Amyotrophy
Extrapyramidal signs
Ophthalmoparesis
Polyglutamine (CAG) repeat expansions are the most prevalent repeat expansion and are responsible for several types of SCAs including SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA).( 13 – 15 ) Of all the repeat expansion disorders, SCA3 is the most frequently observed worldwide.( 13 ) Despite their commonality, the molecular mechanisms for how CAG repeat expansions result in ataxia are not completely understood. Potential mechanisms include toxic gain of function of RNA and protein biomolecules.( 13 )
Several repeat expansions occur in non-coding regions of their corresponding genes and the resulting disease including SCA8, SCA10, SCA12, SCA27B, SCA31, and SCA36.( 12 , 13 ) These expansions most frequently present in intronic regions but may also involve other mechanisms such as anti-sense transcripts (e.g., SCA8).( 16 ) Potential pathogenic causes include disrupted transcription and sequestration of mRNA processing complexes.( 12 , 13 ) Whole genome sequencing and improvements in bioinformatic analytic tools has recently enabled the discovery of novel non-coding repeat expansions, specifically SCA27B, which may be quite common worldwide.( 17 – 19 )
Hereditary ataxias caused by conventional mutations include point mutations, deletions, or duplications.( 20 ) Many of the resulting disorders can be grouped into general categories of function. For example, several genes are associated with ion-channel dysfunction (causing SCA5, SCA13, SCA15, SCA19, SCA27, SCA41, and the episodic ataxias) and others impair signal transduction (causing SCA11, SCA14, and SCA23).( 21 ) Copy number variations are typically causative in SCA15, SCA20, and SCA39.
The autosomal recessive cerebellar ataxias (ARCAs) or SCARs (spinocerebellar ataxias, recessive) represent a heterogenous group of disorders associated with nearly 200 genes ( Table 1 ).( 22 ) Most ARCAs present in childhood or early adulthood, alongside prominent extracerebellar and non-neurological manifestations. Friedrich’s ataxia (FA), an intronic repeat expansion disorder, and ataxia-telangiectasia (AT) are the most common ARCAs worldwide, although the recently discovered non-coding repeat expansion disorder, RFC1- mediated ataxia, may be similarly common.( 23 – 25 ) While many ARCAs are early-onset disorders, there is phenotypic variation within conditions like FA, where both early-onset and late-onset presentations occur.( 26 , 27 ) The molecular pathways associated with the ARCAs are diverse and include defective DNA repair (e.g., AT), mitochondrial dysfunction (e.g., FA), impaired lipoprotein assembly (e.g., vitamin E deficiency), and numerous inborn errors of metabolism, among others.( 27 , 28 )
The X-linked ataxias range from pure cerebellar phenotypes to more complex presentations involving developmental delay, parkinsonism, and dementia.( 29 ) The most common X-linked ataxia is Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by repeat expansion in the FMR1 gene that is also associated with Fragile-X syndrome ( Table 1 ).( 30 ) While X-linked disease primarily affects hemizygous males, variable X-inactivation can occasionally result in female heterozygous presentations.( 29 )
Although several hereditary ataxias involve mitochondrial dysfunction (e.g., FA), mitochondrial ataxias are typically thought of as the maternally inherited disorders resulting from mutations in the mitochondrial genome.( 31 , 32 ) Notable mitochondrial ataxias include mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), and Kearns-Sayre syndrome ( Table 1 ). Given the key role of mitochondria in energy homeostasis, these conditions often have systemic and extracerebellar features including seizures, myopathy, myoclonus, and peripheral neuropathy.( 31 , 32 )
Patients with late-onset hereditary ataxia, generally defined as having onset in adulthood to distinguish from childhood onset conditions, may exhibit features of cognitive impairment and dementia.( 8 , 9 ) Hereditary ataxias commonly associated with dementia include SCA2, SCA17, SCA48, DRPLA, and FXTAS ( Table 2 ). Others SCAs less frequently associated with cognitive impairment include SCA1, SCA3, SCA7, SCA8, and SCA12 ( Table 2 ). Extracerebellar features and radiographic findings may assist with distinguishing these conditions. However, variable progression and expression makes clinical diagnosis challenging. Here, we review the genetic conditions to consider when encountering a late-onset ataxia patient with a dementia phenotype.
