A novel TRPA1 variant is associated with carbamazepine-responsive cramp-fasciculation syndrome.

Cramp-fasciculation syndrome (CFS) is a rare muscle hyperexcitability syndrome that presents with muscle cramps, fasciculations, and stiffness, as well as pain, fatigue, anxiety, hyperreflexia, and paresthesias. Although familial cases have been reported, a genetic etiology has not yet been identified. We performed whole-exome sequencing followed by validation and cosegregation analyses on a father-son pair with CFS. Both subjects manifested other hypersensitivity-hyperexcitability symptoms, including asthma, gastroesophageal reflux, migraine, restless legs syndrome, tremor, cold hyperalgesia, and cardiac conduction defects. Most symptoms improved with carbamazepine, consistent with an underlying cation channelopathy. We identified a variant in the transient receptor potential ankyrin A1 channel (TRPA1) gene that selectively cosegregated with CFS and the other hypersensitivity-hyperexcitability symptoms. This variant (c.2755C>T) resulted in a premature stop codon at amino acid 919 (p.Arg919*) in the outer pore of the channel. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel that is strongly implicated in the pathophysiology of the specific hypersensitivity-hyperexcitability symptoms observed in these subjects. Thus, we have identified a novel TRPA1 variant that is associated with CFS as part of a generalized hypersensitivity-hyperexcitability disorder. These findings clarify the diverse functional roles of TRPA1, and underscore the importance of this channel as a potential therapeutic target.

Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive degeneration of the central nervous system and high basal ganglia iron deposition. The list of identified causative genes for NBIA syndromes continues to expand and includes one autosomal dominant, one X-linked, and a number of recessive forms. Mitochondrial membrane protein-associated neurodegeneration is a recently described NBIA syndrome caused by C19orf12 mutations. In this study, we report two consanguineous families with a homozygous C19orf12 p.Thr11Met mutation. Our patients presented at a later age and had more rapid disease progression, leading to early death in two, than those previously reported. We conclude that C19orf12 mutation is associated with wide phenotypic heterogeneity, and that further research is needed to examine the role of C19orf12 in NBIA and related diseases and to elucidate its protein function as well as other factors that may affect disease progression and expression.

Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control.

BACKGROUND: Mutations in parkin and PTEN-induced protein kinase (PINK1) represent the two most common causes of autosomal recessive parkinsonism. The possibility that heterozygous mutations in these genes also predispose to disease or lower the age of disease onset has been suggested, but currently there is insufficient data to verify this hypothesis conclusively. OBJECTIVE: To study the frequency and spectrum of parkin and PINK1 gene mutations and to investigate the role of heterozygous mutations as a risk factor for early-onset Parkinson's disease (PD). METHODS: All exons and exon-intron boundaries of PINK1 and parkin were sequenced in 250 patients with early-onset PD and 276 normal controls. Gene dosage measurements were also performed, using high-density single-nucleotide polymorphism arrays. RESULTS: In total 41 variants were found, of which 8 have not been previously described (parkin: p.A38VfsX6, p.C166Y, p.Q171X, p.D243N, p.M458L; PINK1: p.P52L, p.T420T, p.A427E). 1.60% of patients were homozygous or compound heterozygous for pathogenic mutations. Heterozygosity for pathogenic parkin or PINK1 mutations was over-represented in patients compared with healthy controls (4.00% vs. 1.81%) but the difference was not significant (p = 0.13). The mean age at disease onset was significantly lower in patients with homozygous or compound heterozygous mutations than in patients with heterozygous mutations (mean difference 11 years, 95% CI 1.4 to 20.6, p = 0.03). There was no significant difference in the mean age at disease onset in heterozygous patients compared with patients without a mutation in parkin or PINK1 (mean difference 2 years, 95% CI -3.7 to 7.0, p = 0.54). CONCLUSIONS: Our data support a trend towards a higher frequency of heterozygosity for pathogenic parkin or PINK1 mutations in patients compared with normal controls, but this effect was small and did not reach significance in our cohort of 250 cases and 276 controls.

Whole genome analysis in a consanguineous family with early onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SNP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease.

R632W mutation in PLA2G6 segregates with dystonia-parkinsonism in a consanguineous Iranian family.

BACKGROUND: PLA2G6 mutations are known to be responsible for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA). In addition, novel mutations in PLA2G6 have recently been associated with dystonia-parkinsonism in two unrelated consanguineous families. METHODS: Direct sequencing analysis of the PLA2G6 gene. RESULTS: Here, we report the segregation of R632W with disease in an Iranian consanguineous dystonia-parkinsonism pedigree. The identical mutation was previously observed in a patient affected with NBIA. CONCLUSION: We conclude that different and even identical PLA2G6 mutations may cause neurodegenerative diseases with heterogeneous clinical manifestations, including INAD, NBIA and dystonia-parkinsonism.

Clinical heterogeneity and genotype-phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11).

