Cerebral abnormalities in adults with ataxia-telangiectasia.

Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular and cutaneous telangiectasia, immunodeficiency, heightened sensitivity to ionizing radiation and susceptibility to developing lymphoreticular malignancy. Supratentorial brain abnormalities have been reported only rarely. In this study, brain MRI was performed in 10 adults with ataxia-telangiectasia having stable neurologic impairment. Intracerebral telangiectasia with multiple punctate hemosiderin deposits were identified in 60% of subjects. These lesions were apparently asymptomatic. They are similar in appearance to radiation-induced telangiectasia and to cryptogenic vascular malformations. Also noted, in the 2 oldest subjects, was extensive white matter T2 hyperintensity, and in 1 of these a space-occupying fluid collection consistent with transudative capillary leak and edema as evidenced by reduced levels of metabolites on MR spectroscopic imaging. Asymptomatic supratentorial vascular abnormalities appear to be common in adults with ataxia-telangiectasia.

Loss of sarcolemmal nNOS is common in acquired and inherited neuromuscular disorders.

OBJECTIVE: Neuronal nitric oxide synthase (nNOS), normally expressed at the sarcolemmal membrane, is known to be mislocalized to the sarcoplasm in several forms of muscular dystrophy. Our objectives were to characterize further the range of patients manifesting aberrant nNOS sarcolemmal immunolocalization and to study nNOS localization in animal models of nondystrophic myopathy. METHODS: We carried out a retrospective cross-sectional study. We performed immunofluorescent staining for nNOS on biopsy specimens from 161 patients with acquired and nondystrophin inherited neuromuscular conditions. The localization of sarcolemmal nNOS correlated with mobility and functional status. Muscle specimens from mouse models of steroid-induced and starvation-related atrophy were studied for qualitative and quantitative nNOS expression. RESULTS: Sarcolemmal nNOS staining was abnormal in 42% of patients with inherited myopathic conditions, 25% with acquired myopathic conditions, 57% with neurogenic conditions, and 93% with hypotonia. Interestingly, we found significant associations between mobility status or muscle function and sarcolemmal nNOS expression. Furthermore, mouse models of catabolic stress also demonstrated mislocalization of sarcolemmal nNOS. CONCLUSION: Our analyses indicate that nNOS mislocalization is observed in a broad range of nondystrophic neuromuscular conditions associated with impaired mobility status and catabolic stress. Our findings suggest that the assessment of sarcolemmal localization of nNOS represents an important tool for the evaluation of muscle biopsies of patients with a variety of inherited and acquired forms of neuromuscular disorders.

Gaze fixation deficits and their implication in ataxia-telangiectasia.

BACKGROUND AND AIMS: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterise the disturbance of visual fixation in A-T. METHODS: Eye movements were recorded from 13 A-T patients (with dual search coils in five patients and video oculography in seven) during attempted fixation. RESULTS: Two abnormalities--nystagmus and saccadic intrusions--were common. Horizontal, vertical and torsional nystagmus was present in straight ahead (spontaneous nystagmus) and eccentric gaze (gaze evoked nystagmus). In eight patients the horizontal nystagmus changed directions--periodic alternating nystagmus (PAN). Two types of saccadic intrusions were seen--micro-saccadic oscillations (SO) and square wave saccadic intrusions (SWSI). SO were small amplitude (0.1-0.9 degrees) and high frequency (14-33 Hz) back to back horizontal saccades. SWSI ranged between 1 degree and 18 degrees (median 3 degrees) with an intersaccadic interval ranging between 50 and 800 ms (median 300 ms). The potential impact of abnormal gaze stabilisation on vision was quantified. DISCUSSION: Degeneration of cerebellar Purkinje neurons disinhibit the caudal fastigial oculomotor region (FOR) and vestibular nuclei (VN). Disinhibition of VN can cause nystagmus, including PAN, while disinhibition of FOR can affect saccade generating mechanisms, leading to SWSI and SO.

Acute transverse myelitis in childhood: center-based analysis of 47 cases.

