Severe Spastic Paraparesis Research Articles

Exome Sequence Analysis to Characterize Undiagnosed Family Segregating Motor Impairment and Dystonia.

Background: Hypermanganesemia with dystonia 1 (HMNDYT1) is a rare genetic disorder characterized by elevated blood manganese levels. This condition is associated with polycythemia, motor neurodegeneration with extrapyramidal features, and hepatic dysfunction, which can progress to cirrhosis in some patients. Materials and Methods: In this study, a consanguineous Saudi family with two affected individuals exhibiting symptoms of severe motor impairment, spastic paraparesis, postural instability, and dystonia was studied. Clinical and radiographic evaluations were conducted on the affected individuals. Whole exome sequencing (WES) was performed to diagnose the disease and to determine the causative variant underlying the phenotype. Moreover, Sanger sequencing was used for validation and segregation analysis of the identified variant. Bioinformatics tools were utilized to predict the pathogenicity of candidate variants based on ACMG criteria. Results: Exome sequencing detected a recurrent homozygous missense variant (c.266T>C; p.L89P) in exon 1 of the SLC30A10 gene. Sanger sequencing was employed to validate the segregation of the discovered variant in all available family members. Bioinformatics tools predicted that the variant is potentially pathogenic. Moreover, conservation analysis showed that the variant is highly conserved in vertebrates. Conclusions: This study shows that exome sequencing is instrumental in diagnosing undiagnosed neurodevelopmental disorders. Moreover, this study expands the mutation spectrum of SLC30A10 in distinct populations.

PNPT1 Spectrum Disorders: An Underrecognized and Complex Group of Neurometabolic Disorders

An 18-year-old man presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. A neurological examination disclosed spastic dysarthria, left eye divergent strabismus, bilateral ophthalmoparesis, impaired smooth pursuit, severe spastic paraparesis of the lower limbs with global brisk tendon reflexes, bilateral extensor plantar responses, and bilateral ankle clonus reflex. Bilateral dysdiadochokinesia of the upper limbs, Stewart-Holmes rebound phenomenon, bilateral dysmetria, and a bilateral abnormal finger-to-nose test were observed. Markedly reduced bilateral visual acuity (right side 20/150, left side 20/400) and moderate to severe optic atrophy were detected. Neuroimaging studies showed cerebellar atrophy and bilateral optic nerves and optic tract atrophy as the main findings. As a complicated Hereditary Spastic Paraplegia, autosomal dominant Spinocerebellar Ataxia, or inherited neurometabolic disorders were suspected, a large next-generation sequencing-based gene panel testing disclosed the heterozygous pathogenic variant c.162-1G>A in intron 1 of the PNPT1 gene. A diagnosis of PNPT1-related spastic ataxia was established. Clinicians must be aware of the possibility of PNPT1 pathogenic variants in cases of spastic ataxia and spastic paraplegias that are associated with optic atrophy and marked cognitive decline, regardless of the established family history of neurological compromise.

TANGO2 Deficiency Disorder: Two Cases of Developmental Delay Preceding Metabolic Crisis

BackgroundTANGO2 deficiency disorder is a rare genetic disease caused by biallelic defects in TANGO2 gene. MethodsWe report the clinical phenotype of two children with TANGO2 deficiency disorder. ResultsPatient 1 is a female child presenting with developmental delay and microcephaly during the second year of life, who evolved with severe cognitive impairment, facial dysmorphisms, spastic paraparesis, and atonic seizures. At age 13 years, she was hospitalized due to an episode of rhabdomyolysis complicated with cardiac arrhythmia and hypothyroidism. Patient 2 is a female child with dysmorphic facial features, cleft palate, and developmental delay who was diagnosed with DiGeorge syndrome. At age three years, she presented with an acute episode of severe rhabdomyolysis in the context of human herpesvirus 6 infection. After the resolution of this acute episode, she maintained recurrent muscle weakness with axial hypotonia and progressive spasticity of the lower extremities. In both patients, diagnosis of TANGO2 deficiency disorder was only confirmed after an acute metabolic crisis. ConclusionsA high index of suspicion for TANGO2 deficiency disorder is needed in patients with developmental delay or other neurological symptoms and episodic rhabdomyolysis.

