Gaucher Disease
Definition (Eur J Pediatr 2004;163:58; Curr Opin Pediatr 2005;17:519)
• Defective glucocerebrosidase activity → accumulation of glucocerebroside in macrophage lysosome
• Autosomal recessive. 1:75,000 births
• Glucocerebroside accumulation → hepatosplenomegaly, anemia, thrombocytopenia, growth retardation, skeletal disease
Non-neuronopathic (Type 1)
• Visceral, hematologic, and skeletal involvement
• Develops in childhood/adulthood; 1:40,000–60,000 (predilection for Ashkenazi Jews)
• Survival 6–80 yr; early dx and Rx with enzyme replacement → better prognosis
Acute Neuronopathic (Type 2)
• Visceral + heme involvement with a neurodegenerative course
• Develops in infancy; <1:100,000; survival <2 yr
• Strabismus, saccadic initiating defects, opisthotonic posturing (decerebrate w/neck and back arched posteriorly), bulbar palsy/paresis within the first 6 mo of life
• No data to support enzyme replacement
Subacute Neuronopathic (Type 3)
• Develops in childhood; <1:100,000; survival 20–40 yr
• Saccadic initiation defects 1st 3 mo of life but little progression of CNS dz until later yrs
• No data to support enzyme replacement
Fabry Disease
Definition (J Inherit Metab Dis 2012;35:227; Genet Med 2006;8:539;
J Pediatr 2004;144:S20)
• Deficiency of α-galactosidase A, which breaks down glycosphingolipids → accumulates in vascular endothelium → ischemia/infarction
• Average age of diagnosis is 29 yo, with a life span of 50 yr
• 1:40,000–60,000 males, X-linked recessive. Female carriers may develop mild manifestations
• Not associated with MR or physical abnormalities
• Angiokeratomas, hypohidrosis, and acroparesthesia (burning/tingling pain in extremities)
Clinical Manifestations (4–16 yo)
• Neuropathic pain (burning/tingling) that usually begins in hands and feet
• May have fever + elevated ESR, diarrhea, abd pain, N/V, FTT
• Triggered by stress, heat, fatigue, or exercise (cannot sweat) Angiokeratomas (purplish/red nonblanching telangiectases); ↑ in size and # w/ age
• Eyes with whorled corneal opacity
Clinical Manifestations (Teens → Adulthood)
• Renal complications → uremia + HTN → ESRD
• May have MI, valve abnormality, arrhythmias, LVH, early strokes, and dyspnea
Diagnosis
• Deficient or absent α-galactosidase A activity
• Can be dx’d prenatally with chorionic villi or cultured amniocyte
Treatment
• α-galactosidase A replacement (J Inherit Metab Dis 2012;35:227)
• Avoid pain triggers such as heat, cold, stress, or exertion
• Some benefit from carbamazepine, gabapentin, diphenylhydantoin, NSAIDs
• GI symptoms are helped with pancrelipase or metoclopramide
• Check baseline renal, heart, and brain MRI before enzyme Rx to follow disease
Follow-up
• CBC, chemistries, U/A, creatinine: Albumin ratio, CrCl
• In adolescents: Every other yr echo and ECG to monitor for cardiac abnormality
Pompe Disease
Definition (J Pediatr 2004;144:S35)
• Glycogen storage type II disease or acid maltase deficiency; lysosomal storage disorder
• Considered a neuromuscular, metabolic myopathy, & glycogen storage disease
• Muscle d/o caused by deficiency of acid α-glucosidase → lysosomal glycogen accumulation in cardiac, skeletal, and smooth muscle cells
Infantile Onset
• Death within 1st yr of life; present in 1st few mo → floppy baby
• Hypotonia, muscle weakness, HCM → death from cardiopulmonary failure
Juvenile and Adult Onset
• Less severe cardiac issue; presents at any age; survival: Early childhood to late adults
• Progressive skeletal muscle dysfunction, calf muscle pseudohypertrophy
• Gower sign → using hands and arms to stand up from a lying position
• Require wheelchairs and eventual artificial ventilation → respiratory failure
Diagnosis
• Clinical syndrome and muscle bx → check acid α-glucosidase activity in skin/muscle fibroblasts
• Other family members should be tested; genetic counseling recommended
Treatment
• Supportive care
Mucopolysaccharide Disorders (MPS)
Definition (Pediatr Rev 2009;30:e22; J Pediatr 2004;144:S27)
• Def of enzyme for degradation of glycosaminoglycans (previously mucopolysaccharides)
• Accumulation of glycosaminoglycans in lysosomes → cell, tissue, organ dysfunction
• Incidence: ∼1:22,500; AR except type II (Hunter syndrome), which is X-linked recessive
Presentation
• Nml at birth → chronic progressive course w/ multisys involv, abn facies, organomegaly
• Loss of developmental skills, frequent pneumonias, cardiomyopathy
Diagnosis
• Specific enzyme assays for each type
• 7 types: I–IV, VI, VII, IX; III and IV having subtypes
• Recommend genetic counseling
Hurler Syndrome
• Most severe form (MPS I)
• Deficiency of α-L-iduronidase → dermatan sulfate and heparan sulfate stored
• Usually normal at birth; death before 10 yo
• Presents in early infancy or childhood w/ severe somatic & neurologic dz, progressive MR
• Bone marrow transplantation is helpful; enzyme replacement also available
Hunter Syndrome (MPS II)
• Severe MPS II disease, X-linked, seen in males
• Deficiency of iduronate sulfatase → dermatan sulfate and heparan sulfate stored
• Supportive therapy