Re: UNAMONOS EN ORACION POR EL HERMANO GATO
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Hermanos del Foro Iglesia. Net
Les saludo en el nombre de nuestro Señor y Salvador Jesucristo.
Tal como les había adelantado ésta semana íbamos a tener el diagnóstico final sobre la enfermedad de mi hija Dommy Alejandra, después de haberle realizado un examen de Electromiografía de extremidades, el resultado arrojó, que no es una Miastenia grave la que tiene, es otra que es peor, y ésta se llama SINDROME ATAXIA ESPINOCEREBELOSA O ATAXIA DE FRIEDREICH, una enfermedad progresiva que causa daño al sistema nervioso.
La Ataxia de Friedreich se produce de la degeneración de tejido nervioso en la médula espinal y de nervios que controlan el movimiento muscular de los brazos y las piernas. La médula espinal se adelgaza y las células nerviosas pierden parte de su vaina de mielina, la estrecha cobertura de todas las células nerviosas que ayuda a trasmitir los impulsos nerviosos. Además del deterioro progresivo de diversos organismo como la vista, el corazón, paralización de los músculos de las extremidades inferiores como superiores, hasta llegar a una parálisis total y quedar en una silla de ruedas, tiene una serie de complicaciones a nivel cardiovascular, ceguera, etc. un pronóstico no muy alentador por que no tiene cura, y la duración del paciente es relativo, su pronóstico de vida aún no lo se, pero creo que no es mucho en algunos casos.
Pido a cada uno de ustedes sus plegarias, que las oraciones de cada uno de nosotros lleguen al trono de la gracia de nuestro Padre Celestial, y pueda recibir mi hija sanación, yo si creo en los milagros, solo la fe y la esperanza en Dios, ésta enfermedad se podrá detener o desaparecer, la otra esperanza que se hayan equivocado los médicos. Si no es así, bajaré mi cabeza y le diré amén Señor, tuya es la vida y la salud, solo dame fuerzas para no desfallecer en momentos de angustia y especialmente que le de fuerzas a mi pequeña hija para que no se desmorone y mire la vida con optimismo y fe.
La gracia de nuestro Señor, sea con cada uno de ustedes.
Su hermano en Cristo
G@TO
PD. Gracias a todos los que me han dado aliento y han orado por mi hijita.
Mi hermano, una disculpa no leí el diagnóstico previamente y ahora que lo leo tomo un poquito del tiempo para pegarle una info en ingles, extraida de "Up to Date" es el libro electrónico de medicina basada en evidencias mas serio y actual, basado en unos 330 artículos de lo mas novedosos y prestigiados aqui le transcribo, disculpe que no lo haya traducido por el tiempo (oraré aun mas por su niña):
--The spino cerebellar ataxias
INTRODUCTION – Numerous classification systems have been proposed for the autosomal dominant ataxias, which are distinct from the autosomal recessive disorder, Friedreich ataxia. (See "Friedreich ataxia"). One system, proposed by Anita Harding in 1984, divided these disorders into autosomal dominant cerebellar ataxia types I, II, and III [1].
• Type I syndromes are ataxias with ophthalmoplegia, optic atrophy, dementia and extrapyramidal features.
• Type II ataxias are associated with pigmented maculopathy with or without ophthalmoplegia or extrapyramidal features.
• Type III syndromes are pure ataxic syndromes.
We have tried to correlate the genetic classification with the Harding classification [2]. However, doing so is often difficult because of the broad overlap of clinical features and phenotypic variations within each disorder (show table 1). Therefore, we now favor a purely genetic classification based upon the genetic loci of the spinocerebellar ataxias (SCA). These loci have been numbered according to their order of identification: SCA1 through 25 (and the number continues to grow).
In addition to these syndromes, there are a few other genetic disorders that are inherited in a dominant manner and often present as ataxia. These are discussed in this review to complete the differential diagnosis of these chronic-progressive ataxic syndromes. (See "Disorders that resemble SCAs" below).
A number of other hereditary ataxias have been identified and are discussed separately. (See "Overview of the hereditary ataxias").
OVERVIEW OF SCA – Several types of SCA (1, 2, 3, 6, 7, and 17) are associated with expansion of CAG repeats in the coding region that encodes for polyglutamine tracts in the protein products, similar to that seen in Huntington disease. (See "Genetics and pathogenesis of Huntington disease").
