====== Monogenic dystonia ======


Monogenic [[dystonia]] refers to forms of dystonia caused by a single [[gene mutation]]. These disorders often have distinct clinical features and inheritance patterns ([[autosomal dominant]], [[autosomal recessive]], or [[X-linked]]).

===== Definition =====


Dystonia characterized by involuntary muscle contractions, resulting in twisting, repetitive movements or abnormal postures, directly attributable to mutations in one specific gene.

===== Inheritance Patterns =====


Autosomal dominant (e.g., DYT1 dystonia due to mutations in TOR1A gene).

Autosomal recessive (e.g., dystonia associated with mutations in TH or GCH1 genes).

X-linked (rare, associated with mutations in the TAF1 gene, causing X-linked dystonia-parkinsonism or Lubag).

<WRAP group>
=== Monogenic Dystonias – Summary Table ===
<WRAP toggle>

^ Dystonia Type ^ Gene ^ Inheritance ^ Key Features ^ Treatment ^
| **DYT1** | TOR1A | Autosomal dominant | Early-onset, limb onset, generalizes, Ashkenazi Jewish | DBS (GPi), anticholinergics, botulinum toxin |
| **DYT5 (A/B)** | GCH1 / TH | AD / AR | Childhood onset, diurnal fluctuation, excellent levodopa response | Levodopa (dramatic response) |
| **DYT6** | THAP1 | Autosomal dominant | Variable onset, cranial/cervical involvement, speech affected | DBS, pharmacologic (limited effect) |
| **DYT11** | SGCE | AD with maternal imprinting | Myoclonus + dystonia, alcohol-responsive | Clonazepam, DBS, alcohol (transient relief) |
| **DYT16** | PRKRA | Autosomal recessive | Early-onset generalized dystonia, rapidly progressive | Limited response to meds; DBS considered |
| **DYT3 (Lubag)** | TAF1 | X-linked recessive | Filipino males, adult-onset dystonia-parkinsonism | Limited; anticholinergics, levodopa |
| **DYT-TUBB4A** | TUBB4A | Autosomal dominant | Whispering dysphonia (laryngeal), adult onset | Botulinum toxin, DBS in select cases |

</WRAP>
</WRAP>

===== Monogenic Dystonias and Their Treatment =====

^ Gene / Syndrome ^ Clinical Features ^ Treatment ^
| **DYT1 (TOR1A)** | Childhood or adolescent-onset generalized dystonia, usually starting in limbs, no other neurological signs | **GPi-DBS** (highly effective)\\ ''Anticholinergics, benzodiazepines, baclofen (variable effect)'' |
| **DYT6 (THAP1)** | Similar to DYT1 but more frequent cranio-cervical involvement; later onset possible | **GPi-DBS** (less predictable response than DYT1)\\ ''Symptomatic treatment'' |
| **DYT11 (SGCE)**\\ (Myoclonus-dystonia) | Myoclonus and dystonia, improves with alcohol, autosomal dominant with maternal imprinting | ''Clonazepam, levetiracetam, other GABAergic drugs''\\ **GPi-DBS** in severe cases |
| **DYT5a (GCH1)**\\ (Dopa-responsive dystonia) | Childhood-onset, fluctuating dystonia, diurnal variation, excellent response to levodopa | **Low-dose levodopa** (dramatic and sustained improvement) |
| **DYT12 (ATP1A3)**\\ (Rapid-onset dystonia-parkinsonism) | Sudden onset, fixed dystonia, ataxia, parkinsonian features | ''Poor response to medications''\\ **DBS** (variable benefit) |
| **DYT-TUBB4A (H-ABC syndrome)** | Dysarthria, dystonia, cerebellar atrophy, mixed symptoms | ''Symptomatic treatment, physiotherapy''\\ **DBS** with experimental results |
| **DYT-PARK (PRKRA)** | Dystonia-parkinsonism, often juvenile onset | ''Levodopa (helpful in some cases)''\\ **GPi-DBS** (variable outcomes) |

==== General Principles ====

  * **Genetic testing** is crucial – some monogenic dystonias have highly specific treatments (e.g., **levodopa in DYT5**).
  * **Early diagnosis and treatment** improve functional outcomes.
  * **Deep Brain Stimulation** (typically targeting **GPi**) is effective in drug-resistant dystonia, especially in **DYT1** and **DYT6**.
  * Consider inclusion in **research protocols or registries** for rare or treatment-resistant cases.

===== Systematic review protocols =====

A [[systematic review protocol]], designed according to [[PRISMA|Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)]] guidelines, to evaluate the efficacy and safety of [[Deep Brain Stimulation]] in patients with [[monogenic dystonia]] — a subset of rare, genetically defined dystonias caused by mutations in single genes
((Carmona-Hidalgo B, Quintero J, Rodríguez-López R, Blasco-Amaro JA, Boesch S, Reinhard C. Efficacy of deep brain stimulation in treating monogenic dystonia symptoms: protocol for a systematic review. BMJ Open. 2025 Apr 9;15(4):e083127. doi: 10.1136/bmjopen-2023-083127. PMID: 40204321.)).

=== Strengths ===
  * **Clear [[scope]] and [[methodology]]:** The study uses a robust systematic framework to identify, extract, and synthesize evidence related to DBS in monogenic dystonias.
  * **Focus on rare diseases:** It addresses a crucial evidence gap in a neglected patient population where clinical guidance is often based on anecdotal reports or small case series.
  * **Planned subgroup analyses:** If data allow, subgroup analyses will help delineate differences across dystonia genotypes (e.g., [[dystonia:monogenic:dyt1|DYT1]], [[dystonia:monogenic:dyt6|DYT6]], [[dystonia:monogenic:dyt11|DYT11]]).
  * **Prospective risk of bias evaluation:** Includes planned bias assessment, increasing reliability of conclusions.

=== Limitations ===
  * **Protocol stage only:** As a protocol, it does not yet present results. Its value depends on the actual quality and quantity of included studies.
  * **Heterogeneity risk:** Variability in patient phenotypes, surgical targets, outcome scales, and follow-up durations may limit the feasibility of meta-analysis.
  * **Potential [[publication bias]]:** Due to the rarity of conditions, the body of evidence may overrepresent positive outcomes (publication bias).

=== Relevance for Neurosurgery ===
This protocol is highly relevant for neurosurgeons involved in functional neurosurgery, especially those performing [[Deep brain stimulation for movement disorders]]. By focusing on genetic subtypes of dystonia, it may inform future patient selection, target choice, and timing of intervention.