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Classic rett syndrome in a boy as a result of somatic mosaicism for a mecp2 mutation

Rett syndrome (RTT) is a neurodevelopmental disorder affecting females in a sporadic manner. In a high proportion of patients the disease is caused by de novo dominant mutations at MECP2 gene (Xq28). The existence of RTT males has been discussed extensively, and less restrictive diagnostic criteria have been proposed to include this variant, which should be considered when evaluating boys with idiopathic developmental regression, autistic features, and loss of hand function. Nevertheless, no MECP2 analysis has been reported from Rett-like males to date. Analysis of 2 familial cases showed that boys carrying the same MECP2 mutation that caused RTT in their sisters suffered from severe–fatal neonatal encephalopathy. Recent data, however, demonstrate that the clinical spectrum of MECP2 mutations is wider than previously expected. With a frequency comparable to that of fragile X syndrome, recessive nonspecific X-linked mental retardation can be caused by missense mutations at MECP2, different than those causing RTT. Mutations have also been described in patients with congenital nonprogressive encephalopathy and in some cases of Angelman syndrome (AS), the only reported AS boy being a somatic mosaic for a MECP2 truncating mutation. We document the first MECP2 analysis of a boy with classic RTT and a normal 46,XY karyotype. The patient is 14 years of age and fulfils eight of nine necessary criteria, seven of eight supportive criteria, and no exclusion criteria, according to the Rett Syndrome Diagnostic Criteria Work Group. Genetic informed consent was obtained and the study was approved by the Ethical and Investigation Commissions of our hospital. MECP2 sequencing of two independent patients’ DNA samples from peripheral lymphocytes revealed the presence of a heterozygous change 398G3A, causing an R133H substitution. The mutation had been previously described in 2 RTT female patients. As the boy had a normal karyotype, heterozygosity could be explained by (1) a low frequency mosaicism for a Klineffelter syndrome, discarded by FISH on prophasic nuclei; (2) a MECP2 locus duplication, rejected by high-resolution karyotype and observation of hemizygosity for X-linked markers and two intragenic MECP2 polymorphisms; or (3) somatic mosaicism for the mutation. To test this last hypothesis, DNA was prepared from the patient’s oral mucosa and sequenced. The normal sequence, with only a small amount of the mutated allele, was observed. These results demonstrated that the RTT boy is a somatic mosaic for the R133H mutation and seemed to indicate that the mutation is present in a high proportion of lymphocytes but at a lower frequency in oral mucous. To specifically test and semiquantify the heterozygous status of the mutation, an amplification–refractory mutation system (ARMS) experiment was designed. Both the normal and mutated alleles were amplified in the patient’s lymphocytes and oral mucosa (Fig). Relative differences in band intensities corroborated the different degree of mosaicism between the two tissues. The infrequent clinical picture of this patient is thus explained by the existence of somatic mosaicism for an RTTcausing MECP2 mutation. Concerning X-linked diseases, this phenomenon in males mimics the result of lyonization naturally occurring in females and may explain the classic Rett syndrome phenotype of the boy.

Tocopherol in inborn errors of intermediary metabolism

Red blood cell tocopherol was measured in a group of 92 children with inborn errors of intermediary metabolism to evaluate the peroxidative damage in different mitochondrial and cytosolic defects, and to consider the need for treatment or vitamin supplementation. Tocopherol was determined by HPLC with UV detection. Results were expressed in nanomoles red blood cell tocopherol per gram protein. Significant differences (Mann-Whitney; P < 0.001) were found between tocopherol levels in untreated patients: 19 with mitochondrial defects versus 23 with cytosolic enzyme or transport defects, and versus 58 age-matched reference values. In conclusion, mitochondrial enzyme deficiencies, either amino and organic acidurias or defects of energy metabolism, seem to produce an excess of free radicals with the consequent utilization of tocopherol as antioxidant. This is not apparent in the cytosolic enzyme defects studied, whose tocopherol levels are in the normal range. Treatment with tocopherol completely corrects the deficient antioxidant status.

Phylloid hypomelanosis and mosaic partial trisomy 13: two cases that provide further evidence of a distinct clinicogenetic entity.

BACKGROUND Phylloid hypomelanosis is a rare neurocutaneous syndrome characterized by a pattern of hypopigmentation consisting of leaflike or oblong macules reminiscent of floral ornaments. Associated extracutaneous anomalies include cerebral, ocular, and skeletal defects. Recently it has been suggested that this phenotype originates from mosaic partial or complete trisomy 13. We report clinical and cytogenetic data for 2 cases. OBSERVATIONS A bizarre pattern of multiple leaflike macules was noted in 2 girls with mental deficiency. In patient 1, additional anomalies included syndactyly, clinodactyly, trichomegaly of the eyelashes, low frontal hairline, and several pale pink telangiectatic macules. In patient 2, epileptic seizures, dental malposition, oligodontia, preauricular fistulas, scoliosis, tethered cord, and syringomyelia were noted. A diagnosis of phylloid hypomelanosis was made in both patients. In both patients, blood lymphocytes showed a normal karyotype 46,XX; however, fibroblasts derived from lesional skin demonstrated tetrasomy of chromosome 13q21-qter in patient 1 and trisomy of 13q22-qter in patient 2. CONCLUSIONS These 2 cases lend further support to the concept that phylloid hypomelanosis is a distinct clinicogenetic entity that should no longer be confused with pigmentary mosaicism of the Ito type. From a comparison of our cytogenetic findings with those documented in previous articles, we infer that phylloid hypomelanosis is most likely related to the 13q region.

Epilepsy spectrum in cerebral creatine transporter deficiency

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