Wild-type chromosomes with a stable CAG repeat have 6 to 34 repeat units; more than 36 repeats results in an unstable, expanded, disease-causing allele [3]. Expansion of CAG repeats is thought to produce a toxic "gain of function" (ie, disease develops because the mutant form of the protein gains a new function, not because the protein loses its normal function). The disorders associated with expansion of CAG repeats share several clinical features:
• They typically present in middle age, with progressive neuronal dysfunction and eventual neuronal loss during the ensuing 10 to 20 years.
• The greater the number of CAG repeats on expanded alleles, the earlier the age of onset and more severe the disease. Thus, juvenile onset disease typically is associated with very large expansions.
• The repeats show both somatic and germline instability. As a result, successive generations of affected families experience anticipation, a phenomenon characterized by earlier onset and a progressively worse phenotype in subsequent generations.
• Only a certain subset of neurons is vulnerable to dysfunction, even though the relevant protein is expressed widely throughout the brain and other tissues.
• Cerebellar atrophy is the most common reported finding. Brainstem atrophy is variable, being more characteristic of SCA types 1, 2, and 7. Neurodegeneration of the reticulotegmental nucleus of the pons has been reported for patients with SCA types 1, 2, and 3; this nucleus plays a role in the performance of horizontal smooth pursuit eye movements and in the accuracy of horizontal saccades [4].
Treatment – No effective treatment is available for the SCAs. One report described transient improvement in cerebellar symptoms with zolpidem 10 mg in four out of five family members with SCA type 2 [5]. This finding requires confirmation in a larger study.
Animal studies suggest that polyglutamine neurotoxicity can be suppressed by overexpression of heat shock proteins [6-8]. The technique of gene silencing with RNA interference has also shown promise in a mouse model of SCA [9]. The potential applicability of these findings to human disease remains speculative.
CLASSIFICATION OF SCA – As noted above, 25 types of SCA have been identified. Cerebellar ataxia is a feature of each type; other distinguishing features may suggest a particular type (show table 2).
However, only 60 to 70 percent of patients with SCA have mutations in the known loci [10]. Furthermore, among patients with apparently idiopathic sporadic cerebellar ataxia (ie, no family history), an SCA mutation (types 1, 2, 3, 6, 7, 8, or 12), most often SCA6, or Friedreich ataxia, can be identified in approximately 20 percent [11]. Online resources such as the Online Mendelian Inheritance of Man database (
http://www.ncbi.nlm.nih.gov/omim/) can be used to keep up with advances in this area.
Type 1 – Spinocerebellar ataxia type 1 is caused by a CAG repeat expansion on chromosome 6p22-23 in the coding region of the SCA1, the product of which is called ataxin-1 [12]. The normal function of ataxin-1 is not known. Mutant ataxin-1 aggregates into single nuclear inclusions [13]. This aggregation reflects, at least in part, resistance of the mutant protein to degradation [14]. In addition to mutant ataxin-1, these inclusions also stain positive for chaperones and components of the ubiquitin-proteasomal pathway, both of which are important for protein clearance [6]. Ubiquitination and proteasomal degradation appear to represent appropriate responses because interventions to prevent these processes in SCA1 and other polyglutamine diseases increase neuronal toxicity [14-16].
The pathogenetic role of the nuclear inclusions themselves is uncertain [15,17]. Mutant ataxin-1 has been found to alter neuronal gene expression, which may be more important in pathogenesis [18]. Another feature that is not well understood is the tissue-specific and brain region-specific instability of the expanded allele [19]. Ataxin-1 interacts with the cerebellar leucine-rich acidic nuclear protein (LANP); this protein is expressed primarily in Purkinje cells, the major site of involvement in SCA1 [20]. The interaction is stronger when the number of CAG repeats is increased.
Ataxin-1 is phosphorylated on serine 776 by Akt kinase and this serine is critical for mediating the pathogenesis of SCA type 1 [21,22]. Several isoforms of the regulatory protein 14-3-3 interact with ataxin-1 in an S776-dependent manner. These interactions are enhanced by an expanded glutamine tract in ataxin-1. In cultured cells and in an SCA1 Drosophila model, the 14-3-3 protein impedes the clearance of ataxin-1 and enhances neurodegeneration; in contrast, haploinsufficiency of Akt suppresses neurodegeneration. These studies identified PI3kinase/Akt as a possible therapeutic target in SCA1.
