Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

Prevention is the Best Therapy: The Geneticist's Approach.

Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life-altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing.

Expanded newborn screening by mass spectrometry: New tests, future perspectives.

Tandem mass spectrometry (MS/MS) has become a leading technology used in clinical chemistry and has shown to be particularly sensitive and specific when used in newborn screening (NBS) tests. The success of tandem mass spectrometry is due to important advances in hardware, software and clinical applications during the last 25 years. MS/MS permits a very rapid measurement of many metabolites in different biological specimens by using filter paper spots or directly on biological fluids. Its use in NBS give us the chance to identify possible treatable metabolic disorders even when asymptomatic and the benefits gained by this type of screening is now recognized worldwide. Today the use of MS/MS for second-tier tests and confirmatory testing is promising especially in the early detection of new disorders such as some lysosomal storage disorders, ADA and PNP SCIDs, X-adrenoleucodistrophy (X-ALD), Wilson disease, guanidinoacetate methyltransferase deficiency (GAMT), and Duchenne muscular dystrophy. The new challenge for the future will be reducing the false positive rate by using second-tier tests, avoiding false negative results by using new specific biomarkers and introducing new treatable disorders in NBS programs.

BK Channels Alleviate Lysosomal Storage Diseases by Providing Positive Feedback Regulation of Lysosomal Ca2+ Release.

Promoting lysosomal trafficking represents a promising therapeutic approach for lysosome storage diseases. Efficient Ca(2+) mobilization from lysosomes is important for lysosomal trafficking. Ca(2+) release from lysosomes could generate a negative potential in the lumen to disturb subsequent Ca(2+) release in the absence of counter ion flux. Here we report that lysosomes express big-conductance Ca(2+)-activated potassium (BK) channels that form physical and functional coupling with the lysosomal Ca(2+) release channel, TRPML1. Ca(2+) release via TRPML1 causes BK activation, which in turn facilitates further lysosomal Ca(2+) release and membrane trafficking. Importantly, BK overexpression rescues the impaired TRPML1-mediated Ca(2+) release and abnormal lysosomal storage in cells from Niemann-Pick C1 patients. Therefore, we have identified a lysosomal K(+) channel that provides a positive feedback mechanism to facilitate TRPML1-mediated Ca(2+) release and membrane trafficking. Our findings suggest that upregulating BK may be a potential therapeutic strategy for certain lysosomal storage diseases and common neurodegenerative disorders.

VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy.

X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.

Newborn screening of lysosomal storage disorders.

BACKGROUND: Newborn screening is a state-based public health program established as a means for the early detection and treatment of certain medical conditions to minimize developmental disability and mortality. The program was initiated more than 40 years ago to detect and prevent phenylketonuria. Recent technological advances have expanded the scope of newborn screening to include more than 30 inborn errors of metabolism. Consideration is now being given to inclusion of screening for lysosomal storage disorders (LSDs). CONTENT: Some lysosomal storage disorders (LSDs) express early in infancy or childhood and are treatable. Initiation of treatment in presymptomatic patients or in syptomatic patients before important symptoms are present may improve the long-term outcome. Therefore, early diagnosis is critical. Based on the availability of therapy and development of a screening method, 6 of the more than 40 known LSDs are candidates for newborn screening in the US: Gaucher disease, Pompe disease, Fabry disease, Niemann-Pick disease, mucopolysaccharidosis I, and Krabbe disease. This report reviews the history of newborn screening, the technology that has allowed for expanded screening during the last decade, LSDs and their treatment, and the evolving methods that might allow additional expansion of newborn screening to include certain LSDs. SUMMARY: Recent and evolving technological advances may be implemented for newborn screening for LSDs. This screening will identify presymptomatic newborns, allowing for early treatment and prevention or limitation of morbidity otherwise associated with these inherited rare diseases.

Therapeutic approaches for neuronopathic lysosomal storage disorders.

Therapy of the central nervous system (CNS) manifestations of lysosomal storage diseases (LSDs) has remained a major challenge because of its inability to deliver therapeutic agents efficiently across the intact blood-brain barrier. Non-specific therapies such as hematopoietic stem cell transplantation have been useful in globoid cell leukodystrophy (Krabbe disease) and in some mucopolysaccharidoses. Anti-inflammatory agents also show promise as adjuvant therapy. High doses of replacement therapy with native or modified enzyme show renewed promise for correction of CNS cells. Alternatively, small molecules can enter the brain relatively easily and promote reduction of accumulated substrate or function as pharmacological chaperones to enhance the level of the deficient enzyme. Gene therapy is still being developed and tested in patients. It is therefore likely that, thanks to a better understanding of disease mechanism, a variety of therapeutic approaches, used alone or in combination, will be useful to treat the devastating neurological complications of LSDs.

Newborn screening.

