Grin2a-Related Speech Disorders And Epilepsy

Watchlist
Retrieved
2021-01-18
Source
Trials
—
Genes
—
Drugs
—

Summary

Clinical characteristics.

GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.

Diagnosis/testing.

The diagnosis of a GRIN2A-related speech disorder and epilepsy is established in a proband by the identification of a GRIN2A heterozygous pathogenic variant on molecular genetic testing.

Management.

Treatment of manifestations: Significant speech/language deficits require therapy from a speech pathologist. Seizures should be treated with antiepileptic drugs (AEDs). Many different AEDs may be effective, and no one medication has been demonstrated to be effective specifically for these disorders.

Prevention of secondary complications: Monitoring for possible adverse effects of AEDs.

Surveillance: Developmental surveillance in all affected children; routine monitoring of speech and language by a speech pathologist should be considered for all children, particularly those diagnosed before reaching school age.

Agents/circumstances to avoid: In individuals with ECSWS, phenytoin, barbiturates and carbamazepine should be avoided as they are rarely effective, may worsen the EEG, and have negative effects on neuropsychological outcomes.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt evaluation for speech disorders and/or seizures and institution of treatment.

Genetic counseling.

GRIN2A-related speech disorders and epilepsy are inherited in an autosomal dominant manner. The proportion of GRIN2A-related speech disorders and epilepsy caused by a de novo pathogenic variant is unknown. Each child of an individual with a GRIN2A-related speech disorder and epilepsy has a 50% chance of inheriting the GRIN2A pathogenic variant. Once the GRIN2A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

In general, a GRIN2A pathogenic variant should be considered in an individual presenting with an otherwise unexplained combination of the following speech disorders and/or epilepsy features, seizure types, epilepsy syndromes [Tsai et al 2013].

Speech disorders

  • Acquired aphasia
  • Auditory agnosia (impaired recognition of sounds)
  • Dysarthria
  • Speech dyspraxia

Epilepsy features

  • Onset in early childhood (usually age 3-6 years)
  • Focal epilepsy with language and/or global developmental regression
  • Electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges

Seizure types

  • Most commonly, focal seizures
  • Sometimes occurring with an aura of perioral paresthesia, and often evolving to generalized tonic-clonic seizures

Epilepsy syndromes

  • Landau-Kleffner syndrome (LKS)
  • Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS)
  • Childhood epilepsy with centrotemporal spikes (CECTS)
  • Atypical childhood epilepsy with centrotemporal spikes (ACECTS)
  • Autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD)
  • Infantile-onset epileptic encephalopathy

Note: Detailed descriptions of each epilepsy syndrome can be found in Clinical Description.

Establishing the Diagnosis

The diagnosis of GRIN2A-related speech disorder and epilepsy is established in a proband by identification of either a heterozygous pathogenic variant in GRIN2A or a heterozygous deletion involving GRIN2A using molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) or genomic testing (chromosomal microarray analysis or comprehensive genomic sequencing).

Gene-targeted testing requires that the clinician develop a hypothesis about which gene(s) are likely involved, whereas genomic testing may not. The phenotypes of many genetic epileptic encephalopathies overlap; thus, most children with a GRIN2A-related speech disorder and epilepsy are diagnosed by CMA or multigene panel (see Recommended Testing) or by comprehensive genomic sequencing (see Testing to Consider).

Recommended Testing

Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays is recommended first when developmental impairment/intellectual disability and/or dysmorphic features are present. The ability to determine the size of the deletion depends on the type of microarray used and the density of probes in the 16p13.2 region.

A multigene panel that incorporates both sequence analysis and deletion/duplication analysis and includes GRIN2A and other genes of interest (see Differential Diagnosis) is recommended when epilepsy associated with speech dyspraxia and dysarthria are the primary findings (see Table 1). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Testing to Consider

Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to support gene-targeted testing). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Single-gene testing (sequence analysis of GRIN2A, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found may be considered first in individuals with features that are highly suggestive of GRIN2A-related speech disorder and epilepsy. However, because many of these features overlap with those of other genetic epileptic encephalopathies, multigene panels or comprehensive genomic testing are often performed in lieu of single-gene testing.

Table 1.

