Glycogen Storage Disease Type II
Glycogen storage disease type II, or acid alpha-glucosidase (acid maltase) deficiency, is an inherited disorder of glycogen metabolism resulting from defective activity of the lysosomal enzyme alpha-glucosidase in tissues of affected individuals. In turn, this defect results in intralysosomal accumulation of glycogen of normal structure in numerous tissues.
Clinical presentations
Two major presentations are (1) infantile acid maltase disease, or Pompe disease, and (2) slowly progressive acid maltase disease.
Infantile acid maltase disease, or Pompe disease, is rapidly progressive and usually has an onset in the first 6 months of life. This manifestation is also characterized by macroglossia; progressive cardiomegaly; and rapidly progressive motor weakness with hypotonia, as indicated by feeding and respiratory difficulties. Death prior to age 2 years may be due to cardiorespiratory failure.
Slowly progressive acid maltase disease is characterized by an onset of symptoms in childhood or adult life. Affected individuals may have progressive proximal weakness with manifestations limited to the skeletal muscles. Respiratory dysfunction with early ventilatory insufficiency may be out of proportion to the degree of limb weakness.
Genetic features
The mode of inheritance is autosomal recessive, and the gene encoding for acid alpha-glucosidase has been localized to chromosome arm 17q23.
The disorder is genetically heterogeneous with missense, nonsense, and frameshift mutation, as well as splice-site and partial deletions.
Phenotypic expression is variable, and the severity is probably correlated with residual acid alpha-glucosidase activity.
Laboratory and imaging findings
Laboratory tests may show increased serum creatine kinase (CK) levels.
Electromyographic (EMG) studies may show myopathic features associated with fibrillation potentials, positive waves, bizarre high-frequency discharge, and myotonic discharges. In adult patients, EMG abnormalities are more evident in the paraspinal muscles than elsewhere.
Electrocardiographic findings of short P-R interval, giant QRS complexes, and left ventricular or biventricular hypertrophy
In infantile forms, massive cardiomegaly is shown on chest radiography.
Results of pulmonary function tests show markedly decreased vital capacity, maximal breathing capacity, maximal expiratory, and inspiratory static pressure, as well as early diaphragmatic fatigue.
Diagnosis and differential diagnosis
The clinical diagnosis of glycogen storage disease type II is confirmed by absent or reduced activity in the slowly progressive form of acid glucosidase in muscle biopsy samples and cultured fibroblasts. Prenatal diagnosis is made by measuring alpha-glucosidase activity in cultures of amniotic cells and samples of chorionic villus.
The differential diagnosis includes Duchenne muscular dystrophy, dystrophy of the limb girdle dystrophy, and polymyositis
Management
Conventional treatment for cardiorespiratory problems is indicated.
Definitive therapy is not currently available.
Enzyme therapy, gene replacement, or both are theoretically feasible, and research in these treatments is in progress. Recombinant human enzyme alpha-glucosidase (rhGAA) has recently been designated an orphan drug by the FDA. It has shown improved infant survival without requiring invasive ventilatory support compared with historical controls without treatment.
Epidemiology
In 2005, Marsden et al compiled a report of physician narratives from an epidemiologic study regarding infantile-onset Pompe disease. In this report, the most common presenting symptom was hypotonia (75%), and muscle weakness was a presenting symptom in 59% of patients. Additionally, the sign most commonly noted during the physical examination was hypotonia (82%); respiratory distress, cardiomegaly, weakness, and cardiac failure were frequently reported but percentages were not specified. Progression of the disease was accompanied by increased respiratory distress (72%), hypotonia (66%), and cardiac failure (58%). The most frequent supportive treatments were cardiac medications (52%) and oxygen supplementation (35%).17
Mucopolysaccharidoses
Mucopolysaccharides
Mucopolysaccharides are sulfated polymers composed of a central protein moiety attached to repeating disaccharide branches normally degraded into inorganic sulfated monosaccharides in lysosomes.
Dermatan sulfate consists of alternating units of L-iduronic acid and N -acetylgalactosamine, usually found in the matrix of many different connective tissues.
Heparan sulfate is formed by the joining of a uronic acid (D-glucuronic acid or L-iduronic acid) alternating with N -acetylglucosamine and is associated with the cell plasma membrane of almost all cells.
Keratan sulfate is made of D-galactose residues alternating with N -acetylglucosamine and is found largely in cartilage, nucleus pulposus, and cornea.