Screening newborns for inherited disorders provides an opportunity for pre-symptomatic identification and early intervention to prevent or mitigate morbidity and mortality associated with these conditions. Since the introduction of newborn screening in 1962 to screen for phenylketonuria, technological advances have enabled the screening panel to expand substantially so that it now includes more than 50 disorders. Newborn screening will continue to evolve,, and deployment of improved methodologies and incorporation of additional disorders are expected. This article provides an overview of the current state of newborn screening, and describes the disorders detectable, the methodologies employed, and the challenges involved in analyses of specimens obtained from newborns.

Prevention of lysosomal storage disorders in Israel.

Prevention programs for the detection of heterozygotes of relatively prevalent autosomal recessive diseases in various ethnic groups are available in recent years in Israel. Several lysosomal storage disorders (LSD) are included in this program. The goal of the program is the ascertainment of high risk couples before the birth of affected offspring. This is performed by a population screening program that addresses the specific needs and requirements of various population groups in Israel. The programs are supervised and designed by medical/clinical geneticists and are accompanied by genetic counseling prior to and after testing. Three types of population screening programs are in operation. The first type is offered to the general population and is directed to premarital and married couples. High risk families mostly opt for prenatal diagnosis. The second type is performed for diseases with a frequency of about 1:1000. This occurrence is common in Israel only in various Arab communities due to the high rate of consanguinity. The third type is a premarital screening performed by the Orthodox Jewish community and is operated by a nonprofit organization--"Dor Yeshorim". Two heterozygotes for a particular disease are advised not to proceed with the marriage and thus avoid the dilemma of prenatal diagnosis. Founder mutations of the relevant genes for each ethnic group are tested and the testing is tailored for each individual according to his/her ethnic background. Genetic counseling presents family planning options to high risk couples. These programs have resulted in a significant reduction in the birth of affected patients of the tested LSD a well as other recessive diseases in recent years.

Enfermedad de Gaucher tipo 1: 10 años de experiencia en el tratamiento enzimático sustitutivo / Type 1 Gaucher disease: 10 years of experience in enzyme replacement therapy

La enfermedad de Gaucher es una enfermedad lisosomal hereditaria, consecuencia de un defecto en el gen que codifica la enzima betaglucosidasa ácida, cuya deficiencia condiciona la acumulación de glucocerebrósidos en los lisosomas de los macrófagos, causando las manifestaciones clínicas de la enfermedad. La forma más frecuente es el tipo I o no neuronopática, caracterizada por la presencia de visceromegalias, alteraciones hematológicas y cambios óseos estructurales. Se caracteriza por su mal pronóstico, especialmente cuando sólo se disponía de esplenectomía y trasplante de medula ósea como únicas posibilidades terapéuticas. Es la primera enfermedad de depósito en que se ha utilizado la terapia enzimática sustitutiva, que ha demostrado su seguridad y eficacia durante la última década, permitiendo mejorar la calidad de vida de los pacientes y disminuir su morbimortalidad. Presentamos la evolución clínica satisfactoria de cuatro pacientes, con normalización de parámetros clínicos, analíticos y radiológicos en los tres primeros, y con disminución de la frecuencia de transfusiones en la paciente con hemoglobinopatía concomitante. Nihguno de los individuos ha padecido ninguna complicación atribuible a la terapia enzimática sustitutiva

Gaucher disease is an inherited Iysosomal storage disorder caused by a defect in the gene encoding the enzyme acid 13glucosidase. This deficiency causes the accumulation of glucocerebrosides in the Iysosomes of visceral macrophages, leading to the clinical manifestations of this disease. The most prevalent form of Gaucher disease is type 1 or the non-neuronopathic variant, which is characterized by clinical features such as hepatosplenomegaly, anemia, thrombocytopenia and bone disease. The prognosis associated with this disorder was especially poor when the only available therapeutic options were splenectomy and bone marrow transplantation. Gaucher disease was the first Iysosomal storage disorder in which enzyme replacement therapy was employed. Over the last decade, this treatment has proven both safe and highly efficacious, leading to an improvement in the quality of life of patients and a decreased morbidity and mortality. We report the satisfactory clinical courses of four patients, two of them treated since 1995, after undergoing enzyme replacement therapy. Three of these patients have normal clinical, radiological and hematological parameters. In the fourth patient. who presents a concomitant hemoglobinopathy, the need for red cell transfusions has decreased. None of these patients have experienced adverse events related to enzyme replacement therapy

Hydrops fetalis: lysosomal storage disorders in extremis.

