DJ‐1 gene mutations have been found to cause early‐onset Parkinson's disease. We report a family from southern Italy with three brothers affected by early‐onset parkinsonism, dementia, and ...amyotrophic lateral sclerosis. Molecular analysis of the DJ‐1 gene in two living patients showed a novel homozygous mutation in exon 7 (E163K) and a new homozygous mutation (g.168_185dup) in the promoter region of the gene. Both mutations cosegregated with the disease and were detected in a heterozygous state in the patients' mother and their healthy siblings. Our findings expand the spectrum of clinical presentations associated with mutations in DJ‐1 gene. Ann Neurol 2005;58:803–807
Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. We herein describe a family from southern Italy whose ...proband was a 49-year-old man presenting with ataxia with progressive gait disturbances, clumsiness and visual impairment. A molecular analysis identified 38 cytosine-adenine-guanine (CAG) repeat expansions within the SCA7 gene. Our study confirms the marked anticipation previously observed in SCA7 and extends the small number of patients studied thus far. In this family, the disease is most likely caused by a de novo expansion of a premutated intermediate allele carried by one parent.
Summary
Heterozygous mutations of PRRT2, which encodes proline‐rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or ...familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6–44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD—mental retardation, episodic ataxia, and absences—who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene.
Summary
Purpose
To report the identification of the T1174S SCN1A (NaV1.1) mutation in a three‐generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the ...pathomechanism.
Methods
The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A; functional studies by expression in tsA‐201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K).
Key Findings
The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures (FS) and later developed BOE. Two additional relatives had FHM without epilepsy or FS. All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (INaP), consistent with gain of function. The INaP increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions.
Significance
Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype–phenotype relationship of SCN1A mutations.
Abstract Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta. This degeneration leads to bradykinesia, muscular rigidity, ...resting tremor, and postural instability. It affects 1%–2% of the population above the age of 60 years. Recently, 2 studies identified the Asp620Asn mutation in the vacuolar protein sorting 35 ( VPS35 ) gene, and the Arg1205His in the eukaryotic translation initiation factor 4 gamma 1 gene ( EIF4G1 ) were reported to be associated an autosomal dominant form of PD. In this study we screened these mutations in a cohort of 250 South Italy patients with familial PD and 250 control subjects from South Italy. VPS35 Asp620Asn mutation and EIF4G1 Arg1205His mutation were not found in our 250 PD patients. This result, with our previous reports on the absence of mutations in LRRK2 and in SNCA, warrant a continuing search for novel causative genes for PD among South Italy.
Primary familial brain calcification (PFBC) is a rare neurodegenerative disease characterized by bilateral calcifications mostly located in the basal ganglia and in the thalami, cerebellum and ...subcortical white matter. Clinical manifestations of this disease include a large spectrum of movement disorders and neuropsychiatric disturbances. PFBC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. Three causative genes have been reported: SLC20A2, PDGFRB and PDGFB.
We screened three PFBC Italian families for mutations in the SLC20A2, PDGFRB and PDGFB genes.
Phenotypic data were obtained by neurologic examination, CT scan and magnetic resonance imaging. Mutation screening of SLC20A2, PDGFRB and PDGFB was performed by sequencing.
We identified a new heterozygous deletion c.21_21delG (p.L7Ffs*10) in SLC20A2 gene in one of these families. No mutations were detected in the other two families.
Our data confirm that mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.
•We screened three PFBC Italian families for mutations in the SLC20A2, PDGFRB and PDGFB genes.•Screening for SLC20A2 gene detected a novel deletion in heterozygous state c.21_21delG.•It consists in a novel frameshift variant p.Leu7Phefs*10 identified in one of these families.•No mutations were detected in the other two families.•Our data confirm that mutations in SLC20A2 are a major cause of IBGC.
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