Chondroitin sulfate is composed of D-glucuronic acid and N -acetylgalactosamine and is largely found in cartilage and cornea.
Mucopolysaccharidoses
MPSs result from abnormal degradation of glycosaminoglycans such as dermatan sulfate, keratan sulfate, heparan sulfate, and chondroitin sulfate resulting in organ accumulation and eventual dysfunction. Glycosaminoglycans or mucopolysaccharides are normally a component of the cornea, cartilage, bone, connective tissue, and the reticuloendothelial system and are therefore target organs for excessive storage. The catabolic enzymes involved in the breakdown of glycosaminoglycans or mucopolysaccharides are deficient. Ten known enzyme deficiencies give rise to 6 distinct MPSs.
The stepwise degradation of the glycosaminoglycans requires 4 glycosidases, 5 sulfatases, and 1 nonhydrolytic transferase. The MPSs share similar clinical features of a chronic and progressive course, multisystem involvement, organomegaly, dysostosis multiplex, and abnormal facies. Mode of transmission is autosomal recessive except for MPS II, which is X-linked. A variety of mutations are described, and correlation of genotype with disease severity is beginning to emerge from mutation analysis.
In general, MPSs are progressive disorders, characterized by involvement of multiple organs, including brain, liver, spleen, heart and blood vessels and many are associated with coarse facial features, clouding of the cornea and mental retardation. Diagnosis can often be made by examination of urine, which reveals increased concentration of glycosaminoglycan fragments.
Clinical presentations
MPS type I includes Hurler, Hurler-Scheie, and Scheie syndromes. Alpha-L-iduronidase, which cleaves terminal L-iduronic acid residues from both dermatan and heparan sulfate, is deficient.
MPS type I H (Hurler syndrome)
Excretion of dermatan sulfate and heparan sulfate in the urine is increased in a ratio of 2 to 1.
A chromosomal abnormality occurs in chromosome arm 4p16.3.
This is a progressive disorder with multiple organ and tissue involvement leading to death by age 10 years.
Affected newborns appear healthy.
At age 6-24 months, hepatosplenomegaly, skeletal deformities, coarse facial features, enlarged tongue, prominent forehead, and joint stiffness develop.
Patients may be large in infancy, but a deceleration of growth occurs at age 6-18 months.
Developmental delay is present by age 12-24 months, with a maximum functional age obtainable at 2-4 years, followed by progressive deterioration.
Patients develop only limited language skills because of the developmental delay, chronic hearing loss, and enlarged tongue.
Most children with Hurler syndrome have recurring upper respiratory tract and ear infections, noisy breathing, and persistent copious nasal discharge.
Ophthalmologic manifestations include corneal clouding and glaucoma. Blindness may develop.
Neurologic manifestations include communicating hydrocephalus with increased intracranial pressure due to decreased resorption of cerebrospinal fluid (CSF).
Life expectancy is markedly reduced with average age of death at 5 years and nearly all succumb by 10 years.
MPS type I H/S
This form is intermediate between the Hurler syndrome and Scheie syndrome.
It is characterized by progressive somatic involvement, with little or no intellectual deterioration.
Corneal clouding, joint stiffness, deafness, valvular heart disease (occurring in the early to middle teenaged years), and micrognathism occur.
Neurologic manifestations include pachymeningitis cervicalis, compression of the cervical cord due to mucopolysaccharide accumulation in the dura, but communicating hydrocephalus appears to be uncommon in patients with normal intelligence.
Onset of symptoms is observed at age 3-8 years, and survival to adulthood is common.
Cardiac involvement and upper airway obstruction lead to mortality.
MPS type I S
Biochemical findings are identical to type I Hurler syndrome, but the clinical features are less severe because of different mutations within the same gene coding for alpha-L-iduronidase on chromosome 4.
Mildly coarsened facies occurs.
Joints are stiffened, and the skeletal abnormalities are most pronounced in the hands, with claw hand deformity. Patients can have a stiff painful foot, pes cavus, and genu valgum.
Patients achieve normal stature and have normal intelligence.
Neurologic manifestations include pachymeningitis cervicalis and deafness. Entrapment neuropathy such as carpal tunnel syndrome is common.
Ocular findings include glaucoma, corneal clouding, and retinal degeneration.
Respiratory symptoms of obstructive airway disease cause sleep apnea.
Cardiac symptoms of aortic valvular disease with stenosis and regurgitation occur due to buildup of mucopolysaccharides on valves and chordae tendinea.
