Lena E. Hjermind

Myoclonus-dystonia due to genomic deletions in the epsilon-sarcoglycan gene

Direct genomic DNA sequencing fails to detect epsilon‐sarcoglycan (SGCE) mutations in up to 30% of familial myoclonus‐dystonia (M‐D) cases. We identified novel large heterozygous deletions of SGCE exon 5 or exon 6 in two M‐D pedigrees. Like nonsense mutations, exon rearrangements result in the generation of premature stop codons downstream of the deleted exon. SGCE exon dosage assays may identify additional families with SGCE mutation and thus reduce “genetic heterogeneity.” Ann Neurol 2005;58:792–797

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.

Novel mutation in ATP13A2 widens the spectrum of Kufor‐Rakeb syndrome (PARK9)

Eiberg H, Hansen L, Korbo L, Nielsen IM, Svenstrup K, Bech S, Pinborg LH, Friberg L, Hjermind LE, Olsen OR, Nielsen JE. Novel mutation in ATP13A2 widens the spectrum of Kufor‐Rakeb syndrome (PARK9).

Amyloid-related biomarkers and axonal damage proteins in parkinsonian syndromes

BACKGROUND Clinical differentiation between parkinsonian syndromes (PS) remains a challenge despite well-established clinical diagnostic criteria. Specific diagnostic biomarkers have yet to be identified, though in recent years, studies have been published on the aid of certain brain related proteins (BRP) in the diagnosing of PS. We investigated the levels of the light subunit of neurofilament triplet protein (NF-L), total tau and phosphorylated tau, amyloid-β(1-42), and the soluble α- and β-cleaved fragments of amyloid precursor proteins in a cohort of patients with various PS. METHODS Seventy-one patients with different PS and cerebellar disorders were included consecutively over 21 months. CSF was collected at inclusion. Clinical follow-up was performed after 16 months (median; range: 9-30). Statistical comparison was performed after follow-up on 53 patients in four subgroups of PS: multiple system atrophy (MSA)(n = 10), progressive supranuclear palsy (PSP)(n = 10), dementia with Lewy bodies (DLB)(n = 11), and Parkinsons disease (PD)(n = 22), using the non-parametric Kruskal-Wallis test. RESULTS A statistically significant difference was found for NF-L (p < 0.0001, lowest values for PD), Aβ(1-42,) (p = 0.002, lowest values for DLB), and sAPPα and sAPPβ (p = 0.03 and 0.02, lower values observed for DLB and MSA). CONCLUSION We demonstrate a potential role for sAPPα and sAPPβ in distinguishing between PS, a finding that needs to be confirmed in future studies of larger cohorts. There is a tendency towards low levels of Aβ(1-42) in DLB patients in our cohort. Further, our results support findings from previous studies, which indicate an ability to separate atypical PS from PD based on levels of NF-L.

Dopa-responsive dystonia and early-onset Parkinson's disease in a patient with GTP cyclohydrolase I deficiency?

We describe a patient with a combination of dystonic and parkinsonian signs. Paraclinical studies revealed a mutation in the GTP cyclohydrolase I gene (GCH1) and a decrease in [123I]‐N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl) nortropane (123I‐FP‐CIT) binding ratios indicative of Parkinsons disease. We conclude that the patient probably suffers from a variant of dopa‐responsive dystonia (DRD) or two separate movement disorders, normally considered to be differential diagnoses, DRD and early‐onset Parkinsons disease with resulting difficulties concerning treatment and prognosis.

Inherited and de novo mutations in sporadic cases of DYT1-dystonia.

A study of Danish probands with primary torsion dystonia is presented. The probands were examined clinically and biochemically to exclude secondary dystonia. Mutation analyses for the GAG-deletion in the DYT1 gene were performed on 107 probands; and the mutation was detected in three. All three probands had the classical phenotype of DYT1-dystonia, but only one had a family history of dystonia. The other two probands had, obviously, sporadic DYT1-dystonia, one of which was caused by a de novo mutation, while the other one had a parent being an asymptomatic carrier. De novo mutations in the DYT1 gene are seldomly reported although independent founder mutations are known to have occurred. The frequency of DYT1-dystonia was low in our study even though several probands had early onset generalised dystonia. None of the probands in our study with other types of dystonia had the GAG-deletion as reported in other studies. The difficulties in genetic counselling concerning the heterogeneity of dystonia examplified by DYT1-dystonia are outlined.