BACKGROUND: Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum is a distinct and usually severe form of complex hereditary spastic paraplegia classified as SPG11. Recently mutations on SPG11 gene (KIAA1840), which is localized to chromosome 15q13-q15, were shown to cause the majority of SPG11 cases. METHODS: We analysed the 40 coding exons of this gene in the probands from eight families with complex ARHSP, four of these families had a thin corpus callosum and two has mild thinning. RESULTS: Three families were identified with novel mutations in the SPG11 gene. One family was of Asian origin with a homozygous nonsense mutation and had a very severe phenotype but only very mild thinning of the corpus callosum. In the other two English families the parents were unrelated and the mutations were compound heterozygotes. In these two families the phenotype was mild and both probands had a thin corpus callosum. CONCLUSION: Given the probable mechanism of action of the mutations in the Spatacsin gene, we discuss the probable genotype phenotype correlations in these families. This study confirms the frequent occurrence of Spatacsin mutations in complex ARHSP with genotype phenotype effects and exposes the spectrum of clinical heterogeneity in SPG11.

SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia.

BACKGROUND: Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common form of complex hereditary spastic paraplegia. The genetic lesion underlying ARHSP-TCC was localized to chromosome 15q13-q15 and given the designation SPG11. Recently, the gene encoding spatacsin (KIAA1840) has been shown to contain mutations that underlie the majority of ARHSP-TCC cases. METHODS: We present a complete analysis of the 40 coding exons of this gene in patients with sporadic (n = 25) or familial (20 probands) complex hereditary spastic paraplegia with and without thinning of the corpus callosum. RESULTS: We identified seven mutations, including deletions, insertions, and nonsense mutations, which were all predicted to lead to premature truncation of the protein. CONCLUSION: We conclude that mutations on KIAA1840 are frequent in complex autosomal recessive hereditary spastic paraplegia but an infrequent cause of sporadic complex hereditary spastic paraplegia.

Apolipoprotein E epsilon4 allele in familial and sporadic Parkinson's disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer's disease (AD). Common risk factors for both diseases have been explored to study potential etiologic interactions between these two neurodegenerative disorders. The APOE epsilon4 allele, previously associated with AD, has also been associated with risk of PD and with the presence of some clinical features in PD patients. However, the role of APOE epsilon4 allele in risk of PD remains unclear. We studied the distribution of APOE alleles in 276 unrelated familial and sporadic PD patients and in 212 controls. Patients and controls were classified by ethnicity. No genetic heterogeneity between Basques and people from other regions of Spain was found. No significant differences in APOE allele distribution between PD patients and controls were found; however, lower epsilon4 allele frequency was observed when the sporadic PD group was analyzed separately. By contrast, an increase in epsilon4 allele frequency was found in familial PD patients with cognitive decline. We conclude that the APOE epsilon4 allele may be associated with the risk of developing PD in isolated cases and that it is linked to the presence of cognitive decline in familial PD in our sample.

Testing association between LRRK2 and Parkinson's disease and investigating linkage disequilibrium.

BACKGROUND: We and others recently identified the gene underlying PARK8 linked Parkinson's disease (PD). This gene, LRRK2, contains mutations that cause an autosomal dominant PD, including a mutation, G2019S, which is the most common PD causing mutation identified to date. Common genetic variability in genes that contain PD causing mutations has previously been implicated as a risk factor for typical sporadic disease. METHODS: We undertook a case-control association analysis of LRRK2 in two independent European PD cohorts using 31 tagging single nucleotide polymorphisms (tSNPs) and five potentially functional SNPs. To assess the structure of this locus in different populations, we have performed linkage disequilibrium (LD) analysis using these variants in a human diversity panel. RESULTS: We show that common genetic variability in LRRK2 is not associated with risk for PD in the European populations studied here. We also show inter-population variability in the strength of LD across this locus. CONCLUSIONS: To our knowledge this is the first comprehensive analysis of common variability within LRRK2 as a risk factor for PD.

LRRK2 gene in Parkinson disease: mutation analysis and case control association study.

BACKGROUND: In addition to the four well-confirmed genes linked to early-onset Parkinson disease (PD) (SNCA, PARKIN, DJ-1, and PINK1), mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have recently been identified in families with autosomal dominant late-onset PD. OBJECTIVE: To perform mutation analysis of LRRK2 in probands of families showing dominant inheritance of PD and to conduct a case control association study to test the hypothesis that common coding variations might be associated with increased susceptibility to PD. METHODS: All 51 LRRK2 coding exons were sequenced in 23 probands and the mutation frequencies were evaluated in 180 neurologically normal control subjects. For the association study the authors genotyped four coding LRRK2 polymorphisms in 250 normal control subjects and 121 patients with PD (predominantly white patients of Canadian origin), 84% of whom had age at onset before 50 years and 42% had a positive family history. RESULTS: The authors identified three probands with heterozygous LRRK2 mutations: two of them have the known G2019S substitution and one proband has a novel I1371V substitution. Mutation analysis of a large family demonstrated complete segregation of the G2019S with PD. However, there was no association between PD and any of the four polymorphisms at the allelic or genotypic levels (p > 0.17). Furthermore, the authors did not detect a modifying effect for any genotype or of APOE genotypes upon the age at onset in the PD group (p > 0.20). CONCLUSIONS: The results support the prior suggestion that LRRK2 mutations cause PD. The disease in the families reported here presents a phenotype indistinguishable from typical PD. All three families demonstrate a very variable age at onset that is not explained by APOE genotypes. The common coding variations in the LRRK2 gene neither constitute strong PD risk factors nor modify the age at onset; however, the possibility of a modest risk effect remains to be assessed in large datasets.