Contributions to the study of spinocerebellar ataxia type 38 (SCA38).

OBJECTIVE: To report clinical and ancillary findings in a kindred with spinocerebellar ataxia 38 (SCA38). PATIENTS AND METHODS: Five family members spanning two generations developed gait ataxia and intermittent diplopia. On examination, a cerebellar syndrome accompanied by downbeat nystagmus and a saccadic head impulse test (HIT) were found. RESULTS: Whole-exome sequencing demonstrated a heterozygous variant in ELOVL5, c.779A > G (p.Tyr260Cys), in four tested patients. Intermittent concomitant esotropia and hypertropia caused transient diplopia in one individual each. Saccadic HIT responses were found in four subjects. Sensorineural hypoacusis was present in every case. Electrophysiological studies demonstrated a sensory neuronopathy in patients from the first generation, with prolonged disease duration. Baseline serum docosahexaenoic acid (DHA) percent was diminished in four individuals. Oral 26-week dietary DHA supplementation, 650 mg/day, raised serum DHA percent and induced a statistically significant reduction in Scale for the Assessment and Rating of Ataxia (SARA) total scores, and in stance and heel-shin slide item scores. CONCLUSION: The mentioned ELOVL5 variant segregated with disease in this kindred. Downbeat nystagmus, intermittent heterotropia causing transient diplopia, vestibular impairment demonstrated by abnormal HIT, and sensory neuronopathy were part of the clinical picture in this series. DHA supplementation raised serum DHA percent in cases with diminished levels, and induced a clinical amelioration and a statistically significant reduction in SARA scores in the study group. Further studies are needed to investigate the role of these findings in SCA38, and to determine the response to prolonged DHA supplementation.

Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

OBJECTIVE: To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia. PATIENTS AND METHODS: Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another. RESULTS: Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results. CONCLUSION: A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.

Estrés oxidativo en la asfixia perinatal y la encefalopatía hipóxico-isquémica / Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy

La asfixia intraparto es una de las causas más frecuentes de muerte neonatal precoz pero también puede, en los supervivientes, evolucionar a una encefalopatía hipóxico-isquémica responsable de una elevada morbilidad neurológica. La presencia de episodios de hipoxia-isquemia prolongados conduce a un rápido agotamiento energético en los tejidos exclusivamente dependientes del metabolismo aeróbico, como el sistema nervioso central. El déficit energético conlleva una paralización de las bombas ATP-dependientes y subsiguiente pérdida del potencial neuronal transmembrana. La población neuronal de las regiones más sensibles del SNC mueren por necrosis, mientras que en otras áreas se produce una hiperexcitabilidad neuronal con entrada masiva de calcio iónico, activación de NO-sintasa, generación de radicales libres que alteran el funcionamiento mitocondrial, provocando un fallo energético secundario y muerte neuronal por apoptosis. Recientemente se ha propuesto una tercera fase en la que factores como la inflamación persistente y los cambios epigenéticos causarían un bloqueo de la maduración de los oligodendrocitos, alteración de la neurogénesis, del crecimiento axonal y de la sinaptogénesis. En este contexto, el estrés oxidativo va a tener un papel protagonista como responsable tanto en causar daño directo al SNC como en activar cascadas metabólicas conducentes a la apoptosis e inflamación. La hipotermia moderada precoz, al preservar las reservas energéticas y disminuir la formación de especies reactivas de oxígeno, atenuará el daño cerebral posreanimación. La combinación de la hipotermia con terapias coadyuvantes para modular el estrés oxidativo podría contribuir a mejorar el pronóstico

Birth asphyxia is one of the principal causes of early neonatal death. In survivors it may evolve to hypoxic-ischaemic encephalopathy and major long-term neurological morbidity. Prolonged and intense asphyxia will lead to energy exhaustion in tissues exclusively dependent on aerobic metabolism, such as the central nervous system. Energy deficit leads to ATP-dependent pumps blockage, with the subsequent loss of neuronal transmembrane potential. The most sensitive areas of the brain will die due to necrosis. In more resistant areas, neuronal hyper-excitability, massive entrance of ionic calcium, activation of NO-synthase, free radical generation, and alteration in mitochondrial metabolism will lead to a secondary energy failure and programmed neuronal death by means of the activation of the caspase pathways. A third phase has recently been described that includes persistent inflammation and epigenetic changes that would lead to a blockage of oligodendrocyte maturation, alteration of neurogenesis, axonal maturation, and synaptogenesis. In this scenario, oxidative stress plays a critical role causing direct damage to the central nervous system and activating metabolic cascades leading to apoptosis and inflammation. Moderate whole body hypothermia to preserve energy stores and to reduce the formation of oxygen reactive species attenuates the mechanisms that lead to the amplification of cerebral damage upon resuscitation. The combination of hypothermia with coadjuvant therapies may contribute to improve the prognosis

[Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy]. / Estrés oxidativo en la asfixia perinatal y la encefalopatía hipóxico-isquémica.

Birth asphyxia is one of the principal causes of early neonatal death. In survivors it may evolve to hypoxic-ischaemic encephalopathy and major long-term neurological morbidity. Prolonged and intense asphyxia will lead to energy exhaustion in tissues exclusively dependent on aerobic metabolism, such as the central nervous system. Energy deficit leads to ATP-dependent pumps blockage, with the subsequent loss of neuronal transmembrane potential. The most sensitive areas of the brain will die due to necrosis. In more resistant areas, neuronal hyper-excitability, massive entrance of ionic calcium, activation of NO-synthase, free radical generation, and alteration in mitochondrial metabolism will lead to a secondary energy failure and programmed neuronal death by means of the activation of the caspase pathways. A third phase has recently been described that includes persistent inflammation and epigenetic changes that would lead to a blockage of oligodendrocyte maturation, alteration of neurogenesis, axonal maturation, and synaptogenesis. In this scenario, oxidative stress plays a critical role causing direct damage to the central nervous system and activating metabolic cascades leading to apoptosis and inflammation. Moderate whole body hypothermia to preserve energy stores and to reduce the formation of oxygen reactive species attenuates the mechanisms that lead to the amplification of cerebral damage upon resuscitation. The combination of hypothermia with coadjuvant therapies may contribute to improve the prognosis.

Ataxia of Charlevoix-Saguenay: MR and Clinical Results in Lower-Limb Musculature.

OBJECTIVE: Peripheral neuropathy is a cardinal manifestation of the autosomal recessive spastic ataxia of Charlevoix- Saguenay (ARSACS), although its type of neuromuscular involvement has not been definitely established, and magnetic resonance imaging (MRI) plays an important role in the assessment of muscle and nerve diseases. The objective of this work has been to define the patterns of muscle weakness and of abnormal muscular MRI in ARSACS. PATIENTS AND METHODS: Five patients with a molecular diagnosis of ARSACS, aged 39 to 59 years, whose electrophysiological findings were consistent with an axonal neuropathy of distal distribution superimposed on a developmental defect of myelinization, underwent neurological and MRI lower-limb examinations. Conventional FSE T1-weighted and STIR sequences were performed, looking for fatty infiltration and oedema in the musculature of the thighs, legs and feet, together with their distribution along the longitudinal axis of the muscle bellies. RESULTS: On clinical examination, paralysis was apparent in foot muscles; moderate weakness, in leg musculature; and normal strength, in thigh muscles. MRI demonstrated massive fat deposition in the foot muscles and medial gastrocnemii in every case, distal fat infiltration and oedema in every leg muscle group, and preservation of thigh muscles, albeit with diffuse minimal non-specific fat infiltration. An inverse correlation between strength and degree of fat infiltration in lower-limb muscles became apparent. CONCLUSION: The preponderance of weakness and MRI abnormalities in distal muscle groups was concordant with the presence of a length-dependent axonopathy, as described in ARSACS.Ataxie de Charlevoix-Saguenay : IRM et observations cliniques au niveau de la musculature des membres inférieurs.

New findings in the ataxia of Charlevoix-Saguenay.