Dominant late-onset hereditary ataxias associated with neurocognitive impairment.
Disorder | Gene | Mutation | Neurocognitive Phenotype | Selected Neuroimaging Findings |
---|---|---|---|---|
SCA1 | CAG repeats | Cognitive impairment | Olivopontocerebellar atrophy. | |
SCA2 | CAG repeats | Dementia | Olivopontocerebellar atrophy Cortical atrophy. | |
SCA3 | CAG repeats | Cognitive impairment | Pontine, cortical, and spinal cord atrophy. | |
SCA7 | CAG repeats | Cognitive impairment | Pontine and spinal cord atrophy. | |
SCA8 | CAG repeats | Cognitive impairment | Pontine atrophy. | |
SCA12 | CAG repeats | Cognitive impairment | Cortical atrophy. | |
SCA17 | CAG repeats | Dementia | Pontocerebellar, cortical, and subcortical atrophy. | |
SCA48 | Conventional mutations | Dementia | Posterior vermis atrophy. | |
DRPLA | CAG repeats | Dementia | Brainstem and superior cerebellar peduncle atrophy. Hyperintensities in brainstem, thalamus, and cerebellum. | |
FXTAS | CGG repeats | Dementia | Cortical atrophy. White matter hyperintensities in cerebrum and middle cerebellar peduncles. |
SCA2 is characterized by slowly progressive ataxia and associated oculomotor deficits.( 33 ) Relevant extracerebellar findings include peripheral neuropathy, parkinsonism, and dementia. Mean age of onset is in the fourth decade of life. Affected individuals have 33 or more CAG repeats in the ATXN2 gene. Radiographic imaging demonstrates cortical, cerebellar, and brainstem atrophy ( Figure 1 ). Observational cohort studies have identified dementia as a relevant clinical feature, including examples of familial segregation.( 34 , 35 )
Sagittal and coronal views are shown. Regions of neurodegeneration typically seen on magnetic resonance imaging are indicated by darker shading.
DRPLA is characterized by ataxia, myoclonus, and epilepsy.( 36 ) DRPLA is most common in Asian populations (primarily Japanese). Affected individuals have 48–93 CAG repeats in the ATN1 gene. While mean age of onset is in the third decade of life, the age of clinical presentation is variable and can occur in the sixth and seventh decades of life. In older adults, core characteristic features include ataxia, choreoathetosis, and dementia. Movement disorders may mask the presentation of ataxia and mimic Huntington disease phenotypes.( 37 ) However, radiographic imaging demonstrates atrophy of the cerebellum and brainstem ( Figure 1 ).( 38 )
FXTAS is an X-linked ataxia, characterized by late-onset ataxia, tremor, and dementia.( 39 , 40 ) Additional extracerebellar findings including mild parkinsonism, peripheral neuropathy, and psychiatric symptoms. The average age of onset is in the sixth decade of life, with hemizygous males more commonly affected than heterozygous females. Clinical presentation is heterogenous with varied dominant signs. Affected individuals have a premutation-sized repeat of 55–200 CGG repeats in the 5’ UTR of the FMR1 gene. Radiographic imaging demonstrates generalized brain atrophy, and white matter hyperintensities in the cerebrum and middle cerebellar peduncles ( Figure 1 ).( 39 , 40 )
SCA17 and SCA48 are dominantly inherited SCAs with significant phenotypic overlap resembling Huntington disease.( 37 , 41 , 42 ) Recent studies highlight the role of digenic interactions in SCA17 and SCA48, with implications for disease penetrance and dementia risk.( 43 – 45 ) These studies have identified genetic interactions between the TBP and STUB1 genes, which are responsible for SCA17 and SCA48 respectively.