Molecular Genetic Testing Used in GRIN2A-Related Speech Disorders and Epilepsy

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method 3
GRIN2ASequence analysis 458/71
Gene-targeted deletion/duplication analysis 513/71 6
CMASee footnote 7
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Based on the combined results of published reports of GRIN2A-related disorders [Endele et al 2010, Reutlinger et al 2010, Lesca et al 2012, Carvill et al 2013, DeVries & Patel 2013, Lemke et al 2013, Lesca et al 2013, Conroy et al 2014, Dimassi et al 2014, Venkateswaran et al 2014, Yuan et al 2014, Allen et al 2016, Fainberg et al 2016]. In one proband, GRIN2A was disrupted by an inherited translocation detectable by karyotype [Endele et al 2010]; this was categorized as "detectable by sequence analysis."

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. These methods will detect from single-exon to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.

6.

Of these 13 probands: 9 had small losses of genetic material (<292 kb), resulting in partial deletion of GRIN2A; 3 had large deletions (>0.9 Mb) affecting multiple genes (in 2 of the 3 GRIN2A was entirely deleted); and 1 had a small intragenic duplication.

7.

CMA is appropriate to define breakpoints of large deletions.

Clinical Characteristics

Clinical Description

The clinical spectrum of GRIN2A-related speech disorders and epilepsy is broad and may vary within a family (e.g., from mild isolated speech impairment to rolandic epilepsy with speech dyspraxia) [Turner et al 2015b].

Disease progression is variable: some individuals have normal development and spontaneous remission of seizures, while others develop medically refractory epilepsy and severe developmental impairment. Language and/or global developmental regression often occurs in those with the more severe epilepsy-aphasia disorders.

Speech and language were impaired in 100% of individuals in a study of the speech manifestations of GRIN2A-related disorders [Turner et al 2015a]. Abnormalities included dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression.

Mildly affected individuals may display subtly impaired intelligibility of conversational speech, most commonly characterized by hypernasality, imprecise consonant production, and impaired pitch and prosody [Turner et al 2015a].

Intellectual disability, observed in 38%-67% of affected individuals, ranges from mild to severe [Carvill et al 2013, Lemke et al 2013].

Epilepsy occurs in approximately 90% of individuals [Lemke et al 2013, Lesca et al 2013].

Seizure onset is typically between ages three and six years (mean 4.6 years), although individuals may present from infancy to adolescence [Endele et al 2010, Lesca et al 2012, Carvill et al 2013, Lemke et al 2013, Venkateswaran et al 2014].

The most common seizure type overall is focal seizures. These are often associated with an aura of perioral paresthesia, and frequently evolve to generalized tonic-clonic convulsions. The predominant seizure type(s) in a given individual vary depending on which clinical syndrome is present.

The most common GRIN2A-related speech disorder and epilepsy is epilepsy-aphasia syndromes (EAS), a spectrum of disorders that includes: Landau-Kleffner syndrome (LKS); epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS); childhood epilepsy with centrotemporal spikes (CECTS); atypical childhood epilepsy with centrotemporal spikes (ACECTS); and autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD) [Tsai et al 2013]. Other epilepsy phenotypes can be broadly divided into infantile-onset epileptic encephalopathy and unclassified childhood epilepsy.

Landau-Kleffner syndrome (LKS) [Landau & Kleffner 1957, Wang et al 2006, Hughes 2011]

  • Onset in childhood (peak age range 5-8 years)
  • Acquired aphasia, with auditory agnosia (impaired recognition of sounds) frequently described as the earliest feature
  • Seizures in approximately 70% of cases, most commonly atypical absence, with focal motor, atonic, and focal seizures evolving to bilateral tonic-clonic seizures also described
  • Developmental regression limited to language domains
  • Normal development prior to onset of aphasia or isolated language impairment
  • EEG showing frequent, sleep-activated, bilateral sharp and slow wave discharges (centrotemporal or perisylvian field), eventually evolving to continuous spike-and-wave in sleep (CSWS)

Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) [Van Bogaert 2013]

