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Storage Diseases
Lysosomal storage diseases are a group of inborn errors of metabolic disorders characterized by accumulation of incompletely metabolized substrates inside lysosomes due to deficiency in one of the numerous enzymes required for substrate degradation. They comprise more than 30 different syndromes and are generally divided into lipidoses, glycogenoses, and mucopolysaccharidoses (MPS). Most of these disorders are severely debilitating and lead to premature death. The focus of this chapter is on MPS and glycogenoses. Only the clinical and radiographic findings are discussed. Detailed biochemical and pathophysiologic aspects of each disorder are extensively covered in many articles and textbooks, some of which are listed in the suggested readings and references at the end of the chapter.
Etiology
Mucopolysaccharidoses
MPS results from the absence or defect of enzymes required for the breakdown of glycosaminoglycan (GAG), also formerly known as mucopolysaccharide. GAGs are long-chain carbohydrates that contribute to the formation of bones, cartilage, tendons, corneas, skin, and connective tissues. A deficiency in one of the enzymes that break down GAG will result in intracellular substrate accumulation, leading to structural and functional abnormalities at the cellular and tissue levels. The specific enzyme deficiencies that lead to a specific substrate accumulation and their corresponding syndromes are listed in eTable 82-1 . The MPS types are inherited in an autosomal recessive pattern, with the exception of MPS II (Hunter syndrome), which is inherited in an X-linked recessive mode.
eTABLE 82–1
Mucopolysaccharidoses
Data from Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver C, Beaudet AL, Valle D, Sly W, editors. The metabolic and molecular bases of inherited disease, vol 3. 8th ed. New York: McGraw-Hill; 2001; p. 3421–52.
| Type | Enzyme Deficiency | Substrate Accumulated |
|---|---|---|
| MPS I H-Hurler | α- l -Iduronidase | Heparan sulfate |
| MPS I H/S-Hurler-Scheie | Dermatan sulfate | |
| MPS I S-Scheie | ||
| MPS II-Hunter | Iduronidase sulfatase | Heparan sulfate |
| Dermatan sulfate | ||
| MPS IIIA-Sanfilippo A | Heparan- N -sulfatase | Heparan sulfate |
| MPS IIIB-Sanfilippo B | N -Acetyl-α-glucosaminidase | |
| MPS IHC-Sanfilippo C | α-Glucosaminidase | |
| MPS IIID-Sanfilippo D | N -Acetylglucosamine-6-sulfate | |
| MPS IV-Morquio | N -Acetylgalactosamine-6-sulfatase | Keratan sulfate, chondroitin sulfate |
| MPS VI-Maroteaux-Lamy | Arylsulfatase B | Dermatan sulfate |
| MPS VII-Sly | β-Glucuronidase | Heparan sulfate |
| Dermatan sulfate | ||
| MPS IX-Natowicz | Hyaluronidase | Chondroitin sulfate |
Glycogenoses
Glycogenoses (glycogen storage diseases [GSDs]) are another group of lysosomal storage disorders that result from deficiency in enzymes required for the breakdown of glycogen. Failure to completely metabolize glycogen results in accumulation and storage of glycogen substrates in lysosomes of hepatic and muscle tissues where glycogen is most abundant. Therefore, these tissues are most commonly and severely affected by the GSDs. The specific enzyme deficiency and its associated syndromes are summarized in eTable 82-2 . The glycogenoses are inherited in an autosomal recessive pattern, with the exception of type IX in which several subtypes are inherited as an X-linked pattern.
eTABLE 82–2
Glycogen Storage Diseases
From Miller JH, Stanley P, Gates GF. Radiography of glycogen storage diseases. AJR Am J Roentgenol 1979;132:379–87; Kishnani PS, Howell RR. Pompe disease in infants and children. J Pediatr 2004;144:S35–43; and Chen YT. Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited diseases, vol 1. 8th ed. New York: McGraw-Hill; 2001. p. 1521–51.
