664 In 1966, Maroteaux and Lamy first described four girls with pseudo-Hurler polydystrophy, a condition milder in severity than the Hurler syndrome and similar to the Scheie syndrome but without hepatosplenomegaly, cloudy cornea or mucopolysacchariduria. In 1970, Spranger and Wiedemann designated pseudo-Hurler polydystrophy as mucolipidosis III because of Hurler-like features and vacuolated bone marrow cells.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal recessive 2. Basic defect
a. Resulting from deficiency of the enzyme UDP-N- acetylglucosamine: lysosomal protein precursor N-acetyl glucosamine
L-phosphate transferase (C1cNAcPT) (mucolipidosis II also caused by deficiency of the same enzyme)
b. Genetic complementation analysis of cultured fibroblasts derived from patients with mucolipido- sis III identified complementation groups A, B, and C
c. Inability to form the correct recognition marker on lysosomal enzymes resulting in a marked intracellular deficiency of most lysosomal enzymes in various tis- sues, impairment of many lysosomal catabolic processes, and concomitant increase in lysosomal enzymes in plasma
3. Recent finding of molecular basis for mucolipidosis IIIC (variant pseudo-Hurler polydystrophy): a mutation, ins C at codon 167, in the γ subunit of the C1cNAcPT in mucol- ipidosis IIIC
CLINICAL FEATURES
1. Onset of disease
a. Usually appear at 2–4 years of age b. Progress slowly
c. First sign: stiffness in the hands and shoulders 2. Short stature
3. Mild Hurler-like facial dysmorphism, usually apparent after age 6 years
4. Ophthalmologic abnormalities a. Constant ocular features
i. Corneal opacities consisting of fine, peripheral infiltrates
ii. Hyperoptic astigmatism b. Optic nerve head swelling c. Surface wrinkling maculopathy d. Retinal vascular tortuosity 5. Mild mental retardation 6. Valvular heart disease
7. Orthopedic problems
a. Stiffness of the hands progressing to claw hand defor- mities by 6 years of age in all patients
b. Slow progression of the skeletal dysplasia during school years, the resulting physical disability most apparent in the hands, hips, elbows, and shoulders c. Generalized joint stiffness (limited joint mobility) d. Spine abnormalities
i. Kyphosis ii. Lordosis iii. Gibbus e. Hip pain
f. Hip dysplasia
g. Carpal tunnel syndrome further complicates the claw hand deformities
h. Recurrent intermittent triggering of the fingers 8. Natural course of the illness: survive beyond the 5–6th
decade
DIAGNOSTIC INVESTIGATIONS
1. Radiography showing dysostosis multiplex a. Pelvis
i. Flaring of the iliac wings ii. Constriction of the iliac bodies iii. Oblique acetabular roofs b. Vertebral bodies
i. Moderately flattened
ii. Presenting as a roughly ovoid contour
iii. Underdevelopment of posterior parts in the dor- sal spine
iv. Hypoplasia of anterior third in the lumbar spine v. Irregular endplates
vi. Scoliosis secondary to vertebral abnormalities c. Tubular bones
i. Shortened and wide
ii. The most striking changes observed in the prox- imal femur
a) A small, flattened and irregular epiphysis b) Coxa valga deformity of the neck c) Subluxation
iii. Hands
a) Short first metacarpals
b) Mild proximal pointing of the metacarpals c) Mild to moderate claw-hand deformities d) Relatively wide diaphysis of some phalanges iv. Retarded bone age
d. Skull: normal despite the presence of craniostenosis in some patients
2. Nerve conduction test and electromyography to confirm the carpal tunnel syndrome
3. Slit lamp examination for cornea opacification
MUCOLIPIDOSIS III (PSEUDO-HURLER POLYDYSTROPHY) 665
4. Normal urinary excretion of acid mucopolysaccharides 5. Presence of cytoplasmic inclusions within cultured
fibroblasts as demonstrated by phase-contrast or dark- field microscopy
6. Bone marrow: large, vacuolated plasmocytes 7. Biochemical studies
a. Normal activity of multiple lysosomal enzymes in white blood cells
b. A marked rise of multiple lysosomal enzymes in serum c. Low levels of multiple lysosomal enzymes in cultured
fibroblast cells
d. Abnormal radioactive sulfate kinetics (accumulations in cultured fibroblasts of radioactive sulfate several times that of normal fibroblasts)
8. Molecular analysis for a mutation, ins C at codon 167, in the γ subunit of the G1NAcPT in mucolipidosis IIIC
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib: 25%
b. Patient’s offspring: not increased unless the spouse is a carrier
2. Prenatal diagnosis
a. Diagnosis confirmed by markedly reduced lysosomal enzyme activities in cultured chorionic villi
b. Identification of the disease-causing mutation in fetal DNA in newly recognized large Bedouin- Moslem kindred, allowing prenatal diagnosis, car- rier detection, and identification of couples at risk
3. Management a. Physiotherapy
b. Padded insoles for clawing of toes
c. Carpal tunnel decompression for the median nerve entrapment
d. Pelvic osteotomy for severe hip dysplasia
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