Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment.

Dopa-responsive dystonia—clinical and genetic heterogeneity

Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related myoclonus-dystonia, these conditions can be collectively classified as "myoclonus-dystonia syndromes." In the present article, we present myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network. © 2019 International Parkinson and Movement Disorder Society.

Twenty years on: Myoclonus‐dystonia and ε‐sarcoglycan — neurodevelopment, channel, and signaling dysfunction

Non-motor symptoms in genetically defined dystonia: homogenous groups require systematic assessment

With the emergence of quality of life measures as an indicator for the impact of medical and surgical interventions in dystonia, focus has shifted toward unraveling the pathophysiology and neuroanatomical basis of the "nonmotor symptoms" (NMS). To date, the NMS are now recognized as the greater determinant of quality of life in dystonia, going above and beyond the motor symptomatology. This chapter highlights what is currently known in available literature on the NMS among patients with early-onset dystonia, adult-onset focal dystonia, and dystonia-plus syndromes with particular focus on the NMS involving cognition, mood, behavior (even suicide), sleep, and pain.

Nonmotor Symptoms in Dystonia

We describe the case of a 42-year-old Japanese woman with childhood-onset myoclonus, dystonia, and psychiatric symptoms, including anxiety, phobia, and exaggerated startle response. The diagnosis was confirmed as myoclonus-dystonia (DYT11) by identifying a mutation in the gene encoding e-sarcoglycan. Interestingly, while motor-related symptoms in DYT11 generally improve with alcohol ingestion, the patient's symptoms were exacerbated by alcohol intake. Her severe and medically intractable symptoms were alleviated by bilateral deep brain stimulation of the globus pallidus internus, with myoclonus and dystonia scores showing 70% improvement after the surgery compared to presurgical scores. This is the first report of a genetically confirmed case of DYT11 in Japan. This paper together with other recent reports collectively demonstrates that DYT11 patients are distributed worldwide, including Asia. Thus, a diagnosis of DYT11 should be considered when clinicians encounter a patient with childhood-onset myoclonus and/or dystonia with psychiatric symptoms, regardless of ethnic background.

https://downloads.hindawi.com/journals/crinm/2014/937095.pdf

An Asian Patient with Myoclonus-Dystonia (DYT11) Responsive to Deep Brain Stimulation of the Globus Pallidus Internus.

Large SGCE deletion contributes to Taiwanese myoclonus–dystonia syndrome

Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan.

Clinical and genetic analysis of four Taiwanese families with autosomal dominant hereditary spastic paraplegia

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Large SGCE deletion contributes to Taiwanese myoclonus–dystonia syndrome

Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan.

Clinical and genetic analysis of four Taiwanese families with autosomal dominant hereditary spastic paraplegia