Iranian Journal of Child Neurology
Year:2012 | Volume:6 | Issue:4 (SUPPL 1)|Papers Count:15

Lysosomes are cytoplasmic organelles containing hydrolytic enzymes that degrade the macromolecules proteins of cellular catabolism. The causes of lysosomal enzyme disorder stem from1. Impaired enzyme synthesis2. Abnormal enzyme targeting3. Defect of structure of Accessory factor which is needed for enzymes function. Clinical manifestations depend on the organ (s) involved.

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by the malfunction of lysosomal enzymes. If untreated, will result in death within several years.At least 50 distinct genetic diseases are known, each one resulting from a deficiency of a particular lysosomal protein/activity or, in a few, from non lysosomal activities that are involved in lysosomal biogenesis. Mutations in the gene encoding for specific enzymes is the basis of the LSDs, which are mostly inherited in an autosomal recessive fashion.

Mucopolysaccharidosis (MPS) are a group of lysosomal storage disorders caused by deficiency of alfa-L-idorinidase. MPS is a progressive multisystem tissue and organ dysfunction, including cardiac, respiratory, musculoskeletal and visceral manifestations.MPS 1 divided into three clinical phenotype: Hurler, Hurler-Scheie, Scheie syndromes.

Fabry disease is an X-linked disorder. This condition is an inherited disorder that begins in childhood, causes signs and symptoms of many parts of body.Characteristic clinical features of disease, include episodes of pain, particularly in the hands and feet (acropares thesia), small dark red spots (on the skin) called angiokeratomas, decreases ability to sweat (hypohidrosis, crnealopacity, disorders in Gastrointestinal tract, ear ringing (tinnitus), Hearing impairment and nephrologic problem.

Introduction and history: The glycogen storage disorders may show two different presentations. One group present with permanent and progressive weakness (such as GSD II, GSD III and GSD IV). Another group have intermittent episodes of weakness, muscle pain and/or myoglobinuria (such as Mc Ardle disease). Glycogen storage disease type 2 is caused by acid maltase deficiency. GSD IIis an autosomal recessive disorder that was first described by Dutch pathologist Joannes C. Pompe in 1932. And can be categorized into two types, based on the age of onset of disease and degree of organ involvement: infantile (the most severe presentation), and late type (childhood and adult). Pompe diseaseis caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) or acid maltase. and is the only membersof glycogen storage diseases that is classified also as a lysosomal storage disorder.

Pompe disease (Acid Maltase deficiency) has been traditionally classified into 3 forms: infantile, childhood and adult. But in fact Patients are distributed in a spectrum of signs and symptoms between severe and lethal infantile form to adult type with minor problem in childhood and mild progressive muscular weakness.Some authorities use “Childhood” or “Juvenile” pompe in view of child’s age at the beginning of the first clinical manifestations. Others utilize this term to specify patients without cardiomyopathy and with exclusive skeletal muscle involvement.

Lysosomal myopathies are hereditary myopathies characterized morphologically by the presence of autophagic vacuoles. Autophagy is an intracellular bulk degradation process, which is used by all cells to eliminate waste materials. Autophagy is considered to be essential for myocytes and the lysosomal system becomes prominent in certain muscle diseases.In muscle pathology, lysosomal abnormalities are seen in three types of vacuoles: rimmed vacuoles which are most likely a secondarily induced lysosomal abnormality, autophagic vacuoles, which are usually large and contain glycogen, seen specifically in acid maltase deficiency and autophagic vacuoles with unique sarcolemmal features with acetyl cholinesterase activity (AVSF), which are seen in Danon disease and other related myopathies.

Gaucher disease it a relatively frequent recessive disease affecting 1 in 400.000 to 1 in 200.000 persons and 1 in 400 to 1 in 2000 persons among Ashkenazi Jews. The gene coding for beta-glucocerebrosidase is located on chromosome 1q21-q31.Type 1 Gauche disease is the most common type but is only occasionally observed in children. There is no involvement of the CNS except in rare cases.Type 2 Gaucher disease or neuropathic type is also due to glucosyl ceramide beta-glucosidase deficiency.

Patients with type 1 Gaucher disease commonly present with painless splenomegaly, anemia, or thrombocytopenia at onset. They may also have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds, bruising, or both.In symptomatic patients, splenomegaly is progressive and can become massive.Children with massive splenomegaly may be short stature because of the energy expenditure required by the enlarged organ.Most patients with type 1 Gaucher disease have radiologic evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal femur, which is an early skeletal change. Clinically apparent bony involvement, which occurs in more than 20% of patients with Gaucher disease, can present as bone pain or pathologic fractures. In patients with symptomatic bone disease, lytic lesions can develop in the long bones, ribs, and pelvis, and osteosclerosis or osteopenia may be evident at an early age. Bone crises with severe pain and swelling can occur in individuals with type 1 Gaucher disease and are frequently mistaken for synovitis or osteomyelitis until other symptoms become apparent.Occasional patients with type 1 Gaucher disease develop pulmonary involvement, parkinsonism, or portal hypertension.Patients with milder presentations of Gaucher disease are diagnosed later in life during evaluations for hematologic or skeletal problems or are found to have splenomegaly during routine examinations. Some patients are overtly asymptomatic, and a diagnosis is made incidentally after evaluation for other medical problems.

