Storage Disorders

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.

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.