The clinical and genetic spectrum of spinocerebellar ataxia 14.

Spinocerebellar ataxia 14 (SCA14) is associated with missense mutations in the protein kinase C gamma gene (PRKCG), rather than a nucleotide repeat expansion. In this large-scale study of PRKCG in patients with ataxia, two new missense mutations, an in-frame deletion, and a possible splice site mutation were found and can now be added to the four previously described missense mutations. The genotype/phenotype correlations in these families are described.

Spinocerebellar ataxia type 8: clinical features in a large family.

OBJECTIVE: To compare the clinical and genetic features of the seven-generation family (MN-A) used to define the spinocerebellar ataxia 8 (SCA8) locus. BACKGROUND: The authors recently described an untranslated CTG expansion that causes a novel form of SCA (SCA8) characterized by reduced penetrance and complex patterns of repeat instability. METHODS: Clinical and molecular features of 82 members of the MN-A family were evaluated by neurologic examination, quantitative dexterity testing, and, in some individuals, MRI and sperm analyses. RESULTS: SCA8 is a slowly progressive, predominantly cerebellar ataxia with marked cerebellar atrophy, affecting gait, swallowing, speech, and limb and eye movements. CTG tracts are longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90, p < 10-8). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. Surprisingly, all 21 affected MN-A family members inherited an expansion from their mothers. The maternal penetrance bias is consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (>107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) are significantly shorter than in the blood (116) of an affected man. CONCLUSIONS: The biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. Diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat.

SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.

We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.

Extrarenal nephroblastic proliferation in spinal dysraphism. A report of 4 cases.

Four cases of extrarenal nephrogenic proliferation in the sacrococcygeal region with spinal dysraphism are presented. In two of the cases, features of Wilm's or incipient Wilm's tumor were present. The previous literature on sacrococcygeal nephrogenic tissue is reviewed, and the impact of these findings on the histogenesis of extrarenal sacrococcygeal Wilm's tumor is discussed.

Spinal cord arteriovenous fistulas involving the conus medullaris: presentation, management, and embryologic considerations.

BACKGROUND: Spinal cord arteriovenous fistulas (SCAVF) are uncommon congenital lesions that usually involve the most caudal aspects of the cord. We present three cases of SCAVF that illustrate the clinical manifestations and possible management options. The characteristic involvement of the conus medullaris and an associated tethered spinal cord in one of our patient suggests that a disorder of secondary neurulation may be involved in the formation of these arteriovenous shunt lesions. METHODS: Review of records and radiologic studies in three consecutive patients with SCAVF's treated at this institution. RESULTS: All three patients had SCAVF involving the lower lumbar spinal cord segments or the conus. One of the conus lesions was associated with tethering of the spinal cord. One small lesion (Type A) was treated surgically, whereas the two larger lesions (Type B) were treated using interventional neuroradiologic techniques. CONCLUSIONS: Both surgical and endovascular method have a role in management of these unusual spinal cord vascular malformations. The association with tethered cord suggests that the propensity for SCAVM to occur in the most caudal portions of the spinal cord may result from failure of secondary neurulation to properly develop the unique and complex vascular anatomy of the region.

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families.

OBJECTIVE: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. BACKGROUND: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. METHODS: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. RESULTS: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. CONCLUSIONS: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.

Brain glyceraldehyde-3-phosphate dehydrogenase activity in human trinucleotide repeat disorders.

BACKGROUND: Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons. OBJECTIVE: To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders. PATIENTS AND METHODS: Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3-Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. RESULTS: Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, -12%) and Alzheimer disease (temporal cortex, -19%). CONCLUSION: The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.

Imaging studies in a unique familial dysmyelinating disorder.

We report the imaging findings in five patients with a unique dysmyelinating disorder. MR studies of these infants showed obstructive hydrocephalus caused by mass effect produced by an enlarged cerebellum. The white matter of an enlarged cerebrum and cerebellum showed delayed myelination. Proton spectroscopy showed normal N-acetylaspartate (NAA) levels. While the dysmyelinating disorder was clearly differentiated from Canavan disease by an absence of elevated NAA and differing histopathologic findings and autosomal-dominant inheritance pattern, there were similarities to this disease in the presentation and, to some extent, in the initial imaging findings.

Motor system changes in the aging brain: what is normal and what is not.

Age-related changes in the nervous system may present with physical signs that are not unlike early manifestations of several clinical disorders. Gait disturbances (immobility), balance difficulties (instability), and certain motor control problems (i.e., tremor) are not necessarily signs of a disease state. The clinician needs to be reminded that most physiologic functions decline at a rate of 1% per year, beginning at age 30. Often compounding "natural" decline are the motor problems related to disuse. This is especially true for the inactive individual suffering from depression, cardiac or pulmonary insufficiency, painful joint and muscle conditions, substance abuse and, sometimes, simply social isolation.

[Chiari malformations and hydrosyringomyelia]. / Malformación de Chiari e hidrosiringomielia.

INTRODUCTION: The association of hindbrain herniation, better known as Chiari malformation, and cystic cavitation of the spinal cord or hydrosyringomyelia has been well described in the literature although there is little consensus regarding its etiology, pathophysiology or optimal treatment. DEVELOPMENT: Despite a well-accepted and utilized classification system of both Chiari malformation and hydrosyringomyelia, there remains considerable disagreement regarding the proper management of these patients. CONCLUSIONS: This article reviews several popular theories on the etiology and pathophysiology of this disorder, briefly discusses the clinical features and radiologic findings associated with Chiari malformation and hydrosyringomyelia, and reviews basic surgical techniques for decompression of the cranial-cervical junction and treatment of the hydrosyringomyelia.

Visual impairment associated with mutism after posterior fossa surgery in children.

OBJECTIVE: To report four children with visual impairment associated with mutism after posterior fossa surgery. Mutism after posterior fossa surgery is a well-described phenomena, but to our knowledge, visual impairment has not been reported in association with it. METHODS: Record review of four children (age range, 3-7 yr) who underwent posterior fossa surgery (via suboccipital craniotomies) for removal of a medulloblastoma (three patients) or ependymoma (one patient). Each presented with headache, ataxia, or nausea and vomiting, but none had preoperative visual complaints other than diplopia. Postoperatively, all patients were mute, and because of apparent visual loss, neuro-ophthalmic consultation was requested. Postoperative scans and examinations were also reviewed. RESULTS: Each child was awake but appeared withdrawn without verbal output. No child blinked to threat or fixed or followed. In each case, pupillary reactivity was normal, and funduscopic examinations revealed only papilledema. One child reached for money. Within weeks or months postoperatively, the mutism spontaneously resolved, and visual behavior in general improved, roughly in parallel. During the follow-up period, papilledema resolved and the disc color was normal in each case. Magnetic resonance images obtained postoperatively revealed nothing remarkable, except surgical defects, without lesions in the retrogeniculate pathway. CONCLUSION: Impaired visual behavior, mimicking cortical visual loss, may be associated with mutism after posterior fossa surgery in children. The prognosis for recovery is excellent and parallels the return of normal speech. The mechanism is unclear.

Spontaneous thrombosis of a basilar artery traumatic aneurysm in a child.

Traumatic aneurysms are rare and occur most commonly in young adults; however, the relative frequency in the pediatric population is high, owing to the low prevalence of congenital saccular aneurysms in children. Traumatic aneurysms typically involve the anterior circulation, and spontaneous thrombosis is uncommon; hence, surgery is usually necessary. We present a case of a posttraumatic aneurysm in a child that occurred after a fall from a large height and that spontaneously thrombosed.

Clinician reliability and accuracy in judging appropriate level of care.

Accurately assigning children to the most appropriate level of care is widely recognized as important. Managed care companies conduct utilization reviews in which they monitor the level of care to which clients are assigned using written placement criteria. However, no research has examined the ability of clinicians to perform this task. In the present study, 47 child and adolescent clinical profiles consisting of 48 variables were developed. Eighteen clinicians, trained to use their agency's level-of-care guidelines, made level-of-care decisions on these profiles. Their interjudge reliability in assigning a child to an appropriate level of care was close to zero (kappa = .07). There was a small, statistically significant correlation between client placement and actual placement, but chance-corrected agreement between client placement and actual placement was very low (kappa = .09). Implications of these findings for clinical research, practice, policy, and training are discussed.

Validating quality indicators. Quality as relationship between structure, process, and outcome.

Theory and research have not kept pace with the growing interest in evaluating quality of mental health care, resulting in the use of unvalidated quality indicators. A framework for validating quality indicators is offered by which quality is viewed as the relationship between service structures, processes, and outcomes. Adoption of this framework will facilitate the measurement of quality using valid indicators and should be useful to agencies in their continuous quality improvement efforts. Valid information about the quality of mental health care services will help purchasers and consumers make more informed health care decisions.

Progressive congenital kyphosis: report of five cases and review of the literature.

For over 60 years congenital kyphotic deformities of the spine have been categorized into two distinct groups, depending on the developmental defect. Those arising from a failure of formation of the vertebral bodies were classified as type 1, while those arising from a failure of segmentation were referred to as type 2. Recognition of the progressive and unstable nature of the type 1 defects alerted physicians to the need for early operative stabilization through decompression and stabilization through instrumentation. As the embryogenesis of the spinal column was further investigated, and as diagnostic imaging methods of the spine improved, unstable congenital kyphoses were further subdivided. Progressive congenital kyphotic deformities now may accompany a host of vertebral column developmental defects as well as genetically mediated mesenchymal tissue defect syndromes. This paper presents 5 patients from The Children's Hospital of Philadelphia with progressive and symptomatic congenital kyphotic deformities of the spine. Two of these lesions resulted from defects of formation of the vertebral bodies, while one resulted from segmental spinal dysgenesis, maldevelopment of both the anterior and posterior vertebral elements. One patient's kyphotic deformity was a result of caudal regression syndrome, and the final case presented experienced a high thoracic kyphosis from a syndrome associated diffuse midline mesenchymal tissue abnormalities known as cerebrocostomandibular syndrome. All patients showed evidence of progressive cord compression and required neural element decompression, fusion, and instrumentation. The cases are discussed individually, and the developmental and clinical aspects of each are explored.

International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology.

Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials-multicentric and international-an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress.

Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease.

Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicism, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.