Intrathecal Baclofen Therapy for Spastic Paralysis

Intrathecal baclofen therapy(ITB)is a recognized treatment for spastic paralysis. Direct injection of baclofen into the intrathecal space through a catheter from a battery-loaded pump implanted in the abdomen allows effective administration of the drug at much lower doses than oral administration. ITB therapy is indicated for patients with severe spastic paraparesis that do not respond sufficiently to first-line medical therapy or in whom the side effects complicate treatment. A pump implantation is considered in cases where spasticity is improved after intrathecal infection of a small amount of baclofen. Postoperative complications include CSF leakage, infection and device malfunction. Postoperatively, the patient requires baclofen refills every 2-3 months and pump replacement surgery every 6-7 years. Currently, ITB therapy is not widespread in Japan, although further popularization is expected.

Hyperacute extensive spinal cord infarction and negative spine magnetic resonance imaging: a case report and review of the literature

Rationale:Spinal cord infarction (SCI) accounts for only 1% to 2% of all ischemic strokes and 5% to 8% of acute myelopathies. Magnetic resonance imaging (MRI) holds a role in ruling out non-ischemic etiologies, but the diagnostic accuracy of this procedure may be low in confirming the diagnosis, even when extensive cord lesions are present. Indeed, T2 changes on MRI can develop over hours to days, thus accounting for the low sensitivity in the hyperacute setting (ie, within 6 hours from symptom onset). For these reasons, SCI remains a clinical diagnosis. Despite extensive diagnostic work-up, up to 20% to 40% of SCI cases are classified as cryptogenic. Here, we describe a case of cryptogenic longitudinally extensive transverse myelopathy due to SCI, with negative MRI and diffusion-weighted imaging at 9 hours after symptom onset.Patient concerns:A 51-year-old woman presented to our Emergency Department with acute severe abdominal pain, nausea, vomiting, sudden-onset of bilateral leg weakness with diffuse sensory loss, and paresthesias on the trunk and legs.Diagnoses:On neurological examination, she showed severe paraparesis and a D6 sensory level. A 3T spinal cord MRI with gadolinium performed at 9 hours after symptom onset did not detect spinal cord alterations. Due to the persistence of a clinical picture suggestive of an acute myelopathy, a 3T MRI of the spine was repeated after 72 hours showing a hyperintense “pencil-like” signal mainly involving the grey matter from T1 to T6 on T2 sequence, mildly hypointense on T1 and with restricted diffusion.Interventions:The patient was given salicylic acid (100 mg/d), prophylactic low-molecular-weight heparin, and began neuromotor rehabilitation.Outcomes:Two months later, a follow-up neurological examination revealed a severe spastic paraparesis, no evident sensory level, and poor sphincteric control with distended bladder.Lessons:Regardless of its relatively low frequency in the general population, SCI should be suspected in every patient presenting with acute and progressive myelopathic symptoms, even in the absence of vascular risk factors. Thus, a clinical presentation consistent with a potential vascular syndrome involving the spinal cord overrides an initially negative MRI and should not delay timely and appropriate management.

Spastic paraplegia with crystalline retinopathy: A recognisable phenotype?

Objective: Genetic diagnosis of hereditary spastic paraparesis (HSP) is often challenging because of lack of typical clinical or biochemical abnormalities. Case: An eight year old girl presented at the consultation with severe spastic paraparesis which had developed slowly over the last two years. More recently, a tremor in the hand became apparent. Perinatal history was unremarkable and early milestones were reached within normal limits. Cognitive functioning was normal. Dysmorphic features and skin lesions were not seen. Cerebral MRI and MRI of the spine were normal. Work-up was done for hereditary spastic paraparesis. Results: Fundoscopy showed a crystalline retinopathy as is typically seen in Sjögren-Larsson syndrome. As ichtyosis was absent in this patient we performed MRI spectroscopy, which did not reveal the abnormal lipid peak as seen in Sjögren-Larsson syndrome. Whole exome sequencing was performed and pathogenic mutations were not detected in ALDH3A2 nor in any other gene related to HSP. However, mutations where detected in an other gene related to aldehyde metabolism. Conclusion: Spastic paraplegia and crystalline retinopathy might be a new recognisable phenotype of HSP. We are looking for additional subjects to validate candidate genes.

