Storage Disorders





Mucolipidosis II (Leroy I-Cell disease)


Early Alveolar Ridge Hypertrophy, Joint Limitation, Thick Tight Skin in Early Infancy


This disorder was recognized by Leroy and DeMars when they noted unusual cytoplasmic inclusions in the cultured fibroblasts of a girl considered to have the Hurler syndrome despite the fact that she did not have cloudy corneas or excessive acid mucopolysaccharide in the urine. Mucolipidosis II (ML II) is a progressive inborn error of metabolism sometimes evident at birth. Fatal outcome occurs most often in early childhood.


Abnormalities





  • Growth. Birthweight less than 5½ pounds; marked growth deficiency with lack of linear growth after infancy.



  • Performance. Weak cry. Slow development from early infancy, reaching a plateau at approximately 18 months with no apparent deterioration subsequently.



  • Craniofacial. Progressive coarsening of facial features; high, narrow forehead; shallow orbits; thin eyebrows; puffy eyelids; inner epicanthal folds; clear or faintly hazy corneas; low nasal bridge, anteverted nostrils; long philtrum; telangiectasia over the cheeks, progressive hypertrophy of alveolar ridges.



  • Skeletal. Early decreased range of motion of shoulders. Moderate progressive joint limitation in flexion, especially of hips; dorsolumbar kyphosis; thoracic deformity; clubfeet; dislocation of the hip; broadening of wrists and fingers; abnormal curvatures of long bones.



  • Skin. Thick, relatively tight skin during early infancy that becomes less tight as the patient ages, most noticeable in the earlobes; cavernous hemangiomata.



  • Cardiac. Thickening and insufficiency of the mitral valve and, less frequently, the aortic valve; in rare cases, cardiomyopathy.



  • Imaging. Increased vertebral body height or rounding, talocalcaneal stippling, periosteal cloaking, sacrococcygeal, and vertebral sclerosis are all early signs seen in the first year. Rickets and hyperparathyroidism-like (pseudohyperparathyroidism) changes are frequent. These changes begin in the newborn period and resolved by 1 year of age. Later, typical radiographic features to dysostosis multiplex changes are predominant. Short and wide diaphyses tubular bones, broad ribs, hypoplastic epiphyses with delayed ossification, and thin calvarium also occur.



  • Other. Minimal hepatomegaly, diastasis recti, inguinal hernia, neonatal cholestasis, proximal tubular dysfunction.



Natural History


By 18 months of age, most patients can sit with support, and some stand with support, but walking and functional speech are usually never acquired. However, severe progressive retardation of growth and development occur. Noisy breathing with obstructive apnea, recurrent bouts of bronchitis, pneumonia, and otitis media are frequent during early childhood. Progressive mucosal thickening narrows the airways and gradually stiffens the thoracic cage, contributing to respiratory insufficiency. Storage in the pulmonary interstitium leads to pulmonary hypertension and congestive heart failure, the most common cause of death, which usually occurs by 5 years of age.


Etiology


This disorder has an autosomal recessive inheritance pattern. Activity of nearly all lysosomal hydrolases is 5- to 20-fold higher in plasma and other body fluids than in normal controls, but normal or decreased in leukocytes and fibroblasts because of improper targeting of lysosomal acid hydrolases (β-D-hexosaminidase, β-D-glucuronidase, β-D-galactosidase, α-L-fucosidase) to lysosomes. Urinary excretion of oligosaccharides is excessive and can be used as a screening test. Lysosomal hydrolase N -acetylglucosamine-1-phosphotransferase (GNPTAB) is the deficient enzyme in this disorder as well as in pseudo-Hurler polydystrophy (mucolipidosis IIIA). Mutations in the GlcNAc-phosphotransferase a/b-subunits precursor gene ( GNPTAB ) are the cause. ML II is caused by two severe mutations leading to almost absent enzyme activity, whereas ML III α/β, a much milder disease with short stature, contractures, and scoliosis occurs when at least one mild mutation can produce some active GlcNAc-phosphotransferase. The prenatal presentation of ML II was previously called Pacman dysplasia. Mutations in GNPTAB have also been identified in this severe variant.


Prenatal diagnosis can be based on demonstration of elevated lysosomal enzyme activity in cell-free amniotic fluid as well as vacuolation of chorionic villus cells on electron microscopy; however, molecular testing with prior identification of the mutations in the family is preferable. Molecular testing is necessary to detect carriers because enzyme levels do not distinguish carriers from noncarriers. Ultrasound findings are not present in all affected fetuses.


