View source for Medicine:SLC6A1 epileptic encephalopathy

{{Short description|Rare genetic disorder}}
'''SLC6A1 epileptic encephalopathy''' is a genetic disorder characterised by the loss-of-function of one copy of the human [[Biology:GABA transporter type 1|SLC6A1]] gene. SLC6A1 epileptic encephalopathy can typically manifest itself with early onset seizures and it can also be characterised by mild to severe learning disability. Not all manifestations of the conditions are present in one given patient. 

==Background==
Research published in 2015 linked mutations on the solute carrier family 6 member 1 protein (SLC6A1) to developmental and epileptic encephalopathies. SLC6A1 is present only on 13% of genetic panel testing, so the condition is very under-diagnosed. Currently an incidence of 1 in 38,000 births is reported.<ref name="Epil">{{cite journal |last1=Johannesen |first1=Katrine M. |last2=Gardella |first2=Elena |last3=Linnankivi |first3=Tarja |last4=Courage |first4=Carolina |last5=de Saint Martin |first5=Anne |last6=Lehesjoki |first6=Anna-Elina |last7=Mignot |first7=Cyril |last8=Afenjar |first8=Alexandra |last9=Lesca |first9=Gaetan |last10=Abi-Warde |first10=Marie-Thérèse |last11=Chelly |first11=Jamel |last12=Piton |first12=Amélie |last13=Merritt |first13=J. Lawrence |last14=Rodan |first14=Lance H. |last15=Tan |first15=Wen-Hann |last16=Bird |first16=Lynne M. |last17=Nespeca |first17=Mark |last18=Gleeson |first18=Joseph G. |last19=Yoo |first19=Yongjin |last20=Choi |first20=Murim |last21=Chae |first21=Jong-Hee |last22=Czapansky-Beilman |first22=Desiree |last23=Reichert |first23=Sara Chadwick |last24=Pendziwiat |first24=Manuela |last25=Verhoeven |first25=Judith S. |last26=Schelhaas |first26=Helenius J. |last27=Devinsky |first27=Orrin |last28=Christensen |first28=Jakob |last29=Specchio |first29=Nicola |last30=Trivisano |first30=Marina |last31=Weber |first31=Yvonne G. |last32=Nava |first32=Caroline |last33=Keren |first33=Boris |last34=Doummar |first34=Diane |last35=Schaefer |first35=Elise |last36=Hopkins |first36=Sarah |last37=Dubbs |first37=Holly |last38=Shaw |first38=Jessica E. |last39=Pisani |first39=Laura |last40=Myers |first40=Candace T. |last41=Tang |first41=Sha |last42=Tang |first42=Shan |last43=Pal |first43=Deb K. |last44=Millichap |first44=John J. |last45=Carvill |first45=Gemma L. |last46=Helbig |first46=Kathrine L. |last47=Mecarelli |first47=Oriano |last48=Striano |first48=Pasquale |last49=Helbig |first49=Ingo |last50=Rubboli |first50=Guido |last51=Mefford |first51=Heather C. |last52=Møller |first52=Rikke S. |title=Defining the phenotypic spectrum of SLC6A1 mutations |journal=Epilepsia |date=February 2018 |volume=59 |issue=2 |pages=389–402 |doi=10.1111/epi.13986 |pmid=33241211|pmc=7677605 }}</ref>

==Signs and symptoms==
Owing to the limited number of patients diagnosed, the full extent of symptoms is not fully understood. Typically, the condition manifests itself via absence seizures, myoclonic-atonic epilepsy and mild-to-moderate learning disability.<ref name="Nord"/> In addition, speech difficulties and behavioral problems have been reported. A 2020 review of 116 cases reported developmental delay, [[Medicine:Cognitive impairment|cognitive impairment]] and autistic traits as widespread clinically.<ref name="BC"/>

