Introduction Classic onset of CLN1 disease is within the first year of life with developmental arrest, epilepsy and rapid progression. In an atypical variant of CLN1 disease onset is later in the juvenile epoch. Although epilepsy in the juvenile form of CLN1 often is less severe than in typical CLN1, treatment of seizures and status epilepticus may be challenging. Case presentation The clinical course, misdiagnosis and epilepsy phenotype are presented in a girl with juvenile CLN1. Cognitive and neurologic regression started at age 5.5 years. Epilepsy was a major clinical issue as the patient suffered from focal seizures, recurrent status epilepticus and epilepsia partialis continua. In one episode of refractory status epilepticus, the patient had significant bradycardia associated with the intravenous infusion of levetiracetam. Diagnosis was made at the age of 12 years, based on palmitoyl protein-thioesterase (PPT) enzyme deficiency and genetic testing that documented a homozygous exon missense mutation in the CLN1 gene (PPT1, c.541G>A, p.Val181Met). Discussion Epilepsy in all NCL patients is a major clinical issue and presumed related to neuronal excitation and epileptogenesis. The treatment of status epilepticus, in juvenile CLN1 patients, presents a particular challenge and requires monitoring of potential serious pharmacologic side effects of therapy.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of alpha-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease-specific treatment utilizing recombinant alpha-galactosidase A enzyme replacement therapy. METHODS: We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low alpha-galactosidase A activity in dried blood spots. Male patients with low alpha-galactosidase A activity levels and all females were tested for mutations in the GLA gene. RESULTS: In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy. CONCLUSIONS: These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease-affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy. (c) 2018 Elsevier Inc. All rights reserved.

Ruth E. Williams, DM, FRCPCH, Heather R. Adams, PhD, Martin Blohm, MD, Jessica L. Cohen-Pfeffer, MD, Emily de los Reyes, MD, Jonas Denecke, MD, Kristen Drago, RN, CHPPN, Charlie Fairhurst, MBBS, FRCPCH, Margie Frazier, PhD, Norberto Guelbert, MD, PhD, Szilárd Kiss, MD, Annamaria Kofler, PT, John A. Lawson, BMed, FRACP, PhD, Lenora Lehwald, MD, Mary-Anne Leung, SRD, Svetlana Mikhailova, MD, Jonathan W. Mink, MD, PhD, Miriam Nickel, MD, Renée Shediac, PhD, Katherine Sims, MD, Nicola Specchio, MD, PhD, Meral Topcu, MD, Ina von Löbbecke, PT, Andrea West, MSc, Boris Zernikow, MD, PhD, Angela Schulz, MD, PhD

CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability. Twenty-four disease experts were surveyed on CLN2 disease management and a subset met to discuss current practice. Management goals and strategies are consistent among experts globally and are guided by the principles of pediatric palliative care. Goals and interventions evolve as the disease progresses, with a shift in focus from maintenance of function early in the disease to maintenance of quality of life. A multidisciplinary approach is critical for optimal patient care. This work represents an initial step toward the development of consensus-based management guidelines for CLN2 disease.

Clinical trials have been conducted for the neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative lysosomal diseases that primarily affect children. Whereas clinical rating systems will evaluate longterm efficacy, biomarkers to measure short-term response to treatment would be extremely valuable. To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3 protein (CLN3 disease). Proteomic and biochemical methods were used to analyze lysosomal proteins, and, in general, we find that changes in protein expression compared with control were most similar between CLN2 disease and CLN3 disease. This is consistent with previous observations of biochemical similarities between these diseases. We also conducted unbiased proteomic analyses of CSF and brain using isobaric labeling/quantitative mass spectrometry. Significant alterations in protein expression were identified in each NCL, including reduced STXBP1 in CLN1 disease brain. Given the confounding variable of post-mortem changes, additional validation is required, but this study provides a useful starting set of candidate NCL biomarkers for further evaluation.

Introduction: Establishing a diagnosis of mitochondrial disease in adults remains a clinician's challenge. We report a case of syndrome reminiscent of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in an adult patient who carries m.10158T>C mutation in complex I respiratory chain gene MT-ND3 (mitochondrially encoded NADH dehydrogenase 3).Case Report: This 26-year-old man from Thailand presented with new-onset headaches, seizures, stroke-like episodes, and poor vision due to optic neuropathy and cortical blindness. Instead of expected mutations in the mitochondrial tRNA gene that are frequently associated with MELAS, the mutation in MT-ND3 with variable tissue heteroplasmy (blood 5.3%, muscle 89.5%) was demonstrated. The patient's clinical features, blood biomarkers, neuroimaging findings, muscle biopsy with histochemical and functional in vitro analysis, and genetic studies were analyzed and compared with all previously reported ND3 disease cases.Conclusions: ND3 disease due to m.10158T>C mutation was previously described only in patients with Leigh or Leigh-like syndrome. Our findings thus indicate that ND3 disease can manifest with atypical phenotype in adults. The diagnosis of mitochondrial disease caused by other than typical MELAS-associated mutations in adults with stroke-like episodes, headaches, and seizures should be considered. An analysis of tissue other than blood, which is more likely to harbor a tissue-specific mitochondrial DNA mutation at a measurable level, may be necessary for diagnosis.

