Clinical characteristics: GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). GM1 gangliosidosis includes phenotypes that range from severe to mild. Type I (infantile) begins before age one year; progressive central nervous system dysfunction leads to spasticity, deafness, blindness, and decerebrate rigidity. Life expectancy is two to three years. Type II can be subdivided into the late-infantile form and juvenile form. Type II, late-infantile form begins between ages one and three years; life expectancy is five to ten years. Type II, juvenile form begins between ages three and ten years with insidious plateauing of motor and cognitive development followed by slow regression. Type II may or may not include skeletal dysplasia. Type III begins in the second to third decade with extrapyramidal signs, gait disturbance, and cardiomyopathy; and can be misidentified as Parkinson disease. Intellectual impairment is common late in the disease; skeletal involvement includes short stature, kyphosis, and scoliosis of varying severity. MPS IVB is characterized by skeletal changes, including short stature and skeletal dysplasia. Affected children have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, and the attenuated form in late childhood or adolescence. In addition to skeletal involvement, significant morbidity can result from respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, corneal clouding, and spinal cord compression. Intellect is normal unless spinal cord compression leads to central nervous system compromise.
Diagnosis/testing: The diagnosis of GLB1-related disorders is suspected in individuals with characteristic clinical, neuroimaging, radiographic, and biochemical findings. The diagnosis is confirmed by either deficiency of β-galactosidase enzyme activity or biallelic pathogenic variants in GLB1.
Management: Treatment of manifestations: Best provided by specialists in biochemical genetics, cardiology, orthopedics, and neurology and therapists knowledgeable about GLB1-related disorders; surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders; occupational therapy to optimize activities of daily living (including adaptive equipment) and physical therapy to optimize gait and mobility (including orthotics and bracing); early and ongoing interventions to optimize educational and social outcomes. For those with GM1 gangliosidosis: Adequate nutrition to maintain growth; speech therapy to optimize oral motor skills; aggressive seizure control; routine management of risk of aspiration, risk of chronic urinary tract infection, and cardiac involvement; when disease is advanced: hospice services for supportive in-home care. Prevention of secondary complications: Anesthetic precautions to anticipate and manage complications relating to skeletal involvement and airway compromise; routine immunization; bacterial endocarditis prophylaxis in those with cardiac valvular disease. Surveillance: Agents/circumstances to avoid: Psychotropic medications because of the risk of worsening neurologic disease; obesity in those with skeletal dysplasia
Genetic counseling: GLB1-related disorders are inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
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