OBJECTIVE: To relate clinical characteristics associated with acute transverse myelitis (ATM) in children with functional outcomes at follow-up. METHODS: We identified 47 patients for whom ATM occurred under the age of 18 years. Chart analysis, clinical evaluation, and administration of functional measures were completed. RESULTS: The age at onset clustered between ages 0 to 2 and 5 to 17. Febrile illness had occurred in 47% and vaccination in 28%. Major disability at the nadir of the clinical course was noted. Eighty-nine percent were unable to walk, required assisted ventilation, or both. At a median of 3.2 years after acute illness, 43% were unable to walk 30 ft and 21% required a walker or other support, 68% experienced urinary urgency, 50% required bladder catheterization, 54% were troubled by persistent dysesthesias, and 75% had numbness. Factors associated with a better functional outcome included older age at time of diagnosis, shorter time to diagnosis, lower sensory and anatomic levels of spinal injury, absence of T1 hypointensity on spinal MRI obtained during the acute period, lack of white blood cells in the CSF, and fewer affected spinal cord segments. Neither rapid progression to maximum impairment in less than 1 day nor any antecedent illness, immunization, or trauma was associated with a worse outcome. CONCLUSION: Persisting disability was present in many children with acute transverse myelitis. Urinary problems and sensory symptoms were the most common issues. Age at onset below 3 years was associated with worse functional outcomes.

Proton MR spectroscopic imaging in ataxia-telangiectasia.

OBJECT: Ataxia-telangiectasia (A-T) is a recessively inherited neurodegenerative disorder with prominent progressive ataxia and cerebellar degeneration, as well as manifest abnormalities of tone, posture, and movement suggesting extrapyramidal dysfunction. In this study, we tested the hypothesis that regional metabolite levels, as measured by proton magnetic resonance spectroscopic imaging, would be abnormal in patients with A-T in the posterior fossa and basal ganglia, reflecting the underlying neurodegenerative processes in these regions. METHODS: Spectroscopic images of N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr) were obtained in 8 patients with A-T and 8 age-matched controls. Normalized metabolite levels were compared between A-T patients and control subjects in various regions of interest, including the cerebellum, brainstem, and basal ganglia. RESULTS: A-T patients were distinguished from controls by the profound loss of all metabolites in the cerebellar vermis (NAA, p < 0.01; Cr and Cho, p < 0.05) and a trend for decreased metabolites within the cerebellar hemispheres. No abnormalities were detected in the basal ganglia. CONCLUSIONS: Proton MR spectroscopic features in A-T closely correlate with the morphologic neuroimaging findings of posterior fossa atrophy. Although symptoms suggesting extrapyramidal dysfunction are part of the A-T phenotype, these are not associated with altered metabolite levels in the basal ganglia.

Survival probability in ataxia telangiectasia.

Ataxia telangiectasia is a rare, multiorgan neurodegenerative disorder with enhanced vulnerability to cancer and infection. Median survival in two large cohorts of patients with this disease, one prospective and one retrospective, is 25 and 19 years, with a wide range. Life expectancy does not correlate well with severity of neurological impairment.

Toxic neuropathy in patients with pre-existing neuropathy.

The authors report significant worsening of a pre-existing neuropathy in six patients who received "non-toxic" dosages of known neurotoxic agents. Before treatment, baseline total neuropathy score (TNS) averaged 9.5 (range 0 to 19). After chemotherapy (Taxol [125 to 175 mg/m(2) x 4]; vincristine [2 to 5 mg]; cisplatin [40 mg/m(2) x 8]; and thalidomide [60 g]), the TNS averaged 22 (range 13 to 29). The authors conclude that functionally disabling toxic neuropathy can occur in patients with pre-existing neuropathy at standard doses.

Quantitative proton MR spectroscopic imaging in acute disseminated encephalomyelitis.

