Mucopolysaccharidoses - Clinical Tree

Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (acid mucopolysaccharides). Glycosaminoglycans (GAGs) are long-chain complex carbohydrates composed of uronic acids, amino sugars, and neutral sugars. The major GAGs are chondroitin-4-sulfate, chondroitin-6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. These substances are synthesized and, with the exception of hyaluronan, linked to proteins to form proteoglycans, major constituents of the ground substance of connective tissue and of nuclear and cell membranes. Degradation of proteoglycans starts with the proteolytic removal of the protein core, followed by the stepwise degradation of the GAG moiety. Failure of this degradation because of absent or grossly reduced activity of mutated lysosomal enzymes results in the intralysosomal accumulation of GAG fragments ( Fig. 107.1 ). Distended lysosomes accumulate in the cell, interfere with cell function, and lead to characteristic patterns of clinical, radiologic, and biochemical abnormalities ( Table 107.1 and Fig. 107.2 ). Within these patterns, specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products ( Table 107.2 ). As a general rule, the impaired degradation of heparan sulfate is more closely associated with mental deficiency , and that of dermatan, chondroitin, and keratan sulfate with mesenchymal abnormalities . Variable expression within a given entity results from allelic mutations and varying residual activity of mutated enzymes. For instance, allelic mutations of the gene encoding l -iduronidase may result in severe Hurler disease (Hurler syndrome) with early death or in mild Scheie disease (Scheie syndrome) manifesting only with limited joint mobility, mild skeletal abnormalities, and corneal opacities.

Table 107.1

Recognition Pattern of Mucopolysaccharidoses

MANIFESTATIONS	MUCOPOLYSACCHARIDOSIS (MPS) TYPE
MANIFESTATIONS	I-H	I-S	II	III	IV	VI	VII
Intellectual disability	+	−	±	+	−	−	±
Coarse facial features	+	(+)	+	+	−	+	±
Corneal clouding	+	+	−	−	(+)	+	±
Visceromegaly	+	(+)	+	(+)	−	+	+
Short stature	+	(+)	+	−	+	+	+
Joint contractures	+	+	+	−	−	+	+
Dysostosis multiplex	+	(+)	+	(+)	+	+	+
Leucocyte inclusions	+	(+)	+	+	−	+	+
Mucopolysacchariduria	+	+	+	+	+	+	+

I-H, Hurler syndrome; I-S, Scheie syndrome; II, Hunter syndrome; III, Sanfilippo syndrome; IV, Morquio syndrome; VI, Maroteaux-Lamy syndrome; VII, Sly syndrome.

+, Presence of manifestation, −, absence of manifestation; ±, possible presence of manifestation; (+), mild manifestation.

Table 107.2

Mucopolysaccharidoses: Clinical, Molecular, and Biochemical Aspects

MPS TYPE	EPONYM	INHERITANCE	GENE CHROMOSOME	MAIN CLINICAL FEATURES	DEFECTIVE ENZYME	ASSAY	MIM NUMBER
I-H	(Pfaundler-) Hurler	AR	IDUA 4p16.3	Severe Hurler phenotype, mental deficiency, corneal clouding, death usually before age 14 yr	α- l -iduronidase	L, F, Ac, Cv	252800 607014
I-S	Scheie	AR	IDUA 4p16.4	Stiff joints, corneal clouding, aortic valve disease, normal intelligence, survive to adulthood	α- l -iduronidase	L, F, Ac, Cv	607016
I-HS	Hurler-Scheie	AR	IDUA 4p16.4	Phenotype intermediate between I-H and I-S	α- l -iduronidase	L, F, Ac, Cv	607015
II	Hunter	XLR	IDS Xq27.3-28	Severe course: similar to I-H but clear corneas Mild course: less pronounced features, later manifestation, survival to adulthood with mild or without mental deficiency	Iduronate sulfate sulfatase	S, F, Af, Ac, Cv	309900
IIIA	Sanfilippo A	AR	SGSH 17q25.3	Behavioral problems, sleeping disorder, aggression, progressive dementia, mild dysmorphism, coarse hair, clear corneas Survival to adulthood possible	Heparan-S-sulfamidase	L, F, Ac, Cv	252900 605270
IIIB	Sanfilippo B	AR	NAGLU 17q21		N -Acetyl-α- d -glucosaminidase	S, F, Ac, Cv	252920
IIIC	Sanfilippo C	AR	HGSNAT 8p11.21		Acetyl-CoA-glucosaminide N -acetyltransferase	F, Ac	252930
IIID	Sanfilippo D	AR	GNS 12q14		N -Acetylglucosamine–6-sulfate sulfatase	F, Ac	252940 607664
IVA	Morquio A	AR	GALNS 16q24.3	Short-trunk dwarfism, fine corneal opacities, characteristic bone dysplasia; final height <125 cm	N -Acetylgalactosamine-6-sulfate sulfatase	L, F, Ac	253000
IVB	Morquio B	AR	GLB1 3p21.33	Same as IVA, but milder; adult height >120 cm	β-Galactosidase	L, F, Ac, Cv	253010 230500
VI	Maroteaux-Lamy	AR	ARSB 5q11-q13	Hurler phenotype with marked corneal clouding but normal intelligence; mild, moderate, and severe expression in different families	N -Acetylgalactosamine-α-4-sulfate sulfatase (arylsulfatase B)	L, F, Ac	253200
VII	Sly	AR	GUSB 7q21.11	Varying from fetal hydrops to mild dysmorphism; dense inclusions in granulocytes	β-Glucuronidase	S, F, Ac, Cv	253220
IX	Hyaluronidase deficiency	AR	HYAL1 3p21.3	Periarticular masses, no Hurler phenotype	Hyaluronidase 1	S	601492
MPSPS	MPS plus syndrome	AR	VPS33A	Mild Hurler phenotype, cognitive deficiency, organomegaly, skeletal dysplasia, pancytopenia, renal insufficiency, optic atrophy, early death	No lysosomal enzyme deficiency		617303