ANTERIOR AND POSTERIOR FUSION OF CERVICAL SPINE IN OSTEOMYELITIC PROCESS OF SEVERAL VERTEBRAL BODIES: A CASE REPORT

A 52-year old male patient was initially examined because of short-term bronchopneumonia by the primary healthcare physician who prescribed antibiotic therapy that calmed the cough and lowered the temperature. In the following period, the patient started to complain of periodic febrile and subfebrile episodes. One month after the first symptoms of bronchopneumonia, the patient experienced pain in the neck and numbness in his right hand. After approximately ten days, the patient began to experience weakness in both legs and in the right hand. During the examination at the Clinic for Infectious Diseases, severe spastic paraparesis developed. MRI and MSCT scans showed compression of the medulla at the C5 and C6 level, with signs of destruction of the C5 and C6 corpuses. The progression of the neurological deficit necessitated complete removal of corpuses C5 and C6 and partial removal of corpus C7 which were then replaced by inserting an artificia limplant made of acrylate. Anterior stabilization was performed, followed by the posterior cervicothoracic stabilization. After the intervention, there was an improvement in the neurological deficit. Neurological restitution was achieved one month after surgery. Regular X-ray and MSCT check-ups were performed after 3 and 6 months, as well as after one year. The finding showed good decompression and stabilization. The patient was stable and with no neurological deficits. Acute osteomyelitic processes of the spine, accompanied by the development of neurological deficits, require urgent surgical procedures and spine reconstruction by using allotransplants and 3D fixation, in combination with intensive antibiotic therapy administered during a long period of time. Acta Medica Medianae 2016;55(2):50-56.

Spinal cord tumour misdiagnosed as seropositive neuromyelitis optica spectrum disorder

A young woman presented with a 2-month history of progressive severe spastic paraparesis. An MR scan of spine showed a longitudinally-extensive myelopathy (figure 1). MR scan of the brain was...

Infantile-onset ascending hereditary spastic paralysis: A case report and brief literature review

BackgroundInfantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early-onset autosomal recessive motor neuron disease associated with mutations in ALS2. AimWe studied a 17-year-old boy who had features of IAHSP. We also reviewed the current literature on ALS2-related syndromes. MethodsClinical and neuroimaging studies were performed. Blood DNA analyses were combined with mRNA studies in cultured skin fibroblasts. ResultsLike previously described cases, the patient presented with severe spastic paraparesis and showed rapid progression of paresis to the upper limbs. He also developed bulbar involvement and severe scoliosis during childhood. In blood DNA we identified a novel splice-site homozygous mutation in ALS2 (c.3836+1G > T), producing exon skipping in fibroblast mRNA and predicting premature protein truncation. ConclusionsThis case adds to the allelic heterogeneity of IAHSP. Review of the pertinent literature indicates a fairly homogeneous clinical picture in IAHSP that should facilitate molecular confirmation and prevention of long-term complications.

The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry

The c.1529C >T change in the SPG7 gene, encoding the mutant p.Ala510Val paraplegin protein, was first described as a polymorphism in 1998. This was based on its frequency of 3 % and 4 % in two separate surveys of controls in the United Kingdom (UK) population. Subsequently, it has been found to co-segregate with disease in a number of different populations. Yeast expression studies support its having a deleterious effect. In this paper a consanguineous sibship is described in which four members who are homozygous for the p.Ala510Val variant present with a spectrum of disease. This spectrum encompasses moderately severe hereditary spastic paraparesis (HSP) with more minor ataxia in two siblings, moderately severe ataxia without spasticity in the third, and a very mild gait ataxia in the fourth. Two of the siblings also manifest vestibular failure. The remaining eight unaffected siblings are either heterozygous for the p.Ala510Val variant, or do not carry it at all. Homozygosity mapping using a high-density SNP array across the whole genome found just 11 genes (on two regions of chromosome 3) outside the SPG7 region on chromosome 16, which were homozygously shared by the affected siblings, but not shared by the unaffected siblings; none of them are likely to be causative. The weight of evidence is strongly in favour of the p.Ala510Val variant being a disease-causing mutation. We present additional data from the Auckland City Hospital neurogenetics clinic to show that the p.Ala510Val mutation is prevalent amongst HSP patients of UK extraction belying any suggestion that European p.Ala510Val haplotypes harbour a disease-causing mutation which the UK p.Ala510Val haplotypes do not. Taken together with previous findings of a carrier frequency of 3-4 % in the UK population (giving a homozygosity rate of 20-40/100,000), the data imply that the p.Ala510Val is the most common mutation causing neurogenetic disease in adults of UK ancestry, albeit the penetrance may be low or the disease caused may be mild.

