TY  - JOUR
AB  - PURPOSE OF REVIEW: Large-scale studies using hypothesis-free exome sequencing have revealed the strong heritability of neurodevelopmental disorders (NDDs) and their molecular overlap with later-onset, progressive, movement disorders phenotypes. In this review, we focus on the shared genetic landscape of NDDs and movement disorders. RECENT FINDINGS: Cumulative research has shown that up to 30% of cases labelled as "cerebral palsy" have a monogenic etiology. Causal pathogenic variants are particularly enriched in genes previously associated with adult-onset progressive movement disorders, such as spastic paraplegias, dystonias, and cerebellar ataxias. Biological pathways that have emerged as common culprits are transcriptional regulation, neuritogenesis, and synaptic function. Defects in the same genes can cause neurological dysfunction both during early development and later in life. We highlight the implications of the increasing number of NDD gene etiologies for genetic testing in movement disorders. Finally, we discuss gaps and opportunities in the translation of this knowledge to the bedside.
AU  - Indelicato, E.*
AU  - Zech, M.
AU  - Eberl, A.*
AU  - Boesch, S.*
C1  - 73676
C2  - 57166
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Insights on the shared genetic landscape of neurodevelopmental and movement disorders.
JO  - Curr. Neurol. Neurosci. Rep.
VL  - 25
IS  - 1
PB  - Springer
PY  - 2025
SN  - 1528-4042
ER  - 

TY  - JOUR
AB  - Purpose of Review To summarize the molecular and clinical findings of KMT2B-related dystonia (DYT-KMT2B), a newly identified genetic dystonia syndrome. Recent Findings Since first described in 2016, 66 different KMT2B-affecting variants, encompassing a set of frameshift, nonsense, splice-site, missense, and deletion mutations, have been reported in 76 patients. Most mutations are de novo and expected to mediate epigenetic dysregulation by inducing KMT2B haploinsufficiency. DYT-KMT2B is characterized phenotypically by limb-onset childhood dystonia that tends to spread progressively, resulting in generalized dystonia with cranio-cervical involvement. Co-occuring signs such as intellectual disability are frequently observed. Sustained response to deep brain stimulation (DBS), including restoration of independent ambulation, is seen in 93% (27/29) of patients. DYT-KMT2B is emerging as a prevalent monogenic dystonia. Childhood-onset dystonia presentations should prompt a search for KMT2B mutations, preferentially via next-generation-sequencing and genomic-array technologies, to enable specific counseling and treatment. Prospective multicenter studies are desirable to establish KMT2B mutational status as a DBS outcome predictor.
AU  - Zech, M.
AU  - Lam, D.D.
AU  - Winkelmann, J.
C1  - 57431
C2  - 47785
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Update on KMT2B-related dystonia.
JO  - Curr. Neurol. Neurosci. Rep.
VL  - 19
IS  - 11
PB  - Springer
PY  - 2019
SN  - 1528-4042
ER  - 

TY  - JOUR
AB  - Restless legs syndrome (RLS) is a highly familial trait with heritability estimates of about 50%. It is a polygenetic disorder in which a number of variants contribute to the phenotype. Linkage studies in families with RLS revealed several loci but have not yet led to the identification of disease-causing sequence variants. Phenocopies, nonpenetrance, and possible intrafamilial heterogeneity make it difficult to define the exact candidate region. Genome-wide association studies identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBOXCOR1. Carriers of one risk allele had a 50% increased risk of developing RLS. MEIS1 and LBXCOR1 are developmental factors and raise new pathophysiologic questions for RLS. These variants have weak and moderate effects and increase the risk of developing RLS. It is still possible that strong effects explain the occurrence of RLS in families. Therefore, linkage and association studies should be used congruently to dissect the complete genetic architecture of RLS.
AU  - Winkelmann, J.
C1  - 5381
C2  - 25084
SP  - 211-216
TI  - Genetics of restless legs syndrome.
JO  - Curr. Neurol. Neurosci. Rep.
VL  - 8
IS  - 3
PB  - Current Science Inc.
PY  - 2008
SN  - 1528-4042
ER  -