SCA1 typically presents between the ages of 20 and 30, but tremendous variability in onset and clinical severity exists. It is characterized clinically by progressive cerebellar ataxia, dysarthria, and bulbar dysfunction. Other findings include hyperreflexia, increased tone, extensor plantar responses, and, in some patients, masking of these upper motor neuron findings by peripheral nervous system disease that results in wasting of the extremities and generalized fasciculations.
In different populations, SCA1 accounts for 3 to 16 percent of autosomal dominant cerebellar ataxias [10,23-26]. Expanded SCA1 genes contain from 36 to 81 uninterrupted CAG repeats (normal alleles have 6 to 44 repeats; when the tract contains more than 21 CAGs, it is interrupted by a few CAT units).
Type 2 – In different populations, spinocerebellar ataxia type 2 (SCA2) accounts for 6 to 18 percent of SCA kindreds [10,24-27]. SCA2 is distinguished clinically from SCA1 by the presence of slow saccadic eye movements [28]. It results from mutations in the SCA2 gene on chromosome 12q24, which encodes a protein called ataxin-2 [29,30]. Ataxin-2 contains structural elements that appear to be important in RNA splicing. In contrast to the nuclear inclusions in SCA1, mutant ataxin-2 is associated with cytoplasmic microaggregates [31].
Disease-causing alleles usually contain 35 to 64 CAG repeats (normal 14 to 31 repeats). An inverse relationship exists between disease onset and severity and the number of CAG repeats [32]. When SCA2 alleles contain more than 200 repeats, the disease can present as early as infancy with hypotonia, developmental delay, dysphagia, and retinitis pigmentosa [33]. On the other hand, disease onset in late adulthood, manifested as ataxia, slow saccades, and hyporeflexia, has been described in two patients with 33 CAG repeats [34]. An inverse relationship also exists between saccadic eye movement velocity and the number of CAG repeats [35].
Genetic background influences the phenotype in geographically distinct families. For example, mental deterioration has been described in an Italian family [33,36], and chorea and dystonia have been described in families from Tunis and Martinique [37,38].
Type 3 (Machado-Joseph disease) – Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (MJD), is the most common of the autosomal dominant spinocerebellar ataxias. It is present in 21 to 23 percent of kindreds in the United States [23-25], 12 percent in Australia [26], and as many as 48 percent in China [10].
The SCA3/MJD gene is on the long arm of chromosome 14 (14q32) [39,40]; it encodes a protein called ataxin-3 or MJD1 [39]. The mutant gene has an increased number of CAG repeats (40 to more than 200 versus 12 to 41 (interrupted) in the wild-type allele). The wild-type protein predominantly is cytoplasmic, whereas mutant ataxin-3 is localized within the nucleus of neuronal cells [41]. The mutant protein forms nuclear inclusions and is associated with cell degeneration [42,43].
SCA3/MJD can be associated with a variety of symptoms other than ataxia. They include:
• Slow saccades and saccadic pursuit
• Lid retraction that gives the impression of a persistent stare
• Signs of brainstem dysfunction such as dysarthria, difficulty in swallowing, poor cough and tongue fasciculations
• Signs of upper and lower motor neuropathy; thus, tone can range from hypotonia to rigidity, reflexes can range from absent to exaggerated, and the plantar response is usually extensor
• Extrapyramidal features including rigidity and dystonia
• Cognitive impairments, such as verbal and visual memory deficits, impairment of verbal fluency, and visuospatial and constructional dysfunction [44]
In the past, MJD was subclassified into three types based upon the pattern of clinical features. Unfortunately, too many patients fell into more than one type for this classification to be clinically useful. Phenotypic variation is most likely a reflection of the number of CAG repeats and other genetic factors.
Type 4 – Spinocerebellar ataxia type 4 has few features that distinguish it from the other hereditary ataxias, except perhaps for an exaggerated sensory axonal neuropathy and extensor plantar reflexes [45]. The gene locus maps to chromosome 16q22, but the gene has not been identified [45,46].