==Diagnosis==
There are a few methods used to diagnose SLC6A1 related disorders. Electroencephalograms (EEGs) can be used to detect irregular brain activity and look for signs of seizures, and MRIs can detect any changes in brain structure.<ref>{{cite web |title=Parent and Family Scientific Overview |url=https://slc6a1connect.org/resources/scientific-overview/ |website=SLC6A1 Connect|date=19 March 2022 }}</ref> Once these methods have been used to diagnose epilepsy, gene panel sequencing detects the specific SLC6A1 mutation. Currently, SLC6A1 is included in many epilepsy-oriented gene panels.<ref name="Nord">{{cite web |title=SLC6A1 Epileptic Encephalopathy |url=https://rarediseases.org/rare-diseases/slc6a1-epileptic-encephalopathy/#:~:text=SLC6A1%20epileptic%20encephalopathy%20is%20an,mild%20to%20severe%20intellectual%20disability. |website=NORD (National Organization for Rare Disorders)}}</ref> Variants of SLC6A1 can also be analysed.<ref name="BC">{{cite journal |last1=Goodspeed |first1=Kimberly |last2=Pérez-Palma |first2=Eduardo |last3=Iqbal |first3=Sumaiya |last4=Cooper |first4=Dominique |last5=Scimemi |first5=Annalisa |last6=Johannesen |first6=Katrine M |last7=Stefanski |first7=Arthur |last8=Demarest |first8=Scott |last9=Helbig |first9=Katherine L |last10=Kang |first10=Jingqiong |last11=Shaffo |first11=Frances C |last12=Prentice |first12=Brandon |last13=Brownstein |first13=Catherine A |last14=Lim |first14=Byungchan |last15=Helbig |first15=Ingo |last16=De Los Reyes |first16=Emily |last17=McKnight |first17=Dianalee |last18=Crunelli |first18=Vincenzo |last19=Campbell |first19=Arthur J |last20=Møller |first20=Rikke S |last21=Freed |first21=Amber |last22=Lal |first22=Dennis |title=Current knowledge of SLC6A1-related neurodevelopmental disorders |journal=Brain Communications |date=1 July 2020 |volume=2 |issue=2 |pages=fcaa170 |doi=10.1093/braincomms/fcaa170|pmid=33241211 |pmc=7677605 }}</ref>

==Treatment==
There is a clear unmet medical need for improved treatment options for SLC6A1-related disorder.<ref name="BC"/>

===Seizures===

* “Treatment will depend on the type and severity of the seizures and associated neurological features. A combination of seizure medications is typically used to control the different seizure types”.  There is insufficient data available to guide pharmacotherapy in SLC6A1-related disorders. Thus treatment is guided by existing strategies for the specific clinical epilepsy syndromes, rather than underlying genetic etiology, using broad-spectrum anti-seizure medications, including valproic acid, lamotrigine or benzodiazepines. In a prior study, 20 of 31 patients became seizure-free with anti-seizure medication, and valproic acid was the most effective drug. Lamotrigine and ethosuximide also showed success.<ref name="BC"/>
* There are recognised "rescue therapies" for seizures, medications given quickly while a seizure occurs.<ref>{{cite journal |last1=Poukas |first1=VS |last2=Pollard |first2=JR |last3=Anderson |first3=CT |title=Rescue therapies for seizures. |journal=Current Neurology and Neuroscience Reports |date=August 2011 |volume=11 |issue=4 |pages=418–22 |doi=10.1007/s11910-011-0207-x |pmid=21509498|s2cid=20170316 }}</ref> Such treatment may reduce or prevent serial seizures.<ref name="CHOP">{{cite web |last1=Philadelphia |first1=The Children's Hospital of |title=SLC6A1-Related Disorders |url=https://www.chop.edu/conditions-diseases/slc6a1-related-disorders |website=www.chop.edu |language=en |date=13 May 2020}}</ref>
* In cases where drugs don't work, [[Biology:Vagus nerve stimulation|vagus nerve stimulation]] or a [[Biology:Responsive neurostimulation device|responsive neurostimulation device]] may be effective.<ref name="CHOP"/>

A [[Chemistry:Ketogenic diet|ketogenic diet]] is known to be an effective treatment for some cases of otherwise intractable seizures, though no mechanism has been established.<ref>{{cite journal |last1=Palmer |first1=S |last2=Towne |first2=MC |last3=Pearl |first3=PL |last4=Pelletier |first4=RC |last5=Genetti |first5=CA |last6=Shi |first6=J |last7=Beggs |first7=AH |last8=Agrawal |first8=PB |last9=Brownstein |first9=CA |title=SLC6A1 Mutation and Ketogenic Diet in Epilepsy With Myoclonic-Atonic Seizures. |journal=Pediatric Neurology |date=November 2016 |volume=64 |pages=77–79 |doi=10.1016/j.pediatrneurol.2016.07.012 |pmid=27600546|pmc=5223550 }}</ref>

===Treatments for other symptoms===

* Cognitive and developmental delays or autism spectrum disorder associated with SLC6A1-related disorders are treated with physical, occupational and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.<ref name="CHOP"/>

===Investigational/future therapies===

* {{As of|2022}}, there is one clinical trial in clinicaltrials.gov, to test if phenylbutyrate is safe and well tolerated in children with STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder. 
* Pre-clinical and experimental work on a gene replacement therapy is currently underway, aiming to produce a custom adeno-associated virus (AAV) suitable for SLC6A1 treatment.<ref name="Nord"/><ref name="BC"/>
* Alternatively, antisense oligonucleotides therapy might be promising to specifically increase productive SLC6A1 mRNA and consequently restore levels of GAT1 protein 
* Observational studies are needed to characterise the natural course of the disease and to identify appropriate end-points for use in future interventional trials.To develop treatments for patients with SLC6A1-related disorders it is critical to define the full phenotypic spectrum of the disease.<ref name="BC"/>

==Prognosis==

==References==
{{Reflist}}

[[Category:Rare diseases]]

{{Sourceattribution|SLC6A1 epileptic encephalopathy}}