Broadening the phenotype of <Emphasis Type="Italic">TARDBP</Emphasis> mutations: the <Emphasis Type="Italic">TARDBP</Emphasis> Ala382Thr mutation and Parkinson’s disease in Sardinia

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson’s disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51–79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.     

Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations

In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in SOD1, FUS, TARDBP, ANG, OPTN, and C9ORF72. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247; p < 0.01). Among patients with OCBs, two patients had the TARDBP p.A382T mutation (one of which in homozygous state), and one the ANG p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both TARDBP and ANG genes may disrupt the blood–brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant TARDBP and ANG genes on BBB integrity of ALS patients warrants further investigation.     

A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism

Juvenile parkinsonism can be caused by recessive mutations in several genes. Among these, homozygous or compound heterozygous mutations in the F-box only protein 7 gene (FBXO7) cause juvenile parkinsonism with variable degrees of pyramidal disturbances (PARK15). So far, only five families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported with this form. Here, we describe a new Turkish family with homozygous FBXO7 mutation (c.1492C > T, p.Arg498*). Three out of nine siblings born from consanguineous parents suffered from juvenile-onset progressive parkinsonism. Mental retardation was also documented in two of them. Of note, pyramidal signs were absent. The response to dopaminergic medications was present, but limited by dyskinesias and psychiatric side effects. Further genetic analysis of this Turkish family and the Italian PARK15 family reported previously revealed that the c.1492C > T mutation is present on two different haplotypes in the Italian family, and one of these haplotypes is shared in homozygous state in the Turkish patients. These findings contribute to the ongoing delineation of the genetic and clinical spectrum of PARK15.     

Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability

Mutations in the ATP13A2 (PARK9) and FBXO7 (PARK15) genes are linked to different forms of autosomal recessive juvenile-onset neurodegenerative diseases with overlapping phenotypes, including levodopa-responsive parkinsonism, pyramidal disturbances, cognitive decline, and supranuclear gaze disturbance. However, the associated genotypes and phenotypes are poorly characterized due to the small number of patients described. Here, we report clinical, instrumental, and genetic findings in an Italian family with novel PARK9 and PARK15 mutations. The proband developed a severe progressive phenotype including juvenile-onset parkinsonism, pyramidal disturbances, cognitive decline, and oculomotor abnormalities. On the contrary, his brother only shows mild abnormalities (pyramidal, cognitive, and oculomotor) on the neurological examination at the age of 31?years. These two brothers both carry a novel homozygous PARK9 missense (p.G877R) and a novel heterozygous PARK15 mutation (p.R481C). The PARK9 mutation replaces a crucial residue for the ATPase activity, and is therefore most likely a loss-of-function mutation and disease-causing in homozygous state. The pathogenic significance of the PARK15 single heterozygous mutation remains unclear. In both sibs, DaTSCAN single photon emission computed tomography showed marked nigrostriatal dopaminergic defects, and transcranial magnetic stimulation detected prolonged central motor conduction time. MRI, including T2*-weighted imaging, detected no evidence of brain iron accumulation. This family, the third reported with homozygous PARK9 mutations and the first with mutations in two genes for atypical juvenile parkinsonism, illustrates that PARK9-linked disease might display wide intra-familial clinical variability and milder phenotypes, suggesting the existence of strong, still unknown, modifiers.     

Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis

Background and objectives

Genetic variants in the gene TARDBP, encoding TDP-43 protein, are associated with amyotrophic lateral sclerosis (ALS) in familial (fALS) and sporadic (sALS) cases. Objectives of this study were to assess the contribution of TARDBP in a large cohort of Italian ALS patients, to determine the TARDBP-associated clinical features and to look for genotype–phenotype correlation and penetrance of the mutations.

Methods

A total of 1992 Italian ALS patients (193 fALS and 1799 sALS) were enrolled in this study. Sanger sequencing of TARDBP gene was performed in patients and, when available, in patients' relatives.

Results

In total, 13 different rare variants were identified in 43 index cases (10 fALS and 33 sALS) with a cumulative mutational frequency of 2.2% (5.2% of fALS, 1.8% of sALS). The most prevalent variant was the p.A382T followed by the p.G294V. Cognitive impairment was detected in almost 30% of patients. While some variants, including the p.G294V and the p.G376D, were associated with restricted phenotypes, the p.A382T showed a marked clinical heterogeneity regarding age of onset, survival and association with cognitive impairment. Investigations in parents, when possible, showed that the variants were inherited from healthy carriers and never occurred de novo.

Conclusions

In our cohort, TARDBP variants have a relevant frequency in Italian ALS patients and they are significantly associated with cognitive impairment. Clinical presentation is heterogeneous. Consistent genotype–phenotype correlations are limited to some mutations. A marked phenotypic variability characterizes the p.A382T variant, suggesting a multifactorial/oligogenic pathogenic mechanism.     

ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation

Kufor Rakeb disease (KRD, PARK9) is an autosomal recessive extrapyramidal‐pyramidal syndrome with generalized brain atrophy due to ATP13A2 gene mutations. We report clinical details and investigational results focusing on radiological findings of a genetically‐proven KRD case. Clinically, there was early onset levodopa‐responsive dystonia‐parkinsonism with pyramidal signs and eye movement abnormalities. Brain MRI revealed generalized atrophy and putaminal and caudate iron accumulation bilaterally. Our findings add KRD to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). KRD should be considered in patients with dystonia‐parkinsonism with iron on brain imaging and we suggest classifying as NBIA type 3. © 2010 Movement Disorder Society     

The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN

IntroductionMutations in the C19orf12 gene cause mitochondrial membrane protein associated neurodegeneration (MPAN), an autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). A limited number of patients with C19orf12 mutations, particularly those with adult onset of symptoms, have been reported.MethodsWe sequenced the entire coding region of C19orf12 in 15 Turkish adult probands with idiopathic NBIA. We also performed haplotype analysis in families with a recurrent C19orf12 mutation. Clinical features were collected using a standardized form.ResultsNine of our 15 probands (60%) carried the homozygous c.32C > T mutation in C19orf12 (predicted protein effect: p.Thr11Met). This homozygous mutation co-segregated with the disease in all affected relatives available for testing (16 homozygous subjects).Haplotypes across the C19orf12 locus were identical for a very small region, closest to the mutation, suggesting an old founder, or, two independent founders. The clinical phenotype was characterized by adult onset in most cases (mean 24.5 years, range 10–36), and broad spectrum, including prominent parkinsonism, pyramidal signs, psychiatric disturbances, cognitive decline, and motor axonal neuropathy, in various combinations. On T2- or susceptibility weighted-MRI images, all patients displayed bilateral hypointensities in globus pallidus and substantia nigra, without an eye-of-the-tiger sign; however, hyperintense streaking of the medial medullary lamina between the external and internal parts of globus pallidus was observed frequently.ConclusionThe C19orf12 p.Thr11Met mutation is frequent among adult Turkish patients with MPAN. These findings contribute to the characterization of this important NBIA form, and have direct implications for genetic testing of patients of Turkish origin.     

Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease

BackgroundMutations in the F-box protein 7 (FBXO7) gene result in autosomal recessive parkinsonism. This usually manifests as early-onset parkinsonian-pyramidal syndrome but patients exhibit high phenotypic variability. Here we describe the findings of a Yemeni family with two novel FBXO7 mutations.MethodsClinical data and DNA were available for three siblings with early-onset parkinsonism together with their parents and three unaffected siblings. A targeted next generation sequencing panel was used to screen the proband for mutations in 14 genes known to cause a parkinsonian disorder. In addition, SNCA, PARK2, PINK1, and PARK7 were screened for copy number variants.ResultsThe proband carried two novel compound heterozygous FBXO7 mutations: a missense mutation in exon 1 (p.G39R; c.115G > A) and a frameshift mutation in exon 5 (p.L280fs; c.838del). The mutations segregated with disease in the family with the exception of a potentially pre-symptomatic individual whose age was below the age of onset in two of their three affected siblings. P.G39R occurred at a highly conserved amino acid residue and both mutations were predicted to be deleterious in silico. In contrast to most reported families, the phenotype in this pedigree was consistent with clinically typical Parkinson's disease (PD) with a lack of pyramidal signs and good response to dopaminergic therapy.ConclusionsOur study expands the phenotype associated with FBXO7 to include early-onset PD and broadens the list of causative mutations. These data suggest that FBXO7 should be included in clinical genetic testing panels for PD, particularly in patients with early onset or a recessive inheritance pattern.     

Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation

We present the clinical, biochemical, and molecular findings of three Greek patients with tyrosine hydroxylase (TH) deficiency. All patients presented with a severe clinical phenotype characterized by prominent motor delay, infantile parkinsonism, oculogyric crises, and signs of autonomic dysfunction. Cerebrospinal fluid analysis disclosed reduced dopamine metabolites and normal pterins. Response to levodopa was favorable though not dramatic. All patients were homozygous for a previously reported mutation (p.L236P). SNP haplotype analysis was consistent with a common ancestral mutation, thus indicating a founder effect in Greek patients with TH deficiency. © 2010 Movement Disorder Society     