SCA17 is characterized by ataxia, dementia, chorea, and dystonia.( 42 ) There is consequently a significant phenotypic overlap with Huntington disease.( 37 ) Radiographic imaging demonstrates variable cortical, brainstem, and cerebellar atrophy ( Figure 1 ).( 46 ) Affected individuals have >50 CAG repeats in the TBP gene, while intermediate-size expansions (41–49 repeats) show incomplete penetrance. These recent studies observed that 49–97% individuals with intermediate-sized TBP expansions also carried a heterozygous sequence variant in the STUB1 gene.( 43 , 44 ) Segregation analyses found that the presence of either the intermediate TBP expansion or the STUB1 variant alone was insufficient to cause disease. These findings suggest that STUB1 modifies SCA17 penetrance in intermediate sized TBP expansions ( Figure 2 ).
Intermediate sized TBP repeat expansions (41–49 repeats) are shown in blue. Such smaller repeat sizes are considered to be incompletely penetrance and, in this model, by themselves they do not cause disease (arrow). In the presence of a heterozygous STUB1 variant (yellow), however, these repeats become penetrant and cause SCA17. These STUB1 variants are insufficient to cause disease in absence of the TBP allele (arrow). However, in patients with a pathogenic STUB1 variant associated with SCA48 (red), the presence of an intermediate TBP repeat expansion modifies the phenotype of SCA48, leading to an increased risk of severe dementia.
SCA48 is characterized by ataxia and dementia.( 41 ) Additional clinical features include neuropsychiatric symptoms, parkinsonism, chorea, and dystonia so it is therefore also considered a phenotypic mimic of Huntington disease.( 41 ) Radiographic imaging demonstrates atrophy of the posterior cerebellar vermis ( Figure 1 ).( 38 ) Affected individuals carry a pathogenic variant in the STUB1 gene. A recent study observed that 40% of SCA48 patients carry an intermediate-sized TBP expansion.( 43 ) The study also observed that the longer the TBP repeat length, the more likely the occurrence of cognitive impairment and the rate of disease progression.( 43 ) This implicates TBP repeat expansions as a disease modifier of SCA48, leading to an increased risk of dementia ( Figure 2 ). Together these studies illustrate how complex interactions among genes can affect disease development, penetrance, progression, and prognosis.( 47 )
The mechanisms mediating dementia in the late-onset genetic cerebellar ataxia are likely multifactorial. This includes the role of the cerebellum in cognition, extracerebellar neurodegeneration, and the presence of co-occurring neurodegenerative pathologies.
The cerebellum is recognized to regulate cognitive processing and emotional control.( 48 ) Functional studies have implicated cerebellar posterior lobe dysfunction in cerebellar cognitive affective syndrome (CCAS).( 49 ) CCAS is characterized by impairments in executive function, visual spatial processing, language, and affect. To quantify cognitive impairment secondary to cerebellar dysfunction, the CCAS scale was developed.( 50 ) Application of the CCAS scale in SCA3 patients detected neuropsychological deficits that correlated with disease severity.( 51 ) Further research is needed, however, to broadly characterize the cerebellar-cognitive affective phenotypes across all the late-onset hereditary ataxias.
Extracerebellar degeneration, such as cortical atrophy, is observed in late-onset hereditary ataxias such as SCA2, SCA17, and FXTAS ( Figure 1 ).( 38 ) In these cases, atrophy of key association areas may contribute to cognitive impairment. In SCA17, extracerebellar atrophy involves the basal ganglia in addition to the frontotemporal lobes. The resulting disruption of fronto-subcortical circuits may result in motor, cognitive, and behavioral dysfunction, similar to a Huntington’s disease pathology.( 52 ) In-depth neurocognitive testing may aid in differentiating the pathways mediating cognitive impairment specifically associated with cerebellar versus extracerebellar degeneration.
Like the general population, patients with hereditary ataxias are at risk for developing age-related neurodegenerative disorders such as Alzheimer’s disease (AD). While intronic variants in ATXN1 have been associated with AD risk, variations in CAG repeat number in AD patients have not been associated.( 53 ) However, neuropathological studies often demonstrate neuronal intranuclear inclusions in CAG disorders and extra-cerebellar degeneration.( 54 , 55 ) Whether or not there are shared genetic risk modifiers between late-onset ataxia and dementia, and whether patients with genetic cerebellar ataxias may have an altered risk for the development of AD, is not well understood.