The aim of the study was to enhance our understanding of the pathogenesis of the ataxia of Charlevoix-Saguenay, based on the findings presented herein. Five patients with a molecular diagnosis of this disease underwent clinical, radiological, ophthalmologic and electrophysiological examinations. Five novel mutations, which included nonsense and missense variants, were identified, with these resulting in milder phenotypes. In addition to the usual manifestations, a straight dorsal spine was found in every case, and imaging techniques showed loss of the dorsal kyphosis. Cranial MRI demonstrated hypointense linear striations at the pons. Tensor diffusion MRI sequences revealed that these striations corresponded with hyperplastic pontocerebellar fibres, and tractographic sequences showed interrupted pyramidal tracts at the pons. Ocular coherence tomography demonstrated abnormal thickness of the nerve fibre layer. Electrophysiological studies showed nerve conduction abnormalities compatible with a dysmyelinating neuropathy, with signs of chronic denervation in distal muscles. The authors suggest that the hyperplastic pontocerebellar fibres compress the pyramidal tracts at the pons, and that the amount of retinal fibres traversing the optic discs is enlarged. These facts point to the contribution of an abnormal developmental mechanism in the ataxia of Charlevoix-Saguenay. Accordingly, spasticity would be mediated by compression of the pyramidal tracts, neuromuscular symptoms by secondary axonal degeneration superimposed on the peripheral myelinopathy, while the cause of the progressive ataxia remains speculative. The distinctive aspect of the dorsal spine could be of help in the clinical diagnosis.

Retinal nerve fiber hypertrophy in ataxia of Charlevoix-Saguenay patients.

PURPOSE: To present full ophthalmologic examination and retinal nerve fiber layer (RNFL) photographs of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patients showing significant increases in RNFL thickness compared to healthy subjects, but without myelinated retinal fibers. METHODS: The study design was observational case series. Ten eyes of five patients with molecular confirmation of ARSACS underwent a full ophthalmologic examination that included clinical history, visual acuity, biomicroscopy of the anterior segment, gonioscopy, Goldmann applanation tonometry, central corneal ultrasonic pachymetry, ophthalmoscopy of the posterior segment, standard automatic perimetry (Humphrey field), simultaneous stereophotographs of the optic disc after mydriasis, a series of five red-free digital fundus photographs for RNFL evaluation, topographic analysis of the optic disc using the Heidelberg retina tomography, and measurement of peripapillary RNFL thickness with Cirrus optical coherence tomography. RESULTS: All patients showed abnormal visual fields, normal optic discs with a mild to strikingly increased visibility of RNFL in color stereophotographs, normal Heidelberg tomography, and moderate to markedly increased RNFL thickness in Cirrus tomography (average thickness ranging from 119 µm to 220 µm). CONCLUSIONS: We found evidence of RNFL hypertrophy in ARSACS patients that may have been interpreted as hypermyelinated retinal fibers in previous reports. A revision of ARSACS diagnostic criteria, particularly with regard to retinal alterations, is necessary.

Is the ataxia of Charlevoix-Saguenay a developmental disease?

The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is considered a neurodegenerative disease caused by mutations in the SACS gene, located on chromosome 13q12.12. It is a syndrome that comprises skeletal, retinal and neurological manifestations, among which feature spasticity, cerebellar ataxia and peripheral neuropathy. Five patients with a molecular diagnosis of ARSACS underwent clinical, radiological, and ophthalmologic examinations. Every one of the identified causal mutations was novel. Spastic ataxia, peripheral neuropathy, pes cavus, and hammertoes were found in every case. T2 and T2-fluid attenuation inversion recovery-weighted MRI sequences demonstrated cerebellar atrophy and a hypointense linear striation at the pons. Tensor diffusion sequences revealed that the hypointense striation corresponded with hyperplasia of the pontocerebellar fibres, which gave place to abnormally thick middle cerebellar peduncles. Stereophotographs of the optic discs showed an increased number of retinal fibres, and ocular coherence tomography, increased thickness of the retinal nerve fibre layer. The authors suggest that the hyperplasic pontocerebellar fibres compress the pyramidal tracts at the pons since a very early stage of central nervous system development, causing spasticity, and may also cause cerebellar atrophy by means of glutamate-induced excitotoxicity. The abnormal amount of retinal fibres traversing the optic discs could have caused the detected mild peripheral visual field defects. Taken together, these facts point to a developmental cause in ARSACS, as it does not exhibit the tissue atrophy characteristic of degenerative diseases. Clinical deterioration in ARSACS seems to be mediated by phenomena (compression of the pyramidal tracts and cerebellar glutamate-mediated excitotoxicity) derived from the developmental anomalies referred to, while the neuromuscular symptoms are caused by a peripheral neuropathy with pathologic features suggestive of a similar origin. These observations should be taken into account when research about the origin of ARSACS is undertaken.