C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis

Mutations in C19orf12 have been recently identified as the molecular genetic cause of a subtype of neurodegeneration with brain iron accumulation (NBIA). Given the mitochondrial localization of the gene product the new NBIA subtype was designated mitochondrial membrane protein-associated neurodegeneration. Frequent features in the patients described so far included extrapyramidal signs and pyramidal tract involvement. Here, we report three C19orf12-mutant patients from two families presenting with predominant upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis with juvenile onset. While extrapyramidal signs were absent, all patients showed neuropsychological abnormalities with disinhibited or impulsive behavior. Optic atrophy was present in the simplex case. T2-weighted cranial MRI showed hypointensities suggestive of iron accumulation in the globi pallidi and the midbrain in all patients. Sequence analysis of C19orf12 revealed a novel mutation, p.Gly66del, compound heterozygous with known mutations in all patients. These patients highlight that C19orf12 defects should be considered as a differential diagnosis in patients with juvenile onset motor neuron diseases. Patients have to be examined carefully for neuropsychological abnormalities, optic neuropathy, and signs of brain iron accumulation in MRI.     

A novel homozygous DJ1 mutation causes parkinsonism and ALS in a Turkish family

ObjectiveDJ1 mutations (PARK7) are among the monogenic causes of early-onset autosomal recessive parkinsonism. Here, we report clinical and genetic findings in a family with Turkish origin carrying a new DJ1 mutation and presenting with early-onset levodopa responsive parkinsonism and signs of amyotrophic lateral sclerosis (ALS).MethodsThe family consisted of 12 members including 10 offsprings of whom three were affected. All family members underwent detailed clinical examination. DNA samples from the index case, his unaffected sister, and his parents were subjected to whole genome sequencing analysis.ResultsThe index case 38-year-old man developed left hand tremor at the age of 24 years. He had progressive asymmetrical parkinsonism, depression and developed signs of ALS within 4 years. His two affected sisters had young-onset asymmetrical tremor-dominant parkinsonism with signs of ALS. A new homozygous p.Q45X mutation in exon 3 in DJ1 was found in all three patients. Their unaffected parents and one clinically healthy sibling were found to be heterozygous for this mutation.ConclusionsThis is the second report of DJ1 mutations associated with parkinsonism and ALS. This is relevant for genetic counseling as well as for understanding the pathogenesis of the broad spectrum of parkinsonism-ALS disease complex.     

Genetic analysis of the fused in sarcoma gene in Chinese Han patients with Parkinson's disease

Background and purposeExome sequencing in a large essential tremor (ET) family identified a novel nonsense mutation (p.Q290X) in the fused in sarcoma gene (FUS) as the cause of this family. Because of the clinical overlap between ET and Parkinson's disease (PD), the role of FUS in an independent cohort of PD patients from China mainland was evaluated.MethodsThe entire coding region of FUS in 508 Chinese Han patients with PD and the identified variants in 633 normal controls were evaluated. A variant was further screened in an additional 382 controls for the frequency in our population.ResultsA novel variant c.696C > T (p.Y232Y) in 2 sporadic patients with PD and six variants (c.52C > A, p.P18T; c.52C > T, p.P18S; c.147C > A, p.G49G; c.291C > T, p.Y97Y; c.684C > T, p.G228G; c.1176G > A, p.M392I) without significant difference in genotypic and allelic distributions in our PD cohort were identified.ConclusionThe FUS gene is not a genetic risk factor for PD in the population of Chinese Han ethnicity.     

How to diagnose MSA early: the role of sphincter EMG

Summary. Multiple system atrophy (MSA) is a degenerative disease manifesting a combination of parkinsonism, cerebellar, pyramidal, and autonomic (including urinary, sexual and anorectal) dysfunction. It is pathomorphologically defined, but lacks a definitive clinical diagnostic test. In patients with probable MSA, abnormal sphincter EMG, as compared to control subjects, has been found in the majority of patients in all the different forms of the disease in most studies, including patients who, as yet, have no urological or anorectal problems. Patients with Parkinson’s disease (PD) as a rule do not show marked sphincter EMG abnormalities in the first five years of the disease. Thus, abnormal spontaneous activity or marked motor unit potential changes in sphincter muscles are helpful in distinguishing MSA from PD in the first five years after the onset of symptoms and signs, and from pure autonomic failure, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out. EMG does not distinguish MSA from progressive supranuclear palsy. How early in the course of MSA these abnormalities become significant enough to support diagnosis remains to be established by prospective studies.     

