Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an extremely rare disorder related to the lysosomal storage disease, Farber lipogranulomatosis. Both disorders are autosomal recessive conditions caused by mutations in the ASAH1 gene encoding acid ceramidase. Farber disease is associated with joint deformities, lipomatous skin nodules, and often is fatal by 2-3 years of age; while SMA-PME is characterized by childhood-onset motor neuron disease and progressive myoclonic epilepsy. We report a case of SMA-PME with a novel mutation in the ASAH1 gene encoding acid ceramidase. The proband presented with childhood-onset of diffuse muscle atrophy and hypotonia. He also had diffuse weakness with greater proximal than distal involvement. Tongue fasciculations were present and his reflexes were either diminished or absent. He ambulated with an unsteady and hesitant gait. He subsequently developed myoclonic epilepsy along with other associated features including tremor, polymyoclonus, and sensorineural hearing loss. Neurophysiological studies revealed a motor neuron disorder and generalized epilepsy. Exome sequencing analysis identified compound heterozygous variants and biochemical analysis indicated acid ceramidase activity was approximately 12 percent of normal controls. Our proband was phenotypically similar to other cases of SMA-PME, albeit with somewhat lesser severity, slower progression, and greater longevity. As lysosomal disorders are sometimes amendable to early interventions, it is important to make early diagnoses in these cases. The combination of motor neuron disease and progressive myoclonic epilepsy should prompt genetic evaluation of ASAH1.

A novel mutation in an atypical presentation of the rare infantile Farber disease.

BACKGROUND: Farber disease (MIM 228000) is a rare autosomal recessive condition caused by deficiency of lysosomal acid ceramidase (EC 3.5.1.23). The disease presents classically during the infantile period with a characteristic triad of clinical manifestations: (a) painful joints, (b) subcutaneous nodules, and (c) progressive hoarseness due to laryngeal involvement. All cases reported in the literature to date have presented with the above features, except for the neonatal-visceral subtype. METHODS: Here we describe a 2-year-old female, a product of a non-consanguineous Emirati union, who was quite well until 8 months of age when presented with failure to thrive, developmental delay with relative sparing of cognitive function, cherry-red spot, painful joint, progressive limitation of joint movement, and hoarseness of voice. The sibling of patient died with similar presentation and the nerve biopsy of deceased sibling showed features consistent with Farber disease. RESULTS: Gene sequencing of the ASAHI gene confirmed the diagnosis of Farber disease. Our patient has two heterozygous novel mutations, one in exon 8 (c.533 T>C) and the other in exon 13 (c.1144 A>C). The carrier status of the parents was confirmed. CONCLUSIONS: Farber disease is well known for its striking unique triad of symptoms. This study demonstrates that not all the cases essentially present with subcutaneous nodules which is considered a hallmark of the disease.