A novel mutation of Twinkle in Perrault syndrome: A not rare diagnosis?

Perrault syndrome is a rare disorder characterized by ovarian dysgenesis, bilateral sensorineural hearing loss and associated with mutations in six mitochondrial proteins. Additional neurological features were also described. Herein, we report on a 27-year-old woman with Perrault syndrome (PS), moderate ataxia and axonal sensory-motor peripheral neuropathy in whom we identified compound heterozygous mutations in the TWNK gene (p.Val507Ile and the novel p.Phe248Ser variant). Fewer than 30 patients with PS have been reported worldwide. Neurological involvement is more frequently associated with mutations in TWNK and indicates possible genotype-phenotype correlations. TWNK mutations should be searched in patients with sensory ataxia, early onset bilateral sensorineural hearing loss, and ovarian dysfunction in women.

Autosomal-dominant transthyretin (TTR)-related amyloidosis is not a frequent CMT2 neuropathy "in disguise".

Transthyretin (TTR)-related familial amyloid polyneuropathy (TTR-FAP) is a life-threatening autosomal dominant, systemic disease. First symptoms usually occur from the second to over sixth decade of life with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure.Early diagnosis is pivotal for effective therapeutic options, but it is hampered by the heterogeneity of the clinical spectrum which can lead to misdiagnosis with other neurological condition/disorder such as axonal sensory-motor neuropathy (CMT2) as described in literature.The aim of our study was to search for TTR mutations in a large cohort of selected undiagnosed axonal sensory-motor neuropathy patients to establish if misdiagnosis is frequent or rare in the Italian population.No TTR pathogenic variants were found in our cohort. In conclusion, our study shows that TTR testing not should be straightforward recommended in CMT2 patients but only when "red flags" TTR's features are present.

Spinocerebellar ataxia 17: full phenotype in a 41 CAG/CAA repeats carrier.

BACKGROUND: Spinocerebellar ataxia 17 (SCA17) is one of the most heterogeneous forms of autosomal dominant cerebellar ataxias with a large clinical spectrum which can mimic other movement disorders such as Huntington disease (HD), dystonia and parkinsonism. SCA17 is caused by an expansion of CAG/CAA repeat in the Tata binding protein (TBP) gene. Normal alleles contain 25 to 40 CAG/CAA repeats, alleles with 50 or greater CAG/CAA repeats are pathological with full penetrance. Alleles with 43 to 49 CAG/CAA repeats were also reported and their penetrance is estimated between 50 and 80%. Recently few symptomatic individuals having 41 and 42 repeats were reported but it is still unclear whether CAG/CAA repeats of 41 or 42 are low penetrance disease-causing alleles. Thus, phenotypic variability like the disease course in subject with SCA17 locus restricted expansions remains to be fully understood. CASE PRESENTATION: The patients was a 63-year-old woman who, at 54 years, showed personality changes and increased frequency of falls. At 55 years of age neuropsychological tests showed executive attention and visuospatial deficit. At the age of 59 the patient developed dysarthria and a progressive cognitive deficit. The neurological examination showed moderate gait ataxia, dysdiadochokinesia and dysmetria, dysphagia, dysarthria and abnormal saccadic pursuit, severe axial asynergy during postural changes, choreiform dyskinesias. Molecular analysis of the TBP gene demonstrated an allele with 41 repeat suggesting that 41 CAG/CCG TBP repeats could be an allele associated with the full clinical spectrum of SCA17. CONCLUSIONS: The described case with the other similar cases described in the literature suggests that 41 CAG/CAA trinucleotides should be considered as critical threshold in SCA17. We suggest that SCA17 diagnosis should be suspected in patients presenting with movement disorders associated with other neurodegenerative signs and symptoms.

Twenty years of molecular analyses in amyotrophic lateral sclerosis: genetic landscape of Italian patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a heterogeneous genetic background. Because mutation analysis by Sanger sequencing is costly and time-consuming, in recent years, next-generation sequencing (NGS) techniques have become of much interest. This study analyses the results of 20 years of molecular analyses in ALS patients in our laboratory using traditional methods and NGS. Almost 300 ALS patients underwent genetic analysis with Sanger sequencing of 7 genes or with an NGS panel of 23 genes. The C9orf72 expansion was tested by fragment size analysis. Sanger sequencing revealed mutations in 23.8% of familial and 3.8% of sporadic cases, whereas NGS detected potentially pathogenic variants in 45.5% of familial and 5.4% of sporadic cases and variants of unknown significance in 30.3% of patients. In 11.8% of patients, potentially causative mutations were found in 2 or more ALS genes. Compared to traditional methods, NGS is more effective in revealing possibly causal variants, but counseling patients becomes more complicated due to frequent variants of unknown significance and potentially oligogenic cases.