Fabry disease is a rare X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement such as diarrhea, abdominal pain, early satiety and nausea. The gastrointestinal symptoms of Fabry disease are thought to be due to neuropathic and myopathic changes leading to symptoms of dysmotility that are encountered in many other disorders. The gastrointestinal symptoms can often be one of the presenting signs of the disease in childhood, but can be misdiagnosed by gastroenterologists for many years due to their nonspecific presentation. As the chief treatment for Fabry is enzyme-replacement therapy that has been shown to stabilize and possibly reverse disease course, recognition of these symptoms and early diagnosis in an attempt to prevent progression with treatment, is critical.

Specific health-risk behaviors are present in older adolescents and young adults wtih Tourette syndrome (TS), but little is known about health-risk behaviors in youth with TS.We compared responses on the Youth Risk Behavior Surveillance System (YRBS) in youth with TS with those in a concurrent community control group. The YRBS evaluates risk behaviors most closely associated with morbidity and mortality in young people. Tic severity, presence of comorbid attention-deficit/hyperactivity disorder (ADHD), measures of ADHD symptom severity, and whether or not the individual had been bullied in school were also compared between the groups.Data from 52 youth with TS and 48 control youth were included. We did not detect any differences between control youth and youth with TS in the reporting of risky behaviors. Tic severity was not significantly associated with high-risk behavior. However, ADHD was significantly more common in youth with TS (P < 0.0002), and youth with TS who identified themselves as victims of bullying had significantly higher ADHD symptom severity scores (P = 0.04) compared with those who were not bullied.Risk behaviors are not reliably or clinically different in youth with TS compared with control youth. ADHD severity, but not tic severity, was associated with being bullied in youth with TS.

Objective: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery.Methods: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL.Results: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis.Conclusions: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.

Objective: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD). Methods: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses. Results: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6–72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm3 (interquartile range 1.8–4.0). Age (β 0.02, p = 0.008) and history of stroke (β 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burden—as well as WMHV predictors—varied by decade of life in this cohort of patients with FD (p < 0.0001). Conclusions: In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31–40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed.

Background: Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death.Methods: This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with agalsidase beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death.Results: The analyses included 969 male and 442 female Fabry patients. The mean age at first agalsidase beta infusion was 35 and 44, and median treatment follow-up 4.3 years and 3.2 years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free.Conclusions: Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies. (C) 2016 The Authors. Published by Elsevier Inc.

The LRRK2 G2019S mutation is found at higher frequency among Parkinson disease (PD) patients of Ashkenazi Jewish (AJ) ancestry. This study was designed to test whether an internet-based approach could be an effective approach to screen and identify mutation carriers. Individuals with and without PD of AJ ancestry were recruited and consented through an internet-based study website. An algorithm was applied to a series of screening questions to identify individuals at increased risk to carry the LRRK2 G2019S mutation. About 1000 individuals completed the initial screening. Around 741 qualified for mutation testing and 650 were tested. Seventy-two individuals carried at least one LRRK2 G2019S mutation; 38 with PD (12.5%) and 34 without (10.1%). Among the AJ PD participants, each affected first-degree relative increased the likelihood the individual was LRRK2+ [OR = 4.7; 95% confidence interval = (2.4-9.0)]. The same was not observed among the unaffected AJ subjects (P = 0.11). An internet-based approach successfully screened large numbers of individuals to identify those with risk factors increasing the likelihood that they carried a LRRK2 G2019S mutation. A similar approach could be implemented in other disorders to identify individuals for clinical trials, biomarker analyses and other types of research studies.