Here we provide an approach for the genetic evaluation of the hereditary ataxias in patients with dementia. A detailed clinical phenotype is important for guiding a differential diagnosis and subsequent genetic testing. In some clinical cases, patients may have a primary dementia presentation with evidence of cerebellar dysfunction on examination and/or neuroimaging.
The history and physical should focus on identifying signs of cerebellar and extracerebellar dysfunction.( 56 ) Features of cerebellar dysfunction include dysarthria, dysphagia, ocular dysmetria, direction-changing nystagmus, limb dysmetria, and gait imbalance. Relevant extracerebellar findings, in addition to cognitive impairment, include tremor, parkinsonism, chorea, dysautonomia, and neuropsychiatric features. If dementia is noted in the presence of ataxia, evaluation for the presence of the common cerebellar cognitive affective syndrome should be considered.( 50 )
A positive family history increases the likelihood of a genetic etiology. Relating the family history to inheritance patterns may further inform the differential. For example, late-onset ataxia with dementia in a male proband with a grandson with intellectual disability and/or autism should raise suspicion for FXTAS.( 39 ) A negative family history should not exclude a genetic basis because family histories may be limited, certain inheritances may not be apparent due to small family trees, or mutations may be de novo .( 4 , 57 )
Magnetic resonance imaging (MRI) of the brain will assess the degree of cerebellar atrophy and associated cortical and brainstem atrophy. Evidence of significant cerebellar atrophy in a primary dementia patient should raise suspicion for a late-onset genetic cerebellar ataxia. Radiographic findings such as the “middle cerebellar peduncle” sign is an indicator of a potential FXTAS diagnosis.( 38 ) Imaging findings that include cerebellar, fronto-temporal, and basal ganglia atrophy should raise suspicion for SCA17.( 42 ) While radiographic findings are not entirely specific, they can guide an initial differential ( Figure 1 ).
Neurocognitive screening should be performed in symptomatic patients. Clinical screening tests include the Mini-Mental Status Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and CCAS scale.( 50 ) In-depth neuropsychological testing may assist with differentiating cerebellar, extracerebellar, and other neurodegenerative processes. Patients who are identified to have hereditary ataxias associated with dementia and cognitive impairment should have baseline and interval testing performed to aid dementia management and assess progression.
The initial evaluation of patients with late-onset cerebellar ataxia and dementia involves the investigation of reversible etiologies. Evaluating treatable causes is essential, especially in sporadic cases with rapid progression. While such acquired evaluations are reviewed in more-depth elsewhere, they broadly evaluate for metabolic, autoimmune, nutritional, paraneoplastic, and infectious etiologies.( 21 ) Once acquired causes are excluded, a systematic examination for genetic etiologies is appropriate for both familial and sporadic cases.( 4 , 5 ) We recommend a two-staged genetic testing approach for the hereditary ataxias in patients with dementia.( 57 )
Initial genetic testing should comprehensively evaluate for the known repeat expansion disorders associated with the late-onset SCAs. SCA1, SCA2, SCA3, SCA6, and SCA7 represent 50–60% of all dominantly inherited ataxia disorders.( 12 , 21 ) Ataxia repeat expansion panel testing is often the most cost-effective and high yield initial testing methodology and should include the genes associated with dementia (SCA2, SCA17, DRPLA, and FXTAS) and cognitive impairment (SCA1, SCA3, SCA7, SCA8, and SCA12).( 2 , 57 ) It is important to note that, at present, repeat expansion testing requires specialized testing that quantifies repeat size and such mutations will not be recognized on the short-read next-generation sequencing platforms typically used for exome or genome sequencing.( 58 )
Once common repeat expansion disorders have been excluded, a comprehensive evaluation for non-repeat expansion disorders is recommended. Whole exome sequencing (WES) is often the preferred modality because it has increases the diagnostic rate of the genetic ataxias in a cost-effective manner.( 58 , 59 ) WES will comprehensively cover virtually all other dominant, recessive, and X-linked disorders, particularly if bioinformatic assessment of copy number variation is included. In an adult-onset cohort of cerebellar ataxia and/or spastic paraplegia patients, WES can typically identify 25–50% of clinically relevant genetic variants.( 4 , 5 )