Life expectancy is longer than in Hurler syndrome and is dependent on degree of cardiac involvement.
Onset of symptoms is usually after 5 years, with the diagnosis commonly made in patients aged 10-20 years.
MPS type II (Hunter syndrome)
Purified human recombinant idursulfase has been shown to alter disease manifestations in individuals with Hunter syndrome. Idursulfase has now been approved in the United States, Europe, Canada, and Japan for the treatment of Hunter syndrome.18
Iduronate-2 sulfatase (known as the Hunter corrective factor), which specifically removes the sulfate group from the 2 position of L-iduronic acid in dermatan sulfate and in heparan sulfate, is deficient.
Transmission is X-linked recessive, with the abnormality mapped to Xq27/28.
The distinctive feature of MPS II is the occurrence of a pebbly ivory-colored skin lesion over the back, upper arms, and lateral aspects of the thigh, but its presence or absence does not correlate with the severity of the disease.
The phenotype is variable, ranging from a severe form similar to Hurler syndrome to a mild form analogous to MPS I S.
In the severe form, the somatic features include coarse facial features, short stature, skeletal deformities, and joint stiffness.
The onset of the disease usually occurs in patients aged 2-4 years, with progressive neurologic involvement and somatic involvement.
Eye findings include severe retinal degeneration, but the cornea remains clear with 1 recorded exception.
The neurologic symptoms include hearing impairment and compression neuropathy.
Neurologic involvement may include mental retardation and moderate-to-severe communicating hydrocephalus with increased intracranial pressure after age 7-10 years. Extensive neurologic involvement similar to late stages of Sanfilippo syndrome precedes death, which usually occurs at age 10-15 years.
Cardiac manifestations include severe diffuse coronary artery disease.
Skeletal abnormalities are described as dysostosis multiplex with a large skull with thickened calvaria, premature closure of the lambdoidal and sagittal sutures, shallow orbits, enlarged J-shaped sella, abnormal spacing of teeth with dentigerous cysts, and anterior hypoplasia of lumbar vertebra with kyphosis.
The diaphyses of the long bones are enlarged with irregular appearances of the metaphyses. Epiphyseal centers are not well developed.
The pelvis is usually poorly formed with small femoral heads and coxa valga. The clavicles are short, thickened, and irregular.
The ribs have been described as oar-shaped, narrowed at their vertebral ends and flat and broad at their sternal ends.
Phalanges are shortened and trapezoidal in shape with widening of the diaphysis.
In the mild form, intelligence is preserved and patients survive into late adulthood but with obvious somatic involvement.
The somatic features may be similar to those of Hunter syndrome but with greatly reduced rate of progression.
The eye findings include corneal opacities detected only by slit-lamp examination, retinal dysfunction, and chronic papilledema.
Patients may survive into the fifth or sixth decades of life, with the longest known survival to age 87 years.
Mortality results from cardiorespiratory dysfunction (ie, obstructive airway disease, cardiac failure due to valvular dysfunction, myocardial thickening, pulmonary hypertension, coronary artery narrowing, myocardial disease).
MPS type III (Sanfilippo syndrome)
This is a biochemically diverse but clinically similar group of 4 types (A, B, C, and D).
Deficiencies in heparan N -sulfatase (type A), alpha N -acetylglucosaminidase (type B), acetyl CoA:alpha-glucosaminide acetyltransferase (type C), and N -acetylglucosamine 6-sulfatase (type D) can occur. All 4 enzymes are required for the degradation of heparan sulfate. All 4 forms have autosomal recessive inheritance.
Alpha-N -acetylglucosaminidase is required for removal of the N -acetylglucosamine residues that exist in heparan sulfate or are generated during lysosomal degradation of this polymer by the action of acetyl CoA transferase.
Heparan N -sulfatase (deficiency occurs in MPS III A) is specific for sulfate groups linked to the amino group of glucosamine.
The enzyme deficient in the very rare MPS III D is localized to chromosome arm 12q14 by in situ hybridization.
MPS III C is not characterized by a deficient hydrolase, but rather, a deficient catalyst for the acetylation of the glucosamine amino groups that have become exposed by the action of heparan-N -sulfatase.
The distinguishing feature is severe central nervous system degeneration but only mild somatic disease.
The onset of clinical features usually occurs at age 2-6 years in a previously normal child.
Presenting features can include hyperactivity with aggressive behavior, delayed development, coarse hair, hirsutism, sleep disorders, and mild hepatosplenomegaly.
