Clinical characteristics: The spectrum of ASAH1-related disorders ranges from Farber disease (FD) to spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME).
Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary.
SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years.
Diagnosis/testing: The diagnosis of an ASAH1-related disorder is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in ASAH1 and/or decreased activity of the enzyme acid ceramidase in peripheral blood leukocytes or cultured skin fibroblasts.
Management: Treatment of manifestations is symptomatic and multidisciplinary.
For FD: Management may include gastrostomy tube placement, surgical removal of oral and airway granulomas, and treatment of seizures as per standard practice. Hematopoietic stem cell transplantation may be an option in affected individuals who do not have significant neurologic involvement.
For SMA-PME: Management may include standard treatment for hearing loss, scoliosis, seizures, and tremor. Weakness can be mitigated with the use of orthotics, wheelchairs, or other assistive devices.
For FD: At each visit assess growth with emphasis on feeding and nutritional status; airway, joint mobility, and developmental milestones.
For SMA-PME: At each visit monitor growth with emphasis on feeding and nutritional status, pulmonary function, back for evidence of scoliosis, strength, seizure control, functional capacity (e.g., mobility, communication); assess hearing annually.
Genetic counseling: ASAH1-related disorders are inherited in an autosomal recessive manner. At conception, 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. Sibs with the same two pathogenic variants would be expected to have the same (or very similar) phenotype. Once the ASAH1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
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