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We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome ( KS2, MIM 300867) and report, for the first time, germ-line missense and splice-site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome ( KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate-severe in boys but mild-moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some patients. [ABSTRACT FROM AUTHOR]

Abstract: We report a case of a girl who presented with typical absence seizures at age of 4.5 years. EEG showed absence seizures of sudden onset with 3Hz spike-and-waves that also correlated with the clinical absences. The seizure semiology included subtle deviation of the eyes which prompted MRI investigation of the brain. This showed a periventricular nodular heterotopia in the mid to anterior horn of the right lateral ventricle. Although possibly coincidental, periventricular heterotopia are considered to be epileptogenic and this association has been reported once before. Migration disorders, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato–thalamo–cortical network involved in the generation of 3Hz spike-waves. [ABSTRACT FROM AUTHOR]

Objective Periventricular heterotopia, one of the most common malformations of cortical development, is caused by extrinsic factors such as infections and prenatal injuries or genetic mutations. The most common genetic cause of periventricular heterotopia is mutations in the gene encoding filamin-A (FLNA) inherited in an X-linked dominant manner. Mutations in the ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) gene constitute another group of factors that cause association of autosomal recessive periventricular heterotopia with microcephaly. Methods A ten year-old girl was referred with severe developmental and growth delay, feeding problems and involuntary movements. The parents had first degree consanguinity. The birth history was unremarkable. Growth retardation and microcephaly were noticed around 4 months of age. Neurological examination revealed generalized hypotonia with poor head control and severe dystonic-choreoathetoid movements. The extended metabolic work-up of the case was unremarkable. The cranial MR imaging revealed bilateral periventricular nodular heterotopia, bilateral hyperintensity of the putamen and caudate nucleus with frontotemporal and hippocampal atrophy. The EEG of the patient who had no previous seizure history was found normal. Her echocardiography showed left ventricular non-compaction cardiomyopathy. Results The genetic analysis of ARFGEF2 gene revealed a homozygote c.5126G>A, p.Trp1709* mutation. Conclusion Mutations in the ARFGEF2 gene must be considered in the presence of bilateral periventricular nodular heterotopia and putaminal hyperintensity in children presented with movement disorders, severe developmental delay and microcephaly. [ABSTRACT FROM AUTHOR]

Abstract: Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy. Patients also show neurological signs and symptoms that have been infrequently reported. We describe a girl with MCD deficiency, whose brain MRI shows white matter abnormalities and additionally diffuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development. MLYCD-gene sequence analysis shows normal genomic sequence but no messenger product, suggesting an abnormality of transcription regulation. Our patient has strikingly low appetite, which is interesting in the light of the proposed role of malonyl-CoA in the regulation of feeding control, but this remains to be confirmed in other patients. Considering the incomplete understanding of the role of metabolic pathways in brain development, patients with MCD deficiency should be evaluated with brain MRI and unexplained malformations of cortical development should be reason for metabolic screening. [Copyright &y& Elsevier]

Abstract: Recently in this journal, Masurel-Paulet et al. reported the association between pulmonary disease and a mutation in X-linked FLNA in a male patient. We confirm this association in a female patient, showing that this complication is not sex-specific. Our patient has a FLNA missense mutation (c.220G > A) and presented with cerebral periventricular nodular heterotopia, cardiovascular abnormalities, and pulmonary disease consisting of lobar emphysema of the right middle pulmonary lobe with severe malacia of the right sided bronchus intermedius. Surgical resection of the right middle lobe was necessary and she had long-term oxygen dependency. Symptoms improved with age. [Copyright &y& Elsevier]