AR, Autosomal recessive; XLR, X-linked recessive; L, Leukocytes; S, serum; F, cultured fibroblasts; Ac, cultured amniotic cells; Af, amniotic fluid; Cv, chorionic villus sampling; MIM, Mendelian Inheritance in Man Catalogue.

Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease (Hunter syndrome), which is X-linked recessive. Their birth prevalence varies between 1.2 per 100,000 births (United States) and 16.9 per 100,000 births (Saudi Arabia). In the United States the most common subtype is MPS-III, followed by MPS-I and MPS-II.

Disease Entities

Mucopolysaccharidosis I

Mucopolysaccharidosis I (MPS-I) is caused by mutations of the IUA gene on chromosome 4p16.3 encoding α- l -iduronidase. Mutation analysis has revealed 2 major alleles, W402X and Q70X, which account for more than half the MPS-I alleles in the white population. The mutations that introduce stop codons with ensuing absence of functional enzyme (null alleles), and in homozygosity or compound heterozygosity, give rise to Hurler syndrome. Other mutations occur in only one or a few individuals.

Deficiency of α- l -iduronidase results in a wide range of clinical involvement, from severe Hurler syndrome to mild Scheie syndrome, which are ends of a broad clinical spectrum. Homozygous nonsense mutations result in severe forms of MPS-I, whereas missense mutations are more likely to preserve some residual enzyme activity associated with a milder form of the syndrome.

Hurler Syndrome

The Hurler form of MPS-I ( MPS I-H ) is a severe, progressive disorder with involvement of multiple organs and tissues that results in premature death, usually by 10 yr of age. An infant with Hurler syndrome appears normal at birth, but inguinal hernias and failed neonatal hearing tests may be early signs. Diagnosis is usually made at 6-24 mo, with evidence of hepatosplenomegaly, coarse facial features, corneal clouding, large tongue, enlarged head circumference, joint stiffness, short stature, and skeletal dysplasia. Acute cardiomyopathy has been found in some infants <1 yr. Most patients have recurrent upper respiratory tract and ear infections, noisy breathing, and persistent copious nasal discharge. Valvular heart disease, notably with incompetence of the mitral and aortic valves, regularly develops, and narrowing of the coronary arteries occurs. Obstructive airway disease, especially during sleep, may necessitate tracheotomy. Obstructive airway disease, respiratory infection, and cardiac complications are the common causes of death ( Table 107.3 ).

Table 107.3

Analysis of Symptom Frequency in Patients With MPS-I ≤2 Yr of Age

From Clarke LA, Atherton AM, Burton BK, et al: Mucopolysaccharidosis type I newborn screening: best practices for diagnosis and management, J Pediatr 182:363–370, 2017 (Table 1, p 364).

SYMPTOMS/COMPLICATIONS	PERCENTAGE OF PATIENTS WITH SYMPTOM
Coarse facies	98
Valvular disease	95
Corneal clouding	90
Hepatomegaly	84
Upper airway obstruction → OSA	82
Kyphosis gibbus	75
Joint contractures	72
Hernia	70
Dysostosis multiplex	70
Cognitive impairment	60
Enlarged tongue	60
Splenomegaly	60
Eustachian tube obstruction → otitis media	55
Hip dysplasia	42
Genu valgum	38
Reactive airway disease	37
Scoliosis	35
Carpal tunnel syndrome	25
Pes cavus	18
Glaucoma	10
Heart failure	3
Cor pulmonale	2

OSA, Obstructive sleep apnea.

Most children with Hurler syndrome acquire only limited language skills because of intellectual disability, combined conductive and neurosensory hearing loss, and an enlarged tongue. Progressive ventricular enlargement with increased intracranial pressure caused by communicating hydrocephalus also occurs. Corneal clouding, glaucoma, and retinal degeneration are common. Radiographs show a characteristic skeletal dysplasia known as dysostosis multiplex ( Figs. 107.3 and 107.4 ). The earliest radiographic signs are thick ribs and ovoid vertebral bodies. Skeletal abnormalities (in addition to those shown in the figures) include enlarged, coarsely trabeculated diaphyses of the long bones with irregular metaphyses and epiphyses. With disease progression, macrocephaly develops with thickened calvarium, premature closure of lambdoid and sagittal sutures, shallow orbits, enlarged J -shaped sella, and abnormal spacing of teeth with dentigerous cysts.

Hurler-Scheie Syndrome

The clinical phenotype of the Hurler-Scheie form of MPS-I ( MPS I-H/S ) is intermediate between Hurler and Scheie syndromes and is characterized by progressive somatic involvement, including dysostosis multiplex with little or no intellectual dysfunction. The onset of symptoms is usually observed between 3 and 8 yr of age. Survival to adulthood is common. Cardiac involvement and upper airway obstruction contribute to clinical morbidity. Some patients have spondylolisthesis, which may cause cord compression.

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