Wheels within wheels: multifocal autoimmune myelitis in a woman with Huntington’s disease

Hungtington’s disease (HD) is an autosomal dominant inherited genetic/neurodegenerative disorder. Early clinical manifestation varies widely, including cognitive and behavioural abnormalities. In later stages, the full clinical picture of HD is not limited to choreiform movements, but may comprise various other symptoms and eventually imitate other neurologic disorders, e.g., rigidity in juvenile HD and even signs of motor neuron disease [1, 2]. Besides clinical examination and family history, if available, diagnosis consists of CAG repeats in the huntingtin gene, with CAG [ 39 certainly predicting HD. Despite current research efforts, the only available consensus surrogate marker for age of onset and disease progression, though limited in sensitivity, is the number of CAG repeats [3, 4]. A 47-year-old female patient was transferred to us from the psychiatric clinic for further clarification of dyskinesia and walking inability. She had previously been treated in an outpatient clinic after being found in her apartment in a cachectic and disoriented state unable to walk. She had been divorced for about 10 years and ever since without social contacts, accounting for the scarce medical and family history. After exclusion of apparent somatic deficits she had been referred to the psychiatric clinic suspecting a psychotic disorder, which was excluded, and she was referred to us. On admission she demonstrated a reduced cognitive performance, responding inadequately, and was unable to summarise her symptoms in an organised chronological order. On neurological examination she had mild distal choreiform hyperkinesias in the upper limbs and mild dysarthria, which in combination with behavioural abnormalities supported clinically manifest Huntington’s disease (HD). No further clinical HD signs were evident. Furthermore, she had severe spastic paraparesis [2/5 for the hip flexors on the Medical Research Council (MRC) scale] with brisk reflexes of the lower limbs and positive leftsided Babinski sign. No paresis or reflex abnormalities were present in the upper limbs. On genetic testing, 44 CAG repeats on one huntingtin allele and 17 on the other were detected. Total motor score on Unified Huntington’s Disease Rating Scale was 16 (range 0–124). As to the spastic paraparesis, external cranial MRI scans a week prior to admission had not revealed any abnormalities in terms of neuroinflammation, generalised or focal cortical/subcortical atrophy, or any neoplastic changes or neurovascular events. In addition, we performed electrophysiology (motor evoked potentials) showing prolonged central latencies (M. peroneus), cerebrospinal fluid (CSF) sampling demonstrating oligoclonal bands (OCB), and spinal MRI showing several increased T2-weighted signals in the cervical (C3/ 4, C6/7; Fig. 1a, b) and thoracic spine (Th2, Th4; Fig. 1c) with a gadolinium-enhancing lesion (C6/7; Fig. 1d). Further serological and CSF analyses excluded infectious, paraneoplastic or other autoimmune entities as neuromyelitis optica spectrum diseases (antibodies against A. Haghikia and B.F. Decard contributed equally to this case presentation.

Neurophysiological evidence for muscle tone reduction by intrathecal baclofen at the brainstem level

Objective Intrathecal baclofen (ITB) is an efficient treatment modality for severe spasticity that is considered to act at the spinal level. Its influence on phasic spasticity is usually determined clinically by testing muscle reflexes, and on tonic spasticity by using scores such as the Modified Ashworth Scale (MAS). Neurophysiological techniques, e.g., soleus H reflex, may provide additional information regarding ITB efficacy. There is, however, only scarce information available on time–response relationships of clinical and neurophysiological measures of spasticity obtained at different levels along the neuroaxis. Methods Fourteen patients with severe spastic paraparesis underwent serial evaluation of MAS in upper and lower limbs and serial testing of H reflex in soleus and flexor carpi radialis muscles, T wave in quadriceps and biceps brachii muscles, and blink reflex (BR) with and without prepulse, at baseline, and 15, 30, 60, 90, 120, and 180 min following ITB bolus application. Results ITB bolus application caused significant suppression of soleus H reflex after 15 min and of quadriceps T wave after 30 min, while MAS dropped significantly after 60 min together with significant suppression of BR R2 area without and with prepulse stimulation. H reflex in flexor carpi radialis and T wave in biceps brachii were not significantly suppressed by ITB. The time course of early changes in soleus H max/ M max ratio and quadriceps T wave indicates a suppression of hyperreflexia at the spinal level, while a later reduction of MAS synchronously with suppression of BR with and without prepulse concurs with a brainstem effect of ITB. Conclusion Temporal concurrence between suppression of brainstem reflexes and desired suppression of lower limb muscle hypertonia after ITB bolus application suggests that both may be at least partially mediated from a common CNS region of activity. Significance Our data concur with a significant brainstem action of ITB.