  • Onset in childhood (peak age range 4-5 years)
  • Seizures in approximately 80% of cases, most commonly hemiclonic or generalized tonic-clonic in sleep and atypical absence while awake
  • Global developmental regression (as distinct from the pure language regression of LKS)
  • EEG showing near-continuous (>85% of recording), bilateral sharp and slow wave discharges in slow wave sleep (i.e., CSWS)

Childhood epilepsy with centrotemporal spikes (CECTS) [Guerrini & Pellacani 2012]

  • Onset is in childhood (peak age range 5-8 years; range 3-13 years).
  • Seizures have a characteristic aura of perioral paresthesia which may involve the tongue, cheeks, and mouth. There is often speech arrest and a motor component involving the oropharyngeal muscles, unilateral facial tonic or clonic activity, and (less commonly) an upper limb. The majority of events occur during sleep, and classically involve drooling. Bilateral tonic-clonic seizures are also commonly observed.
  • Seizure frequency is low: half of patients have fewer than six seizures in their lifetime.
  • Epilepsy follows a self-limited course with duration less than five years in the majority of individuals.
  • Development is essentially normal, though mild deficits in language, computation, and motor skills may be apparent when compared to healthy controls [Staden et al 1998, Lillywhite et al 2009, Garcia-Ramos et al 2015].
  • EEG background is normal and shows focal epileptiform discharges from the centrotemporal regions, potentiated in sleep. In 40% of affected individuals, the centrotemporal discharges are bilateral and independent.

Atypical childhood epilepsy with centrotemporal spikes (ACECTS) [Aicardi & Chevrie 1982]

  • Epilepsy course is similar to CECTS with onset and spontaneous remission occurring in childhood.
  • Seizures are different from those seen in CECTS, and include negative myoclonus and atypical absence seizures.
  • Developmental regression or slowing is coincident with seizure onset; however, long-term developmental outcome may be normal.
  • EEG is similar to CECTS in that focal centrotemporal discharges potentiated in sleep are seen; however, focal or diffuse background slowing is also often present.

Autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD) [Scheffer 2000, Turner et al 2015b]

  • Seizure characteristics and epilepsy course are identical to CECTS in most family members. One individual had an encephalopathic presentation associated with cognitive regression.
  • Affected individuals have oral and speech dyspraxia with dysarthria.
  • Individuals may have isolated speech dysfunction without seizures.
  • Cognitive function is usually within the normal range.

Infantile-onset epileptic encephalopathy [Endele et al 2010, Venkateswaran et al 2014, Yuan et al 2014, Allen et al 2016]

  • Multiple different seizure types may be present, including tonic seizures, focal impaired awareness with evolution to bilateral seizures, infantile spasms, and myoclonic seizures.
  • Severe intellectual disability was seen in the three individuals reported.
  • EEG findings vary in the few reported cases and include background slowing, hypsarrhythmia, and focal spikes.
  • Brain MRI may show bilateral parenchymal volume loss and thin corpus callosum.

Unclassified childhood-onset epilepsy [Reutlinger et al 2010, DeVries & Patel 2013]

  • Focal seizures are the most commonly seen; myoclonic, eyelid myoclonia, and atypical absence have also been reported.
  • Development ranges from normal to severely impaired.
  • Mild dysmorphic features may be present in individuals with a contiguous gene deletion.
  • EEG usually shows multifocal epileptiform discharges.

Contiguous gene deletions. Reutlinger et al [2010] described three individuals with 16p13 deletions involving multiple genes and complete or partial heterozygous deletion of GRIN2A. All had mild dysmorphic features, intellectual disability, and epilepsy involving the rolandic region.

EEG most commonly shows bilateral epileptiform discharges (usually spike or spike-wave) in the central-temporal or temporal-parietal regions which may be independent or bilaterally synchronous. These abnormalities become more frequent in sleep, often evolving to continuous spike-and-wave in sleep (CSWS). CSWS is defined as near-continuous (>85% of non-REM sleep recording) bilateral sharp and slow wave discharges in slow wave sleep. CECTS is classically associated with a horizontal dipole; tangential dipole across the Sylvian fissure has been reported in LKS [Morrell et al 1995, Dalla Bernardina et al 2005].

