Miguel Leão

MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review.

INTRODUCTION MEF2C haploinsufficiency syndrome is characterized by severe intellectual disability, epilepsy, stereotypic movements, minor dysmorphisms and brain abnormalities. We report the case of a patient with a new MEF2C mutation, comparing his clinical and imaging features to those previously reported in the literature. CASE REPORT A 10 year-old boy first came to pediatric neurology clinic at the age of 11 months because of severe psychomotor delay, without regression. He presented generalized hypotonia, poor eye contact, hand-mouth stereotypies, strabismus and minor facial dimorphisms. Epileptic seizures started at 26 months of age and were refractory. Brain MRI showed a slight increase in periventricular white matter signal and globally enlarged CSF spaces. Molecular analysis revealed a de novo, pathogenic and causative MEF2C mutation. DISCUSSION MEF2C haploinsufficiency syndrome was recently recognized as a neurodevelopmental disorder. Severe intellectual disability with inability to speak and epilepsy are universal features in patients with MEF2C mutations, although mild cognitive and speech disorders have been reported to occur in patients with duplications. Epilepsy might be absent in patients with partial deletions. Abnormal movement patterns are very common in patients with MEF2C haploinsufficiency. Delayed myelination seems to be more commonly observed in patients with MEF2C mutations, while malformations of cortical development were only reported in patients with microdeletions. Although MEF2C haploinsufficiency prevalence is yet to be determined, it should be considered in the differential diagnosis of patients with severe intellectual disability and Rett-like features.

Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL): a pediatric case report.

The syndrome of transient headache and neurologic deficits associated with cerebrospinal fluid lymphocytosis (HaNDL) is characterized by 1 or more episodes of severe headache, transient neurologic deficits, and lymphocytic pleocytosis in the cerebrospinal fluid. It is a benign and self limited disorder seldom reported in pediatric age. We report the case of a 14-year-old girl who suffered from 2 episodes of headache with transient focal neurologic deficits and pleocytosis consistent with the syndrome of HaNDL. This entity should be taken into account as a differential diagnosis in otherwise healthy children presenting with recurrent headache and acute neurologic deficits. Repeated use of invasive and expensive laboratory and imaging investigations can be avoided when the diagnosis of the syndrome of HaNDL is correctly established.

Moyamoya Vascular Pattern in Alagille Syndrome

We describe a girl with Alagille syndrome and a moyamoya angiographic pattern on magnetic resonance angiography. She was referred for genetic consultation because of posterior embryotoxon and peripheral pulmonary stenosis. Her facial appearance was typical, but she had no cholestasis or vertebral involvement. A heterozygous duplication of one nucleotide (a c.715dupA mutation) not previously described was identified in exon 5 of the JAG1 gene. We review similar cases in the literature and possible pathophysiologic mechanisms (e.g., the Jagged 1 and Notch signaling pathway) of this association.

Gene dosage evidence for the regional assignment of GPT (glutamate-pyruvate transaminase; E. C. 2.6.1.2) locus to 8q24.2→8qter

SummaryThe results of a study on the expression of GPT (glutamate-pyruvate transaminase; E. C. 2.6.1.2) in a child with a partial trisomy of chromosomes 8 and 14 are presented. A gene dosage effect supporting the regional assignment of the GPT locus to 8q24.2→8qter is demonstrated.

Novel STXBP1 Mutations in 2 Patients With Early Infantile Epileptic Encephalopathy

The authors describe 2 patients with early infantile epileptic encephalopathy caused by 2 novel mutations involving the STXBP1 gene. The authors suggest that in spite of the rarity of STXBP1 mutations, molecular analysis of STXBP1 gene should be performed in patients with early infantile epileptic encephalopathy, after exclusion of ARX mutations in male patients and CDKL5 mutations in female patients. The potential mechanisms explaining the variable clinical phenotypes caused by STXBP1 mutations are discussed and the designation of early-onset epileptic encephalopathies, including an updated genetic classification, is proposed to encompass the epileptic encephalopathies beginning in the first 6 months of life.

Expanding the phenotype of IFAP/BRESECK syndrome: A new case with severe hypogammaglobulinemia

The ichthyosis follicular with atrichia and photophobia syndrome (IFAP) is a rare X-linked multiple congenital malformation syndrome. Some male patients have additional features including brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies and kidney dysplasia/hypoplasia (BRESEK syndrome) sometimes associated with Hirschsprung disease and cleft palate or cryptorchidism (BRESHECK syndrome). We report a 5 months-old male patient with the p.R429H mutation in MBTPS2 protein, which has been reported to be associated with the most severe phenotype of patients with IFAP/BRESHECK syndrome. This patient presented with a severe IFAP/BRESHECK phenotype including ichthyosis follicular, atrichia, photophobia, brain anomalies, global developmental delay, Hirschsprung disease and kidney hypoplasia. Additional features not previously reported in IFAP syndrome, include severe hypogammaglobulinemia and congenital rectourethral fistula.

Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype.

Loss of function of GPR56 causes a specific brain malformation called the bilateral frontoparietal polymicrogyria (BFPP), which has typical clinical and neuroradiological findings. So far, 35 families and 26 independent mutations have been described.We present a Portuguese 5-year-old boy, born from nonconsanguineous parents, with BFPP. This patient has a novel GPR56 mutation (R271X) and an unusual phenotype, because he presents hot water epilepsy.To the best of our knowledge, this is the first reported case of BFPP evolving hot water epilepsy.

Alsin Related Disorders: Literature Review and Case Study with Novel Mutations

Mutations in the ALS2 gene cause three distinct disorders: infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and autosomal recessive juvenile amyotrophic lateral sclerosis. We present a review of the literature and the case of a 16-year-old boy who is, to the best of our knowledge, the first Portuguese case with infantile ascending hereditary spastic paraplegia. Clinical investigations included sequencing analysis of the ALS2 gene, which revealed a heterozygous mutation in exon 5 (c.1425_1428del p.G477Afs*19) and a heterozygous and previously unreported variant in exon 3 (c.145G>A p.G49R). We also examined 42 reported cases on the clinical characteristics and neurophysiological and imaging studies of patients with known ALS2 gene mutations sourced from PubMed. This showed that an overlap of phenotypic manifestations can exist in patients with infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and juvenile amyotrophic lateral sclerosis.

Lateral Meningocele Syndrome: Additional Report and Further Evidence Supporting a Connective Tissue Basis

Lateral meningocele syndrome is a rare disorder of unknown etiology, first described in 1977 and subsequently reported in nine other patients. These patients present distinctive craniofacial features and skeletal abnormalities in addition to multiple lateral meningoceles, suggesting a connective tissue disorder. Autosomal dominant inheritance is clearly suggested in one family and could explain familiar aggregation in another. We describe a simplex case of lateral meningocele syndrome with bicuspid aortic valve, supporting the hypothesis of a connective tissue basis for this disorder and further expanding the phenotype.

Intellectual disability and overgrowth-A new case of 19p13.13 microdeletion syndrome with digital abnormalities.

19p13.13 microdeletion has been consistently associated with intellectual disability, overgrowth, and macrocephaly. We report a 19p13.13 microdeletion, detected by array CGH, in a girl with moderate intellectual disability, overgrowth with macrocephaly, prominent digit pads and deep digital creases, hypotonia, ataxia, and strabismus. This clinical report helps to delineate the role of some of the deleted genes, as well as the phenotype of recently described 19p13.13 microdeletion syndrome, including the description of novel digital abnormalities.