound detection, individuals in both disease groups showed electrophysiological evidence of auditory neuropathy with delayed or low amplitude auditory brainstem responses. Auditory perception was also affected, with >60% of subjects with Charcot–Marie–Tooth type 1 and >85% of Charcot–Marie–Tooth type 2 suffering impaired processing of auditory temporal (timing) cues and/or abnormal speech understanding in everyday listening conditions.

Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ~0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5–14 hexanucleotide repeats, expanded alleles range from ~650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ~1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration.