Pediatric palliative care for metabolic diseases: 20-year epidemiological survey of outpatients at a Brazilian quaternary hospital.

The interface between pediatric palliative care (PPC) and inborn metabolic diseases (IMD) remains incipient, though these conditions fill the state of art of complex chronic diseases, eligible to this health approach. We analyzed the medical records of PPC clinic during the years 2001 to 2021 and the IMD outpatients. We established a parallel with the world scientific literature concerning the epidemiology of PPC and IMD. Among outpatients, 14% were diagnosed with IMD, which were referred to the PPC service earlier compared to Non-IMD cases. The Group 3 (complex molecules) was the most frequent (64.7%), following by Group 1 representing by small molecules (21.6%), the latter having a lower median age at diagnosis when compared to the former (0.7 vs. 5.2 years, p = 0.001). The sphingolipidoses were the pathologies most frequent in our cohort, in line with what was observed in the literature. There were no differences between IMD groups in terms of diagnosis and PPC referral age, however in Non-IMD conditions, the age of diagnosis were earlier than IMD. Nevertheless, IMD group showed lower age of referral to PPC. The IMD comprises large fraction of outpatients in the PPC setting, thus further studies are needed in this field.

Sleep bruxism and associated physiological events in children with obstructive sleep apnea: a polysomnographic study.

STUDY OBJECTIVES: The aim of this study was to evaluate the physiological events associated with sleep bruxism (Sleep Bruxism [SB]; presence of mandibular movement activity) and the control window (4 minutes prior to SB event, where no mandibular movement activity was detected) in a polysomnography study in children with mild sleep apnea. METHODS: Polysomnography data from children aged 4 to 9 years old diagnosed with mild sleep apnea were analyzed by 2 trained examiners. The mandibular movement activity (bruxism event; SB) was classified into phasic and tonic. The control window was selected 4 minutes prior to the SB event. All physiological events were recorded in both bruxism and control windows, including sleep phase (N1, N2, N3, and rapid eye movement), arousal, leg movements, tachycardia, bradycardia, oxygen desaturation, and number of obstructive and central sleep apnea events. The moment in which those phenomena occurred when associated with SB was also analyzed (before/after). Data were analyzed using 95% confidence intervals (α = 5%). RESULTS: A total of 661 mandibular movements were analyzed and classified as tonic (n = 372) or phasic (n = 289). The mean apnea-hypopnea index was 1.99 (SD = 1.27) events/h. The frequency of leg movements, microarousal, and tachycardia was increased in SB events when compared with the control window (P < .05). There was an increase in bradycardia frequency in the control window when compared with SB (in both tonic and phasic events). The frequency of obstructive and central apnea during SB was lower when compared with the other physiological phenomena. CONCLUSIONS: There is a difference in the physiological parameters evaluated in children with mild sleep apnea when comparing the 2 windows (SB and control). Sleep bruxism is associated with other physiological phenomena, such as leg movements, tachycardia, and microarousal. The use of a control window (where no mandibular activity was detected) was representative since it did not show activation of the sympathetic nervous system. CITATION: Bonacina CF, Soster LMSFA, Bueno C, et al. Sleep bruxism and associated physiological events in children with obstructive sleep apnea: a polysomnographic study. J Clin Sleep Med. 2024;20(4):565-573.

Subacute Partially Reversible Leukoencephalopathy Expands the Aicardi-Goutières Syndrome Phenotype.

OBJECTIVE: To report a series of atypical presentations of Aicardi-Goutières syndrome. METHODS: Clinical, neuroimaging, and genetic data. RESULTS: We report a series of six unrelated patients (five males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val). CONCLUSIONS: This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM.

BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening.

There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Arginase 1 deficiency presenting as complicated hereditary spastic paraplegia.

INTRODUCTION: Argininemia or arginase deficiency is a metabolic disorder caused by pathogenic variants in ARG1 and consists of a variable association of progressive spastic paraplegia, intellectual disability, and seizures. Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder characterized by lower limb spasticity. This study presents 7 patients with arginase 1 deficiency from 6 different families, all with an initial diagnosis of complicated HSP. METHODS: We evaluated the clinical data of 7 patients belonging to six independent families who were diagnosed with hyperargininemia in a neurogenetics outpatient clinic. RESULTS: All patients had lower limb spasticity and six had global developmental delay. Five individuals had intellectual disability and two had epilepsy. Psychiatric abnormalities were seen in two patients. In two participants of this study, MRI disclosed thinning of the corpus callosum. Molecular diagnosis was made by whole exome sequencing. All variants were present in homozygosis; we identified two novel missense variants, one novel frameshift variant, and one previously published missense variant. DISCUSSION: Clinical diagnosis of early onset complicated hereditary spastic paraplegia was made in all patients. Two patients were initially suspected of having SPG11 due to thinning of the corpus callosum. As argininemia may present with a highly penetrant phenotype of spastic paraplegia associated with additional symptoms, this disease may represent a specific entity amongst the complicated HSPs.

