Genotype-phenotype characterization of familial hyperkinetic movement disorders : emphasis on ataxia and brain calcifications

Differential diagnosis of familial chorea encompasses Huntington’s disease along with a group of conditions referred to as Huntington’s disease-like (HDL). One such HDL is an inherited prion disorder (IPD) caused by pathological insertions of 8 additional OPRIS in the prion protein gene (PRNP). Only four 8-OPRI families have been reported, one of which was Swedish. Polymorphism in codon 129 of the PRNP gene, alternating between methionine (M) and valine (V), is the primary modulator of prion diseases. The Swedish family had the longest survival of any 8-OPRI family. Patients carrying 129M in the mutated allele demonstrated earlier age of onset (AO), longer survival and earlier age of death than those with 129V. PRNP polymorphism in codon 129 together with gender determined as much as 50% of the variability in AO. An inverse correlation between early AO and length of survival was observed (Paper I).

Ataxia with oculomotor apraxia type 4 (AOA4) is caused by mutations in the gene encoding polynucleotide kinase 3-prime phosphatase (PNKP) gene. A Swedish patient withAOA4 due to compound PNKP mutations, progressive symptoms and cerebellar atrophy was characterized (Paper II). Novel AOA4 features in this case were chorea during childhood, slower disease progression than previously described and low levels of the PNKP protein in her lymphocytes.

Spinocerebellar ataxia type 4 (SCA4), a rare disease first described in a Scandinavian family in the American Midwest in 1996 has been found to be linked to chromosome 16q22.1. A second SCA4 family was later identified in Germany. Two Swedish SCA4 families with novel symptoms such as dystonia and dysautonomia are described here. Symptom onset was at middle age and anticipation was suggested in one family. Variable infratentorial atrophy and spinal cord atrophy was evident in all the tested patients. Flumazenil-PET revealed reduced binding in several brain regions including the insula, thalamus, hypothalamus and cerebellum. The candidate region was sequenced but no pathogenic variants were found. Widespread neurodegeneration was exhibited by two cases (Paper III).

Primary familial brain calcifications (PFBC) are heterogeneous diseases. One Swedish-Finnish family (F13) with such calcifications and associated migraine, hyperkinesias and psychiatric symptoms associated is described along with five other PFBC families. The F13 family harbors the L9R mutation in the platelet-derived growth factor beta polypetide (PDGFB) gene. Other PDGFB mutations were identified in the remaining families. A hypomorphic PDGFB ret/ret mouse model displays brain calcifications and an impaired blood-brain barrier (BBB). Paper IV established mutations in PDGFB as the second most common cause of PFBC, after mutations in SLC20A2. Later, cognitive deficits, progressive hyperkinesias and calcifications in the F13 family were documented; CSF-NfL was elevated, but oxysterol levels were normal in all tested patients indicating that the BBB was intact (Paper V). One patient harboring the R467X mutation in SLC20A2 and affected by ataxia, dementia, and progressive brain calcifications is described (Paper VI). SLC20A2 encodes sodium-dependent phosphate transporter 2. As in SLC20A2 knockout mouse models, the level of phosphate in her CSF was elevated as was her CSF-NfL. In both the F13 family and the carrier of SLC20A2 mutation a coregistration was employed to evaluate the progression of calcification.

GBA1 mutations and variants are risk factors for Parkinson’s disease (PD) and other types of parkinsonism. The GBA1 gene is mutated in connection with Gaucher disease (GD). A GD1 cohort (n =13) and a GD3 cohort (n=12) were examined. In the GD1 cohort two PD cases were identified but none in the GD3 cohort. Abnormal DAT scan was found in 1 GD3 patient and hyposmia was present in 44%. Six GD3 patients have lived beyond 40 years of age. Dystonia was documented as a novel feature in GD3. Neither group had detectable neurological progression during 3 years (Paper VII).

List of scientific papers

I. Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation. Paucar M, Xiang F, Moore R, Walker RH, Winnberg E and Svenningsson P. Prion. 2013; 7(6):501-10.
https://doi.org/10.4161/pri.27260

II. Expanding the AOA4 phenotype. Paucar M, Malmgren H, Taylor M, Reynolds J, Svenningsson P, Press, R and Nordgren, A. Neurology Genetics. 2016; 2 (1): e49.
https://doi.org/10.1212/NXG.0000000000000049

III. Broad clinical spectrum and widespread neurodegeneration associated with spinocerebellar ataxia type 4. M. Paucar, M. Engvall, C. Söderhäll, M. Skorpil, P. Fazio, K. Lagerstedt-Robinson, G. Solders, T. Skoog, C. X. Zhang, C. Freyer, A. Wredenberg, M. Angeria, A. Varrone, I. Nennesmo, M. Söderberg, H. Jiao, A. Wedell and P. Svenningsson. [Manuscript]

IV. PDGFB mutations cause brain calcifications in humans and mice. Keller A, Westenberger A, Sobrido MJ, García-Murias M, Domingo A, Sears RL, Lemos RR, Ordoñez-Ugalde A, Nicolas G, da Cunha JE, Rushing EJ, Hugelshofer M, Wurnig MC, Kaech A, Reimann R, Lohmann K, Dobričić V, Carracedo A, Petrović I, Miyasaki JM, Abakumova I, Mäe MA, Raschperger E, Zatz M, Zschiedrich K, Klepper J, Spiteri E, Prieto JM, Navas I, Preuss M, Dering C, Janković M, Paucar M, Svenningsson P, Saliminejad K, Khorshid HR, Novaković I, Aguzzi A, Boss A, Le Ber I, Defer G, Hannequin D, Kostić VS, Campion D, Geschwind DH, Coppola G, Betsholtz C, Klein C, Oliveira JR. Nature Genetics. 2013; 45(9):1077-82.
https://doi.org/10.1038/ng.2723

V. Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene. Paucar M, Almqvist H, Saeed A, Bergendal G, Ygge J, Holmin S, Björkhem I, Svenningsson P. Neurology Genetics. 2016; 2(4): e84.
https://doi.org/10.1212/NXG.0000000000000084

VI. Ataxia and increased cerebrospinal fluid phosphate associated with a mutation in the SLC20A2 gene. Paucar M, Almqvist H, Jelic V, Hagman G, Jörneskog G, Holmin, S, Björkhem I and Svenningsson, P. [Accepted]

VII. Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients. Machaczka M, Paucar M, Björkvall CK, Smith NJ, Cox TM, Forsgren L, Svenningsson P. Blood Cells Mol Dis. 2016.
https://doi.org/10.1016/j.bcmd.2016.10.011