Although most lysosomal storage disorders follow an autosomal recessive inheritance pattern, there are exceptions. Fabry disease and Hunter syndrome follow an X-linked recessive inheritance pattern. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder.
However, it has been noted that some carriers of Fabry disease do experience significant clinical problems. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The genes associated with many, but not all, lysosomal storage disorders have been identified. To learn more about the genetic locations associated with specific diseases, search the Rare Disease Database for reports on those topics. As a group, lysosomal storage diseases are believed to have an estimated frequency of about one in every 5, live births.
Although the individual diseases are rare, the group together affects many people around the world. Some of the diseases have a higher incidence in certain populations. For instance, Gaucher and Tay-Sachs diseases are more prevalent among the Ashkenazi Jewish population. A mutation associated with Hurler syndrome is known to occur more frequently among Scandinavian and Russian peoples. Prenatal diagnosis is possible for all lysosomal storage disorders. Early detection of lysosomal storage diseases, whether before birth or as soon as possible afterward, is important because when therapies are available, either for the disease itself or for associated symptoms, they may significantly limit the long-term course and impact of the disease.
There is no cure for lysosomal storage disorders, and there are not yet specific treatments for many of these diseases. However, progress is being made in the search for therapies, and there are treatments available for some lysosomal storage disorders that greatly improve the quality of life for those affected.
Bone marrow transplantation BMT is effective in preventing the progressive mental retardation in children with MPS IH Hurler disease if it is done before two years of age. It is less effective in correcting or preventing the bone and joint complications of the disease. BMT is considered standard treatment for infants with MPS IH if a suitable matched bone marrow donor can be found and the procedure done before the child reaches the age of two years. The principle of BMT is to replace the bone marrow, and therefore the whole blood system, of an individual affected by a particular disease with marrow from another person who is healthy.
BMT is under investigation for the treatment of other lysosomal storage diseases. Anemia and low platelet counts have improved, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved. The orphan drug alglucerase injection Ceredase , which is a placenta-derived enzyme, was approved by the U.
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The synthetic form of this drug, imiglucerase Cerezyme , was approved by the FDA in Recombinant DNA technology, or genetic engineering, is used to produce Cerezyme. This was an important step in overcoming limitations of the availability of Ceredase, which is derived from human tissue sources. They replace, glucocerebrosidase, the enzyme that individuals with Gaucher lack. In , the FDA approved the use of miglustat Zavesca tablets as the first oral treatment option for individuals with Gaucher disease type I.
Zavesca is the first of a new class of drugs known as substrate reduction therapy. Zavesca is used for individuals with mild to moderate Gaucher disease type I who do not respond to enzyme replacement therapy. For information on Zavesca, contact:. The FDA approved Fabrazyme for Fabry disease making it the first specific treatment approved for that disease.
Fabry results from a deficiency of the enzyme alpha-galactosidase A, and Fabrazyme is a version of the human form of this natural enzyme produced by recombinant DNA technology. It is given intravenously. The replacement of this missing enzyme reduces lipid accumulation in many types of cells, including blood vessels in the kidney and other organs.
Fabrazyme was approved under an accelerated or early approval mechanism that expedites the approval of therapies that treat serious or life-threatening illnesses when studies indicate early favorable outcomes that are likely to predict clinical benefit. Aldurazyme is indicated for patients with the Hurler and Hurler-Scheie forms of MPS I, and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.
Neurology of Hereditary Metabolic Diseases of Children: Third Edition
MPS I is caused by a deficiency of the enzyme alpha L-iduronidase, leading to the accumulation of a carbohydrate called glycosaminoglycan GAG in tissues and organ systems. Until the approval of Aldurazyme, it was possible to treat only the neurological symptoms of MPS I by bone marrow transplantation.
Treatment with Aldurazyme is the first specific treatment for the non-neurological complications of this disease. Aside from these therapies for specific disorders, much of the treatment that is currently available for lysosomal storage diseases involves treating symptoms rather than treating the underlying disease. Information on current clinical trials is posted on the Internet at www. All studies receiving U. Gene therapy is also being studied as another possible approach to therapy for some lysosomal storage disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent pathology.
However, at this time, there are many technical difficulties to resolve before gene therapy can succeed. NORD provides referrals to many patient organizations dealing with specific lysosomal storage diseases. Please see our reports on the specific topics for those organizations. The following organizations offer general information on lysosomal storage diseases.
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McGraw-Hill Companies. New York, NY; Neurology of Hereditary Metabolic Diseases in Childhood. Cox TM. Substrate reduction therapy for lysosomal storage diseases. Acta Paediatr Suppl. Views Total views. Actions Shares.