Lysosomal disorders are a heterogeneous group of Over 40 inherited disorders that individually are rare but as a group have an incidence of 1 in 10000 live births. LDs are caused by enzyme, enzyme activator, membrane transporter, or membrane protein defects that result in accumulation of complex macromolecules normally degraded in lysosomes. LDs classified to Mucopolysaccharidoses, disorders of lysosomal enzyme localization (Mucolipidoses), sphingolipidoses, sialic acid disorders, Oligosaccharidoses, Neuronal ceroid lipofuscinoses and a number of disease that are more difficult to classify in to specific category such as Wolman disease and cystinosis Ox/ostisis, pompe disease Danon disease.Biochemical and genetic diagnosis of LSDs should be performed in specialized laboratories. Various clinical samples can be used for analysis, such as blood, urine, amniotic fluid, skin fibroblasts and tissue biopsies.

MucopolysaccharidosesThe mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs), previously known as mucopolysaccharides (1-5). Fragments of partially degraded GAGs accumulate in the lysosomes, resulting in cellular dysfunction and clinical abnormalities. These are rare conditions, with an estimated total incidence of all types of MPS of approximately 1 in 20.000 live births. Mucopolysaccharidoses are hereditary, progressive disease caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminooglycans. Mucopolysaccharidoses are autosomal recessive disorders, with the exception of hunter disease which is x-linked recessive. Their overall frequency is between 3.5/100000 and 4.5/100000. The most common subtype is MPS–III (Sanfilippo), followed by MPS-I (Hurler) and MPS-II (Hunter).

Lysosomal storage disorders (LSD) include more than 40 diseases caused by a deficiency of lysosomal enzymes, membrane transporters or proteins involved in lysosomal biology.Clinical organ involvement usually occurs in the presence of substrate excess.Different diseases may affect various parts of the body, including the skeleton, brain, skin, heart, liver, kidney and central nervous system.Cardiac disease is particularly important in lysosomal glycogen storage diseases (Pompe and Danon disease), mucopolysaccharidoses and in glycosphingolipidoses (Fabry disease).Various disease manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular disease.

The Neurometabolic disorders are generally applies to monogenic diseases with a deficient activity in an enzyme, or a transporter in a pathway of cellular metabolism. This defects cause accumulation of the primary substrate or deficiency of product and lead to neurologic or developmental symptoms.Inborn errors of metabolism are individually uncommon but important diseases and many of them have neurologic manifestations. In some cases enzyme replacement therapy or diet may be effective.Noticed in their incidence (15.7/100000 live birth) and difficulties in their diagnosis, confrontation with them is not possible for all physicians and medical students and for this reason some of disease keep unknown for mentioned group. We try to instigate a site for registration of Neurometabolic cases with their history, signs and symptoms, lab tests and imaging’s.Only clinical and biochemical well-defined diseases are registered and exclusively data of patients with confirmed diagnosis are being processed.This is a collaborate project of all pediatric neurology centers in Iran and the main reason for initiating it is the fact that, in daily practice it is very difficult to find patients with metabolic diseases.There is no disease specific registration for Neurometabolic diseases, making it impossible to give reliable incidence rates for them in Iran.

Lysosomal storage disorders (LSDs) are relatively rare inborn errors of metabolism, resulting from the accumulation of substrates within the lysosomes. They represent a group of more than 40 distinct genetic disorders. Most of these disorders are inherited in an autosomal recessive manner, except Fabry’s disease and mucopolysaccharidoses type II (MPS II) which are inherited in an X-linked recessive manner. Most disorders present clinically with multi-system involvement. Common clinical features involve bony dysplasia, hepatosplenomegaly, central nervous system dysfunction, haematological abnormalities, and coarse hair and facial features. There are many phenoltypical similarities within the categories. Potential treatments for some of these disorders are available in the form of enzyme replacement therapy and bone marrow transplantation. PCR-sequencing methods were used for genetic investigation of 236 pediatric cases referred or diagnosed in our department over a period of 3 years from Nov 2009 to Nov 2012.Detailed clinical data, including sex, age of onset of disease, age at diagnosis, mode of presentation, family history, consanguinity rates, and high-risk screening results were collected. Biochemical analysis was done in different laboratories in abroad.

Pompe disease is a neuromuscular disorder that was progressive and fatal prior to enzyme replacement therapy (ERT). The advent of treatment has made early recognition imperative. Electrodiagnostic (EDx) studies represent a valuable diagnostic tool in Pompe disease, but there has been little contemporary data.The clinical characteristics in children and adults are very similar. Needle electromyography demonstrated spontaneous activity (SA) in 80% of children and 83% of adults. Myotonic discharges were found in 53% of children and 72% of adults, often isolated to the paraspinal muscles in adults. There could be some improvements in EDX findings after enzyme replacement therapy.EDx studies remain a helpful tool in diagnosing Pompe disease, but do not appear to be sensitive for monitoring response to ERT.Paraspinal examination is necessary in adults with symptoms suggestive of Pompe disease, as abnormalities may be isolated to this region. Standard EDx studies are not sufficient to monitor early response to ERT and further research on potential biomarkers is needed.• Electrodiagnostic abnormalities are present in most patients with Pompe disease.• Myotonic discharges and other abnormalities may be seen in this type of Mahmoud MOHAMMADI MD1 Electrodiagnostic Studies, “Role in The Diagnosis And Follow-Up in Children With Pompe Disease” How to