BACKGROUND:The Argentinean program was initiated more than a decade ago as the first experience of systematic translational research focused on NCL in Latin America. The aim was to overcome misdiagnoses and underdiagnoses in the region. SUBJECTS:216 NCL suspected individuals from 8 different countries and their direct family members. METHODS:Clinical assessment, enzyme testing, electron microscopy, and DNA screening. RESULTS AND DISCUSSION:1) The study confirmed NCL disease in 122 subjects. Phenotypic studies comprised epileptic seizures and movement disorders, ophthalmology, neurophysiology, image analysis, rating scales, enzyme testing, and electron microscopy, carried out under a consensus algorithm; 2) DNA screening and validation of mutations in genes PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), and CLN8: characterization of variant types, novel/known mutations and polymorphisms; 3) Progress of the epidemiological picture in Latin America; and 4) NCL-like pathology studies in progress. The Translational Research Program was highly efficient in addressing the misdiagnosis/underdiagnosis in the NCL disorders. The study of "orphan diseases" in a public administrated hospital should be adopted by the health systems, as it positively impacts upon the family's quality of life, the collection of epidemiological data, and triggers research advances. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".

HomeStrokeVol. 46, No. 1Cerebrovascular Involvement in Fabry Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCerebrovascular Involvement in Fabry DiseaseCurrent Status of Knowledge Edwin Kolodny, MD, Andreas Fellgiebel, MD, Max J. Hilz, MD, Katherine Sims, MD, Paul Caruso, MD, Thanh G. Phan, FRACP, PhD, Juan Politei, MD, Renzo Manara, MD and Alessandro Burlina, MD, PhD Edwin KolodnyEdwin Kolodny From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author , Andreas FellgiebelAndreas Fellgiebel From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author , Max J. HilzMax J. Hilz From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author , Katherine SimsKatherine Sims From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author , Paul CarusoPaul Caruso From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author , Thanh G. PhanThanh G. Phan From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author , Juan PoliteiJuan Politei From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author , Renzo ManaraRenzo Manara From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author and Alessandro BurlinaAlessandro Burlina From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Search for more papers by this author Originally published9 Dec 2014https://doi.org/10.1161/STROKEAHA.114.006283Stroke. 2015;46:302–313Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 Fabry disease (FD) is a rare and highly debilitating lysosomal storage disorder that results from a total lack of, or deficiency in, the enzyme α-galactosidase A (α-Gal A) because of mutations in the GLA gene.1 FD is inherited as an X-linked trait; many of the male patients develop a classic severe phenotype with early onset of symptoms, whereas heterozygous females exhibit phenotypes ranging from asymptomatic to major involvement of vital organs.2 Most families inherit private mutations; to date, >600 mutations have been identified and are listed in the online FD database (Fabry-database.org).3 The deficiency in α-Gal A causes the accumulation of globotriaosylceramide (GL-3; also abbreviated Gb3) in various cellular compartments, particularly lysosomes, causing structural damage and cellular dysfunction, as well as triggering secondary, tissue-level responses, such as inflammation, ischemia, hypertrophy, and the development of fibrosis resulting in progressive organ dysfunction.4 Deacylated globotriaosylceramide (lyso- globotriaosylceramide [lyso-GL-3]) has also been shown to be present in increased concentrations in the plasma of patients with FD. It has been suggested that lyso-GL-3 promotes GL-3 accumulation, induces proliferation of smooth muscle cells in vitro, and may have deleterious effects on the intima and media of small arterioles.5 Many cell types are involved in FD pathology, including vascular cells (endothelial and smooth muscle cells), cardiac cells (cardiomyocytes and valvular cells), a variety of renal cells (tubular and glomerular cells, and podocytes), and nerve cells.2The underlying pathophysiological mechanisms of FD are complex and incompletely understood.6 Early pathophysiological changes are thought to predominantly involve the microvasculature.7 As age increases, arterial remodeling and intima-media thickening in medium-to-large caliber vessels occur.2 The first clinical symptoms of FD occur in childhood (eg, neuropathic pain, hypohidrosis, and gastrointestinal problems)8 and are primarily because of autonomic neuropathy.9 As the disease pathology progresses, organ damage occurs and patients are at risk of developing life-threatening complications mainly because of damage to the kidneys, heart, and the brain. Cerebrovascular complications caused by cerebral vasculopathy are a major cause of morbidity and early mortality in both male and female patients with FD.10This review is based on a roundtable discussion that was held