Development of Oseltamivir Resistance During Oseltamivir Therapy in a Child With Severe 2009 H1N1 Influenza

Development of Oseltamivir Resistance During Oseltamivir Therapy in a Child With Severe 2009 H1N1 Influenza

Regarding unexpected severe and life-threatening donor-transmitted viral infections and use of high-risk behavior donors

Regarding unexpected severe and life-threatening donor-transmitted viral infections and use of high-risk behavior donors

Association of multiple vertebral hemangiomas and severe paraparesis in a patient with aPTENhamartoma tumor syndrome

The PTEN hamartoma tumor syndrome, manifestations of which include Cowden disease and Bannayan-Riley-Ruvalcaba syndrome, is caused by various mutations of the PTEN gene located at 10q23. Its major criteria are macrocephaly and a propensity to develop breast and thyroid cancers as well as endometrial carcinoma. Minor diagnostic criteria include hamartomatous intestinal polyps, lipomas, fibrocystic disease of the breasts, and fibromas. Mutations of PTEN can also be found in patients with Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum). The authors report the case of a 17-year-old girl who had a severe cyanotic cardiac malformation for which surgery was not advised and a heterozygous missense mutation (c.406T>C) in exon 5 of PTEN resulting in the substitution of cysteine for arginine (p.Cysl36Arg) in the protein, which was also found in her mother and sister. The patient presented in the pediatric emergency department with severe spastic paraparesis. A magnetic resonance imaging study of the spine showed vertebral hemangiomas at multiple levels, but stenosis and compression were maximal at level T5-6. An emergency T5-6 laminectomy was performed. The decompression was extremely hemorrhagic because the rapid onset of paraparesis necessitated prompt treatment, and there was no time to perform preoperative embolization. The patient's postoperative course was uneventful with gradual recovery. This represents the first report of an association of a PTEN mutation and multiple vertebral angiomas. The authors did not treat the remaining angiomas because surgical treatment was contraindicated without previous embolization, which in itself would present considerable risk in this patient with congenital cyanotic heart disease.

Phenotypes of female adrenoleukodystrophy

Adrenoleukodystrophy-adrenomyeloneuropathy (ALD-AMN) is an X-linked disorder of the peroxisomal beta oxidation characterized by the accumulation of saturated very long chain fatty acids (VLCFA) predominantly in adrenal cortex and central as well as peripheral myelin.1 ALD-AMN is caused by mutations of the ABCD1 gene, a member of the ATP-binding cassette (ABC) transporter superfamily, and more than 400 pathogenic ABCD1 mutations have been described (www.x-ald.nl).2 The incidence of ALD-AMN is estimated to be between 1:20,000 and 1:100,000. Affected men may present with childhood cerebral ALD, adult-onset AMN, or Addison disease only.1,3 Approximately 20% of heterozygous women develop mild AMN with a mean onset age around 40 years.1 Childhood onset, cognitive decline, visual disturbances, or adrenal dysfunction are exceptional.1,3,4 Herein, we describe two female ALD-AMN heterozygotes presenting with particular cerebral phenotypes, thereby expanding the clinical spectrum of female ALD-AMN and demonstrating a substantial intrafamilial variability. #### Case 1. This patient was diagnosed with manic-hebephrenic disorder at age 8 years, and had recurrent psychotic episodes thereafter. At age 25 years, neurologic examination revealed spastic paraparesis. Twenty years later, neurologic examination documented moderate cognitive deficits, severe spastic paraparesis, and a cerebellar syndrome with unsteady smooth pursuit gaze movements, dysarthria, and intention tremor. Cerebral MRI …

Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation.