Adenosine kinase deficiency presenting with tortuous cervical arteries: A risk factor for recurrent stroke.

Adenosine kinase (ADK) deficiency is a very rare inborn error of methionine and adenosine metabolism. It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects. Only 26 cases (16 families) of ADK deficiency have been published since its identification in 2011. Vascular abnormalities in cervical arteries and cerebral stroke have never been reported in this condition. Here, we describe two patients with ADK deficiency and vascular tortuosity leading to stroke in one of them. ADK deficiency is a rare inborn error of methionine metabolism with a complex phenotype that might be associated with cerebrovascular abnormalities and stroke.

Cardiac autonomic control during non-REM and REM sleep stages in paediatric patients with Prader-Willi syndrome.

Cardiac death is the second most prevalent cause in Prader-Willi syndrome (PWS). Paediatric patients with PWS often present cardiac autonomic dysfunction during wakefulness, obesity and sleep-disordered breathing. However, the extent of cardiac autonomic modulation during sleep in PWS has not been documented. The objective of this study was to assess alterations in cardiac autonomic modulation of paediatric patients with PWS during different sleep stages. Thirty-nine participants in three groups: 14 PWS, 13 sex and age-matched lean controls (LG) and 12 obese-matched controls (OB). All participants underwent overnight polysomnography, including continuous electrocardiogram recordings. Heart rate variability (HRV) was analysed during representative periods of each sleep stage through time and frequency domains calculated across 5-min periods. Between-within ANOVAs were employed (p < .05). The results show that total HRV was lower in PWS than OB and LG during slow-wave sleep (SWS) (standard deviation of all NN intervals [SDNN] ms, p = .006). Parasympathetic modulation assessed by time-domain analysis was lower during SWS in PWS compared to both OB and LG (square root of the mean of the sum of the squares of differences between adjacent NN intervals [RMSSD] ms, p = .004; SDSD, standard deviation of differences between adjacent NN intervals [SDSD] ms, p = .02; number of adjacent NN intervals differing by >50 ms [NN50] ms, p = .03; proportion of adjacent NN intervals differing by >50 ms [pNN50] ms, p = .01). Sympathovagal balance assessed by frequency-domain analysis was lower during both N2 and SWS than during the rapid eye movement (REM) sleep stage, but not different among groups. In conclusion, this group of paediatric patients with PWS had impaired cardiac autonomic balance due to reduced parasympathetic modulation during SWS. This result could imply an underlying increased cardiovascular risk in PWS even during early age and independent of obesity.

Electrical status epilepticus during sleep in patients with congenital Zika virus syndrome: An unprecedented clinical finding.

BACKGROUND: Brazil experienced a disproportionately higher rate of microcephaly cases in November 2015 with evidence of a causal link with Zika virus (ZIKV) infections during pregnancy. Epilepsy is a major neurological feature seen as part of congenital Zika virus syndrome (CZVS). Different seizure types and electroencephalographic (EEG) abnormalities have been described in association with this syndrome. However, clinical and neurophysiological features of epilepsy seen in children with CZVS are not fully understood. METHODS: We evaluated children with CZVS showing an EEG pattern of electrical status epilepticus during slow-wave sleep (ESES). Information on gender, age of onset of seizures, head circumference at birth, gross motor function at the time of diagnosis, of clinical and EEG aspects of seizures, EEG features and response to drug treatment was assessed. RESULTS: Our case series included four patients. They were diagnosed with epilepsy between one month to 18 months of age and showed an ESES pattern at the age of three. They presented with a wide range of epileptic symptoms, but all experienced tonic seizures. Multiple drug treatment was the management approach for three patients; however, they showed poor response to treatment with conventional drugs used in the treatment of ESES. CONCLUSIONS: Children with CZVS may develop an EEG pattern of ESES. Clinicians and neurologists should be aware of this neurological presentation to improve the management of these patients.

Melatonin Therapy Improves Cardiac Autonomic Modulation in Pinealectomized Patients.