Serial MR imaging and quantitative proton MR spectroscopic imaging (MRSI) findings of a 4-year-old boy with acute disseminated encephalomyelitis (ADEM) are reported. Over a 2-month period characterized by an initial illness and two relapses, each with full recovery, MR imaging exhibited the appearance and disappearance of multifocal lesions throughout the CNS that correlated only partly with the neurologic impairment. During one relapse, MRSI revealed low levels of N-acetylaspartate (NAA) within the regions of prolonged T2 signal intensity. All other metabolites were normal. At follow-up, the MR imaging and MRSI abnormalities had fully resolved. MRSI might play an important role in the diagnosis of ADEM, as well as in the elucidation of underlying pathophysiologic processes in this poorly defined disorder of children. This case demonstrates that reduced levels of NAA are not always associated with neuronal loss, irreversible tissue damage, or poor neurologic outcome.

A novel nemaline myopathy in the Amish caused by a mutation in troponin T1.

The nemaline myopathies are characterized by weakness and eosinophilic, rodlike (nemaline) inclusions in muscle fibers. Amish nemaline myopathy is a form of nemaline myopathy common among the Old Order Amish. In the first months of life, affected infants have tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity develop before the children die of respiratory insufficiency, usually in the second year. The disorder has an incidence of approximately 1 in 500 among the Amish, and it is inherited in an autosomal recessive pattern. Using a genealogy database, automated pedigree software, and linkage analysis of DNA samples from four sibships, we identified an approximately 2-cM interval on chromosome 19q13.4 that was homozygous in all affected individuals. The gene for the sarcomeric thin-filament protein, slow skeletal muscle troponin T (TNNT1), maps to this interval and was sequenced. We identified a stop codon in exon 11, predicted to truncate the protein at amino acid 179, which segregates with the disease. We conclude that Amish nemaline myopathy is a distinct, heritable, myopathic disorder caused by a mutation in TNNT1.

Quantitative neurologic assessment of ataxia-telangiectasia.

BACKGROUND: Ataxia telangiectasia (A-T) is a rare disorder with many distinctive neurologic features. Although there is substantial individual variation in the rate of progression of these features, their relationship to one another or to age has not been characterized. METHODS: We formulated and tested multiple elements that assess different neurologic functions known to be affected by A-T. The overall index was applied to 52 patients with A-T, 2 to 29 years of age. RESULTS: Seven elements items proved to be informative, and three elements were added based on face validity. In a linear regression model of individuals under 19 years of age, controlled for correlation within sibships, age accounted for 87% of the variation in the A-T Index. CONCLUSION: Despite substantial individual variability of the phenotypic elements of A-T, scores on this multidimensional index have a very high correlation with age, indicating that there is a characteristic rate of progression of the disease, although functional domains in the brain are differentially affected. The pattern of scores suggests that a severe and a mild form of A-T may be distinguished by this quantitative measure. With further development this index may become useful as an outcome measure for treatment studies and prognosis.

Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia.

OBJECTIVES: To determine whether patients with ataxia-telangiectasia exhibit oropharyngeal dysphagia with concomitant aspiration and to examine the relationships among swallowing function, age, and nutritional status. STUDY DESIGN: Seventy patients (mean age, 10.7 years; range, 1.8 to 30 years) had feeding/swallowing and nutritional evaluations. Fifty-one patients, in whom there were concerns about swallowing safety, were examined with a standardized videofluoroscopic swallow study. RESULTS: Fourteen of the 51 patients (27%) with histories suggestive of dysphagia demonstrated aspiration. Of these, silent aspiration (aspiration without a cough) occurred in 10 (71%) patients. Aspirators were significantly older than non-aspirators (mean age, 16.9 vs 10.8 years; P =.002). Advancing age was the strongest factor associated with aspiration during continuous drinking (P =.01). In patients with ataxia-telangiectasia, weight and weight/height were abnormally low at all ages and most compromised in older patients. Patients who aspirated had significantly lower mean weight (P <.002) and weight/height z scores (P <.001) than did patients who did not aspirate. CONCLUSIONS: Oropharyngeal dysphagia is common and appears to be progressive in patients with ataxia-telangiectasia. Older patients also have a higher incidence of poorer nutritional status. The relationship between dysphagia and nutritional status deserves further investigation.

Stimulation single-fiber EMG in infant botulism.