| Type | Enzyme Deficiency | Target Organ | Key Clinical Findings |
|---|---|---|---|
| I: von Gierke, hepatorenal glycogenosis | IA: Glucose-6-phosphatase IB: Glucose-6-phosphate translocase |
Liver, spleen, kidney, intestines, leukocytes | Hypoglycemia, hyperuricemia, hyperlipidemia, lactic acidosis, hepatosplenomegaly nephromegaly |
| II: Pompe, acid maltase deficiency | α-1,4-Glucosidase (acid maltase) | Heart, skeletal muscles | Hypotonia, cardiomyopathy |
| III: Forbes-Cori, limit dextrinosis | Amylo-1,6-glucosidase (debrancher) | Liver, heart, muscle, leukocytes | Hypotonia, hepatomegaly, cirrhosis, fasting ketosis |
| IV: Andersen, amylopectinosis | Amylo-1,4–1,6-transglucosidase (debrancher) | Liver | Hepatomegaly, cirrhosis |
| V: McArdle | Muscle phosphorylase | Skeletal muscles | Exercise intolerance, rhabdomyolysis, renal failure |
| V: Hers | Liver phosphorylase | Liver, leukocytes | Hepatomegaly, mild hypoglycemia |
| VII: Tarui | Phosphofructokinase | Skeletal muscles, erythrocytes | Exercise intolerance, rhabdomyolysis, renal failure |
| IX | Liver phosphorylase kinase | Liver, skeletal muscles, heart, erythrocytes | Hepatomegaly, hyperlipidemia, fasting ketosis |
Prevalence and Epidemiology
The incidence for all types of MPS is estimated to be 1 in 25,000 births. There is no known racial or gender predilection for any of these disorders, except for Hunter syndrome (MPS II), which is inherited as X-linked recessive, therefore affecting predominantly males.
The cumulative incidence of GSDs is estimated to be around 1 : 20,000 to 1 : 25,000 births. There are no racial differences for most of the GSDs. However, the highest incidence for GSD III has been recorded in non-Ashkenazi Jews in Northern Africa, and GSD VI has been most commonly reported in Japanese and Ashkenazi Jews. There is no gender preference, except for subtypes of GSD IX that are inherited in an X-linked pattern in which mostly male patients are affected.
Clinical Presentation
Mucopolysaccharidoses
Hurler Syndrome (MPS I H)
Hurler syndrome is the most severe form and one of the most commonly encountered MPS. Infants with Hurler syndrome usually appear normal at birth and are not diagnosed until early in their second year of life. Clinical features begin to develop after 6 to 12 months with coarsening of facial features. The head is enlarged with widely spaced eyes, corneal clouding, frontal bossing, flattened nasal bridge, everted lips, protruded tongue, and widely separated and hypoplastic teeth. Umbilical or inguinal hernias may be present. Hepatosplenomegaly results in a protuberant abdomen. Lumbar gibbus leads to a stooped posture accentuated by flexion contractures of the hip and knee joints. Flexion contracture of the hand leads to a clawhand deformity, stiff joints, and carpal tunnel syndrome. Mucopolysaccharide deposition in the trachea, nasopharynx, and esophagus leads to aerodigestive tract obstruction with persistent rhinitis, adenotonsillar hypertrophy, sleep apnea, recurrent upper respiratory tract infection, and feeding difficulties. Deposition in cardiac valves and coronary arteries eventually results in valvular dysfunction, coronary artery disease, and ischemic cardiomyopathy. Deposition in the leptomeninges leads to communicating hydrocephalus and an enlarged cranium with sutural diastasis. Growth disturbance results in severe dwarfism. There is progressive mental deterioration. These children eventually die between 10 and 15 years of age from pneumonia or cardiac failure. Many of the other MPS, with the exception of MPS IV or Morquio syndrome, have clinical and radiographic findings similar to Hurler syndrome, although with different degrees of severity ( eFig. 82-1 ).