at an International Expert Panel on Cerebrovascular Involvement in FD, in Boston, MA, in January 2013. The panel comprised 9 experts in cerebrovascular complications in FD and clinical neuroimaging from Europe, South America, Australia, and the United States. Relevant literature published during the development of this review was also considered. This review provides a synopsis of the state of knowledge on the clinical and neuroradiological aspects, as well as the neurophysiology of cerebrovascular involvement in Fabry patients. It aims to identify developments that could lead to improved prediction and monitoring of cerebrovascular events in patients with FD. Of note, the expert panel also discussed therapeutic aspects (enzyme replacement therapy: agalsidase β [Fabrazyme; Genzyme, a Sanofi company] and agalsidase α [Replagal; Shire Human Genetic Therapies], conventional treatment) and intends to describe these separately.Cerebral Manifestations of FDAlthough ischemic strokes and transient ischemic attacks are the most prevalent types of overt cerebrovascular events in FD,10 cases of intracerebral hemorrhages,11 subarachnoid hemorrhage,12 microbleeds,13 cerebral venous thrombosis,14 and cervical carotid dissection15 have also been reported. To our knowledge, no cases of vertebral dissection or spinal cord infarction have been documented in the literature to date. Although silent infarcts are common events, also among young patients with stroke,16 there are no reports on the frequency of silent brain infarcts in FD. Aseptic meningitis can occur concomitantly in Fabry patients who have had cerebrovascular complications.17 One case of prolonged transient global amnesia has been reported in a Fabry patient.18 Dementia, cognitive impairment, and depression occur in patients with FD19 although additional studies are needed to establish a direct link to FD.StrokePrevalence, Age at Onset, and Influence of SexRetrospective studies in small cohorts of Fabry patients have reported a wide range of stroke incidence (24%–48%).20 In patients with Fabry-related stroke, the neurological symptoms experienced are normally consistent with the vascular territory affected and the extent of the stroke.2 Although many patients have clear neuroradiological findings on MRI, the causes of clinically asymptomatic brain lesions and chronic white matter hyperintensities (CWMH) in Fabry patients remain controversial.21An analysis of a large cohort of 2446 patients in the Fabry Registry (Fabryregistry.com) reported that stroke occurs in 6.9% of men and 4.3% of women. Of these, 87% of first strokes were found to be ischemic, with hemorrhagic stroke reported in 13% of cases. Although the incidence of stroke increases with age in patients with FD,10 as in the general population,22 analysis of the Fabry Registry has indicated that the incidence of stroke among patients with FD is markedly higher than that observed in the general US population across all age categories (Figure 1).10 For example, in men aged 35 to 45 years, the relative risk of stroke is 12.2× higher in Fabry patients when compared with healthy subjects. The relative risk of stroke is lower in women when compared with that in men, but still higher in Fabry patients when compared with that in healthy subjects: risk is highest at 4.2 in the 35 to 45 year age category. In the Fabry Registry cohort, a majority of Fabry patients experienced a first stroke between the age of 20 and 50 years, with 22% of patients having a first stroke at <30 years.10 For the majority of patients (>70%), stroke was the first serious FD complication and a high proportion (50% of men and 38% of women) had, therefore, not yet been diagnosed with FD.10 Another large-scale analysis of the Fabry Outcome Survey reported that 13.2% (15.1% men and 11.5% women) of a cohort of 688 Fabry patients had either a stroke or transient ischemic attack. In the Fabry Outcome Survey, the mean age at first stroke was <30 years (men) and <45 years (women).23 Smaller studies reported that the median age at first stroke ranged from 28 to 54 years.20,24–27Download figureDownload PowerPointFigure 1. The incidence of stroke in patients in the Fabry Registry compared with the general US population. *There were no Fabry Registry males in the age group 65 to <75 years. †None of the 11 women in the age group 75 to <85 years experienced any stroke. Reprinted from Sims et al10 with permission of the publisher. Copyright ©2009, American Heart Association, Inc.Data from the Fabry Registry reported that women with FD were more likely to experience a stroke than men with FD10 although female patients were likely to be older at first stroke.10,20,27 However, hemorrhagic stroke has also been reported to be more common among men than women with FD (16.9% versus 6.9%, respectively).10 The observed differences in cerebrovascular involvement among male and female Fabry patients are difficult to explain. It seems that, physiologically, hemizygous male Fabry patients are unable to compensate for the physiological effect of the GL-3 accumulation, whereas heterozygous female Fabry patients may be able to compensate for the deleterious effects of the GL-3 accumulation, at least to some extent, resulting in a later onset of cerebrovascular complications.Data from a recent in vivo