TY  - JOUR
AB  - High-throughput sequencing has been instrumental in uncovering the spectrum of pathogenic genetic alterations that contribute to the etiology of dystonia. Despite the immense heterogeneity in monogenic causes, studies performed during the past few years have highlighted that many rare deleterious variants associated with dystonic presentations affect genes that have roles in certain conserved pathways in neural physiology. These various gene mutations that appear to converge towards the disruption of interconnected cellular networks were shown to produce a wide range of different dystonic disease phenotypes, including isolated and combined dystonias as well as numerous clinically complex, often neurodevelopmental disorder-related conditions that can manifest with dystonic features in the context of multisystem disturbances. In this chapter, we summarize the manifold dystonia-gene relationships based on their association with a discrete number of unifying pathophysiological mechanisms and molecular cascade abnormalities. The themes on which we focus comprise dopamine signaling, heavy metal accumulation and calcifications in the brain, nuclear envelope function and stress response, gene transcription control, energy homeostasis, lysosomal trafficking, calcium and ion channel-mediated signaling, synaptic transmission beyond dopamine pathways, extra- and intracellular structural organization, and protein synthesis and degradation. Enhancing knowledge about the concept of shared etiological pathways in the pathogenesis of dystonia will motivate clinicians and researchers to find more efficacious treatments that allow to reverse pathologies in patient-specific core molecular networks and connected multipathway loops.
AU  - Di Fonzo, A.*
AU  - Jinnah, H.A.*
AU  - Zech, M.
C1  - 68074
C2  - 54552
SP  - 61-103
TI  - Dystonia genes and their biological pathways.
JO  - Int. Rev. Neurobiol.
VL  - 169
PY  - 2023
SN  - 0074-7742
ER  - 

TY  - JOUR
AB  - Beta-propeller protein-associated neurodegeneration (BPAN) is the most recently identified subtype of neurodegeneration with brain iron accumulation (NBIA), being unique with respect to the underlying disease genetics, the associated clinical presentation, and the suggested pathomechanism. Mutations in X-chromosomal WDR45 arise de novo; however, the dominant pattern of inheritance is unusual for an X-linked disorder and additional mechanisms such as X-inactivation or somatic mosaicism are likely to contribute to the phenotype that is indistinguishable between males and females. The course of the disease is two-staged with developmental delay and intellectual disability in childhood and a second phase of rapid neurological deterioration characterized by parkinsonism and dementia occurring in adolescence or early adulthood. At this time, neuroimaging findings are characteristic and provide excellent diagnostic guidance. There is increasing evidence that human WDR45 deficiency impairs autophagy, thereby raising the possibility that this rare disorder will offer insights into more common neurodegenerative disorders such as Parkinson or Alzheimer disease.
AU  - Haack, T.B.
AU  - Hogarth, P.*
AU  - Gregory, A.*
AU  - Prokisch, H.
AU  - Hayflick, S.J.*
C1  - 28440
C2  - 33380
SP  - 85-90
TI  - BPAN: The only X-linked dominant NBIA disorder.
JO  - Int. Rev. Neurobiol.
VL  - 110
PB  - Academic Press - Elsevier
PY  - 2013
SN  - 0074-7742
ER  - 

TY  - JOUR
AB  - Neurodegeneration with brain iron accumulation (NBIA) is a group of rare and devastating disorders characterized by iron deposition in the brain. Mutations in C19orf12 cause autosomal recessive inherited mitochondrial membrane protein-associated neurodegeneration (MPAN), which may account for up to 30% of NBIA cases. The C19orf12 gene product is an orphan mitochondrial membrane protein, and most mutations are predicted to cause loss of function. From 67 MPAN cases so far reported, we describe here the clinical, radiological, and genetic features. Key clinical features are pyramidal and extrapyramidal signs, cognitive decline, neuropsychiatric abnormalities, optic atrophy, and motor axonal neuropathy. Magnetic resonance imaging shows the eponymous brain iron accumulation in globus pallidus and substantia nigra and in some cases a hyperintense streaking of the medial medullary lamina. The latter sign may discriminate MPAN from other NBIA subtypes. In two postmortem MPAN cases, neuropathology showed axonal spheroids, Lewy bodies, and hyperphosphorylated tau-containing inclusions.
AU  - Hartig, M.*
AU  - Prokisch, H.
AU  - Meitinger, T.
AU  - Klopstock, T.*
C1  - 28175
C2  - 32988
SP  - 73-84
TI  - Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN).
JO  - Int. Rev. Neurobiol.
VL  - 110
PB  - Elsevier
PY  - 2013
SN  - 0074-7742
ER  -