Type 5 – Spinocerebellar ataxia type 5 is characterized by an almost pure cerebellar syndrome. It is a relatively mild disorder that typically begins between the ages of 20 and 30 and progresses slowly [47]. Magnetic resonance imaging (MRI) reveals global cerebellar atrophy [47]. The gene locus is in the centromeric region of chromosome 11, but the gene has not been identified [48]. The original kindred was descended from the paternal grandparents of Abraham Lincoln.
Type 6 – Spinocerebellar ataxia type 6 shares many clinical features with type 5 [49-51]. It is associated with slowly progressive cerebellar ataxia that begins between the ages of 20 and 60; global cerebellar atrophy is seen on MRI [50,51]. Other clinical features that may be seen include horizontal and vertical nystagmus and an abnormal vestibuloocular reflex [49].
SCA 6 accounted for 15 to 17 percent of dominant cerebellar ataxias in two series [25,26]. A population based molecular genetic study found that the point prevalence of SCA 6 in northeast region of England was 1.59 in 100,000, and the number of individuals who had or were at risk of developing SCA was at least 1 in 19,000 [52].
SCA6 is a polyglutamine disorder, but the CAG tract expansion is relatively small (21 to 33 repeats versus less than 18 in normal subjects). In one series of Japanese patients with SCA6, 9 of 35 had no apparent family history of ataxia; these patients had smaller CAG repeats (21 or 22) and later age of onset (65 years) [51]. A similar finding was noted in another report of patients with apparently idiopathic sporadic cerebellar ataxia. A mutation could be identified in 19 percent; SCA6 was the disorder most commonly identified in patients with late onset disease (47 to 68 years of age) [11]. One patient who was homozygous for the SCA6 mutation had an earlier age of onset and more severe disease than did her heterozygous sister [51].
The product of the SCA6 gene on 19p13 is the alpha-1A subunit of the P/Q type calcium channel [53]. Possible mechanisms of neuronal cell degeneration include increased calcium entry and cytoplasmic aggregates of channel protein [54,55].
The same gene has been implicated in two other disorders: episodic ataxia type 2 and familial hemiplegic migraine [56,57]. Although the mutations are different, some overlap of symptoms exists among these disorders. SCA6 can present with intermittent ataxia in the early stages, similar to episodic ataxia, and all three conditions often are associated with cerebellar atrophy.
Type 7 – SCA7 accounts for approximately 2 to 5 percent of dominant spinocerebellar ataxias [25,26]. It has a variable clinical expression, depending in part upon the age at onset [58].
• When the onset is in childhood, seizures, myoclonus, and cardiac involvement accompany the ataxia, and visual loss develops early in the disease course. Extremely long (>150) CAG repeats are associated with onset in infancy and evidence of systemic disease [59]. A severe infantile phenotype associated with over 200 CAG repeats has also been described [58].
• In adult-onset cases, smaller repeat expansions tend to manifest first as ataxia, whereas larger repeats can cause pigmentary macular degeneration leading to visual loss before ataxia develops [60].
This visual loss had been thought to be unique to SCA7 [61], but retinal degeneration has been documented in childhood-onset cases of SCA2 and SCA1 caused by very large repeats. Nevertheless, in adults, defects in color vision and electroretinogram abnormalities might suggest the diagnosis early in the disease course [60].
SCA7 is a glutamine repeat disorder that maps to chromosome 3p12 [60,61]. The number of CAG repeats varies between 37 and 306 (normal 4 to 35). Marked intergenerational instability is present, with expansion particularly likely upon paternal transmission [61,62].
The product of the SCA7 gene is called ataxin-7 and is preferentially expressed in neurons [63]. Mice overexpressing mutant ataxin-7, but not wild-type ataxin-7, have features similar to those of the human disease, with neurodegeneration involving the cerebellum and retina [64].
Type 8 – SCA8 is difficult to distinguish clinically from the other SCAs. Affected patients typically have a slowly progressive, predominantly cerebellar ataxia affecting gait, swallowing, speech, and limb and eye movements, with variable age at onset [65,66]. Marked cerebral atrophy is found on MRI or CT scan [66].