Comment


Bone marrow transplant, reported in only a few children with I-cell disease, has prevented progressive cardiac and pulmonary disease and allowed the attainment of neurodevelopmental milestones, although at a much slower than normal rate 5 years following transplantation, in one 7-year-old child. In most cases, however, the neurologic outcome and survival for patents with ML II after hematopoietic stem cell transplantation have been poor.


References





  • Leroy JG, DeMars RI: Mutant enzymatic and cytological phenotypes in cultured human fibroblasts, Science 157:804, 1967.



  • Leroy JG, et al: I-cell disease, a clinical picture, J Pediatr 79:360, 1971.



  • Grewal S, et al: Continued neurocognitive development and prevention of cardiopulmonary complications after successful BMT for I-cell disease: A long-term follow-up report, Bone Marrow Transplant 32:957, 2003.



  • Kudo M, et al: Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-Hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha/beta-subunits precursor gene, Am J Hum Genet 78:451, 2006.



  • Cathey SS, et al: Phenotype and genotype in mucolipidoses II and III alpha/beta: A study of 61 probands, J Med Genet 47:38, 2010.



  • Lund TC, et al: Outcomes after hematopoietic stem cell transplantation for children with I-cell disease, Biol Blood Marrow Transplant 20:1847, 2014



  • Lai LM, Lachman RS: Early characteristic radiographic changes in mucolipidosis II. Pediatr Radiol 46:1713, 2016.




    FIGURE 1


    Leroy I-cell syndrome.

    A–C, A 9-year-old child. Note the high, narrow forehead, puffy eyelids, anteverted nares, long philtrum, hypertrophy of alveolar ridges, and joint contractures.

    Courtesy Dr. Lynne M. Bird, Rady Children’s Hospital, San Diego.



Mucopolysaccharidosis I H, I H/S, 1 S (Hurler Syndrome, Hurler-Scheie Syndrome, Scheie Syndrome)


Coarse Facies, Stiff Joints, Gibbus, Intellectual Disability, Cloudy Corneas


Hurler set forth the disorder mucopolysaccharidosis I H (MPS IH) in 1919, now called severe form. Scheie and colleagues described the milder form in 1962 (MPS IS), and Stevenson and colleagues set forth the intermediate form IH/S (MPS IH/S) in 1976. The latter are today called attenuated forms. At least 80% of individuals with MPS I fall at the severe or Hurler syndrome end of the spectrum. No significant biochemical differences are seen among the three forms, all caused by deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA). Mainly the phenotype of Hurler syndrome is set forth below.


Abnormalities





  • Growth. Deceleration of growth between 6 and 18 months; maximal stature, 110 cm.



  • Performance. Significant delay by 6 to 12 months, with developmental plateau by 2 to 5 years.



  • Craniofacial. Scaphocephalic macrocephaly with frontal prominence; coarse facies with full lips; flared nostrils; low nasal bridge; tendency toward hypertelorism; epicanthal folds; visual cortical damage; open-angle glaucoma; hypertrophied alveolar ridge and gums with small malaligned teeth; enlarged tongue.



  • Ocular. Corneal clouding (all forms of MPS I); retinal pigmentation and degeneration; optic nerve compression and atrophy.



  • Skeletal. Joint limitation results in the clawhand and other joint deformities, with more limitation of extension than flexion; flaring of the rib cage; kyphosis and thoracolumbar gibbus secondary to anterior vertebral wedging: short neck, genu valgum.



  • Cardiac. Intimal thickening in the coronary vessels or the cardiac valves; valvular dysfunction; cardiomyopathy; sudden death from arrhythmia.



  • Imaging. Cranial thickening with narrowing of cranial foramina; J-shaped sella turcica; odontoid hypoplasia; diaphyseal broadening of short misshapen bones; widening of medial end of clavicle; dysostosis multiplex, including abnormally shaped vertebrae and ribs, enlarged thickened skull with narrowing of cranial foramina, odontoid hypoplasia, spatulate ribs, hypoplastic epiphyses, thickened diaphyses and bullet-shaped metacarpals, hip dysplasia.



  • Other. Hirsutism, hepatosplenomegaly, inguinal hernia, umbilical hernia, dislocation of hip, tracheal stenosis, compression of the spinal cord, chronic mucoid rhinitis, middle ear fluid, craniosynostosis, cranial nerve compressions, deafness, urinary excretion of dermatan sulfate and heparan sulfate.



Occasional Abnormalities


Communicating hydrocephalus, presumably a result of thickened meninges; arachnoid cysts; hydrocele; nephrotic syndrome; carpal tunnel syndrome; trigger thumb; hypoplasia of mandibular condyles.


