AIM To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation.METHOD We retrospectively reviewed the clinical presentation. Investigations included radiological findings and COL4A1 mutation analysis of the four cases. Affected family members were identified. COL4A1 mutation analysis was performed in all index cases and, where possible, in affected family members. RESULTSThe three male and one female index cases presented with recurrent childhood-onset stroke, infantile hemiplegia ⁄ spastic quadriplegia, and infantile spasms. Additional features such as congenital cataracts and anterior segment dysgenesis were present. Microcephaly and developmental delay ⁄ learning difficulties were present in three cases. Three cases had one or more family member affected in multiple generations, with a total of 11 such individuals identified. The clinical features showed a wide intrafamilial variation. Magnetic resonance imaging (MRI) showed bilateral white matter change in all cases, except in one mutation-positive family member. Unilateral or bilateral porencephaly was present in cases with infantile hemiplegia, and a diagnosis of clinical stroke was supported by the presence of intracerebral haemorrhage. The age at diagnosis was between 1 year and 6 years for the children with presentation in infancy and 12 months after stroke in a 14-year-old male. Three new pathogenic mutations were identified in the COL4A1 gene.INTERPRETATION COL4A1 mutations can present in children with infantile hemiplegia ⁄ quadriplegia, stroke or epilepsy, and a motor disorder. The presence of eye features and white matter change on MRI in childhood can help point towards the diagnosis. Once the diagnosis is made, a careful search can identify affected family members.

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X-linked hereditary motor sensory neuropathy type 1 (CMTX 1) is caused by mutation in the GJB1 gene that codes for the connexin 32 protein. Central nervous system involvement with or without white matter changes on magnetic resonance imaging (MRI) has rarely been reported in this condition. We report the case of a 7-year-old, previously well male who presented with a stroke-like episode that manifested as left hemiparesis and dysphasia. An initial brain MRI showed white matter signal changes affecting the corpus callosum and periventricular areas with a posterior predominance. Our patient made a complete clinical recovery in 36 hours. Clinical examination at this stage showed no evidence of a peripheral neuropathy. A repeat brain MRI 6 weeks later showed almost complete resolution of the changes seen initially. Subsequent investigations showed a Val177Ala mutation in the GJB1 gene. This mutation has so far not been described in the Caucasian population and has been only described once before. Electrophysiological studies showed a mixed demyelinating and axonal sensorimotor neuropathy in keeping with CMTX 1. Five months after the initial presentation our patient developed clinical evidence of a peripheral neuropathy in the form of absent ankle reflexes, weak dorsiflexors, and evertors of both feet. CASE REPORTA 7-year-old male of Caucasian origin presented with a sudden onset stroke-like episode manifesting as left hemiparesis and dysphasia following an upper respiratory tract infection. His pre-and perinatal history were uneventful. He had attained all his milestones at appropriate times but there had been a long-standing history of problems with coordination and this had been put down as developmental coordination disorder. He had no learning difficulties. There was no family history of any neurological illness and certainly nothing to suggest an X-linked disorder. Brain magnetic resonance imaging (MRI) done within 24 hours of onset of symptoms showed diffuse mild signal abnormalities in the periventricular and deep cerebral white matter with a posterior predominance. The corpus callosum was affected as well with associated swelling. Our initial thoughts were that of a leucodystrophy or an acute disseminated encephalomyelitis (Figs 1 and 2). His investigations showed normal blood counts and inflammatory markers, renal, liver, and thyroid function tests. He also had normal blood glucose, lactate, plasma amino acids, serum ammonia, biotinidase, copper, ceruloplasmin, white cell enzymes, and very long chain fatty acids. Blood and urine tested for creatine, creatinine, and guanidoacetate did not show evidence of creatine deficiency syndromes. He had a normal male karyotype. The m.3243A>G, m.8344A>G, and m.8993T>C ⁄ G mitochondrial DNA mutations and major mitochondrial DNA rearrangements were not detected. A lumbar puncture was not performed as the patient became extremely anxious and distressed. Clinically, he fully recovered in 36 hours. He had normal power in all muscle groups (Medical Research Council [MRC] Grad...

Alexander disease (AxD) is a usually fatal astrogliopathy primarily caused by mutations in the gene encoding GFAP, an intermediate filament protein expressed in astrocytes. We describe three patients with unique characteristics, and whose mutations have implications for AxD diagnosis and studies of intermediate filaments. Patient 1 is the first reported case with a non-coding mutation. The patient has a splice site change producing an in-frame deletion of exon 4 in about 10% of the transcripts. Patient 2 has an insertion and deletion at the extreme end of the coding region, resulting in a short frameshift. In addition, the mutation was found in buccal DNA but not in blood DNA, making this patient the first reported chimera. Patient 3 has a single base deletion near the C-terminal end of the protein, producing a short frameshift. These findings recommend inclusion of intronic splice site regions in genetic testing for AxD, indicate that alteration of only a small fraction of GFAP can produce disease, and provide caution against tagging intermediate filaments at their C-terminal end for cell biological investigations.

We report a genetic syndrome combining myasthenic features and severe neurodegeneration with therapy-refractory epilepsy. The underlying cause is a glycosylation defect due to mutations in . These cases broaden the phenotypic spectrum associated with congenital disorders of glycosylation as previously only isolated myasthenia has been described.