A clinical classification acknowledging neuropsychiatric and cognitive impairment in Huntington's disease

BackgroundInvoluntary movements, neuropsychiatric symptoms, and cognitive impairment are all part of the symptom triad in Huntington’s disease (HD). Despite the fact that neuropsychiatric symptoms and cognitive decline may be early manifestations of HD, the clinical diagnosis is conventionally based on the presence of involuntary movements and a positive genetic test for the HD CAG repeat expansion. After investigating the frequencies of the triad manifestations in a large outpatient clinical cohort of HD gene-expansion carriers, we propose a new clinical classification.MethodsIn this cross-sectional study, 107 gene-expansion carriers from a Danish outpatient clinic were recruited. All participants underwent neurological examination, psychiatric evaluation and neuropsychological testing. Participants were categorised according to motor symptoms, neuropsychiatric symptoms, the use of psychotropic medication, and cognitive impairment.ResultsAmong the motor manifest HD gene-expansion carriers, 51.8% presented with the full symptom triad, 25.0% were defined as cognitively impaired in addition to motor symptoms, and 14.3% had neuropsychiatric symptoms along with motor symptoms. Only 8.9% had isolated motor symptoms. Among gene-expansion carriers without motor symptoms, 39.2% had neuropsychiatric symptoms, were cognitively impaired, or had a combination of the two.ConclusionThis is the first study to report the frequencies of both motor symptoms, cognitive impairment, and neuropsychiatric symptoms in HD gene-expansion carriers in a national outpatient HD clinical cohort. We found that almost 40% of the gene-expansion carriers without motor symptoms had either neuropsychiatric symptoms, cognitive impairment or both, emphasising that these patients are not premanifest in psychiatric and cognitive terms, suggesting that the current clinical classification is neither necessarily suitable nor helpful for this patient group. Some premanifest gene-expansion carriers may have psychiatric and/or cognitive symptoms caused by reactive stress or other pathology than HD. Acknowledging this fact we, however, suggest classifying all HD gene-expansion carriers into three clinical categories: premanifest, non-motor manifest, and motor manifest.

A germline chromothripsis event stably segregating in 11 individuals through three generations.

Purpose:Parentally transmitted germ-line chromothripsis (G-CTH) has been identified in only a few cases. Most of these rearrangements were stably transmitted, in an unbalanced form, from a healthy mother to her child with congenital abnormalities probably caused by de novo copy-number changes of dosage sensitive genes. We describe a G-CTH transmitted through three generations in 11 healthy carriers.Methods:Conventional cytogenetic analysis, mate-pair sequencing, and polymerase chain reaction (PCR) were used to identify the chromosome rearrangement and characterize the breakpoints in all three generations.Results:We identified an apparently balanced translocation t(3;5), later shown to be a G-CTH, in all individuals of a three-generation family. The G-CTH stably segregated without occurrence of additional rearrangements; however, several spontaneous abortions were reported, possibly due to unbalanced transmission. Although seven protein-coding genes are interrupted, no clinical features can be definitively attributed to the affected genes. However, it can be speculated that truncation of one of these genes, encoding ataxia–telangiectasia and Rad3-related protein kinase (ATR), a key component of the DNA damage response, may be related to G-CTH formation.Conclusion:G-CTH rearrangements are not always associated with abnormal phenotypes and may be misinterpreted as balanced two-way translocations, suggesting that G-CTH is an underdiagnosed phenomenon.Genet Med 18 5, 494–500.

Transthyretin as a potential CSF biomarker for Alzheimer! s disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors

Background:  Previous studies have indicated that transthyretin (TTR) levels in cerebrospinal fluid (CSF) are altered in depression and dementia. The present study aimed to investigate whether CSF TTR can be used to discriminate between patients with Alzheimer’s disease (AD) and patients with dementia with Lewy bodies (DLB) with or without medication, as well as to reveal whether CSF TTR correlates with depression in dementia.

Reduced CSF CART in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia after Alzheimers disease (AD). The underlying neurobiological mechanism of DLB is not fully understood and no generally accepted biomarkers are yet available for the diagnosis of DLB. In a recent MRI study, DLB patients displayed hypothalamic atrophy whereas this region was not affected in AD patients. Cocaine and amphetamine regulated transcript (CART) is a neuropeptide expressed selectively in neurons in the hypothalamus. Here, we found that CSF CART levels were significantly reduced by 30% in DLB patients (n = 12) compared to controls (n = 12) as well as to AD patients (n = 14) using radioimmunoassay. Our preliminary results suggest that reduced CSF CART is a sign of hypothalamic dysfunction in DLB and that it may serve as a biomarker for this patient group.