study did not support the hypothesis that the number of X chromosomes could affect the degree of cerebral ischemia.28 However, differences in X-chromosome gene expression between men and women with ischemic stroke have been reported previously. Moreover, α-Gal A showed sex-specific gene upregulation at 5 hours after an ischemic stroke for women and at 24 hours for men, in comparison with control subjects.29The severity of FD manifestations in heterozygous female patients is complex because of the process of X chromosome inactivation (XCI). In female mammals, this process leads to a selective, irreversible inactivation of the maternal or paternal X chromosome in somatic cells during early embryogenesis. The pattern of XCI is clonally inherited; therefore, human females are mosaics of cell populations with different patterns of XCI and consequently, in female heterozygous Fabry patients, a mosaic of cells with different GLA expression and α-Gal A activity levels.30 Both random and skewed patterns of XCI have been reported in female heterozygous Fabry patients.31 Patients with random XCI patterns exhibited age-dependent worsening of the clinical severity of their condition.31 In contrast, heterozygous females with skewed XCI leading to the predominant expression of the wild-type GLA gene experienced an attenuated clinical phenotype, and disease progression was no longer correlated with age. These data suggest that even if the incidence of acute events, such as ischemic stroke, may not be directly linked to sex, XCI could be a general prognostic factor for FD in heterozygous female patients.31Prevalence of FD in Patients With Ischemic StrokeThe cause of ischemic stroke remains undetermined in a significant proportion of younger patients. Previous hypotheses about FD prevalence in the cryptogenic (undetermined) young stroke cohort32 could not be supported by several subsequent studies (Table 1).14,15,32–38 Therefore, a regular FD screening tool remains out of reach. Three screening studies did not identify any patients with FD,33,35,36 but others have reported FD in 0.5% to 3.9% of the stroke population.14,15,32,34,37,38 This variation in reported prevalence may be because of differences in the studied stroke populations (age and sex ratios), the stroke types studied, and the diagnosis of FD. Some studies investigated ischemic stroke, whereas others included hemorrhagic stroke, which may have underestimated the prevalence of FD.39,40 In addition, the screening methods used to test for the presence of FD were inconsistent across studies.Table 1. Incidence of Fabry Disease Among Younger Patients With Stroke in the General PopulationTrialPatients Screened, nPatients With Fabry Disease, n (%)Age Range, YMean Age at First Stroke, YMenWomenRolfs et al3272121 (4.9)7 (2.4)18–5538.4 (men); 40.3 (women)Brouns et al331030016–6051.3Wozniak et al341541* (0.6)...15–49Not statedBrouns et al151000 (573 ischemic stroke)2 (0.4)3 (0.7)18–6048.2Rolfs et al385023 (3396 ischemic stroke)11 (0.4)16 (0.8)18–55Not statedBaptista et al14493 (364 ischemic stroke)7 (2.3)5 (2.6)18–5545.4Marquardt et al3510460024–103...Sarikaya et al36150 (135 ischemic stroke)0018–5543Dubuc et al371001 (1.0)016–5540.5*All patients in this study were men.Although analyses of dried blood spots and whole blood samples are practical for screening for enzyme activity in male patients with FD,41,42 all suspected cases of FD must be confirmed using the gold standard mutation analysis.1 Assessment of other biomarkers, such as GL-3 and lyso-GL-3 levels in blood, and GL-3 levels in urine, can be useful in suggesting a diagnosis of FD, particularly in female patients with FD who show partial enzyme activity.38 Despite this, screening for FD using urinary GL-3 levels is not recommended because these markers have been shown to be increased in patients who do not have FD but have common forms of heart disease, such as coronary artery disease or valvular dysfunction.43 An FD screening study of patients with stroke reported biologically significant Fabry mutations in 21 male (4.9%) and 7 (2.4%) female patients with stroke,32 but did not publish details on the type of mutations identified. This study could, therefore, have included intronic mutations and other mutations of undetermined clinical significance.In FD screening studies, the screening population must be well defined, and a thorough family history remains crucial. It is clear that the prevalence of FD in young patients with stroke is low, notwithstanding the variations in FD incidence among young patients with stroke. Nevertheless, in case of cryptogenic strokes in younger patients, a clinical and biochemical workup for FD is appropriate.Genotype–Phenotype CorrelationsMore than 600 different mutations are known in the GLA gene coding for α-Gal A.3 Mutations are not limited to active site residues, but include those predicting changes related to stability, and indirectly, to catalytic activity.44,45 Most mutations are family specific, but few occur with sufficient frequency to permit genotype–phenotype correlation.46 Even within families, phenotypic heterogeneity is often present, suggesting the possibility of gene–environment interaction. In a study of 210 male and female Fabry patients, Froissart et al47 identified 55 different mutations in 65 