Brain imaging. Brain MRI is normal in the vast majority. Severely affected individuals may have enlargement of extra-axial spaces and a thin corpus callosum [Reutlinger et al 2010, Pierson et al 2014, Venkateswaran et al 2014, Yuan et al 2014]. One individual with focal cortical dysplasia was reported [Lesca et al 2013].

Positron emission tomography (PET) showing diffuse cortical hypometabolism was reported in one individual [DeVries & Patel 2013].

Genotype-Phenotype Correlations

Genotype-phenotype correlation is observed in a number of families in which all individuals heterozygous for the GRIN2A pathogenic variant have an epilepsy-aphasia syndrome (EAS) phenotype. However, the specific EAS phenotype may vary considerably within the family, including one individual with isolated speech dysfunction and another with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) [Carvill et al 2013, Lemke et al 2013, Lesca et al 2013, Turner et al 2015a].

For single-nucleotide variants (SNVs) and small intragenic copy number variants (CNVs), the genomic region in which the pathogenic variant occurs does not appear to have any relationship to the phenotype. Specifically, the pathogenic variants associated with infantile-onset epileptic encephalopathies do not cluster in a region distinct from the location of pathogenic variants associated with the epilepsy-aphasia syndromes (EAS).

Penetrance

GRIN2A-related speech disorders and epilepsy show incomplete but high penetrance and variable expressivity.

Penetrance is not clearly different for males and females.

Nomenclature

Landau-Kleffner syndrome (LKS) has also been referred to as epileptic acquired aphasia.

Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) has also been referred to as continuous spike-and-wave during slow-wave sleep (CSWS) and electrical status epilepticus during sleep (ESES).

Childhood epilepsy with centrotemporal spikes (CECTS) has been commonly referred to as benign epilepsy with centrotemporal spikes (BECTS) and benign rolandic epilepsy of childhood (BREC).

Atypical childhood epilepsy with centrotemporal spikes (ACECTS) has been known as atypical benign partial epilepsy (ABPE), pseudo-Lennox syndrome, and atonic-benign childhood epilepsy with centrotemporal spikes.

Prevalence

The prevalence of GRIN2A-related speech disorders and epilepsy in the general population is unknown; however, estimates can be made for some of the classic disorders.

GRIN2A pathogenic variants account for 9%-20% of epilepsy-aphasia syndrome (EAS), with pathogenic variants more likely to be present in persons with more severe phenotypes and a positive family history [Lesca et al 2012, Carvill et al 2013].

GRIN2A pathogenic variants are present in [Lemke et al 2013, Conroy et al 2014, Allen et al 2016]:

  • 4.8%-7.7% of Landau-Kleffner syndrome (LKS)
  • 17.6% of epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS)
  • 0%-4.9% of childhood epilepsy with centrotemporal spikes (CECTS)
  • 13.5% of atypical childhood epilepsy with centrotemporal spikes (ACECTS)
  • 2% of early-onset epileptic encephalopathy

Differential Diagnosis

Non-GRIN2-related genetic epilepsy

  • Epilepsy-aphasia syndrome (EAS). While GRIN2A is the gene most commonly associated with EAS, the majority of individuals with this group of syndromes do not have an identified genetic cause. A number of CNVs have been associated with EAS in individual cases. Pathogenic variants in RBFOX1 and RBFOX3 may play a contributory role in some cases [Lal et al 2013, Turner et al 2015b]. At present, no clinical features differentiate GRIN2A-related EAS from EAS of other genetic causes.
  • Non-EAS childhood-onset focal epilepsy and infantile-onset epileptic encephalopathy. Each phenotype has only a small number of reported cases associated with a GRIN2A pathogenic variant. Clinical data currently available are insufficient to distinguish those with a GRIN2A pathogenic variant from those with other genetic causes.

Non-genetic causes of epilepsy. Focal epilepsy and epileptic encephalopathy may have many non-genetic causes, including autoimmune and infectious processes. A non-genetic cause should be more strongly considered when a history of any of the following is present:

  • Maternal substance abuse during pregnancy
  • Significant complications in the perinatal period
  • Significant cerebral insult (e.g., central nervous system infection, hypoxic-ischemic injury, major head trauma, toxic ingestion/exposure)

Non-GRIN2A-related genetic language impairment. A severe speech and language disorder that primarily involves developmental verbal dyspraxia is caused by pathogenic variants in FOXP2 (see FOXP2-Related Speech and Language Disorders) [Lai et al 2001]. FOXP2 regulates CNTNAP2, and CNTNAP2 missense variants and deletions have been associated with childhood apraxia of speech; however, evidence of a causative link is at present limited [Worthey et al 2013, Centanni et al 2015].