Transcallosal diffusion tensor abnormalities in predominant gait disorder parkinsonism

BackgroundThere have been no previous diffusion tensor imaging (DTI) studies comparing Parkinson's disease (PD) with postural instability and gait disorder (PIGD) parkinsonism.ObjectiveUtilizing DTI with 2-region tractography, we conducted a case control study to determine if different brain regions representing the neural network of the motor system are differentially affected in PIGD compared to PD and controls.MethodsOn a 3 T MR machine, using manual ROI (regions of interest) we determined the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values on DTI in anatomical brain regions representing the extrapyramidal, pyramidal, and transcallosal tracts, aided by 2-region tractography. FA and ADC were correlated with the Tinetti score (measure of gait and balance).ResultsSixty-five subjects (21 PD, 25 PIGD, 19 controls) were included in the analysis. We demonstrated greater ADC abnormalities in the extrapyramidal, pyramidal and transcallosal motor systems in PIGD compared to controls. Multivariate analysis taking into consideration various clinical variables showed that the FA (p = 0.02) and ADC (p = 0.001) values in the corpus callosum body differentiated PIGD from PD. PIGD with low Tinetti score had a lower FA (p = 0.02) and a higher ADC value (corpus callosum body) (p = 0.03) compared to those with a high score.ConclusionsWe demonstrated for the first time that DTI abnormalities along the transcallosal motor tract in the body of the corpus callosum, but not the substantia nigra, differentiated PIGD from PD, and the degree of corpus callosum body abnormality correlated with the Tinetti score (a measure of risk of falls).     

Clinical and neuroimaging characteristics in neurodegenerative overlap syndrome

Neurodegenerative overlap syndrome has been considered as a wide spectrum of motor neuron disease (MND), parkinsonism, or dementia. Specially, clinically overt parkinsonism occurs more often than expected in patients with motor neuron disease (MND), and diverse clinical manifestations of concurrent parkinsonism have been reported. We aimed to clarify clinical and functional imaging characteristics in patients with combined MND and parkinsonism. Of 732 patients diagnosed with MND over 22 consecutive years, eight patients (all men; mean age 62.8 years) exhibited parkinsonism. According to their parkinsonian features and presence of other neurologic signs including dementia, extraocular movement abnormalities, and cerebellar or autonomic dysfunction, they were classified into two groups: MND-parkinsonism (MND-P, n = 5) and MND-parkinsonism-plus syndrome (MND-Plus, n = 3). In the MND-P group, parkinsonism was asymmetric, dominated by resting tremor, and responsive to levodopa. [¹⁸F] N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) in two patients disclosed asymmetrically reduced uptakes in the dorsolateral putamen. In the MND-Plus group, parkinsonism was symmetric, with akinetic rigidity and postural instability dominance, and unresponsive to levodopa. [¹⁸F] FP-CIT PET scan in one patient showed decreased uptake in bilateral caudate nuclei and putamina. In conclusion, patients with MND and concurrent parkinsonism have heterogeneous clinical and imaging characteristics, which could be classified as features of PD and parkinsonism-plus syndrome. Patients with MND-P may have nigrostriatal dysfunction, and their parkinsonism may respond to levodopa treatment.     

Extrapyramidalism in Alzheimer''s disease: prevalence, psychiatric, and neuropsychological correlates.

The prevalence and clinical correlates of extrapyramidal signs in a consecutive series of 78 patients with Alzheimer's disease attending a neurology clinic, and 20 age comparable normal controls, were examined. Based on the unified Parkinson's disease rating scale (UPDRS) findings, 18 patients (23%) met criteria for parkinsonism, 44 (56%) had isolated extrapyramidal signs, and 16 (21%) had no extrapyramidal signs. Whereas the control group showed a similar prevalence of isolated extrapyramidal signs (57%), none of them showed parkinsonism. No significant differences were found for age, sex, duration of illness, and severity of dementia among the three Alzheimer's disease groups. Patients with Alzheimer's disease-parkinsonism, however, showed a significantly higher frequency of major depression and dysthymia and significantly higher Hamilton depression scores than patients with isolated or no extrapyramidal signs. Patients with Alzheimer's disease-parkinsonism also showed significantly more deficits on frontal lobe related tasks such as the Wisconsin card sorting test, trail making test, and verbal fluency, as well as on tests of constructional praxis and abstract reasoning than patients with Alzheimer's disease but no extrapyramidal signs. In conclusion, the study showed a specific association between Alzheimer's disease and parkinsonism, as well as significant relations between parkinsonism, deficits in executive functions, and depression among patients with Alzheimer's disease.     

Comparison of dystonia between Parkinson's disease and atypical parkinsonism: The clinical usefulness of dystonia distribution and characteristics in the differential diagnosis of parkinsonism

Objective

Dystonia is occasionally found in patients with Parkinson's disease (PD) and atypical parkinsonisms. However, systematic comparative analysis of the association between dystonia and parkinsonism have seldom been reported. The goals of this study are to compare the clinical characteristics and distributions of dystonia between PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).