Natural History


Infants appear normal at birth. Growth during the first year may be more rapid than usual, with subsequent slowing. Subtle changes in the facies, macrocephaly, hernias, limited hip motility, noisy breathing, and frequent respiratory tract infections may be evident during the first 6 months in the severe Hurler type. Deceleration of developmental and mental progress is evident during the latter half of the first year. By age 3 years, linear growth ceases. Intellectual disability is progressive and profound. Upper airway obstruction secondary to thickening of the epiglottis and tonsillar and adenoidal tissues, as well as tracheal narrowing caused by mucopolysaccharide accumulation, can lead to sleep apnea and serious airway compromise. Because of the upper airway problems, as well as odontoid hypoplasia with or without C1-C2 subluxation, cervical myelopathy can require intervention and anesthesia is a significant risk. Hearing loss is almost always present. These patients are usually placid, easily manageable, and affectionate. Hypertension frequently occurs and is either centrally mediated or secondary to aortic coarctation. Death usually occurs in childhood secondary to respiratory tract or cardiac complications, and survival past 10 years of age is unusual. In the attenuated forms of the disorder, onset of symptoms will be between 3 and 8 years in MPS I H/S, and survival into the 20s is common, whereas in MPS I S, symptoms will be evident during the second and third decades and life span is normal. Growth is only affected in MPS I IH and H/S, a short trunk being most common. Performance can be mildly impaired in the intermediate form, with slow but evident deterioration, but will be normal in MPS I S, where late-onset psy chiatric manifestations can occur. Corneal clouding, skeletal deformities leading to pain, cardiac valvular abnormalities, and hearing impairment will develop by the early to mid teens in MPS I H/S and will cause significant disability. In MPS I S, vision impairment and pain and limitations owing to skeletal problems will occur later in life.


Etiology


This disorder has an autosomal recessive inheritance pattern. The primary defect is an absence of the lysosomal hydrolase α-L-iduronidase (IDUA), which is responsible for the degradation of the glycosaminoglycans, heparan sulfate, and dermatan sulfate. The pathologic consequence is an accumulation of mucopolysaccharides in parenchymal and mesenchymal tissues and the storage of lipids within neuronal tissues. The gene encoding IDUA is located on chromosome 4p16.3. Intragenic mutations can all be detected through sequencing; no deletions or other rearrangements have been reported. Mutations are often recurrent and can predict severity. Up to 70% of mutations are recurrent and thus may be helpful in phenotype prediction. In the remaining 30%, prediction of the severity of the phenotype is not possible


Diagnosis is suspected by the physical appearance and the excretion of dermatan sulfate and heparan sulfate in the urine, and is confirmed by the absence or decreased activity of α-L-iduronidase in cultured fibroblasts, leukocytes, or plasma, but levels do not predict severity. Mutation analysis is the only reliable method for heterozygote carrier detection. In cases of homozygosity, parental testing is mandatory given multiple cases of uniparental disomy (UPD) 17 with only one carrier parent. Prenatal diagnosis is possible by measuring α-L-iduronidase in cultured amniotic fluid cells or through detection of the previously known familial mutations in chorionic villi or amniotic fluid.


Comment


Bone marrow transplantation (BMT), also known as hematopoietic stem cell transplantation (HSCT), has been effective in the treatment of selected patients with MPS I H before age 2 to 3 years and is today standard of care. BMT can increase survival, reduce facial coarseness and hepatosplenomegaly, improve hearing and airway problems, and maintain normal heart function, although valvular abnormalities often progress. Skeletal manifestations and corneal clouding continue to progress. In children with a baseline Mental Developmental Index greater than 70, who are engrafted before 24 months, a favorable neurobehavioral outcome has occurred. Enzyme replacement therapy (ERT) using recombinant human α-L-iduronidase (Aldurazyme) improves liver size, linear growth, joint mobility, breathing, and sleep apnea, and can also be expected to stabilize cardiac dysfunction in persons with attenuated disease (MPS I S and MPS I H/S). However, its lack of central nervous system penetration is a major drawback to its use in patients with α-L-iduronidase deficiency for whom the central nervous system is already severely involved. Survival was better for HSCT when comparing ERT with HSCT; the incidence of severe complications, such as hydrocephalus and cervical spinal cord compression, were greater in ERT.


Even with HSCT and ERT residual disease burden remains very significant particularly when the diagnosis is late. Wide awareness of pediatricians of the early signs to suspect the diagnosis, such as growth velocity decline and bone and joint involvement, in attenuated cases and the inclusion of the disease in newborn screening programs in all countries are needed.


References



Jun 28, 2021 | Posted by in PEDIATRICS | Comments Off on Storage Disorders
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