The principal electrodiagnostic feature of infant botulism, an incremental response on high rates of repetitive nerve stimulation, has variable sensitivity and may not always be useful as a diagnostic test given the vagaries of test timing and severity of illness. We report the use of stimulation single fiber EMG (S-SFEMG) in making this clinical diagnosis. Four infants between 1 and 5 months of age presented with rapidly progressive bulbar and limb weakness, internal and external ophthalmoplegia, areflexia, and compromised ventilation. Incremental response with high-rate repetitive nerve stimulation and a typical clinical course for infant botulism confirmed the diagnosis in all; stool toxin studies were positive for type B botulinum in 2 of the 3 cases in which they were obtained. S-SFEMG was performed by surface stimulation of median and ulnar nerves and recording with a single fiber needle in the thenar, hypothenar, or first dorsal interosseous muscles. A total of eight single fiber recordings were studied at rates of 2, 5, 10, and 20 Hz. All single fibers studies showed an improvement with higher rates of stimulation, beginning at 10 Hz and peaking at 20 Hz. Compared to baseline study at 2 Hz (100%), the mean percent changes in jitter at 5, 10, and 20 Hz were 109, 60, and 47, respectively. This is the first report of the usefulness of S-SFEMG in the diagnosis of infant botulism.

Ocular motor abnormalities in ataxia telangiectasia.

Although abnormal eye movements are a prominent feature of ataxia telangiectasia, the characteristics of the oculomotor dysfunction in the disease have been reported only in small groups of patients. We have examined eye movements clinically in 56 patients with ataxia telangiectasia, and obtained electrooculographic recordings of eye movements in 33 subjects. Deficits were observed in the eye movement systems that stabilize images on the retina, including pursuit, gaze holding, convergence, vestibular and optokinetic slow phases, and cancellation of vestibular slow phases. Abnormalities in the systems that maintain fixation and shift gaze were also prominent, including abnormal reflexive and voluntary saccades (characterized by prolonged latency, hypometric amplitude, and the use of head movements to initiate gaze shifts), impaired fixation, and a reduction in vestibular and optokinetic quick phases. The abnormalities in image stabilization most likely result from dysfunction in the cerebellar flocculus and paraflocculus. The basis of the saccadic and fixation disturbance is less certain but may be the result of abnormal supranuclear control of the superior colliculus resulting from dysfunction in the cerebellar vermis or the basal ganglia.

Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects.

Gangliosides are a family of sialic acid-containing glycosphingolipids highly enriched in the mammalian nervous system. Although they are the major sialoglycoconjugates in the brain, their neurobiological functions remain poorly defined. By disrupting the gene for a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase; EC 2.4.1.92) we generated mice that express only simple gangliosides (GM3/GD3) and examined their central and peripheral nervous systems. The complex ganglioside knockout mice display decreased central myelination, axonal degeneration in both the central and peripheral nervous systems, and demyelination in peripheral nerves. The pathological features of their nervous system closely resemble those reported in mice with a disrupted gene for myelin-associated glycoprotein (MAG), a myelin receptor that binds to complex brain gangliosides in vitro. Furthermore, GM2/GD2 synthase knockout mice have reduced MAG expression in the central nervous system. These results indicate that complex gangliosides function in central myelination and maintaining the integrity of axons and myelin. They also support the theory that complex gangliosides are endogenous ligands for MAG. The data extend and clarify prior observations on a similar mouse model, which reported only subtle conduction defects in their nervous system [Takamiya, K., Yamamoto, A., Furukawa, K., Yamashiro, S., Shin, M., Okada, M., Fukumoto, S., Haraguchi, M., Takeda, N., Fujimura, K., et al. (1996) Proc. Natl. Acad. Sci. USA 93, 10662-10667].

Abnormal fatty acid metabolism in childhood spinal muscular atrophy.