Hearing impairment is a common cause of language-specific developmental delay or regression, thus in children with delayed speech development or regression in speech, the auditory system should be assessed (see Hereditary Hearing Loss and Deafness Overview).

Structural brain abnormality. Brain malformations and acquired structural brain anomalies can present with a constellation of symptoms that can mimic the GRIN2A-related disorders. Worster-Drought syndrome (OMIM 185480) involves congenital bilateral perisylvian lesions, most commonly polymicrogyria [Christen et al 2000]. Affected children typically have seizures, expressive language delay, dysarthria, and oromotor apraxia.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a GRIN2A-related speech disorder and epilepsy, the following evaluations are recommended:

  • Consultation with a speech and language pathologist
  • Epilepsy consultation (if not done at the time of initial assessment)
  • Sleep-deprived or sleep EEG with monitoring to capture slow-wave sleep (if not done at the time of initial assessment), as this is essential to diagnosing or excluding continuous spike-and-wave in sleep (CSWS).
  • Neuropsychological assessment
  • Hearing testing
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Speech/language deficits. Individuals with significant speech/language deficits may benefit from therapy by a speech pathologist. The therapies, which are individualized to the specific speech disorder, often include linguistic approaches and augmentative and alternative communication [Murray et al 2014].

Seizures, if present, should be treated with antiepileptic drugs (AEDs). Many different AEDs may be effective, and no one medication has been demonstrated to be effective specifically for GRIN2A-related disorders.

In one individual a good response to refractory epilepsy was achieved with topiramate [Venkateswaran et al 2014].

In one individual seizure burden was reduced with the addition of memantine; however, cognitive function did not improve [Pierson et al 2014].

Ketogenic diet and vagal nerve stimulator may also be considered in patients with refractory epilepsy.

Treatment for epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) and Landau-Kleffner syndrome (LKS) includes AEDs such as valproic acid, benzodiazepines, and corticosteroids. Sulthiame, ethosuximide, and levetiracetam may also be effective.

Of note, intravenous immunoglobulin has not been proven to be efficacious [Striano & Capovilla 2013, Van Bogaert 2013].

Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Prevention of Secondary Complications

AEDs are associated with possible adverse reactions (e.g., sedation, gastrointestinal symptoms, changes in appetite [increase or decrease], weight gain or loss, and rash) which vary according to the specific medication. Patients on AEDs should be monitored closely for adverse reactions and, if they develop, a change to an alternate AED should be considered.

Corticosteroids are associated with a wide variety of possible adverse reactions, including weight gain with cushingoid appearance, skin thinning and purpura, alopecia, acne, posterior subscapular cataract, glaucoma, exophthalmos, cardiac arrhythmias, hypertension, gastrointestinal upset, pancreatitis, hypokalemia, osteoporosis, avascular necrosis, myopathy, behavioral/psychiatric disturbance, diabetes mellitus, adrenal insufficiency, and increased infection risk. If complications of corticosteroid therapy become of concern, gradual tapering and alternate therapy should be considered.

Surveillance

Routine monitoring of speech and language by a speech pathologist should be considered for all children, particularly those diagnosed before reaching school age.

Developmental surveillance should be conducted in all affected children.

Agents/Circumstances to Avoid

In individuals with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), phenytoin, barbiturates and carbamazepine should be avoided as they are rarely effective, may worsen the EEG, and have negative effects on neuropsychological outcomes [Striano & Capovilla 2013, Van Bogaert 2013].

Evaluation of Relatives at Risk

Using molecular genetic testing for the GRIN2A pathogenic variant found in an affected family member, it is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from institution of treatment. Of note, some individuals heterozygous for a GRIN2A pathogenic variant who have only relatively mild speech dysfunction may benefit from early evaluation and intervention by a speech and language pathologist.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.