families, with only 8 mutations occurring in >1 family and 2 mutations in >2 families. The study also found an occurrence of cerebrovascular disease in a patient with R112H, a mutation that has been found to be associated with myocardial hypertrophy. Therefore, a clear genotype–phenotype correlation in FD has not yet been established, underlining the need for additional studies.Several surveys have revealed a small percentage of young patients with stroke and a D313Y alteration in the GLA gene (Gly937Ala alteration at cDNA level).14,15,48 Although these individuals were presumed to have FD, there was no evidence of other FD manifestations. It has been suggested that the D313Y variant mutation, which results in normal α-Gal A activity in leukocytes and severely reduced α-Gal A activity in plasma, is a pseudodeficiency polymorphism. The identification of D313Y in 0.45% of normal X chromosomes further supports this theory.49 Nevertheless, an association between the D313Y variant and CWMH has been shown in the absence of other FD-specific symptoms, suggesting that D313Y carriers may be more susceptible to neural tissue damage.44 Nevertheless, the pathogenic role of the D313Y GLA variant continues to be debated.50,51 Recently, Rolfs et al38 also hypothesized that the mutations S126G and A143T, previously reported by Brouns et al,15 are associated with a stroke-only phenotype in FD.The question of whether there is a cerebrovascular variant of FD can be approached by classifying mutations by their effect on residual enzyme activity.47 Lukas et al52 divided GLA mutations into 4 classes according to in vitro enzyme activity measurement. In those with severe mutation and classic disease, mutation-specific enzyme activity correlated well with elevation in lyso-GL-3, albeit less so in heterozygous female patients. However, Lukas et al52 did not specifically address stroke risk of the 171 mutations that were studied.Risk Factors of Ischemic Stroke in FDSeveral modifiable, lifestyle-related factors are likely to increase the risk of stroke in Fabry patients, as in the general population. These factors include smoking, obesity, lack of physical exercise, dyslipidemia, and arterial hypertension.53 However, genetic modifiers, such as paraoxonase gene polymorphisms,54 angiotensin promoter, and angiotensin II receptor type I gene polymorphism, interleukin-6, protein Z,55 inflammatory factors (myeloperoxidase, C-reactive protein),56,57 and hyperhomocysteinemia,58,59 could also predispose a young Fabry patient to stroke. It has been suggested that the presence of factor V Leiden may be a link between FD and stroke.60,61 However, caution must be exercised in drawing strong conclusions from case reports because the factor V Leiden mutation is also common in the general community.62 Further evidence is needed to clarify the role of factor V Leiden, the above-mentioned genetic modifiers, and serum molecules in the genesis of stroke in patients with FD.Fabry-related cardiac and renal disease may also affect the risk of cerebrovascular complications. The vasoregulation of the microvasculature of the brain shares similar hemodynamic properties with the kidney, and the 2 organs have common vascular risk factors, such as hypertension and diabetes mellitus. Accordingly, researchers have looked for associations between cerebrovascular involvement (determined as severity of CWMH load) and kidney function, as well as possible links to stroke risk.63 A recent study reported that Fabry patients with the most stable estimated glomerular filtration rate had fewer strokes than those Fabry patients with rapidly progressing renal disease.64 An analysis of 2500 patients in the Stroke In Young Fabry Patients (SIFAP) study65 demonstrated that lower estimated glomerular filtration rates within the normal range were associated with the presence of a moderate to severe CWMH load. In this study, increasing severity of CWMH was significantly associated with a lower estimated glomerular filtration rate,65 raising the possibility that reduced estimated glomerular filtration rates could indicate an increased risk of CWMH and early stroke in patients with FD. Evidence is also emerging of an age-independent association between CWMH load and cardiomyopathy in patients with FD,66 which may relate to the risk of ischemic stroke.Other possible influences on stroke severity in FD include polymorphisms in interleukin-6, endothelial nitric oxide synthase, and protein Z67; fibrinolysis and angiogenesis factors68,69; elevations in serum myeloperoxidase56 and C-reactive protein57; paraoxonase gene polymorphism54; and angiotensinogen promoter and angiotensinogen receptor type I.55 The risk of stroke in FD seems, therefore, to be related to residual enzyme activity as determined by GLA mutations, as well as other genetic and epigenetic factors not yet characterized fully. Careful follow-up studies for clinical manifestations of FD in young patients with cryptogenic stroke and sequence alterations in the GLA gene are needed to elucidate these factors further.Cerebral Arteries/Territories Involved in FD-Related StrokeCerebral manifestations in patients with FD can be classified as either large- or small-vessel disease. Large-vessel stroke occurs because of occlusion of the large intracranial vessels or