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From 34 ALF cases, 18 were related to IMD: galactosemia 4 , mitochondrial DNA depletion syndrome MDS 3 , ornithine transcarbamilase deficiency 3 , congenital defects of glycosylation 2 , tyrosinemia type 1 2 , long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 1 , hereditary fructose intolerance 1 , classic methylmalonic aciduria 1 and citrulinemia type 1 1. The median age was 1. The peak laboratorial findings were: mean international normalizad ratio 4. The identification of IMD as a frequent cause of ALF allowed specific therapeutic measures and adequate family counseling. Particular clinical features and moderated ALT and bilirubin levels can lead to its suspicion..
La edad mediana fue de 1,3 meses. Pediatric acute liver failure ALF is a rare life-threatening condition that may progress quickly, with severe impairment of hepatic function. It can be recognized by hepatocellular necrosis and refractory coagulopathy with or without encephalopathy. The etiology of ALF varies according to the age of the patient and geographic areas. In neonates and infants, viral infections enteroviruses, herpes simplex and others , neonatal hemochromatosis, inherited metabolic diseases IMD and hemophagocytic lymphohistiocytosis are the main causes.
In older children, the most common causes are drug-induced ALF, autoimmune hepatitis and viral infections, being hepatitis A virus the most frequent in developing countries. To improve IMD diagnosis and intervention in ALF cases, a better knowledge of their clinical presentation and biochemical markers is fundamental.
The aim of this study was to characterize the clinical presentation, laboratory profile and outcome of young children admitted to a pediatric and neonatal intensive care unit ICU with ALF related to IMD, during a year period.. This is a descriptive study conducted in the pediatric and neonatal ICU of a tertiary university hospital, the national referral center for pediatric liver transplantation. Demographic data, family background, medical history and clinical signs and symptoms at admission were analyzed. Peak levels of white blood cell WBC count, INR, lactate, ammonia, total bilirubin and alanine aminotransferase ALT , as well as initial glycemia and minimum levels of albumin were recorded.
Baseline metabolic work-up included: acyl-carnitine profile, plasma and urinary amino acids and urinary organic acids profiles, plasma carbohydrate-deficient transferrin, urinary reducing substances and ketones. Other laboratory and metabolic investigations were carried out in a case by case approach. Other information collected included results of molecular tests, timing of the confirmation of etiological diagnosis in vivo or post-mortem , decision on liver transplantation, time to ICU discharge, mortality to discharge and overall mortality..
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Quantitative variables were evaluated by measures of central tendency and of dispersion and qualitative variables by determination of frequencies.. The etiological IMDs identified and the results of genetic investigation are depicted in Table 1. The youngest patients were diagnosed during the neonatal period with galactosemia 3 , mitochondrial DNA depletion syndrome MDS 2 , ornithine transcarbamilase OTC deficiency 1 , classic methylmalonic aciduria cMMA 1 and citrulinemia type 1 ALF etiologies and genetic investigations..
Family history was unremarkable in all but two cases: one of a patient with MDS, whose brother died in another hospital with the diagnosis of neonatal hemochromatosis, later proved to also be a MDS due to deoxyguanosine kinase DGUOK deficiency; and a case of a newborn, sister of an elder patient already included in this study, who died with ALF and whose post - mortem investigation allowed to make the diagnosis of galactosemia due to galactose epimerase GALE deficiency in both siblings.. The physical signs at admission, according to the underlying IMD, are described in Table Presenting physical signs of ALF according to etiology..
Etiological diagnosis was confirmed by further investigations requested on a child-to-child basis, except in 5 cases in which the diagnostics were done in the post-mortem period [2 MDS, 1 long chain Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency LCHAD , 1 congenital defect of glycosylation CDG and 1 galactosemia due to GALE deficiency]..
Laboratorial parameters according to etiology.. The retrospective analysis of physical and laboratorial features allowed the identification of some particular characteristics in patients with the same IMD. Both patients with tyrosinemia type 1 presented renal tubulopathy. In the galactosemia due to GALE deficiency, hypotonia, bilateral hip dysplasia and short stature were features common to both cases. Short stature, some facial dysmorfisms and hepato-splenomegaly were present in both cases of CDG. It was decided by a multidisciplinary team at the age of 4 months due to recurrent liver failure, before the molecular confirmation of DGUOK deficiency, despite neurologic dysfunction and rotatory nystagmus.
However, he died at 4 years of age due to an intercurrence with metabolic acidosis, hyperlactacidemia and cardiorespiratory arrest. Another patient with tyrosinemia was submitted to LT later on, at the age of 7 years, due to unsatisfactory metabolic control, osteopenia, renal tubulopathy and hepatic nodules..
The major causes of death were due to progression to multiorgan failure or cardiogenic shock. Although ammonia levels decreased afterwards, no neurological improvement was achieved. The patient progressed to multiorgan failure, exacerbated by a Klebsiella oxytoca sepsis; 3 In the cMMA case, despite prompt providing of specific therapeutics and reduction of ammonia levels, the clinical evolution was unfavorable since admission with rapid progression to multiorgan failure.. This high number of identified IMDs results from a progressive effort to carry out a more comprehensive diagnostic investigation, even in the post-mortem period.