Additional clinical genetic testing not adequately covered by repeat expansion panels and WES can be considered on a case-by-case basis and the patient’s phenotype. For example, ataxia repeat expansions tests are panel based and typically do not cover other disease-causing expansions such as C9orf72 , which has rarely been reported to present with ataxia and cerebellar degeneration.( 60 ) Likewise, Huntington disease shares phenotypic overlap with DRPLA, SCA48, and SCA17 and HTT expansion may need to be considered. Technical limitations of WES should be considered, including the detection of chromosomal variants, repeat expansions, non-coding variants, and mitochondrial genomic variants.( 58 )
In the future, whole genome sequencing (WGS) may prove a more efficient means to overcome the disease-specific limitations of directed panel testing and the technical limitations of WES.( 58 ) WGS can already evaluate and discover causative genetic variants in coding and non-coding regions, including structural changes such as copy number variations (CNVs).( 58 , 61 ) A recent study demonstrated, both retrospectively and prospectively, how advances in bioinformatic technologies have the potential to enable WGS to detect most individuals with certain repeat expansions.( 62 )
The hereditary ataxias are a clinically heterogeneous group of disorders with significant phenotypic overlap. Dementia is an important extracerebellar feature of several late-onset hereditary ataxias and is most frequently associated with SCA2, SCA17, SCA48, DRPLA, and FXTAS. Cognitive dysfunction and subclinical cognitive impairment are likely unrecognized features in the SCAs. An evolving challenge is understanding the interplay between incomplete penetrance, variable phenotypes such as dementia, and disease prognosis in the late-onset hereditary ataxias. Recent advances in genomics are beginning to uncover such relationships. As we leverage comprehensive genomic information from exome and genome sequencing, a future goal will be to identify multigenic risk factors that may better inform clinicians and patients about disease development and progression.
Funding sources for the study:.
AJL was supported by the National Institutes of Health R25 NS065723.
Financial disclosure/Conflict of Interest:
All authors declare that there is no conflict of interest.
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Fragile X syndrome (FXS), also known as Martin-Bell syndrome in the past, is a non-Mendelian trinucleotide repeat disorder. FXS is the most prevalent inherited cause of mild-to-severe intellectual disability and the most common monogenic cause of autism spectrum disorder.[1][2] It accounts for about one-half of cases of X-linked intellectual disability and is the most common cause of mental ...
Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. ... Fragile X syndrome: clinical presentation, pathology and treatment Gac Med Mex. 2020;156(1):60-66. doi: 10.24875/GMM.19005275.
This review aims to assemble many years of research and clinical experience in the fields of neurodevelopment and neuroscience to present an up-to-date understanding of the clinical presentation, molecular and brain pathology associated with Fragile X syndrome, a neurodevelopmental condition that develops with the full mutation of the FMR1 gene, located in the q27.3 loci of the X chromosome ...
Patients may have recurrent sinusitis, otitis media, and decreased visual acuity. During the history taking, ask about apnea. [ 16] Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation, intellectual disability, and autism and is the second most common cause of ...
Fragile X syndrome (FXS) is an X-linked disorder and the most common inherited cause of intellectual disability [ 1 ]. Both males and females can be affected. The clinical features and diagnosis of FXS in children and adolescents are discussed in this topic review. Prenatal screening and the management of FXS in children and adolescents are ...
Fragile X syndrome (FXS) is a genetic disorder and one of the most common causes of inherited intellectual disability. FXS affects both males and females. However, females often have milder symptoms than males. A diagnosis of FXS can be helpful to the family because it can provide a reason for a child's intellectual disabilities and behavior ...