SCA8 is unusual because of a possibly novel mechanism of pathogenesis for triplet repeat disorders that involves a CTG expansion in the non-coding region of the relevant gene on chromosome 13q21 (80 to 250 repeats compared to 15 to 37 in normals) [67,68]. Oddly, it is this particular range of repeats that is pathogenic, as opposed to any expansion; some unaffected individuals bear hundreds of repeats. The SCA8 gene possibly encodes an antisense RNA that regulates the level of a brain-specific, actin-binding protein [69]. Genetic analysis of 37 families with SCA8 ataxia found that SCA8 expansions arose independently on three different haplotypes, supporting the direct role of CTG expansion in disease pathogenesis [70].
The CTG expansion found in SCA8 shows dramatic genetic instability and age dependent reduced disease penetrance. As an example, only one or two individuals in a given family may be affected by the disease, despite dominant inheritance. A maternal penetrance bias may exist, as CTG repeats tend to expand in mothers and contract in fathers (ie, fewer repeats in sperm than blood) [65,68]. The reduced penetrance in fathers may make the disease appear recessive or sporadic [65].
Types 9 to 25 – The remaining types of SCA are rare and less well characterized.
• SCA9 has not been assigned to a clinical disorder.
• SCA10 exhibits anticipation, and the locus maps to chromosome 22q13-qter [71,72]. The disease is caused by expansion of ATTCT pentanucleotide repeats initially identified in five Mexican families; normal alleles bear 10 to 22 repeats, while disease-causing alleles contain 800 to 4500 repeats [73].
SCA10 is manifested by seizures in association with pure cerebellar ataxia in Mexican families. A different phenotype of cerebellar ataxia without epilepsy was subsequently identified in five Brazilian families [74]. As is the case with most SCAs, family-dependent factors influence the phenotype and transmission of repeats. In a report of 22 affected individuals in two large Mexican-American pedigrees, seizure frequency and intergenerational changes in the size of repeats differed between the families [75].
• SCA11 is a relatively mild, pure cerebellar ataxia with a disease locus at 15q14-q21 [76].
• SCA12 is a trinucleotide repeat disorder caused by a CAG trinucleotide expansion in the 5' UTR of a gene encoding a brain-specific regulatory subunit of protein phosphatase 2A [77]. The normal range of repeats is 7 to 28; disease alleles bear 66 to 78 repeats. This ataxia often is complicated by tremors and dementia in the later stages. The genetic locus is 5q31-q33.
• SCA13 is characterized by cerebellar ataxia and mental retardation [78]. The gene locus is on chromosome 19q13.
• SCA14 can have either a late onset (> or =39 years) as pure cerebellar ataxia or an earlier onset with intermittent myoclonus followed by ataxia. The disorder is caused by mutations in the protein kinase C gamma (PRKCG) gene, located on chromosome 19q13 [79,80].
• SCA15 is a slowly progressive pure cerebellar ataxia first identified in an Australian family, with onset occurring from mid childhood to middle age [81], and linked to chromosome 3p24.2-3pter [82]. A similar SCA phenotype with the additional feature of postural and action tremor was identified in two Japanese families and was linked to chromosome 3p26.1-25.3 [83]. Subsequently, an autosomal dominant nonprogressive cerebellar ataxia (NPCA) was linked to chromosome 3pter, overlapping with the two SCA15 loci [84]. The clinical features of this particular NPCA phenotype that distinguish it from SCA15 include congenital onset, no progression of ataxia, and cognitive impairment.
• SCA16 is an autosomal dominant cerebellar ataxia identified in a four-generation Japanese family. The age of onset ranges from 20 to 66 years. Linkage analysis suggests the locus is on chromosome 8q22.1-24.1 [85].
• SCA 17 is an autosomal dominant cerebellar ataxia described in four Japanese pedigrees [86]. It is caused by an abnormal CAG expansion in the TATA-binding protein (TBP) gene, a general transcription initiation factor. The age of onset ranges from 19 to 48 years and is inversely related to the number of CAG repeats in the TBP gene (4 to 35 normally, 37 to over 200 on mutant alleles). The presentation is variable but most individuals present between the ages of 20 and 30 with gait ataxia and dementia, progressing over several decades to include bradykinesia, dysmetria, dysdiadokokinesis, hyperreflexia, and paucity of movement. None of the patients have abnormal eye movements. Diffuse cortical and cerebellar atrophy is present on neuroimaging in all patients.