Role of MAPT in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients.

The aim of our study was to evaluate the role of mutations in the MAPT gene in patients with pure amyotrophic lateral sclerosis (ALS). A cohort of 120 ALS patients, both sporadic and familial, without cognitive impairment was analyzed by next-generation sequencing with a multiple-gene panel comprising 23 genes, including MAPT, known to be associated with ALS and frontotemporal dementia. The presence of the C9orf72 expansion was also investigated. Twelve patients had mutations in the SOD1, TARDBP, MATR3, and FUS genes, while 10 patients carried the C9orf72 expansion. One female patient was found to carry the D348G mutation in MAPT, previously reported in an Italian family with lower motor neuron disease. Our patient presented both upper and lower motor neuron signs, early development of dyspnea, resting and kinetic tremor, and a slow disease course (> 11 years). The present case further broadens the clinical phenotype associated with MAPT mutations and suggests that, although rarely, MAPT mutations can cause ALS and, therefore, should be analyzed in ALS patients, especially in those with early breathing difficulties and long-lasting disease.

1993-2014: two decades of predictive testing for Huntington's disease at the Medical Genetics Unit of the University of Genoa.

BACKGROUND: Predictive testing for Huntington's disease has been available at the Medical Genetics Unit of the University of Genoa from 1987. In 1989, an integrated counseling protocol (geneticist, psychologist, and neurologist) was developed following International Guidelines. METHODS: This is a retrospective analysis of the clinical charts and motivation questionnaires of persons seeking predictive testing through direct DNA analysis from 1993 until 2014, with the aim to evaluate their individual characteristics, motivations, and the outcomes of the counseling protocol. RESULTS: A total of 299 persons (164 women, 135 men) applied for predictive testing. Most applicants' features and motivations were similar to those previously described, but surprisingly the percentage of completed protocols was higher among men, 68.5% versus 53.5% (P = 0.011). Likewise, persons over 25 years of age were more likely to take the test than younger applicants (18-25 years): 63.4% versus 48.1% (P = 0.043). In addition, relationship status, having children, and the gender of the affected parent showed different effects on the decision about testing in males and females. No catastrophic reactions were reported during the study period. CONCLUSIONS: We observed that factors influencing the decision-making process might differ between males and females, and that predictive testing appears a safe procedure if framed within an integrated counseling protocol.

Two novel cases of compound heterozygous mutations in mitofusin2: Finding out the inheritance.

MFN2 is the major gene involved in the axonal form of Charcot-Marie-Tooth disease. It usually has an autosomal dominant pattern of inheritance, but a few cases of homozygous or compound heterozygous mutations have been described. These patients usually present an earlier onset, more severe phenotype and their inheritance pattern can span from autosomal recessive to semidominant. Here we report two unrelated patients carrying two compound heterozygous MFN2 mutations. Both present a pure axonal neuropathy without any additional features. The first patient presents a mild clinical phenotype with onset in the 2nd decade, while the second patient shows a severe, early onset phenotype with loss of independent ambulation. Only a careful clinical examination as well as neurophysiological and genetic studies allowed us to establish the role and the transmission pattern of the identified variants. We discuss practical consequences of this finding in genetic counseling.

Neuroimaging features in C9orf72 and TARDBP double mutation with FTD phenotype.

Increasing evidence has shown that morphological and functional neuroimaging may help to understand the pathophysiological mechanisms leading to behavioral disturbances in patients with genetic or sporadic frontotemporal dementia (FTD). The C9orf72 expansion was found in association with the N267S TARDBP mutation in two siblings with behavioral-variant FTD (bvFTD). In one of them with very mild dementia, MRI showed symmetric atrophy of temporal, inferolateral and orbital frontal cortex, while [18F]FDG-PET disclosed more extended hypometabolism in dorsolateral and inferolateral frontal cortex, anterior cingulate, and caudate nucleus. Hypometabolism in right lateral and orbital frontal cortex was confirmed also in comparison with a group of sporadic bvFTD patients. These findings appear as the neuroimaging hallmark of double C9orf72 and TARDBP gene mutation with a bvFTD phenotype.

Survivin promoter polymorphisms and autoantibodies in endometriosis.

