Children with spinal muscular atrophy (SMA) may present symptoms indicative of other genetic disorders, such as Farber disease, according to a case study. Researchers also highlighted the importance of analyzing DNA mutations, in addition to clinical observations, in more accurately diagnosing and treating rare diseases.
The study, “Polyarticular Arthritis and Spinal Muscular Atrophy in Acid Ceramidase Deficiency,” published in the journal Pediatrics, reported the case of a 9-year-old girl with joint symptoms initially attributed to seronegative polyarticular arthritis and a known form of SMA, called SMA with progressive myoclonic epilepsy (SMAPME).
SMAPME is caused by mutations in the ASAH1 gene, resulting in deficient levels of the enzyme acid ceramidase. This causes accumulation of a certain type of lipids (sphingolipids) that promote inflammation and cell death in various tissues. Clinical manifestations include progressive muscle weakness and amyotrophy (loss of muscle tissue), with onset during childhood, and the development of myoclonic epilepsy (brief muscle seizures).
Mutations in the ASAH1 gene can also cause Farber disease, which is characterized by arthritis, subcutaneous nodules, and dysphonia (hoarse voice). Although both diseases result from mutations in the same gene, no reports of SMAPME have identified the classic features of Farber disease, or vice-versa.
However, the patient in this study had both diseases.
At age 3, the girl showed signs of joint stiffness, swelling, and pain with increasing functional limitation, which led to doctors prescribing corticosteroids to treat polyarticular arthritis. Although she achieved normal development milestones, by age 5 she started to have difficulty in getting up from the floor, which worsened in the following year, with progressive weakness. To control joint disease, the girl received a combination of Enbrel (etanercept) and methotrexate, both anti-inflammatories.
Although the patient still conserved sensory responses in her arms and legs, the doctors detected chronic and active nerve loss, indicative of motor neuron disease. Because they attributed this occurrence to Enbrel, they replaced this treatment for Orencia (abatacept) (a treatment for rheumatoid arthritis), which is not known to cause neurologic complications. However, muscle weakness continued to the point where the patient was no longer able to rise from the ground or lift her arms over her head. Also, cognitive decline and memory deficits were present at age 7, which worsened when Orencia was given between longer intervals. At 9 years old, the girl died of an acute respiratory infection.
Analysis of the patient’s DNA showed mutations in the ASAH1 gene, which led to reduced levels of acid ceramidase.
“Here, we demonstrate a novel overlapping … of moderate Farber disease, subsequent SMA, with no epilepsy, confirmed mutations in ASAH1, and acid ceramidase deficiency,” the researchers concluded. “This report confirms the importance of considering acid ceramidase deficiency in patients with features of SMA who remain undiagnosed and also in those patients presenting with polyarticular arthritis and hoarseness.”
They continued, “Further, the present case demonstrates the utility of [DNA] sequencing combined with clinical phenotyping in yielding a diagnosis in rare diseases.”
According to the authors, certain therapeutic strategies are under-development for Farber disease, including stem cell transplants and the replacement of acid ceramidase.