• SCA18 has no published clinical or genetic information.
• SCA19 is identified in four generations of a single Dutch family and manifests as a relatively mild cerebellar ataxia with cognitive impairment, myoclonus, and tremor [87]. The genetic locus links to chromosome 1p21-q21 [88], a region that overlaps with SCA22.
• SCA20 has no published clinical or genetic information.
• SCA21 is identified in a four generation French family. Manifestations include gait ataxia and akinesia, with variable features of dysarthria, hyporeflexia, and mild cognitive impairment [89]. The responsible locus maps to chromosome 7p21.3-p15.1 [90].
• SCA22 is identified in a four generation Taiwanese family. Clinically this is a slowly progressive ataxia with variable dysarthria and hyporeflexia [91]. The genetic locus links to chromosome 1p21-q23 and overlaps with SCA19. Therefore, SCA19 and SCA22 may be identical conditions [92,93].
• SCA23 has no published clinical or genetic information.
• SCA24 has no published clinical or genetic information.
• SCA25 is described in a large French family and is characterized by cerebellar ataxia and sensory neuropathy [94]. The responsible locus maps to chromosome 2. The phenotype is highly variable regarding age of onset, severity and clinical manifestations, ranging from infantile-onset cerebellar ataxia with pure sensory neuropathy, suggestive of Friedreich's ataxia, to a form with mild cerebellar ataxia and prominent sensory neuropathy suggestive of Charcot-Marie-Tooth.
DISORDERS THAT RESEMBLE SCAs – Three other autosomal dominant ataxic disorders may resemble the SCAs: dentatorubral pallidoluysian atrophy, fragile X associated tremor ataxia syndrome, and prion disorders. In addition, episodic ataxias are dominantly inherited and are discussed here briefly.
Dentatorubral pallidoluysian atrophy (DRPLA) – Dentatorubral pallidoluysian atrophy is a disease that is relatively common in Japan. It should be suspected when ataxia and rigidity are accompanied by choreoathetosis, myoclonic epilepsy, and dementia [95]. Other features include hyperreflexia and slowing of saccades. MRI or CT scan often reveals atrophy of the cerebellum and brainstem, calcification of the basal ganglia, and leukodystrophic changes [96].
DRPLA is caused by CAG tract expansion of 49 to 88 repeats on chromosome 12p and presents with anticipation, especially when transmission is via the father [95,97]. Normal CAG tracts in DRPLA bear 6 to 35 repeats. The product of the DRPLA gene is a cytoplasmic protein called atrophin-1 [98]. The action of other enzymes on mutant atrophin-1, such as transglutaminase and caspases, may be involved in the neurotoxicity [99,100].
Haw River syndrome – Haw-River syndrome, a variant of DRPLA without the characteristic myoclonic epilepsy, has been described in a few families of African-American descent in North Carolina. It is caused by the same expanded repeat as DRPLA [101].
Fragile X associated tremor ataxia syndrome – The fragile X associated tremor-ataxia syndrome (FXTAS) occurs in older men who carry a so-called premutation in the fragile X mental retardation 1 gene (FMR1) [102]. The premutation consists of a trinucleotide CGG repeat length ranging from 50 to 200 in the FMR1 gene.
Fragile X syndrome is caused by a trinucleotide CGG expansion typically greater than 200 in the same FMR1 gene. It is a common cause of mental retardation in males [103]. (See "Etiology of birth defects-I", section on Unstable DNA). Carriers of the FMR1 gene premutation who have intermediate repeat lengths of 50 to 200 were originally thought to be unaffected, and most do not have the more severe neurodevelopmental problems associated with the full mutation [104]. However, premutation carriers can present with one or more of the following three clinical syndromes [105]:
• Mild cognitive and behavioral deficits on the spectrum of those seen in fragile X syndrome
• Premature ovarian failure
• Fragile X associated tremor-ataxia syndrome (FXTAS)
Approximately 20 to 33 percent of adult male premutation carriers display the FXTAS phenotype of late-onset ataxia associated with postural tremor. Additional clinical features of FXTAS can include dementia, parkinsonism, and autonomic dysfunction [104]. Since the prevalence of the premutation carrier state is as high as 1 in 813 males, this syndrome could prove to be a common genetic cause of ataxia.