The purpose of this investigational study was to assess the effects of melatonin replacement therapy on cardiac autonomic modulation in pinealectomized patients. This was an open-label, single-arm, single-center, proof-of-concept study consisting of a screening period, a 3-month treatment period with melatonin (3 mg/day), and a 6-month washout period. The cardiac autonomic function was determined through heart rate variability (HRV) measures during polysomnography. Pinealectomized patients (n = 5) with confirmed absence of melatonin were included in this study. Melatonin treatment increased vagal-dominated HRV indices including root mean square of the successive R-R interval differences (RMSSD) (39.7 ms, 95% CI 2.0-77.4, p = 0.04), percentage of successive R-R intervals that differ by more than 50 ms (pNN50) (17.1%, 95% CI 9.1-25.1, p = 0.003), absolute power of the high-frequency band (HF power) (1,390 ms2, 95% CI 511.9-2,267, p = 0.01), and sympathetic HRV indices like standard deviation of normal R-R wave interval (SDNN) (57.6 ms, 95% CI 15.2-100.0, p = 0.02), and absolute power of the low-frequency band (LF power) (4,592 ms2, 95% CI 895.6-8,288, p = 0.03). These HRV indices returned to pretreatment values when melatonin treatment was discontinued. The HRV entropy-based regularity parameters were not altered in this study, suggesting that there were no significant alterations of the REM-NREM ratios between the time stages of the study. These data show that 3 months of melatonin treatment may induce an improvement in cardiac autonomic modulation in melatonin-non-proficient patients. ClinicalTrials.gov Identifier: NCT03885258.

A questionnaire study on sleep disturbances associated with Prader-Willi syndrome.

Background This study aimed to investigate the presence of sleep disturbances in children with Prader-Willi syndrome (PWS) using the Sleep Disturbance Scale for Children (SDSC). Methods The SDSC, which was designed to identify the presence and severity of different sleep disorders, was applied to 50 patients with PWS and 112 controls. Results Patients with PWS achieved worse scores in the sleep-disordered breathing and disorders in initiating and maintaining sleep in the SDSC questionnaire as compared with controls. We also observed that patients with PWS were more prone to having hyperhidrosis. We did not observe significant differences in the presence of other types of sleep disorders (such as hypersomnolence) between the PWS and control groups. Conclusions The results obtained with the SDSC questionnaire showed that children with PWS have more sleep breathing disorders and disorders in initiating and maintaining sleep as compared to controls. Additionally, we demonstrated that patients with PWS associates significantly with the presence of hyperhidrosis during sleep. However, SDSC was not reliable to identify the excessive daytime somnolence in patients with PWS, as previously reported in the literature.

Melatonin Increases Brown Adipose Tissue Volume and Activity in Patients With Melatonin Deficiency: A Proof-of-Concept Study.

Melatonin, a pineal hormone synthesized at night, is critical for the synchronization of circadian and seasonal rhythms, being a key regulator of energy metabolism in many animal species. Although studies in humans are lacking, several reports, mainly on hibernating animals, demonstrated that melatonin supplementation and a short photoperiod increase brown adipose tissue (BAT) mass. The present proof-of-concept study is the first, to our knowledge, to evaluate BAT in patients with melatonin deficiency (radiotherapy or surgical removal of pineal gland) before and after daily melatonin (3 mg) replacement for 3 months. All four studied patients presented increased BAT volume and activity measured by positron emission tomography-MRI. We also found an improvement in total cholesterol and triglyceride blood levels without significant effects on body weight, liver fat, and HDL and LDL levels. Albeit not statistically significant, fasting insulin levels and HOMA of insulin resistance decreased in all four patients. The present results show that oral melatonin replacement increases BAT volume and activity and improves blood lipid levels in patients with melatonin deficiency, suggesting that melatonin is a possible BAT activator. Future studies are warranted because hypomelatoninemia is usually present in aging and appears as a result of light-at-night exposure and/or the use of ß-blocker drugs.

Haploidentical bone marrow transplantation with post transplant cyclophosphamide for patients with X-linked adrenoleukodystrophy: a suitable choice in an urgent situation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment that enhances survival and stabilizes neurologic symptoms in X-linked adrenoleukodystrophy (X-ALD) with cerebral involvement, a severe demyelinating disease of childhood. Patients with X-ALD who lack a well-matched HLA donor need a rapid alternative. Haploidentical HSCT using post transplant cyclophosphamide (PT/Cy) has been performed in patients with malignant and nonmalignant diseases showing similar outcomes compared to other alternative sources. We describe the outcomes of transplants performed for nine X-ALD patients using haploidentical donors and PT/Cy. Patients received conditioning regimen with fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and 2 Gy total body irradiation (TBI) with or without antithymocyte globulin. Graft-vs.-host disease prophylaxis consisted of cyclophosphamide 50 mg/kg/day on days +3 and +4, tacrolimus or cyclosporine A and mycophenolate mofetil. One patient had a primary graft failure and was not eligible for a second transplant. Three patients had secondary graft failure and were successfully rescued with second haploidentical transplants. Trying to improve engraftment, conditioning regimen was changed, substituting 2 Gy TBI for 4 Gy total lymphoid irradiation. Eight patients are alive and engrafted (17-37 months after transplant). Haploidentical HSCT with PT/Cy is a feasible alternative for X-ALD patients lacking a suitable matched donor. Graft failure has to be addressed in further studies.