It can also be explained by the recognition of this tertiary hospital as the unique referral center in Portugal for LT and ALF since and , respectively. Patients without a readily identifiable cause of ALF must be considered for further screening for metabolic causes of ALF, especially in this age group. Early recognition of IMDs is crucial, because some require immediate initiation of specific therapy or diets that can be life-saving, mainly in the case of galactosemia, hereditary fructose intolerance and hereditary tyrosinemia type 1, 1 which can present during neonatal period with jaundice, hypoglycemia and sometimes with ALF.
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According to Hegarty et al. Particularities of the familial history, such as recurrent abortions, sibling deaths and previously affected children, are other features that must always be explored, since they can raise the suspicion of IMDs, as found in the cases of MDS and galactosemia due to GALE deficiency.. Other reason that could contribute to this result was the possible delay in referral to our center occurred prior to , date of its inception as national referral center for ALF.
These patients can also have high levels of ferritin and tyrosine, leading to the differential diagnosis of neonatal haemochromatosis and tyrosinemia type 1. Regarding the laboratorial parameters, the slight to moderate elevation of ALT observed is consistent to levels found in other studies of IMD related ALF 9,14 and inferior than in other etiologies, especially in viral infection. The recognition of IMD is crucial to optimize the management with targeted intervention, to evaluate the need for LT and to do adequate parental counseling in future pregnancies.
However, it did not prevent disease progression, with neurologic and visual impairment, severe psychomotor delay and failure to thrive. In this hepato-cerebral mitochondrial DNA depletion syndrome, the contra-indication for LT is unclear, since there are also some descriptions in the literature of a significant proportion of patients who benefit from LT with good long-term survival and a stable neurological situation despite initial neurological abnormalities. However, the comparison of mortality rates is hampered by group heterogeneities concerning the age, the different etiologies of ALF and the small case series numbers.
In fact, while Sundaram 14 studied ALF in infants up until 3 months of age, in Hegarty's series 9 children were aged up to 5 years old and the majority of diagnosis were galactosemia or tyrosinemia, to which a good prognosis is generally attributed. In our study, the high percentage of patients with multisystem involvement or with rapid progression to multiorgan failure could explain the mortality rate.
Over the last years, the implementation of expanded newborn screening programs in several countries, as well as the availability of new specific therapies for some diseases and advanced supportive devices have contributed to modify some IMD's natural history and progression. The main limitations of this study are related to the small number of cases, the large period considered and the retrospective data collection, that could limit the information obtained. This sample selection could create a bias.. This study points out the high frequency of IMD related ALF in this particular age group and the importance of an exhaustive diagnostic work-up to reach a correct diagnosis.
The effort to have a post - mortem diagnosis allows for an adequate family counseling. The early diagnosis of this etiology can lead to a prompt therapeutic decision, contributing to achieving a better outcome. Future directions must strive to optimize therapeutic decisions regarding LT, which may be achieved by large and homogeneous multicentric studies.. The authors declare that they have no conflict of interest..
An Pediatr Barc. ISSN: Previous article Next article. Issue 2. Pages 01 February Acute liver failure related to inherited metabolic diseases in young children. Download PDF. Filipa Dias Costa a ,. Corresponding author. This item has received. Article information.
Table 1. Table 2. Show more Show less. Introduction Pediatric acute liver failure ALF due to inherited metabolic diseases IMD is a rare life-threatening condition with a poor prognosis. Early intervention may be lifesaving. Material and methods Retrospective review of the medical records of children aged up to 24 months, admitted to a tertiary pediatric and neonatal Intensive Care Unit during a year period, fulfilling the ALF criteria, with documented metabolic etiology.
Results From 34 ALF cases, 18 were related to IMD: galactosemia 4 , mitochondrial DNA depletion syndrome MDS 3 , ornithine transcarbamilase deficiency 3 , congenital defects of glycosylation 2 , tyrosinemia type 1 2 , long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 1 , hereditary fructose intolerance 1 , classic methylmalonic aciduria 1 and citrulinemia type 1 1.
Particular clinical features and moderated ALT and bilirubin levels can lead to its suspicion. Palabras clave:. Introduction Pediatric acute liver failure ALF is a rare life-threatening condition that may progress quickly, with severe impairment of hepatic function. The aim of this study was to characterize the clinical presentation, laboratory profile and outcome of young children admitted to a pediatric and neonatal intensive care unit ICU with ALF related to IMD, during a year period. Methods This is a descriptive study conducted in the pediatric and neonatal ICU of a tertiary university hospital, the national referral center for pediatric liver transplantation.
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