The molecular mechanism causing FXTAS differs from that causing the fragile X syndrome. In fragile X syndrome, methylation of DNA sequences in the promoter where the expanded CGG resides causes silencing of the FMR1 gene and complete loss of FMR1 protein. In FXTAS, fragile X RNA is produced but it is poorly translated into protein. This translational deficit is thought to cause a compensatory increase in the levels of FMR1 transcripts. Unfortunately, the RNA bearing the expansion now causes a toxic gain-of-function effect triggering downstream protein accumulation and neurodegeneration [104].
Experimental mouse and Drosophila models have highlighted the similarity between FXTAS and polyglutamine induced ataxias [106,107]. This is an active area of research, with implications for some of the other repeat disorders in untranslated regions of RNA, including SCAs 8, 10, and 12 [103].
Gerstmann Straussler Scheinker syndrome – The prion diseases, particularly the ataxic variant of the Gerstmann Straussler Scheinker (GSS) syndrome, can mimic a spinocerebellar syndrome. GSS is diagnosed when autosomal dominant ataxia coexists with cognitive and motor decline plus pathologic findings of prion protein-containing amyloid plaques. (See "Diseases of the central nervous system caused by prions-I"). GSS results from mutations in the PRNP gene. The ataxic variant of GSS is caused by a proline to leucine missense at codon 102 [108]. (See "Biology and genetics of prions", section on Gerstmann Straussler Scheinker syndrome).
EVALUATION OF THE PATIENT WITH AUTOSOMAL DOMINANT ATAXIA – Many of the types of autosomal dominant ataxia have clinical features that may be suggestive of that disorder (show table 2).
Genetic testing – If a patient has a positive family history, genetic testing is the most efficient and definitive way to determine the cause of the symptoms and to identify the ataxia subtype. The Harding clinical classification and the few clinical differentiating features (show table 1 and show table 2) may suggest the likely candidate(s) for a step-wise screen.
In most cases, however, a blood sample is tested for mutations in all the known SCA-causing genes at once. This list includes SCA1,SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA17, and DRPLA. It is likely to expand as more genes are discovered or as novel phenotypes of other genetic defects are discovered; this has been the case with the fragile X premutation. Online resources (eg,
www.geneclinics.org) can be used to determine which types can be tested.
Neuroimaging – If genetic testing is not revealing and/or if a question exists about a co-existing disease process, additional studies are warranted. Neuroimaging with MRI or CT scan often reveals the typical cerebellar atrophy. Ruling out other causes of ataxia including space occupying lesions, demyelinating, or vascular events, also is important.
Among the spinocerebellar ataxias, atrophy is most prominent in SCA2 and least prominent in the milder diseases, SCA5 and SCA6. Brain stem atrophy, which would be expected to be almost universal, is characteristic of SCA1, SCA2, and SCA7. In one study, the degree of atrophy correlated with the neurologic deficit in SCA1 but not SCA2 [109]. Brain stem atrophy is minimal in SCA3 and DRPLA, and is rare in SCA6. Cerebral atrophy with compensatory enlargement of the lateral ventricles can be seen in SCA2, the infantile variant of SCA7, and DRPLA.
Less widely used and more expensive imaging studies such as magnetic resonance spectroscopy and positron emission tomography (PET) scanning are sensitive markers for deterioration and can demonstrate abnormalities not seen on MRI. At present, however, these modalities should be reserved for research rather than diagnosis.
Electrophysiologic testing – Most spinocerebellar ataxias cause defects in nerve conduction, especially SCA4. The predominant axonal neuropathy primarily affects sensory neurons, and sural nerve action potentials often are absent. However, these studies are rarely useful in determining the type of ataxia. On the other hand, visual-evoked potentials may suggest SCA7 because of the characteristic macular degeneration, whereas interictal electroencephalographic (EEG) abnormalities may suggest DRPLA. Seizures also are common in SCA10, but the interictal EEG is typically normal.-- (Up To Date 13.1)
Disculpe que las referencias al pie de página no se pueden copiar mas que de una por una, pero lo mas importante es la info, un abrazo seguiré orando, mucho animo y fuerza el Señor sea propicio.
