Spinal muscular atrophy (SMA) that co-occurs with progressive myoclonic epilepsy (PME) is a rare inherited syndrome referred to as SMA-PME. It is caused by a mutation in the ASAH1 gene, which is a gene that encodes acid ceramidase.1 ASAH1 is located on chromosome 8, and the mutation associated with SMA-PME is a missense mutation in exon 2.
Those with SMA-PME show clinical manifestations consistent with lower motor neuron disease, developing progressive symmetric weakness and atrophy of the muscles in the lower limbs, and subsequently, in the upper limbs, between the ages of roughly 2.5 and 6.2 Eventually, those with the disease are unable to sit or stand without support and lose the ability to control the head and to swallow. They also experience tongue fasciculations, scoliosis, and respiratory difficulties.
The myotonic epilepsy aspect of SMA-PME usually presents after the onset of weakness, when patients are between 3 and 12 years old. Seizures are brief, involve myoclonic jerks, and do not involve a loss of consciousness.2 Magnetic resonance imaging (MRI) usually produces normal results or demonstrates mild supratentorial and subtentorial cortical atrophy in these patients, but subcortical myoclonic epileptiform abnormalities are readily observable in electroencephalograms (EEGs). The myotonic seizures observed in those with SMA-PME tend to be refractory to antiepileptic drugs.
Cause and Pathogenesis
The enzyme acid ceramidase, which plays an essential role in ceramide catabolism, is deficient in its activity in SMA-PME.2 Normally, ceramide is first synthesized in the endoplasmic reticulum and transported to the trans-Golgi membrane to be converted to sphingomyelin. Both ceramide and its metabolites act as lipid mediators during a variety of cellular events.
Ceramidase facilitates ceramide catabolism, which occurs in lysosomes, and each type of ceramidase – the acid, ASAH1, the neutral form, ASAH2, and the alkaline, ASAH3 – has a distinct function in the metabolism of sphingolipids. This sphingolipid metabolism is crucial for normal brain functioning during both development and maturity. Interestingly, another ceramide enzyme, CERS1, has been associated with SMA-PME. Specifically, a mutation in the gene that encodes ceramide synthase 1, CERS1, has been shown to lead to SMA-PME.3
Relationship to Farber Disease
Like SMA-PME, Farber disease is a rare inherited disorder that involves deficiencies in acid ceramidase activity that are linked to the ASAH1 gene.2,4,5 While SMA-PME and Farber disease have overlapping etiologies and symptoms, Farber disease appears to reduce the enzymatic activity of acid ceramidase to a significantly greater extent than is seen in SMA-PME. Consistent with the notion of Farber disease as a more severe manifestation of mutations in the ASAH1 gene, Farber disease usually presents earlier than SMA-PME, at between 2 weeks and 4 months of age.2 While cognitive impairment has been observed in both SMA-PME and Farber disease, only those with Farber disease have demonstrated abnormalities of the skin and joints and hoarseness of the voice.
Therapy and Counseling
While there is no cure for SMA-PME, preclinical research into potential therapeutics has seen progress in recent years. For instance, a knock-in mouse model that includes a single nucleotide ASAH1 gene mutation has been created to help further our understanding of diseases associated with this mutation.6 Work with this mouse model has shown that a single injection of lentivector that expresses human acid ceramidase can minimize the severity of Farber disease manifestations observed in these mice. Future work with this model with hopefully elucidate aspects of SMA-PME and provide insights into how to combat the condition.
Given the ability to identify ASAH1 gene mutations, patients can now be easily tested for and diagnosed with SMA-PME, which facilitates family planning. According to experts, families should be educated on SMA-PME and its heritability as early as possible after diagnoses are made because the risk of SMA-PME is 25% for each sibling of an SMA-PME patient. As the molecular basis of SMA-PME becomes clearer through more research and clinical observation, both the therapies and counseling for these patients and their families will likely evolve and provide better solutions for those affected by this rare disorder.
1. Zhou J, Tawk M, Tiziano FD, et al. Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. Am J Hum Genet. 2012;91(1):5-14. doi:10.1016/j.ajhg.2012.05.001
2. Topaloglu H, Melki J. Spinal muscular atrophy associated with progressive myoclonus epilepsy. Epileptic Disord. 2016;18(S2):128-134. doi:10.1684/epd.2016.0858
3. Vanni N, Fruscione F, Ferlazzo E, et al. Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. Ann Neurol. 2014;76(2):206-212. doi:10.1002/ana.24170
4. Dyment DA, Bennett SAL, Medin JA, Levade T. ASAH1-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. Seattle (WA); 1993.
5. Sugita M, Dulaney JT, Moser HW. Ceramidase deficiency in Farber’s disease (lipogranulomatosis). Science. 1972;178(4065):1100-1102.
6. Alayoubi AM, Wang JCM, Au BCY, et al. Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol Med. 2013;5(6):827-842. doi:10.1002/emmm.201202301