GLB1-Related Disorders

Clinical characteristics GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. Diagnosis/testing The diagnosis of a GLB1-related disorder is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in GLB1 by molecular genetic testing, or of significantly reduced activity of the β-galactosidase enzyme activity in peripheral blood leukocytes or fibroblasts. 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; early and ongoing interventions to optimize comfort, mobility, educational and social outcomes. Anesthetic expertise and precautions are necessary to anticipate and manage complications relating to skeletal involvement and airway compromise. Surveillance: GM1 gangliosidosis. Assess yearly: quality of life by neurologist, physiotherapist and nutritionist; seizure risk by a neurologist; cervical spine stability; and hip dislocation risk. Perform every one to three years: electrocardiogram, echocardiogram, and eye examination. MPS IVB. Yearly: ocular exam; assess lower extremities for malalignment, hips for dysplasia/subluxation, thoracolumbar spine for kyphosis, and cervical spine for instability; assessment by physiotherapist to optimize ambulation; perform endurance tests to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. Perform electrocardiogram and echocardiogram every one to three years. Agents/circumstances to avoid: Unplanned anesthesia management due to increased risk for complications; psychotropic medications because of the risk of worsening neurologic disease; positioning that increases aspiration risk during feedings, seizure medication dosages that result in excessive sedation, and circumstances that exacerbate fall risk for those with GM1 gangliosidosis; excessive weight gain in those with MPS IVB. Genetic counseling GLB1-related disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GLB1 pathogenic variant, each sib of an affected individual has at conception 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. Once the GLB1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.