because of cardiac embolism (from the heart or large-vessel disease).68 Small-vessel disease is more commonly seen in patients with FD, manifesting as either subcortical stroke or the frequently asymptomatic CWMH and subcortical infarcts seen in neuroimaging studies.68In patients with FD, stroke occurs in both the anterior and the posterior circulatory systems, as well as in cortical and subcortical locations. However, the mechanism and topography of stroke in FD have not been systematically studied because of the fact that the evaluation of FD has been focused on patients with cryptogenic stroke rather than all types of stroke. Because patients with FD can have large artery disease and arrhythmia as a result of cardiomyopathy, the observed pattern of infarcts in descriptive studies may not reflect the true topography of infarcts in FD.10,20A significantly enlarged basilar artery diameter has been reported in patients with FD (compared with the general population),70 the cause of which is postulated to be insufficient autoregulation leading to aberrant vascular remodeling. Importantly, the basilar artery diameter seems to be a promising radiological parameter for separating patients with FD from controls70 and may be a useful predictive tool for Fabry-related stroke. Recently, the basilar artery diameter was confirmed to be significantly increased in male patients with FD when compared with healthy controls.71 Furthermore, a recent study of 70 Fabry patients suggested that vertebrobasilar dolichoectasia could serve as an early marker of neurovascular involvement, as it was present in 56% of men and 35% of women and was apparent at a younger age when c

Lysosomes are ubiquitous membrane-enclosed organelles filled with an acidic interior and are central to the autophagic, endocytic, or phagocytic pathway. In contrast to its classical function as the waste management machinery, lysosomes are now considered to be an integral part of various cellular signaling processes. The diverse functionality of this single organelle requires a very complex and coordinated regulation of its activity with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, at its core. However, mechanisms by which TFEB is regulated are poorly understood. This study demonstrates that gemfibrozil, an agonist of peroxisome proliferator-activated receptor (PPAR) , alone and in conjunction with all-trans-retinoic acid is capable of enhancing TFEB in brain cells. We also observed that PPAR, but not PPAR and PPAR, is involved in gemfibrozil-mediated up-regulation of TFEB. Reporter assay and chromatin immunoprecipitation studies confirmed the recruitment of retinoid X receptor , PPAR, and PGC1 on the PPAR-binding site on the Tfeb promoter as well. Subsequently, the drug-mediated induction of TFEB caused an increase in lysosomal protein and the lysosomal abundance in cell. Collectively, this study reinforces the link between lysosomal biogenesis and lipid metabolism with TFEB at the crossroads. Furthermore, gemfibrozil may be of therapeutic value in the treatment of lysosomal storage disorders in which autophagy-lysosome pathway plays an important role.

A female patient born (birth: 3.5 kg; 49 cm; 90th percentile) to non-consanguineous parents was taken to the local pediatrician in Mexico for rhinorrhea and fever in June 2012 when she was 2.5 months old. Her pediatrician noted hepatosplenomegaly (liver: 7 cm below the right costal margin at the mid-clavicular line; spleen 9 cm below the left costal margin), moderate jaundice, and evidence of growth failure (4.7 kg; 59 cm; 5th percentile) and the patient was admitted for further evaluation. The patient had 2 healthy, older brothers. In 2005, a sister developed similar symptoms at 3 months and died soon after. Laboratory examination was: hemoglobin: 8.8 g/dL; WBC: 29 × 109 cells/L; platelets: 107 × 109 cells/L; international normalized ratio: 4.5; partial thromboplastin time: 74.4 sec; alanine transaminase: 109 U/L; aspartate aminotransferase: 662 U/L; GGT: 256 U/L; total bilirubin: 1.8 mg/dL; direct bilirubin: 1.4 mg/dL; ammonia: 31 μmol/L; cholesterol: 200 mg/dL (5.1 mmol/L); triglycerides: 949 mg/dL (10.7 mmol/L). Foamy macrophages on peripheral blood smear are shown in Figure 1A. Gaucher and Niemann Pick were ruled out by a normal bone marrow examination and enzyme assay. Abdominal computed tomography revealed hepatosplenomegaly and bilateral adrenal calcifications (Fig. 1B).FIGURE 1: A, Peripheral blood smear showing foamy macrophages in lysosomal acid lipase deficiency. B, Abdominal computed tomography demonstrates hepatosplenomegaly and bilateral adrenal calcifications. C, Mutation analysis showed 2 mutations in the LIPA gene on chromosome 10: E8 c.894G>C, p.Gln298His, and E10 c.1024G>A, p.Gly342Arg.The infant was started on intravenous fluids, albumin, ursodeoxycholic acid, and fat-soluble vitamins and was transfused. Moderate anemia and thrombocytopenia persisted and liver failure progressed. The presumptive diagnosis of lysosomal acid lipase (LAL) deficiency was made because testing was not available at local laboratories. The patient continued to deteriorate and developed liver failure, severe anemia, thrombocytopenia and respiratory failure. Ascites, edema, and oliguria progressed to pulmonary edema and cardiogenic