Scheie Syndrome (MPS I S)
Scheie syndrome is the least severe form of the MPS I group. There is nearly normal height, intellect, and life span, although the life span may be somewhat shortened by the presence of aortic valve disease, which is seen in almost all cases. Somatic presentations include corneal clouding, joint stiffness, and carpal tunnel syndrome. Psychosis is common.
Hurler-Scheie Syndrome (MPS I H/S)
Hurler-Scheie syndrome is intermediate in severity between Hurler syndrome and Scheie syndrome. The clinical and skeletal features more closely resemble those of Hurler syndrome, but the patients survive slightly longer into their twenties, and the psychomotor retardation and dwarfism are less severe.
Hunter Syndrome (MPS II)
Hunter syndrome is the only mucopolysaccharidosis that is X-linked recessive. The clinical features are similar to those of Hurler syndrome but are less severe. Coarse facies, hepatosplenomegaly, growth failure, and joint stiffness occur later than in Hurler syndrome. Psychomotor retardation is less severe. Seizures are common. Corneal clouding is not apparent but can be detected on slit-lamp examination. Half of the children become deaf. Cutaneous nodules over the scapula and upper back are uniquely seen with Hunter syndrome. The patients are typically diagnosed around 
to 5 years old. Patients with the severe form of Hunter syndrome usually die in 10 to 15 years secondary to cardiac causes, and those with the mild form may survive into the fourth decade or later.
Sanfilippo Syndrome (MPS III)
The Sanfilippo syndrome can result from four different enzyme deficiencies (see eTable 82-1 ) that lead to accumulation of the same substrate—heparan sulfate—and result in clinically indistinguishable features. The patients appear normal until 3 to 5 years old when there is progressive and profound mental deterioration, which is the most striking feature in this mucopolysaccharide group. There are learning difficulties and behavioral disturbances characterized by severe hyperactivity and aggression. Seizures are common. The patients do not have dwarfism and do not have cardiac disease. Corneal clouding is minimal and detected on slit-lamp examination. Joint stiffness is mild. Other clinical and skeletal changes are similar to those of Hurler syndrome and Hunter syndrome but are milder. Most patients die between 10 and 30 years of age.
Morquio Syndrome (MPS IV)
Previously, Morquio syndrome was divided into types A and B, with both types thought to occur from defects in separate enzymes. However, MPS IVB is now considered a variant of GM 1 -gangliosidosis. Morquio syndrome does not closely resemble other mucopolysaccharide disorders; it has distinctive skeletal manifestations that are usually diagnostic. Morquio syndrome is usually not apparent at birth but can be diagnosed by 1 year old. There is striking dwarfism, with height rarely exceeding 4 feet in adult life. Intelligence is normal; mental retardation is rare. The cornea is slightly clouded, which is detectable on slit-lamp examination only. The head is of normal size. Morquio syndrome is one of the most commonly encountered MPS, along with Hurler syndrome.
Maroteaux-Lamy Syndrome (MPS VI)
The striking clinical features of this syndrome are dwarfism and corneal clouding without mental impairment. The somatic and skeletal changes are very similar to those of Hurler syndrome. Patients have coarse facial features, hepatosplenomegaly, inguinal hernias, severe cardiac abnormalities, hydrocephalus, and hearing defects. Growth slows down at 4 years old and stops completely by 8 years of age, resulting in severe dwarfism.
Sly Syndrome (MPS VII)
The clinical and radiographic findings of Sly syndrome are similar to those of Hurler syndrome, but there is great variation in severity. In general, there is restricted growth and mental development. Sly syndrome often presents as nonimmune hydrops fetalis, and the patients rarely survive more than a few months.
Natowicz Syndrome (MPS IX)
There has only been one patient reported to date with this syndrome. Mild short stature and periarticular soft tissue masses were noted, but there were no neurologic or ocular findings.
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