In recent years there has been an increased recognition that hydrops fetalis may be an extreme presentation of many of the lysosomal storage disorders. Hydrops fetalis, the excessive accumulation of serous fluid in the subcutaneous tissues and serous cavities of the fetus, has many possible etiologies, providing a diagnostic challenge for the physician. Ten different lysosomal storage disorders have now been diagnosed in infants with hydrops fetalis, including mucopolysaccharidosis (MPS) VII and IVA, type 2 Gaucher disease, sialidosis, GMI gangliosidosis, galactosialidosis, Niemann-Pick disease type C, disseminated lipogranulomatosis (Farber disease), infantile free sialic acid storage disease (ISSD), and mucolipidosis II (I-cell disease). Frequently, these inborn errors of metabolism are recognized only after the unfortunate recurrence of hydrops fetalis in several pregnancies of a family. Making the diagnosis relies on the physician having a high index of suspicion and ordering appropriate testing, which can often be performed prenatally. In several of these disorders, including MPS VII, infantile galactosialidosis, type 2 Gaucher disease, and ISSD, hydrops fetalis is a relatively common presentation. A greater physician awareness of hydrops fetalis as a presentation of lysosomal disease will facilitate establishing a diagnosis in cases that would have previously been considered idiopathic and will enable a better estimation of the incidence of this association. Lysosomal disorders are among the few causes of nonimmune hydrops fetalis in which an accurate recurrence risk can be ascertained. With an early and accurate diagnosis, genetic counseling and family planning can be offered in these difficult cases.

Postnatal and prenatal diagnosis of lysosomal storage diseases in the former Soviet Union.

Diagnosis and prevention of lysosomal storage diseases (LSD) in the former Soviet Union (FSU) is based on the interaction of various local counselling units with the Department of Inherited Metabolic Diseases (DIMD) at the Research Center of Medical Genetics (RAMS). Work began in 1982 using standard, as well as newly developed biochemical techniques. 25 different LSD were diagnosed in 445 patients from 404 families. 106 pregnancies in families at risk were monitored prenatally, and 25 affected fetuses were diagnosed and aborted. The clinical spectrum of diagnosed lysosomal storage diseases (LSD) was surprisingly heterogeneous. Besides classical forms of LSD numerous atypical forms were discovered. They included juvenile and adult forms of some sphingolipidoses manifesting as progressive dystonia, spinocerebellar degeneration and hebephrenic schizophrenia, as well as an atypical form of mucolipidosis III in which the clinical phenotype bore an obvious resemblance to that of mucopolysaccharidosis (MPS) VI. The incidence of MPS was much higher than that of other LSD. It was evaluated as 1:15000 for two regions of the FSU. This investigation revealed some peculiarities of the ethnic distribution of MPS in populations of the FSU and supported the high prevalence of the gene for Tay-Sachs disease gene in Ashkenazi Jews.

Nonimmune hydrops fetalis with galactosialidosis: consequences for family planning.

At the 28th week of gestation a hydrops fetalis was first detected by ultrasound. At birth a generalized hydrops with Hurler-like craniofacial dysmorphism, hepatosplenomegaly and a moderate dystostosis multiplex was noted. High urinary excretion of oligosaccharides and a severe deficiency of neuraminidase and of beta-galactosidase in cultured skin fibroblasts could be found. Thus, a rare early infantile type of galactosialidosis was diagnosed. The patient died at the age of 3 months because of cardiac failure. The consanguineous but otherwise healthy parents received genetic counselling for further pregnancies and have been informed about the possibility of prenatal diagnosis. In view of this possibility, the parents decided to have more children. In the second pregnancy a severe combined enzyme deficiency had been detected and the pregnancy interrupted. In the third pregnancy prenatal diagnosis revealed normal fetal enzyme activities. It resulted in a healthy female child and in the fourth pregnancy reduced but still in the heterozygote level enzyme activities had been found, a healthy boy was born.

[Screening methods for the diagnosis of lysosomal storage disease].

Lysosomal storage disease is one of the inborn errors of metabolism caused by a deficiency of lysosomal acid hydrolase activity. We describe here the details of screening methods for the diagnosis of this disorder. It is definitely important to perform both enzyme assay of acid hydrolases and the detection of accumulated materials in patient's tissues. Leukocytes (lymphocytes), serum or plasma, and cultured skin fibroblasts are commonly used as the enzyme source for the assay. Although most lysosomal storage diseases can be diagnosed using leukocytes as the enzyme source, enzymatic activities of beta-glucosidase and sialidase in leukocytes are sometimes normal even in patients. At present, the most reliable enzyme source is considered to be cultured skin fibroblasts. Nevertheless, we should remind that we cannot detect a deficiency of galactocerebroside beta-galactosidase activity even using fibroblasts, if we use synthetic substrate. Natural substrates should be employed for the correct diagnosis and for the study of the nature of patient's enzyme. Deficiency of the enzymatic activity in patients should be confirmed by the demonstration of accumulated materials due to the enzyme defect in patient's tissues and urine. The accumulation of mucopolysaccharides and oligosaccharides in urine is obvious in patients with mucopolysaccharidoses and mucolipidoses, respectively. In case of sphingolipidoses, rectal biopsy specimen and blood could be a target of the investigation. In final, the choice of these screening methods should be made solely based on the detailed clinical manifestation of patients.

Screening for lysosomal disorders.

Patients at any age who develop regression of learned skills, onset of dementia, loss of motor control and organ enlargement should be considered for lysosomal screening. Morphological and biochemical screening methods may reinforce the clinical suspicion, but they are not diagnostic. A widespread use of enzyme assays that appear to be related to the clinical problems is recommended.