shock, resulting in death at approximately 5 months of age. LAL deficiency was confirmed post-mortem by documentation of deficient LAL activity from a dry blood spot (DBS) sample taken a few days before death and was analyzed at Massachusetts General Hospital (Neurogenetics Diagnostic Laboratory, Cambridge, MA). Mutation analysis (HIBM Research Group, Los Angeles, CA) revealed compound heterozygosity with 2 mutations, E8c.894G>C and E10c.1024G>A (Fig. 1C). DISCUSSION LAL deficiency is an autosomal recessive disease caused by deficiency or absence of LAL enzyme activity resulting from mutations in the lysosomal acid lipase A (LIPA) gene on chromosome 10 (1). This deficiency results in the accumulation of cholesteryl esters and triglycerides within the lysosome (1). LAL deficiency in infants, also known as Wolman disease, often present shortly after normal birth with diarrhea, hepatomegaly, and growth failure and die within the first year of life. Anemia, elevated transaminases, and bilateral adrenal calcification may also be seen. LAL-deficient infants have significant lipid accumulation in intestinal villi that impairs normal intestinal absorption and nutrition leading to malabsorption and growth failure (1). Given the rapid deterioration, LAL deficiency is a medical emergency and should be considered in the differential diagnosis for infants with acute gastroenterological signs/symptoms and growth failure (Table 1). In contrast, LAL deficiency in children and adults typically presents with elevated transaminases, hepatomegaly, microvesicular steatosis, and/or dyslipidemia, which often progresses to cirrhosis, liver failure, and accelerated atherosclerosis. The estimated incidence of LAL deficiency is widely variant depending on the population (1:4200–528,000) (2,3).TABLE 1: Typical findings and differential diagnoses of lysosomal acid lipase deficiency in infantsDiagnosis of LAL deficiency has typically been confirmed by demonstration of markedly decreased enzyme activity, in leukocytes/fibroblasts; however, both of these sample types are subject to sample handling deterioration during shipping and skin biopsies are required to obtain fibroblasts. The recent development of the LAL fluorometric enzymatic assay in DBS provides an alternative to traditional testing (4). A few drops of whole blood are collected on filter paper via capillary puncture or spotted after venipuncture. The blood saturates the paper and is then air-dried for a minimum of 4 hours. DBS samples are best stored refrigerated or frozen to enhance the stability before processing and should be shipped in low gas permeability plastic bags with desiccant. The DBS sample is not considered biohazardous, which can be a logistical advantage over other sample types when shipping to a reference laboratory. LAL enzyme activity in DBS is determined by subtracting LAL enzyme activity, in the presence of a specific inhibitor of LAL (Lalistat 2), from total lipase enzyme activity. DBS testing provides a minimally invasive, rapid, and low-cost method compared with traditional assays, and has been validated at multiple laboratories across the globe (Table 2).TABLE 2: Lysosomal acid lipase deficiency dry blood spot testing centers*There are no approved pharmacological therapies for LAL deficiency. Hematopoietic stem cell transplant and liver transplant have been attempted and reported in the literature. Three long-term survivors of hematopoietic stem cell transplant have been reported (maximal survival of >12 years after transplant), but complications related to poor growth and cognitive development were noted in all 3 cases (5–7). The high mortality rates may be related to the necessary intensive conditioning regimens in patients with significant preexisting liver disease (8). Liver transplantation may provide an option for those with liver failure, but extrahepatic organ involvement has also been reported resulting in morbidity and mortality in some cases (9). Clinical trials to assess the safety and efficacy of sebelipase alfa, a recombinant human lysosomal acid lipase, are underway (Synageva BioPharma Corp, Lexington, MA). There is an open-label trial for LAL-deficient infants presenting with growth failure within the first 6 months of life (http://www.clinicaltrials.gov/ct2/show/NCT01371825). Additionally, open-label, long-term data with sebelipase alfa from an ongoing phase 1/2 trial in LAL-deficient adults demonstrated a reduction from baseline of 56% in alanine transaminase, 40% in aspartate aminotransferase, 63% in low-density lioprotein cholesterol, and 47% in triglycerides, along with a 29% improvement in low-density lioprotein cholesterol after 1 year of treatment (P = 0.031 for each parameter) (10,11). Presently, a double-blind, placebo-controlled phase 3 trial in LAL-deficient patients (≥4 years of age) is enrolling (http://www.clinicaltrials.gov/ct2/show/NCT01757184). Unfortunately, this infant rapidly declined and diagnosis was only confirmed postmortem. The delay in diagnosis underscores the importance of disease awareness and rapid diagnosis. As such, clinicians should have heightened clinical suspicion in infants with the relevant symptoms/signs (Table 1), so that patients may have access to potential trials for LAL deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.