Our previous experience with abnormal fatty acid metabolism in several children with spinal muscular atrophy (SMA) prompted evaluation of fatty acid metabolism in a larger cohort. Thirty-three infants with severe infantile SMA were shown to have a significantly increased ratio of dodecanoic to tetradecanoic acid in plasma compared with normal infants and 6 infants affected with equally debilitating, non-SMA denervating disorders. Seventeen children with milder forms of SMA had normal fatty acid profiles. In addition, all 5 infants with severe SMA evaluated in a fasting state developed a distinctive and marked dicarboxylic aciduria, including saturated, unsaturated, and 3-hydroxy forms, comparable in severity with the dicarboxylic aciduria of children with primary defects of mitochondrial fatty acid beta-oxidation. Nine children with chronic SMA and 23 control patients did not develop an abnormal dicarboxylic aciduria during fasting. No known disorder of fatty acid metabolism explains all of the abnormalities we find in SMA. Our data suggest, however, that the abnormalities are not a consequence of SMA-related immobility, systemic illness, muscle denervation, or muscle atrophy. These abnormalities in fatty acid metabolism may be caused by changes in cellular physiology related to the molecular defects of the SMA-pathogenic survival motor neuron gene or neighboring genes.

Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.

Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.

Neurofilament-dependent radial growth of motor axons and axonal organization of neurofilaments does not require the neurofilament heavy subunit (NF-H) or its phosphorylation.

Neurofilaments are essential for establishment and maintenance of axonal diameter of large myelinated axons, a property that determines the velocity of electrical signal conduction. One prominent model for how neurofilaments specify axonal growth is that the 660-amino acid, heavily phosphorylated tail domain of neurofilament heavy subunit (NF-H) is responsible for neurofilament-dependent structuring of axoplasm through intra-axonal crossbridging between adjacent neurofilaments or to other axonal structures. To test such a role, homologous recombination was used to generate NF-H-null mice. In peripheral motor and sensory axons, absence of NF-H does not significantly affect the number of neurofilaments or axonal elongation or targeting, but it does affect the efficiency of survival of motor and sensory axons. Loss of NF-H caused only a slight reduction in nearest neighbor spacing of neurofilaments and did not affect neurofilament distribution in either large- or small-diameter motor axons. Since postnatal growth of motor axon caliber continues largely unabated in the absence of NF-H, neither interactions mediated by NF-H nor the extensive phosphorylation of it within myelinated axonal segments are essential features of this growth.

Consequences of the delayed diagnosis of ataxia-telangiectasia.

OBJECTIVES: Ataxia-telangiectasia (AT) is a rare, autosomal recessive neurodegenerative disorder in which the diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests. The purpose of this study is to identify factors responsible for delays in the diagnosis of AT. DESIGN: The records of all patients seen at the Ataxia-Telangiectasia Clinical Center from July 1, 1995 to April 1, 1997 were reviewed to determine age of onset of gait abnormality, recognition of telangiectasia, and diagnosis. RESULTS: In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months). In the majority of cases (34/48), telangiectasia appeared before the diagnosis was established. The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. CONCLUSIONS: The term AT, although a concise and memorable label for the disorder, is also a barrier to early diagnosis. We recommend the use of routine serum alpha-fetoprotein testing for all children with persistent ataxia.

Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases.

We describe the clinical features, natural history, and neuropathology of 32 patients presenting with "burning feet," for whom no specific cause was identified. All had neuropathic pain in the feet and morphological abnormalities of cutaneous innervation in skin obtained using punch biopsy. Most (29) had an abnormal sensory examination. All had normal strength, proprioception, tendon reflexes, and nerve conductions. Two clinical patterns were apparent, based on natural history and spatial distribution of cutaneous denervation. Most (28) patients presented with neuropathic pain initially restricted to the feet and toes but extending more proximally to involve the legs and hands with time. Intraepidermal nerve fiber (IENF) density was most severely reduced distally, with more normal IENF densities in skin from proximal sites. In contrast, a minority (4) presented with the abrupt onset of generalized cutaneous burning pain and hyperesthesia. In these patients, IENF densities were reduced in skin from both proximal and distal sites. Absolute IENF densities in calf skin were reduced below the lower limit of normal (5th percentile) in 26 (81%). Of the 6 who underwent sural nerve biopsy, 4 had selective loss of small myelinated and/or unmyelinated axons and 2 had normal histology and fiber densities despite reduced IENF densities in skin biopsy specimens. Punch skin biopsy from proximal and distal sites is a useful means of assessing these distinctive patients and may provide further insight into pathophysiology.