The patient with mild diencephalic-mesencephalic junction dysplasia - Case report and review of literature.

Diencephalic-mesencephalic junction dysplasia (DMJD) is very rare congenital brain malformation. We present a 66-years-old man with mild cognitive impairment, dysarthria, deafness, gait abnormality, and involuntary movements of the trunk. The first symptoms, psychomotor excitation and anxiety begun when he was over thirty years old however the symptoms gradually intensified and slowly progressed. The magnetic resonance imaging scans showed partial DMJD. According to recent date it represented type-B of the malformation with relatively mild phenotype in relation to the previously described in literature type-A. To the best of our knowledge this is the first description of an adult patient diagnosed with DMJD anomaly.

Intrafamilial variability of the primary dystonia DYT6 phenotype caused by p.Cys5Trp mutation in THAP1 gene.

Mutations localized in THAP1 gene, locus 18p11.21 have been reported as causative of primary dystonia type 6 (DYT6). Disease which is characterized mainly by focal dystonia, frequently involving the craniocervical region, however associated also with early-onset generalized dystonia and spasmodic dysphonia. Here we report a novel mutation in the THAP1 gene identified in a Polish family with DYT6 phenotype - the c.15C>G substitution in exon 1 introducing the missense mutation p.Cys5Trp within the N-terminal THAP domain. The mutation was described in two generations, in patients showing a broad spectrum of focal and generalized dystonia symptoms of variable onset. Our results indicate that certain mutations in the THAP1 gene may lead to primary dystonia with remarkable intrafamilial clinical variability.

PLP1 gene duplication as a cause of the classic form of Pelizaeus-Merzbacher disease - case report.

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked dysmyelination disorder of the central nervous system (CNS). PMD is caused by mutations in the PLP1 gene located at Xq22 and encoding the major myelin component in CNS, proteolipid protein 1 (PLP1). The disease is clinically heterogeneous. Phenotypes are generally categorized into classic and connatal forms. Connatal PMD has more rapid progression with early death, while patients with classic PMD generally survive to adulthood. Both forms of the disease are caused by point mutations as well as rearrangements - multiplication (mainly duplication) and deletion of the PLP1 gene. We present a case of a male patient affected by the classic form of PMD with benign course, except severe dysarthria with the characteristic laryngeal stridor, which is more typical for connatal form of the disease. The diagnosis has been confirmed at the molecular level. The patient has duplication of all 7 exons of the PLP1 gene. This duplication was inherited from the patient's mother, who is an unaffected carrier of the mutation. The patient's family pedigree analysis revealed the interfamilial variability of the phenotype among affected male relatives.

The spectrum of PLP1 gene mutations in patients with the classical form of the Pelizaeus-Merzbacher disease.

UNLABELLED: The Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive hypomyelination disorder caused by mutations of the proteolipid protein1 gene (PLP1). There is a spectrum of PLP1-related disorders from very severe connatal PMD, through classical PMD to mild spastic paraplegia type 2 (SPG2), with some correlation between the type of mutation and the phenotype. In general, missense mutations give rise to more severe forms of the disease, deletions and null mutations to mild PMD and SPG2. The most common variations, duplications, result in the classical-intermediate form of PMD. THE AIM: To report the analysis of mutations in the PLP1 gene and phenotype di!erences in ten male patients diagnosed with PMD. Although they had different types of PLP1 mutations (duplications, missense and nonsense mutations), all of them were clinically classi"ed with the classical form of PMD (clPMD). MATERIAL AND METHODS: The subjects of analysis were ten male patients aged 1.5 to 21 years who were diagnosed with PMD. All patients developed the "rst clinical symptoms between 1 an 8 months of age and showed developmental delay, mainly in motor skills. All were classified with the classical form of the disease, according to international clinical criteria and the electrophysiological and brain MRI criteria of hypomyelination. The molecular analysis of the PLP1 gene involved dosage analysis and direct sequencing of all exons and promotor region of the gene. RESULTS: The clinical diagnosis of PMD was con"rmed for all subjects by molecular analysis of the PLP1gene. Although all had the classical form of PMD, it was caused by mutations of di!erent types: duplications of the entire gene, missense and nonsense mutations. CONCLUSIONS: Our clinical and molecular "ndings showed that the phenotypic spectrum resulting from PLP1 mutations seems to be broader in patients with the PLP1 gene duplication compared to patients with both nonsense and missense mutation. Nevertheless, apart from the type of mutation, all our patients' clinical manifestation falls into the category of the classical form of PMD according to international criteria. Obviously the type of mutations, but also other unidentified factors may a!ect the clinical course of PMD.The Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive hypomyelination disorder caused by mutations of the proteolipid protein 1 gene (PLP1). There is a spectrum of PLP1-related disorders from very severe connatal PMD, through classical PMD to mild spastic paraplegia type 2 (SPG2), with some correlation between the type of mutation and the phenotype. In general, missense mutations give rise to more severe forms of the disease, deletions and null mutations to mild PMD and SPG2. The most common variations, duplications, result in the classical-intermediate form of PMD. THE AIM: To report the analysis of mutations in the PLP1 gene and phenotype differences in ten male patients diagnosed with PMD. Although they had di!erent types of PLP1 mutations (duplications, missense and nonsense mutations), all of them were clinically classi"ed with the classical form of PMD (clPMD). MATERIAL AND METHODS: The subjects of analysis were ten male patients aged 1.5 to 21 years who were diagnosed with PMD. All patients developed the "rst clinical symptoms between 1 an 8 months of age and showed developmental delay, mainly in motor skills. All were classified with the classical form of the disease, according to international clinical criteria and the electrophysiological and brain MRI criteria of hypomyelination. The molecular analysis of the PLP1 gene involved dosage analysis and direct sequencing of all exons and promotor region of the gene. RESULTS: The clinical diagnosis of PMD was con"rmed for all subjects by molecular analysis of the PLP1 gene. Although all had the classical form of PMD, it was caused by mutations of di!erent types: duplications of the entire gene, missense and nonsense mutations. CONCLUSIONS: Our clinical and molecular findings showed that the phenotypic spectrum resulting from PLP1 mutations seems to be broader in patients with the PLP1 gene duplication compared to patients with both nonsense and missense mutation. Nevertheless, apart from the type of mutation, all our patients' clinical manifestation falls into the category of the classical form of PMD according to international criteria. Obviously the type of mutations, but also other unidentified factors may a!ect the clinical course of PMD.