Incidence of false-negative results is usually high in the urinary screening test for MPS.
Gastrointestinal symptoms include recurrent and severe diarrhea.
Neurologic manifestations include delayed speech development, severe hearing loss, and seizures. Deterioration is severe by age 6-10 years and is accompanied by severe rapid deterioration in social and adaptive skills. Progressive dementia occurs, with cortical atrophy visible on CT scanning. Sleep disturbances and insomnia are common.
Severe behavioral problems occur, with poor attention span, uncontrollable hyperactivity, temper tantrums, destructive behavior, and physical aggression.
Although any of the 4 types may be difficult to distinguish clinically, type A is the most severe, with earlier onset, more rapid progression of symptoms, and shorter survival. Type B may be heterogeneous, with severe and mild forms reported even within the same family. Type C appears to be intermediate between type A and milder type B forms. Type D appears heterogeneous also.
MPS type IV (Morquio syndrome)
MPS IV results from defective degradation of keratan sulfate.
Two enzyme deficiencies are recognized: N -acetylgalactosamine-6-sulfatase (also known as galactose-6-sulfatase) in type IV A, and beta-galactosidase in type IV B.
MPS IV A is localized to chromosome arm 16q24.
The somatic manifestations include short trunk dwarfism and a skeletal dysplasia (spondyloepiphyseal) distinct from that of the other MPSs, with joint laxity, genu valgus, kyphosis, growth retardation with short trunk and neck, and a waddling gait and a tendency to fall.
Typical skeletal anomalies include dwarfism with short trunk, platyspondyly, odontoid hypoplasia, kyphosis, hyperlordosis, scoliosis, ovoid deformities of the vertebrae, genu valgum, ulnar deviation of the wrist, valgus deformity of the elbow, inclination of the distal ends of the radius and ulna toward each other, deformities of the metacarpals and short phalanges and epiphyses, deformities of the tubular bones, widened metaphyses, and osteoporosis. Joints tend to be hypermobile secondary to ligamentous laxity, but decreased joint mobility can occur in the large joints, especially hips, knees, and elbows.
Odontoid hypoplasia occurs with instability resulting in atlantoaxial subluxation as well as cervical myelopathy; this is also reported in MPS I and VII.
Extraskeletal manifestation may include mild corneal clouding, hepatomegaly, cardiac valvular lesion, and small teeth with abnormally thin enamel and frequent caries formation. Unusual facial features (eg, coarsening of facies, prognathism, broad mouth) are commonly found.
Cardiac signs of aortic regurgitation or congenital heart defects may be present.
Birth is normal, with onset of symptoms at age 1-3.5 years, although the diagnosis is usually established in patients aged 3-15 years.
MPS type VI (Maroteaux-Lamy syndrome)
A deficiency in arylsulfatase B (ie, N -acetylgalactosamine 4-sulfatase) occurs. It hydrolyses the sulfate group in the 4 position of N -acetylgalactosamine residues of dermatan sulfate.
The chromosome abnormality is localized to 5q13-q14.
The phenotype similar to Hurler syndrome involves preservation of intelligence and excretion of predominantly dermatan sulfate in urine. Corneal clouding and hepatosplenomegaly also occur.
The gene abnormality is located in chromosome arm 5q13.3.
Severe skeletal anomalies occur, with limitation of joint movement and stunted linear growth in early childhood.
Cardiac involvement is related to aortic and mitral valvular dysfunction from thickened calcified stenotic valves.
Neurologic complications include hydrocephalus secondary to pachymeningitis, nerve entrapment syndrome, and myelopathy from dural thickening or vertebral body abnormalities or both.
Death typically occurs from heart failure.
MPS type VII (Sly syndrome)
MPS VII is caused by a deficiency in beta-glucuronidase, which removes the glucuronic acid residues present in dermatan sulfate, heparan sulfate, and chondroitin sulfates.
The abnormality is localized to chromosome arm 7q21.1-q22.
Excessive urinary excretion of dermatan and heparan sulfate occurs.
An abnormal gene location on chromosome arm 7q21.1-q22 produces a milder form of later onset.
Features include dysmorphic facies, protruding sternum, hepatosplenomegaly, umbilical hernia, thoracolumbar gibbus, marked vertebral deformities, find corneal opacities, moderate mental deficiency, and radiologic changes of moderately severe dysostosis multiplex.
The distinguishing features are excess glycosaminoglycan excretion and granulocytes showing striking coarse metachromatic granules.
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