Cerebral palsy is the most common cause of spastic paraplegia affecting infants. However, spasticity characterized by progressive gait impairment may also be the first sign of infantile onset hereditary spastic paraplegia (HSP).1 We studied a family with six affected members (figure). Figure. Pedigree of the family with SPG3A . Arrow indicates the index case; blackened and unblackened symbols represent affected and unaffected individuals. Physic map is according to information from the UCSC Genome Browser. Boxes represent the disease-bearing chromosome. The first patient (II-3) had slowly progressive leg spasticity and weakness that started in infancy. She and her second son (III-2) had mild cyanosis at birth, and for that reason their first diagnosis was cerebral palsy. The clinical history is similar for all affected members: normal pregnancy and delivery, motor impairment starting before gait acquisition, and normal cognitive and language development. Clinical characteristics are summarized in table E-1 (see www.neurology.org). All affected members presented delayed motor milestones and gait impairment. There was no sphincteric disturbance. Current neurologic examination revealed severe spastic paraparesis, …

Cerebellar and medullar histoplasmosis

M.J. Vos, MD, Y.J. Debets-Ossenkopp, MD, PhD, F.A.P. Claessen, MD, G.J. Hazenberg, MD, J.J. Heimans, MD, PhD, Amsterdam, the Netherlands A 16-year-old Surinam boy presented with a 3-month history of progressive paraparesis and periods of fever and neck stiffness. Neurologic examination demonstrated a severe spastic paraparesis, Babinski signs, and sensory disturbance under level T4. The patient was …

Apoptosis induced by beta-N-oxalylamino-L-alanine on a motoneuron hybrid cell line.

It has been suggested that beta-N-oxalylamino-L-alanine, a non-protein amino acid present in the Lathyrus Sativus seeds, may play a role in the etiopathogenesis of neurolathyrism, a toxic form of motor neuron disease clinically characterized by a severe spastic paraparesis. In order to investigate the mechanisms of beta-N-oxalylamino-L-alanine-mediated cell death, we studied the effect of this neurotoxin as well as other excitatory amino acids agonists on the growth and survival of motoneuron hybrid ventral spinal cord 4.1 cells. beta-N-oxalylamino-L-alanine was toxic to ventral spinal cord 4.1 cells in a concentration-dependent fashion (0.5-10 mM). Among the excitatory amino acids tested, only glutamate (1-10 mM), quisqualate (1 mM) and, with less extent, beta-N-methylamino-L-alanine (10 mM) induced a significant reduction of cell survival. The effect of Lathyrus Sativus neurotoxin was a slow process, becoming apparent only after 24-48 h of incubation. Interestingly, a mathematical analysis applied to the time course and dose curve of beta-N-oxalylamino-L-alanine toxicity suggested that even for very low concentrations of the amino acid it is theoretically possible to predict a time-dependent effect. The cell death was not blocked by antagonists of N-methyl-D-aspartate or non-N-methyl-D-aspartate receptors; aurintricarboxylic acid and alpha-tocopherol gave a partial protection; cysteine (1 mM) prevented the toxic effect of both Lathyrus Sativus neurotoxin and glutamate as well as quisqualate. Morphologically, in the presence of either beta-N-oxalylamino-L-alanine, glutamate or quisqualate, ventral spinal cord 4.1 cells showed apoptotic features also confirmed by ISEL technique and agarose gel electrophoresis of genomic DNA. Thus, our results suggest that in ventral spinal cord 4.1 motoneuron hybrid cells, in the absence of functional synaptic excitatory amino acid receptors, beta-N-oxalylamino-L-alanine induces cell degeneration through an apoptotic mechanism, possibly mediated by a block of cystine/glutamate Xc antiporter.

Duane's retraction syndrome and spastic paraparesis

Duane's retraction syndrome (DRS) is a neurogenic eye movement abnormality frequently associated with other congenital defects involving ocular, skeletal and neural structures. The authors report on a patient who had DRS associated with a severe spastic paraparesis, which progressed from childhood until young adulthood with subsequent stabilization. The patient had severe limitation of abduction of the left eye, narrowing of the palpebral fissure, and globe retraction in adduction. Neurological examination revealed a severe spastic paraparesis. Extensive clinical neurophysio-logical evaluation, including electromyography, nerve conduction studies, somatosensory evoked responses and transcranial magnetic stimulation, was consistent with a severe myelopathy. Magnetic resonance imaging of the spinal cord demonstrated significant thinning of the cervical and thoracic spinal cord. This previously unreported association is unlikely coincidental, given the rarity of both findings, and may be explained by the abn...