Abstract. Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition. of CGG triplets (> 200) and their methylation entail the ...
Genetics of fragile X. Fragile X syndrome (FXS), an X-linked condition first described by Martin and Bell (), is the leading cause of inherited intellectual disability (ID).Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3).FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 ...
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Screening for fragile X syndrome is performed by polymerase chain reaction and current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual ...
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome.Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions ...
The first clinical clue in children often is delayed attainment of one or more developmental milestones. 2, 3 On average, boys with fragile X syndrome sit without support at 10 months of age and ...
This review aims to assemble many years of research and clinical experience in the fields of neurodevelopment and neuroscience to present an up-to-date understanding of the clinical presentation, molecular and brain pathology associated with Fragile X syndrome, a neurodevelopmental condition that develops with the full mutation of the FMR1 gene, located in the q27.3 loci of the X chromosome ...
The following sections describe pathophysiology and clinical presentation of FXS, as well as a variety of therapeutic approaches. 2. The Pathophysiology of Fragile X Syndrome. FXS is the most common form of inherited intellectual disability (ID) and monogenic cause of Autism Spectrum Disorder (ASD) [ 22 ].
The clinical spectrum of FXS is wide, presenting not only as an isolated intellectual disability but as a multi-systemic condition, involving predominantly the central nervous system but potentially affecting any apparatus. ... Background: Fragile X Syndrome (FXS) is the second cause of intellectual disability after Down syndrome and the most ...
Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its ...
Fragile X syndrome: clinical presentation, pathology and treatment ... Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition
Summary. The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated promoter. The full mutation is the almost always the cause of fragile X syndrome (FXS). The prevalence of FXS is about 1 in 4,000 to 1 in 7,000 in the general population although ...
Presented by Elizabeth Berry-Kravis, MD, PhD, Craig A. Erickson, MD, and Randi J. Hagerman, MD. This session will be a family-friendly joint presentation of results from recently completed, and a description of all currently active clinical trials and development programs for new medications in fragile X syndrome (FXS).
Keynote: Clinical Trials in Fragile X Syndrome — Presentation Dany Petraska 2023-12-20T16:57:25-05:00 Jul 15, 2022 | This keynote session explore completed and active clinical trials relating to Fragile X syndrome.
11560 Ciudad de México (México) Mallorca, 310. 08037 Barcelona (España) Legal Notice (Aviso Legal) | Permissions & Reprints | Data Protection Policy | Ethics Code | Conflicts of Interest. Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200...
Fragile X syndrome (FXS) is the most common monogenic form of inherited intellectual disability and autism spectrum disorder (ASD). More than 99% of individuals with FXS are caused by the unstable expansion of CGG repeats located within the 5'-untranslated region of the FMR1 gene. The clinical features of FXS include various degrees of ...
Background Dermatofibromas, also known as benign fibrous histiocytomas, are among the most common cutaneous soft-tissue lesions. Association of multiple dermatofibromas with some diseases was described and it has not been reported with Ehlers-Danlos syndrome before. We present a case with Ehlers-Danlos syndrome and multiple dermatofibromas. Case presentation An 18-year-old Iranian woman ...
The UC Davis MIND Institute is an internationally recognized research, education and clinical care center. It brings together researchers and providers in many different specialties, all dedicated to neurodevelopmental conditions such as autism, fragile X syndrome and Down syndrome.
AGENCY: Centers for Medicare & Medicaid Services (CMS), Department of Health and Human Services (HHS). ACTION: Final rule. SUMMARY: This final rule revises the Medicare hospital inpatient prospective payment systems (IPPS) for operating and capital-related costs of acute care hospitals; makes changes relating to Medicare graduate medical education (GME) for teaching hospitals; updates the ...
The X-linked ataxias range from pure cerebellar phenotypes to more complex presentations involving developmental delay, parkinsonism, and dementia. The most common X-linked ataxia is Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by repeat expansion in the FMR1 gene that is also associated with Fragile-X syndrome (Table 1). While X ...