Melanopsin System Dysfunction in Smith-Magenis Syndrome Patients.

Purpose: Smith-Magenis syndrome (SMS) causes sleep disturbance that is related to an abnormal melatonin profile. It is not clear how the genomic disorder leads to a disturbed synchronization of the sleep/wake rhythm in SMS patients. To evaluate the integrity of the intrinsically photosensitive retinal ganglion cell (ipRGC)/melanopsin system, the transducers of the light-inhibitory effect on pineal melatonin synthesis, we recorded pupillary light responses (PLR) in SMS patients. Methods: Subjects were SMS patients (n = 5), with molecular diagnosis and melatonin levels measured for 24 hours and healthy controls (n = 4). Visual stimuli were 1-second red light flashes (640 nm; insignificant direct ipRGC activation), followed by a 470-nm blue light, near the melanopsin peak absorption region (direct ipRGC activation). Blue flashes produce a sustained pupillary constriction (ipRGC driven) followed by baseline return, while red flashes produce faster recovery. Results: Pupillary light responses to 640-nm red flash were normal in SMS patients. In response to 470-nm blue flash, SMS patients had altered sustained responses shown by faster recovery to baseline. SMS patients showed impairment in the expected melatonin production suppression during the day, confirming previous reports. Conclusions: SMS patients show dysfunction in the sustained component of the PLR to blue light. It could explain their well-known abnormal melatonin profile and elevated circulating melatonin levels during the day. Synchronization of daily melatonin profile and its photoinhibition are dependent on the activation of melanopsin. This retinal dysfunction might be related to a deficit in melanopsin-based photoreception, but a deficit in rod function is also possible.

Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls.

BACKGROUND: Inborn errors of cobalamin (Cbl) metabolism form a large group of rare diseases. One of these, Cbl deficiency type C (CblC), is a well-known cause of thrombotic microangiopathy (TMA), especially in infants. However, there has only been a single published case of TMA associated to Cbl deficiency type G (CblG), also known as methionine synthase deficiency (MSD). CASE DIAGNOSIS/TREATMENT: A 21-month-old boy presented with pallor and oral ulcers during episodes of upper respiratory infection (URI). Further examination revealed signs of TMA, and the patient progressed to acute renal failure (ARF). Renal biopsy showed TMA. Evaluation for infection and autoantibodies were negative. The C3 and C4 complement fractions were normal. Analysis of the bone marrow aspirate suggested megaloblastic anemia and signs of hematopoiesis activation (secondary to peripheral hemolysis). Although the serum vitamin B12 level was normal, the patient was treated with cyanocobalamin, with no improvement. The ARF and hematologic parameters improved with conservative treatment. A severe relapse occurred during the follow-up, with normal ADAMTS13 activity. The presumed diagnosis was atypical hemolytic uremic syndrome, and the patient was started on eculizumab, but his response was poor, even when the dosage was increased. At this point it was also recognized that his developmental speech was delayed. Based on these findings, whole exome sequencing was performed, leading to the detection of two novel deleterious variants in the gene coding for methionine synthase, confirming the diagnosis of MSD. Subsequent treatment consisted of elevating the patient's serum homocysteine level and starting him on hydroxicobalamin, with normalization of all hematologic parameters although the microalbuminuria remained. CONCLUSIONS: Methionine synthase deficiency is very rare and characterized by megaloblastic anemia and neurological symptoms. We report the second case of MSD associated to TMA previously diagnosed as aHUS in which the patient had a poor response to eculizumab.

Development of sleep/wake, activity and temperature rhythms in newborns maintained in a neonatal intensive care unit and the impact of feeding schedules.