Sensory neuronopathy in ataxia with oculomotor apraxia type 2.

The objective of this article has been to describe the presence of a sensory neuronopathy in a patient harbouring ataxia with oculomotor apraxia type 2 (AOA2). A 40 year-old woman, born to consanguineous parents, presented with ataxia, decreased vibration sense, areflexia, indifferent plantar responses, preserved muscle volume and strength, and oculomotor apraxia; elevated levels of serum alpha-fetoprotein and creatine-kinase were found. A homozygous missense mutation, causing a substitution of a molecule of arginine for histidine at the helicase domain of the senataxin protein, was found. Two electrophysiological studies were performed, in which decreased amplitudes of the sensory action potentials were followed some years later by an absence of sensory action potentials in the lower limbs, and increased latencies in the somatosensory evoked potentials. Motor nerve conduction velocities were normal, and electromyographic recordings did not show abnormalities. Taken together, these findings are suggestive of a progressive sensory neuronopathy. The patterns of neuromuscular disturbance in AOA2 have not been thoroughly defined; therefore, a sensory neuronopathy should be considered part of the spectrum of neuromuscular manifestations in this disease. Genetic analysis may be of help to diagnose cases with unusual neuromuscular characteristics, like the one presented here.

Sensorimotor neuronopathy in ataxia with oculomotor apraxia type 2.

Two siblings with ataxia with oculomotor apraxia type 2 (AOA2) exhibited electrophysiological findings suggestive of a sensorimotor neuronopathy, and primary ovarian failure was detected in one of them. Genetic analysis disclosed a novel, homozygous frameshift mutation in the senataxin gene, 2755_2756delGT, responsible for a premature stop codon at position 2760. It is suggested that a neuronopathy might cause the neuromuscular disturbance in AOA2, and that ovarian failure should be looked for in female patients with the disease.

Flash visually evoked potentials in the newborn and their maturation during the first six months of life.

The aim of this paper has been to obtain normative data for the major components of the visually evoked potentials obtained by flash stimulus (F-PEV) in the newborn, and to analyse the evolution of these responses during the first 24 weeks of life. In order to do so, F-VEP were recorded in 109 normal full-term newborn infants. Fifty-five of these infants were also studied longitudinally at 4, 8, 12 and 24 weeks. We recorded responses in all newborns. A great morphological variability was observed. P2 was the only component present in all of these infants. Early components, which were always present from the fourth week of life on, were recorded in 34% of the newborns. There were significant differences according to waking/sleep state. At 24 weeks the most characteristic response was a triphasic waveform with clear negative-positive-negative components at 67.9, 110 and 158.3 ms. The morphological variability observed in the F-PEV of the newborn and the presence of early components in some cases, suggest differences in the maturation of the specific and unspecific visual system at birth. The study of these responses provides us with information about certain aspects of visual maturation. The relative stability of P2 response of the newborn and of the early negative components later on, made them the most useful components to be used in paediatric clinical work . The latency of P2 in the newborn is the parameter that showed lower variability, and therefore the most suitable one to establish normative data.

Treatment of ataxia in cortical cerebellar atrophy with the GABAergic drug gabapentin. A preliminary study.

The aim of this work was to investigate the efficacy of the GABAergic drug gabapentin in the treatment of the cerebellar signs caused by cortical cerebellar atrophy (CCA). Ten patients with CCA received gabapentin in single doses of 400 mg in an open-label study; thereafter, daily administration of 900-1,600 mg of gabapentin was continued during at least 4 weeks. An ataxia scale based on clinical findings was used to evaluate the cerebellar signs at baseline and after administration of the drug. A statistically significant improvement of the ataxia scores was found after single doses of 400 mg of gabapentin and after the administration of 900-1,600 mg of this drug during 4 weeks, as compared to the results obtained at baseline. An important clinical amelioration was also evident. Gabapentin has been demonstrated to be capable of improving the cerebellar signs in cases of CCA, after single doses and after continued administration of the drug during 4 weeks. GABAergic enhancement or supplementation could play an important role in the treatment of diseases of the cerebellar cortex associated with a deficit of GABA.