Expression of survivin, an inhibitor of apoptosis, is increased in endometriotic lesions and probably favors the survival of endometrial fragments in the peritoneal cavity. The aim of this study was to evaluate associations between survivin promoter polymorphisms and the risk of endometriosis, as well as to compare the immunoreactivity to survivin in sera of patients with and without endometriosis. We studied 149 women with endometriosis, 196 fertile women from the general population (control group A) and 47 women who had undergone diagnostic laparoscopy and had no evidence of endometriosis (control group B). There were no significant differences in the genotypic distribution of the survivin gene promoter region -241C/T, -235G/A and -31G/C single nucleotide polymorphisms (SNP) between endometriosis patients and the two control groups. In addition, also median anti-survivin autoantibody levels were similar among patients and controls (group B). However, anti-survivin antibody concentrations seemed to be influenced by cigarette smoking, being significantly lower in sera of actively smoking women compared to non-smokers (median OD: 0.019 vs. 0.155, respectively, P<0.001), and by the -235G/A SNP, as A allele carriers were significantly more frequent among women with a high antibody level (OD≥2.0) compared to those with lower concentrations (OD<2.0) (23.1% vs. 4.1%, respectively, P=0.008). Based on these results, we conclude that survivin promoter polymorphisms are not associated with susceptibility to endometriosis in the Estonian population, and though the expression of survivin is increased in endometriotic lesions, autoimmune reactivity against it is similar in women with and without the disease.

Polymorphisms in ESR1, ESR2 and HSD17B1 genes are associated with fertility status in endometriosis.

OBJECTIVE: To investigate whether polymorphisms in genes involved in biosynthesis and signalling of sex steroids influence susceptibility to endometriosis and to infertility associated with it. MATERIALS AND METHODS: Patients with endometriosis (n = 150) and fertile controls (n = 199) were genotyped for polymorphisms in oestrogen receptor genes ESR1 (rs2234693 - T/C single nucleotide polymorphism (SNP), dinucleotide (TA)(n) repeat) and ESR2 (dinucleotide (CA)(n) repeat), progesterone receptor gene PGR (rs10895068 - G/A SNP, 306-bp Alu-insertion), 17ß-hydroxysteroid dehydrogenase type 1 gene HSD17B1 (rs605059 - A/G SNP), and aromatase gene CYP19A1 (rs10046 - C/T SNP, (TTTA)(n) tetranucleotide repeat, 3-bp TCT insertion/deletion polymorphism). RESULTS: The HSD17B1 A/G SNP A allele increased overall endometriosis risk and the risk of stage I-II disease, while ESR1 longer (TA)(n) repeats only correlated with susceptibility to stage I-II endometriosis. When considering patients' fertility status, HSD17B1 A/G SNP A allele and ESR1 longer (TA)(n) repeats were associated with endometriosis accompanied by infertility, while ESR2 shorter (CA)(n) repeats were linked with endometriosis without infertility. Other polymorphisms were distributed similarly among patients and controls. CONCLUSIONS: Genetic variants in ESR1, ESR2, and HSD17B1 genes could modify susceptibility to endometriosis and might influence the fertility status in endometriosis patients.

Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women.

OBJECTIVE: To determine plausible associations between endometriosis and vascular endothelial growth factor gene (VEGF -2578 A/C, -1154 G/A, -634 G/C and 936 C/T), also angiotensin I-converting enzyme gene (ACE -240 A/T and 2350 A/G) single nucleotide polymorphisms (SNPs), as well as their respective haplotypes. STUDY DESIGN: PCR-based restriction fragment length polymorphism analysis was used to detect SNPs in VEGF and ACE genes in 150 Estonian women with endometriosis and 199 control subjects. RESULTS: The CC genotype of the VEGF -2578 A/C SNP was correlated with a decreased risk of endometriosis (OR=0.40, 95% CI 0.20-0.78). Other VEGF and ACE SNPs and haplotypes were not associated with endometriosis. CONCLUSION: This case-control study demonstrated that the VEGF -2578 A/C SNP may influence susceptibility to endometriosis in the Estonian population, while associations between endometriosis and other VEGF and ACE SNPs, as well as the respective haplotypes are unlikely.

Polymorphisms in MMP-2 and MMP-9 promoter regions are associated with endometriosis.

In this case-control study, we investigated the potential associations of MMP-2 and MMP-9 gene promoter region polymorphisms as well as MMP-2 promoter haplotypes with susceptibility to endometriosis in women of caucasian origin. The results demonstrated that polymorphisms in MMP-2 (-735 C/T) and MMP-9 (-1562 C/T) were associated with elevated risk of endometriosis and that certain MMP-2 promoter haplotypes were more common in control group.