UNLABELLED: Biological rhythms in infants are described as evolving from an ultradian to a circadian pattern along the first months of life. Recently, the use of actigraphy and thermistors with memory has contributed to the understanding of temporal relations of different variables along development. The aim of this study was to describe and compare the development of the rhythmic pattern of wrist temperature, activity/rest cycle, sleep/wake and feeding behavior in term and preterm newborns maintained in a neonatal intensive care unit (NICU). METHODS: Nineteen healthy preterm and seven fullterm newborns had the following variables monitored continuously while they were in the NICU: activity recorded by actigraphy, wrist temperature recorded with a thermistor and observed sleep and feeding behavior recorded by the NICU staff with diaries. Subjects were divided in 3 groups according to their gestational age at birth and rhythmic parameters were compared. RESULTS: A dominant daily rhythm was observed for wrist temperature since the first two weeks of life and no age relation was demonstrated. Otherwise, a daily pattern in activity/rest cycle was observed for most preterm newborns since 35 weeks of postconceptional age and was more robust in term babies. Feeding and sleep/wake data showed an almost exclusive 3h rhythm, probably related to a masking effect of feeding schedules. CONCLUSIONS: We found that wrist temperature develops a daily pattern as soon as previously reported for rectal temperature, and with acrophase profile similar to adults. Moreover, we were able to find a daily rhythm in activity/rest cycle earlier than previously reported in literature. We also suggest that sleep/wake rhythm and feeding behavior follow independent developmental courses, being more suitable to masking effects.

Environmental factors influencing biological rhythms in newborns: From neonatal intensive care units to home.

Photic and non-photic environmental factors are suggested to modulate the development of circadian rhythms in infants. Our aim is to evaluate the development of biological rhythms (circadian or ultradian) in newborns in transition from Neonatal Intensive Care Units (NICU) to home and along the first 6 months of life, to identify masking and entraining environment factors along development. Ten newborns were evaluated in their last week inside the NICU and in the first week after being delivered home; 6 babies were also followed until 6 months of corrected age. Activity, recorded with actimeters, wrist temperature and observed sleep and feeding behavior were recorded continuously along their last week inside the NICU and in the first week at home and also until 6 months of corrected age for the subjects who remained in the study. Sleep/wake and activity/rest cycle showed ultradian patterns and the sleep/wake was strongly influenced by the 3 h feeding schedule inside the NICU, while wrist temperature showed a circadian pattern that seemed no to be affected by environmental cycles. A circadian rhythm emerges for sleep/wake behavior in the first week at home, whereas the 3 h period vanishes. Both activity/rest and wrist temperature presented a sudden increase in the contribution of the circadian component immediately after babies were delivered home, also suggesting a masking effect of the NICU environment. We found a positive correlation of postconceptional age and the increase in the daily component of activity and temperature along the following 6 months, while feeding behavior became arrhythmic.

Further diffusion tensor imaging contribution in horizontal gaze palsy and progressive scoliosis / Contribuição adicional das imagens por tensores de difusão em paralisia do olhar conjugado horizontal associada a escoliose progressiva

In two siblings with clinical diagnosis of horizontal gaze palsy associated with progressive scoliosis (HGPPS) we could demonstrate by diffusion tensor imaging: (1) An anterior displacement of the transverse pontine fibers; (2) Posterior clumping of the corticospinal, medial lemniscus and central tegmental tracts and of the medial and dorsal longitudinal fasciculi complex; (3) Absent decussation of superior cerebellar peduncle. Those findings can contribute as surrogate markers for the diagnosis.

Em dois irmãos com diagnóstico clínico de paralisia do olhar conjugado horizontal associada a escoliose progressiva, foi possível determinar através de imagens por tensores de difusão: (1) Deslocamento anterior das fibras pontinas transversas; (2) Agrupamento posterior do trato córtico-espinhal, lemnisco medial e trato tegmentar central e complexos dos fascículos longitudinais medial e dorsal; (3) Ausência da decussação dos pedúnculos cerebelares superiores. Tais achados podem contribuir como marcadores para o diagnóstico.

Spastic paraplegia, optic atrophy, and neuropathy: new observations, locus refinement, and exclusion of candidate genes.

SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive.

Further diffusion tensor imaging contribution in horizontal gaze palsy and progressive scoliosis.

In two siblings with clinical diagnosis of horizontal gaze palsy associated with progressive scoliosis (HGPPS) we could demonstrate by diffusion tensor imaging: (1) An anterior displacement of the transverse pontine fibers; (2) Posterior clumping of the corticospinal, medial lemniscus and central tegmental tracts and of the medial and dorsal longitudinal fasciculi complex; (3) Absent decussation of superior cerebellar peduncle. Those findings can contribute as surrogate markers for the diagnosis.