Genetic Causes of Cerebrovascular Disorders in Childhood

__Abstract__ Cerebrovascular disorders in childhood comprise ischemic stroke and hemorrhagic stroke. This thesis comprises a escription of genetic causes of childhood cerebrovascular disorders. Two examples of genetic causes of ischemic stroke, comprising a case of ACTA2 mutation and a review of the neurological findings in incontinentia pigmenti. In addition, genetic causes of childhood hemorrhagic stroke, mainly in the perinatal period, are provided. These comprise descriptions of special phenotypes linked to COL4A1 mutations, i.e. hydranencephaly, anterior segment disorders and a case of putative autosomal recessive inheritance of a COL4A1 mutation. The identification of COL4A2 mutations as a novel cause of porencephaly and small vessel disease is described. In addition, USP18 mutations were identified as novel causes of severe pseudo-TORCH syndrome with cerebral hemorrhage and early demise

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic die

Neurological findings in incontinentia pigmenti; a review

Incontinentia Pigmenti is a rare X-linked multisystem disorder with well described and pathognomonic skin manifestations. Neurological manifestations are found in 30% of IP patients, forming one of the major causes of morbidity and mortality of the condition. In this review, clinical and brain imaging data of 45 IP patients with a neurological phenotype are reviewed. Several clinical presentations could be identified, comprising seizures, infantile encephalopathy, acute disseminated encephalomyelitis and ischemic stroke. Most neurological features presented during the neonatal period. No patients presented during adolescence or at adult age. Seizures of different type are reported in about 20% of the patients at young age and seem to correlate with the degree of cerebrovascular damage. Brain MRI findings include periventricular and subcortical white matter disease, haemorrhagic changes, corpus callosum hypoplasia, cerebral atrophy and cerebellar hypoplasia. Ocular findings comprise a range of retinal vascular changes and optic atrophy, but also developmental defects like microphthalmia and cataract. Most findings may reflect changes following brain injury. Both (ischemic) vascular and inflammatory components may play a role in the cerebral and ocular phenotype. However, a role of disturbed apoptosis during development may also be a contributing factor. (c) 2012 Elsevier Masson SAS. All rights reserved

Osteomalacia with low alkaline phosphatase : a not so rare condition with important consequences

Hypophosphatasia is a genetic disorder, characterised by a dysfunctional tissue-non-specific isoenzyme of alkaline phosphatase that impacts bone metabolism and predisposes to osteomalacia or rickets. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease. Several forms of hypophosphatasia are recognised. We present a case of a 50-year-old woman with low impact fractures and loss of teeth at a young age. She also had a low alkaline phosphatase and was diagnosed with adult hypophosphatasia. Although the severe forms of hypophosphatasia are rather rare, the adult form is thought to occur quite frequently. As this condition is not well known by healthcare professionals, the time to diagnosis and initiation of adequate treatment is often postponed. When encountering a patient with low alkaline phosphatase, low bone density or a history of bone fractures, the possibility of hypophosphatasia should be considered